From Systems Biology to Traditional Medicine: Unraveling Garlic's Pharmacological and Genetic Targets in Respiratory Infections

Document Type : Review Article

Authors

1 Department of Traditional Pharmacy (Phytopharmaceuticals), School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract

Allium sativum L. (garlic) has been widely used in Traditional Persian Medicine (TPM) for the management of cough, fever, and respiratory infections. This study aimed to elucidate the molecular mechanisms underlying these traditional applications using a network pharmacology approach supported by literature-based validation. Garlic-derived bioactive compounds were collected from the Dictionary of Natural Products and published literature, and their chemical structures were verified using PubChem. Compound-target interactions were predicted using the STITCH database, while respiratory disease-associated genes were retrieved from DisGeNET. Protein-protein interaction (PPI) networks, topological analyses, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using Cytoscape and related bioinformatics tools. A PRISMA-guided PubMed review was conducted to summarize experimental evidence supporting the predicted targets. Network analysis identified TNF, MMP9, IL6, CASP3, CASP9, AKT1, and XIAP as major hub genes involved in inflammatory, apoptotic, and immune-related pathways. GO and KEGG enrichment analyses highlighted the NF-κB, MAPK, apoptosis, and cytokine signaling pathways as key biological processes associated with garlic activity. Literature-based validation confirmed the central roles of TNF and MMP9 in respiratory inflammation and supported the predicted pharmacological actions of garlic-derived compounds. Garlic demonstrates a multi-target pharmacological profile that may contribute to the prevention or adjunctive management of respiratory infections through coordinated regulation of inflammation, immune responses, and apoptosis. These findings provide a molecular basis for the traditional use of garlic in TPM and identify potential therapeutic targets for future investigation. Further experimental studies are required to validate these findings.

Highlights

  • Garlic exerts multi-target pharmacological effects in respiratory diseases.
  • TNF, MMP9, IL6, CASP3, and CASP9 were identified as key hub genes.
  • GO and KEGG analyses highlighted NF-κB, MAPK, apoptosis, and cytokine signaling.
  • Literature-based validation confirmed the biological relevance of TNF and MMP9.
  • Network pharmacology provides molecular support for Traditional Persian Medicine

Keywords

Main Subjects


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    1. Teka A., Maryo M. Ethiopian medicinal plants used for respiratory tract disorders: Ethnomedicinal review. Evidence-Based Complementary and Alternative Medicine. 2023;2023:7612804.
    2. Pokorski M. Advances in Experimental Medicine and Biology: Neuroscience and Respiration. Cham: Springer; 2015.
    3. Ludwig J., McWhinnie H. Antipyretic drugs in patients with fever and infection: Literature review. British Journal of Nursing. 2019;28(10):610-618.
    4. Schneider Y.K. Bacterial natural product drug discovery for new antibiotics: Strategies for tackling the problem of antibiotic resistance by efficient bioprospecting. Antibiotics. 2021;10:842.
    5. Mariano A., Bigioni I., Marchetti M., Scotto d'Abusco A., Superti F. Repositioned natural compounds and nanoformulations: A promising combination to counteract cell damage and inflammation in respiratory viral infections. Molecules. 2023;28:4045.
    6. Fatima N., Qamar M.T., Ashfaq U.A., Albutti A., Alwashmi A.S.S., Aljasir M.A. Network pharmacology approach for medicinal plants: Review and assessment. Pharmaceuticals. 2022;15:572.
    7. Rouf R., Uddin S.J., Sarker D.K., Islam M.T., Ali E.S., Shilpi J.A. Antiviral potential of garlic (Allium sativum) and its organosulfur compounds: A systematic update of pre-clinical and clinical data. Trends in Food Science & Technology. 2020;104:219-234.
    8. Bielory L. Complementary and alternative interventions in asthma, allergy, and immunology. Annals of Allergy, Asthma & Immunology. 2004;93:S45-S54.
    9. Donma M.M., Donma O. The effects of Allium sativum on immunity within the scope of COVID-19 infection. Medical Hypotheses. 2020;144:109934.
    10. The Canon of Medicine (Qanoon-Fil-Tib). Vol. 3. Translated by Sharafkandi A. Tehran: Soroush Publication; 1025.
    11. Aghili Khorasani M.H. Makhzan-al-Adviah. Rewritten by Shams Ardakani M.R., Rahimi R., Farjadmand F. 1st ed. Tehran: Tehran University of Medical Sciences; 1771.
    12. The Dictionary of Natural Products. Garlic. 2016. Available from: http://dnp.chemnetbase.com.
    13. National Center for Biotechnology Information. PubChem. Bethesda (MD): National Library of Medicine; 2023. Available from: https://pubchem.ncbi.nlm.nih.gov.
    14. STITCH: Search Tool for Interactions of Chemicals. 2023. Available from: http://stitch.embl.de.
    15. DisGeNET: A Database for Gene-Disease Associations. 2023. Available from: https://www.disgenet.org.
    16. Venn Diagram Web Tool. 2023. Available from: https://bioinformatics.psb.ugent.be/webtools/Venn.
    17. Franz M., Rodriguez H., Lopes C., Zuberi K., Montojo J., Bader G.D., Morris Q. GeneMANIA update 2018. Nucleic Acids Research. 2018;46(W1):W60-W64.
    18. Ashburner M., Ball C.A., Blake J.A., Botstein D., Butler H., Cherry J.M., et al. Gene ontology: Tool for the unification of biology. Nature Genetics. 2000;25:25-29.
    19. Kanehisa M., Goto S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Research. 2000;28:27-30.
    20. Huang D.W., Sherman B.T., Lempicki R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols. 2009;4:44-57.
    21. Verma T., Aggarwal A., Dey P., Chauhan A.K., Rashid S., Chen K.T., Sharma R. Medicinal and therapeutic properties of garlic, garlic essential oil, and garlic-based snack food: An updated review. Frontiers in Nutrition. 2023;10:1120377.
    22. Rauf A., Abu-Izneid T., Thiruvengadam M., Imran M., Olatunde A., Shariati M.A. Garlic (Allium sativum L.): Its chemistry, nutritional composition, toxicity, and anticancer properties. Current Topics in Medicinal Chemistry. 2022;22:957-972.
    23. Ozma M.A., Abbasi A., Ahangarzadeh Rezaee M., Hosseini H., Hosseinzadeh N., Sabahi S. A critical review on the nutritional and medicinal profiles of garlic (Allium sativum L.) bioactive compounds. Food Reviews International. 2023;39:6324-6361.
    24. Melguizo-Rodríguez L., García-Recio E., Ruiz C., De Luna-Bertos E., Illescas-Montes R., Costela-Ruiz V.J. Biological properties and therapeutic applications of garlic and its components. Food & Function. 2022;13:2415-2426.
    25. Bhatwalkar S.B., Mondal R., Krishna S.B.N., Adam J.K., Govender P., Anupam R. Antibacterial properties of organosulfur compounds of garlic (Allium sativum). Frontiers in Microbiology. 2021;12:613077.
    26. Rodrigues C., Percival S.S. Immunomodulatory effects of glutathione, garlic derivatives, and hydrogen sulfide. Nutrients. 2019;11:295.
    27. Borlinghaus J., Albrecht F., Gruhlke M.C.H., Nwachukwu I.D., Slusarenko A.J. Allicin: Chemistry and biological properties. Molecules. 2014;19:12591-12618.
    28. Bátai I.Z., Horváth Á., Pintér E., Helyes Z., Pozsgai G. Role of transient receptor potential ankyrin 1 ion channel and somatostatin sst4 receptor in the antinociceptive and anti-inflammatory effects of sodium polysulfide and dimethyl trisulfide. Frontiers in Endocrinology. 2018;9:55.
    29. Shao X., Li J., Zhang H., Zhang X., Sun C., Ouyang X. Anti-inflammatory effects and molecular mechanisms of bioactive small molecule garlic polysaccharide. Frontiers in Nutrition. 2023;9:1092873.
    30. Quintero-Fabián S., Ortuño-Sahagún D., Vázquez-Carrera M., López-Roa R.I. Alliin, a garlic (Allium sativum) compound, prevents LPS-induced inflammation in 3T3-L1 adipocytes. Mediators of Inflammation. 2013;2013:381815.
    31. Arreola R., Quintero-Fabián S., López-Roa R.I., Flores-Gutiérrez E.O., Reyes-Grajeda J.P., Carrera-Quintanar L., Ortuño-Sahagún D. Immunomodulation and anti-inflammatory effects of garlic compounds. Journal of Immunology Research. 2015;2015:401630.
    32. Hodge G., Hodge S., Han P. Allium sativum (garlic) suppresses leukocyte inflammatory cytokine production in vitro: Potential therapeutic use in the treatment of inflammatory bowel disease. 2002;48(4):209-215.
    33. Keiss H.P., Dirsch V.M., Hartung T., Haffner T., Trueman L., Auger J., et al. Garlic (Allium sativum L.) modulates cytokine expression in lipopolysaccharide-activated human blood thereby inhibiting NF-κB activity. Journal of Nutrition. 2003;133(7):2171-2175.
    34. Shih P.C., Kuo C.H., Juang J.Y., Liu C.H., Hsu L., Liu C.T. Effects of garlic oil on the migration of neutrophil-like cells studied using a chemotactic gradient lab chip. Journal of Biomedicine and Biotechnology. 2010;2010:319059.
    35. Hitchcock J.K., Mkwanazi N., Barnett C., Graham L.M., Katz A.A., Hunter R., Schäfer G., Kaschula C.H. The garlic compound Z-ajoene S-thiolates COX-2 and STAT3 and dampens the inflammatory response in RAW264.7 macrophages. Molecular Nutrition & Food Research. 2021;65:e2000854.
    36. You S., Nakanishi E., Kuwata H., Chen J., Nakasone Y., He X., et al. Inhibitory effects and molecular mechanisms of garlic organosulfur compounds on the production of inflammatory mediators. Molecular Nutrition & Food Research. 2013;57(11):2049-2060.
    37. Shin I.S., Hong J., Jeon C.M., Shin N.R., Kwon O.K., Kim H.S., et al. Diallyl disulfide, an organosulfur compound of garlic, attenuates airway inflammation via activation of the Nrf2/HO-1 pathway and NF-κB suppression. Food and Chemical Toxicology. 2013;62:506-513.
    38. Wang Y.L., Guo X.Y., He W., Chen R.J., Zhuang R. Effects of alliin on LPS-induced acute lung injury by activating PPARγ. Microbial Pathogenesis. 2017;110:375-379.
    39. Shen N., Cheng A., Qiu M., Zang G. Allicin improves lung injury induced by sepsis via regulation of the Toll-like receptor 4 (TLR4)/MyD88/NF-κB pathway. Medical Science Monitor. 2019;25:2567-2576.
    40. Ko J.W., Jeong S.H., Kwon H.J., Shin N.R., Seo Y.S., Kim J.C. Preventive effect of garlic oil and its organosulfur component diallyl disulfide on cigarette smoke-induced airway inflammation in mice. 2018;10:1659.
    41. Park J.M., Han Y.M., Kangwan N., Lee S.Y., Jung M.K., Kim E.H., et al. S-allyl cysteine alleviates nonsteroidal anti-inflammatory drug-induced gastric mucosal damages by increasing cyclooxygenase-2 inhibition, heme oxygenase-1 induction, and histone deacetylase inhibition. Journal of Gastroenterology and Hepatology. 2014;29(Suppl. 4):80-92.
    42. Clement F., Pramod S.N., Venkatesh Y.P. Identity of the immunomodulatory proteins from garlic (Allium sativum) with the major garlic lectins or agglutinins. International Immunopharmacology. 2010;10(3):316-324.
    43. Wlosinska M., Nilsson A.C., Hlebowicz J., Fakhro M., Malmsjö M., Lindstedt S. Aged garlic extract reduces IL-6: A double-blind placebo-controlled trial in females with a low risk of cardiovascular disease. Evidence-Based Complementary and Alternative Medicine. 2021;2021:6636875.
    44. Liu C.T., Su H.M., Lii C.K., Sheen L.Y. Effect of supplementation with garlic oil on activity of Th1 and Th2 lymphocytes from rats. Planta Medica. 2009;75(3):205-210.
    45. Feng Y., Zhu X., Wang Q., Jiang Y., Shang H., Cui L., et al. Allicin enhances host pro-inflammatory immune responses and protects against acute murine malaria infection. Malaria Journal. 2012;11:268.
    46. Kang N.S., Moon E.Y., Cho C.G., Pyo S. Immunomodulating effect of garlic component, allicin, on murine peritoneal macrophages. Nutrition Research. 2001;21(4):617-626.
    47. Makris A., Thornton C.E., Xu B., Hennessy A. Garlic increases IL-10 and inhibits TNF-α and IL-6 production in endotoxin-stimulated human placental explants. Placenta. 2005;26(10):828-834.
    48. Moutia M., Seghrouchni F., Abouelazz O., Elouaddari A., Al Jahid A., Elhou A. Allium sativum L. regulates in vitro IL-17 gene expression in human peripheral blood mononuclear cells. BMC Complementary and Alternative Medicine. 2016;16:377.
    49. Saud S.M., Li W., Gray Z., Matter M.S., Colburn N.H., Young M.R. Diallyl disulfide (DADS), a constituent of garlic, inactivates NF-κB and prevents colitis-induced colorectal cancer by inhibiting GSK-3β. Cancer Prevention Research. 2016;9(7):607-615.
    50. Gruhlke M.C.H., Antelmann H., Bernhardt J., Kloubert V., Rink L., Slusarenko A.J. The human allicin-proteome: S-thioallylation of proteins by the garlic defence substance allicin and its biological effects. Free Radical Biology and Medicine. 2019;131:144-153.
    51. Hanieh H., Narabara K., Piao M., Gerile C., Abe A., Kondo Y. Modulatory effects of two levels of dietary alliums on immune response and certain immunological variables following immunization in White Leghorn chickens. Animal Science Journal. 2010;81(6):673-680.
    52. Washiya Y., Nishikawa T., Fujino T. Enhancement of intestinal IgA production by ajoene in mice. Bioscience, Biotechnology, and Biochemistry. 2013;77(11):2298-2301.
    53. Panyod S., Wu W.K., Ho C.T., Lu K.H., Liu C.T., Chu Y.L. Diet supplementation with allicin protects against alcoholic fatty liver disease in mice by improving anti-inflammatory and antioxidative functions. Journal of Agricultural and Food Chemistry. 2016;64(37):7104-7113.
    54. Larypoor M.B., Zuhair M.H., Akhavan Sepahy A., Amanlou M. Evaluation of the number of CD4⁺CD25⁺FoxP3⁺ Treg cells in normal mice exposed to AFB1 and treated with aged garlic extract. Cell Journal. 2013;15(1):37-44.
    55. Anandasadagopan S.K., Pandurangan A.K., Nagarajan V., Srinivasan K., Ganapasam S. S-Allyl cysteine alleviates inflammation by modulating the expression of NF-κB during chromium(VI)-induced hepatotoxicity in rats. Human & Experimental Toxicology. 2017;36(11):1186-1200.
    56. Charron C.S., Dawson H.D., Albaugh G.P., Solverson P.M., Vinyard B.T., Solano-Aguilar G.I., et al. A single meal containing raw, crushed garlic influences expression of immunity- and cancer-related genes in whole blood of humans. Journal of Nutrition. 2015;145(11):2448-2455.
    57. Percival S.S. Aged garlic extract modifies human immunity. Journal of Nutrition. 2016;146(2):433S-436S.
    58. Mehrbod P., Amini E., Tavassoti-Kheiri M. Antiviral activity of garlic extract on influenza virus. Iranian Journal of Virology. 2009;3(1):19-23.
    59. Ming L., Li Z., Li X., Tang L., He G. Antiviral activity of diallyl trisulfide against H9N2 avian influenza virus infection in vitro and in vivo. Virology Journal. 2021;18:171.
    60. Kyo E., Kasuga S., Itakura Y. Immunomodulatory effects of aged garlic extract. Journal of Nutrition. 2001;131(3 Suppl):1075S-1079S.
    61. Zare A., Pourpak Z. Purified aged garlic extract modulates allergic airway inflammation in Balb/c mice. Iranian Journal of Allergy, Asthma and Immunology. 2008;7(3):133–141.
    62. DeBerge M.P., Ely K.H., Cheng G.S., Enelow R.I. ADAM17-mediated processing of TNF-α expressed by antiviral effector CD8+ T cells is required for severe T-cell-mediated lung injury. PLoS ONE. 2013;8(11):e79340.
    63. Lin C.C., Lin W.N., Cho R.L., Wang C.Y., Hsiao L.D., Yang C.M. TNF-α-induced cPLA2 expression via NADPH oxidase/reactive oxygen species-dependent NF-κB cascade on human pulmonary alveolar epithelial cells. Frontiers in Pharmacology. 2016;7:447.
    64. Ablamunits V., Lepsy C. Blocking TNF signaling may save lives in COVID-19 infection. Molecular Biology Reports. 2022;49(3):2303–2309.
    65. Cheng Y.D., Lu C.C., Hsu Y.M., Tsai F.J., Bau D.T., Tsai S.C. In silico and in vitro studies of Taiwan Chingguan Yihau (NRICM101) on TNF-α/IL-1β-induced human lung cells. BioMedicine. 2022;12(2):56–71.
    66. Karki R., Sharma B.R., Tuladhar S., Williams E.P., Zalduondo L., Samir P., et al. Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes. Cell. 2021;184(1):149–168.e17.
    67. Keewan E., Beg S., Naser S.A. Anti-TNF-α agents modulate SARS-CoV-2 receptors and increase the risk of infection through Notch-1 signaling. Frontiers in Immunology. 2021;12:641295.
    68. Alshevskaya A.A., Kireev F.D., Laushkina Z.A., Lopatnikova J.A., Gladkikh V.S., Sennikova J.A., et al. Enhanced expression of TNF-α type-1 receptors by immune cells in active pulmonary tuberculosis. International Journal of Tuberculosis and Lung Disease. 2018;22(2):212–220.
    69. Holla S., Trinath J., Balaji K.N. TNF-α modulates TLR2-dependent responses during mycobacterial infection. Methods in Molecular Biology. 2014;1155:133–150.
    70. Shi J., Sun B.H., Zhou L.R., Wang X.S. Role of IL-10 and TNF-α during Mycobacterium tuberculosis infection in murine alveolar macrophages. Genetics and Molecular Research. 2016;15(3).
    71. Catal F., Mete E., Tayman C., Topal E., Albayrak A., Sert H. A human monoclonal anti-TNFα antibody (adalimumab) reduces airway inflammation and ameliorates lung histology in a murine model of acute asthma. Allergologia et Immunopathologia. 2015;43(1):14–18.
    72. Desai P., Tahiliani V., Hutchinson T.E., Dastmalchi F., Stanfield J., Abboud G., et al. The TNF superfamily molecule LIGHT promotes the generation of circulating and lung-resident memory CD8 T cells following an acute respiratory virus infection. Journal of Immunology. 2018;200(8):2894–2904.
    73. Ziltener P., Reinheckel T., Oxenius A. Neutrophil and alveolar macrophage-mediated innate immune control of Legionella pneumophila lung infection via TNF and ROS. PLoS Pathogens. 2016;12(4):e1005591.
    74. Castellucci M., Rossato M., Calzetti F., Tamassia N., Zeminian S., Cassatella M.A., et al. IL-10 disrupts the Brd4-docking sites to inhibit LPS-induced CXCL8 and TNF-α expression in monocytes: implications for chronic obstructive pulmonary disease. Journal of Allergy and Clinical Immunology. 2015;136(3):781–791.e9.
    75. Ding Y., Hou Y., Liu Y., Yu T., Cui Y., Nie H., et al. MiR-130a-3p alleviates inflammatory and fibrotic phases of pulmonary fibrosis through proinflammatory factor TNF-α and profibrogenic receptor TGF-βRII. Frontiers in Pharmacology. 2022;13:863646.
    76. Couch Y., Xie Q., Lundberg L., Sharp T., Anthony D.C. A model of post-infection fatigue is associated with increased TNF and 5-HT2A receptor expression in mice. PLoS ONE. 2015;10(7):e0130643.
    77. Roy A., Sarkar A., Nayak D., Das S. Ultradiluted SARS-CoV-2 spike protein mitigates hyperinflammation in lung via ferritin and MMP-9 regulation in BALB/c mice. Virus Research. 2023;329:199091.
    78. Villalta P.C., Rocic P., Townsley M.I. Role of MMP2 and MMP9 in TRPV4-induced lung injury. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2014;307(8):L652–L659.
    79. Zhou P., Song N.C., Zheng Z.K., Li Y.Q., Li J.S. MMP2 and MMP9 contribute to lung ischemia-reperfusion injury via promoting pyroptosis in mice. BMC Pulmonary Medicine. 2022;22:230.
    80. Wu Z., Ruan Y., Chang J., Li B., Ren W. Angiotensin II is related to the acute aortic dissection complicated with lung injury through mediating the release of MMP9 from macrophages. American Journal of Translational Research. 2016;8(3):1426–1436.
    81. Oriss T.B., Krishnamoorthy N., Raundhal M., Morse C., Chakraborty K., Khare A., et al. Cutting edge: MMP-9 inhibits IL-23p19 expression in dendritic cells by targeting membrane stem cell factor affecting lung IL-17 response. Journal of Immunology. 2014;192(12):5471–5475.
    82. El-Fatah M.F., Ghazy M.A., Mostafa M.S., El-Attar M.M., Osman A. Identification of MMP-9 as a biomarker for detecting progression of chronic obstructive pulmonary disease. Biochemistry and Cell Biology. 2015;93(6):541–547.
    83. Lv C., Zhang Q., Tang P., Guo L., Ding Q. Serum MMP-9, SP-D, and VEGF levels reflect the severity of connective tissue disease-associated interstitial lung diseases. Advances in Rheumatology. 2022;62:37.
    84. Cheng B., Li T., Li F. Study on the multitarget mechanism of alliin activating autophagy based on network pharmacology and molecular docking. Journal of Cellular and Molecular Medicine. 2022;26(21):5590–5601.
    85. Menon R.T., Shrestha A.K., Barrios R., Reynolds C., Shivanna B. Tie-2 Cre-mediated deficiency of extracellular signal-regulated kinase 2 potentiates experimental bronchopulmonary dysplasia-associated pulmonary hypertension in neonatal mice. International Journal of Molecular Sciences. 2020;21(7):2594.
    86. Martel G., Rousseau S. TPL2 signalling: from Toll-like receptors-mediated ERK1/ERK2 activation to cystic fibrosis lung disease. International Journal of Biochemistry and Cell Biology. 2014;52:146–151.
    87. Sun Y.L., Zhao P.P., Zhu C.B., Li X.M., Yuan B. Qingfei formula protects against human respiratory syncytial virus-induced lung inflammatory injury by regulating the MAPK signaling pathway. Combinatorial Chemistry and High Throughput Screening. 2023;26.
    88. Nacken W., Anhlan D., Hrincius E.R., Mostafa A., Wolff T., Sadewasser A., et al. Activation of c-Jun N-terminal kinase upon influenza A virus infection is independent of pathogen-related receptors but dependent on amino acid sequence variations of influenza A virus NS1. Journal of Virology. 2014;88(16):8843–8852.
    89. Alam A., Imam N., Siddiqui M.F., Ali M.K., Ahmed M.M., Ishrat R. Human gene expression profiling identifies key therapeutic targets in tuberculosis infection: a systematic network meta-analysis. Infection, Genetics and Evolution. 2021;87:104649.
    90. Huang Y.F., Bai C., He F., Xie Y., Zhou H. Review on the potential action mechanisms of Chinese medicines in treating coronavirus disease 2019 (COVID-19). Pharmacological Research. 2020;158:104939.
    91. Ganda I.J., Rauf P.T., Laompo S., Pelupessy A., Lawang N.M. IL-6 serum level, ARDS, and AKI as risk factors for the COVID-19 infection’s mortality in children. PLOS ONE. 2023;18:e0293639.
    92. Bahmani M., Chegini R., Ghanbari E., Sheykhsaran E., Shiri Aghbash P., Leylabadlo H.E. Severe acute respiratory syndrome coronavirus 2 infection: Role of interleukin-6 and the inflammatory cascade. World Journal of Virology. 2022;11:113–128.
    93. Copaescu A., Smibert O., Gibson A., Phillips E.J., Trubiano J.A. The role of IL-6 and other mediators in the cytokine storm associated with SARS-CoV-2 infection. Journal of Allergy and Clinical Immunology. 2020;146:518–534.e1.
    94. Smetana K. Jr., Brábek J. Role of interleukin-6 in lung complications in patients with COVID-19: Therapeutic implications. In Vivo. 2020;34:1589–1592.
    95. Li Y.S., Ren H.C., Cao J.H. Roles of interleukin-6-mediated immunometabolic reprogramming in COVID-19 and other viral infection-associated diseases. International Immunopharmacology. 2022;110:109005.
    96. Durham G.A., Palmer T.M. Is there a role for prostanoid-mediated inhibition of IL-6 trans-signalling in the management of pulmonary arterial hypertension? Biochemical Society Transactions. 2019;47:1143–1156.
    97. Xu W.J., Wu Q., He W.N., Wang W., Zhao S., Huang Y.L., Huang J.X. Interleukin-6 and pulmonary hypertension: From physiopathology to therapy. Frontiers in Immunology. 2023;14:1181987.
    98. Iwase S., Nakada T.A., Hattori N., Takahashi W., Takahashi N., Aizimu T. Interleukin-6 as a diagnostic marker for infection in critically ill patients: A systematic review and meta-analysis. American Journal of Emergency Medicine. 2019;37:260–265.
    99. Meanwatthana J., Majam T. Interleukin-6 antagonists: Lessons from cytokine release syndrome to the therapeutic application in severe COVID-19 infection. Journal of Pharmacy Practice. 2022;35:752–761.
    100. Liu S., Wang B., Chen T., Wang H., Liu J., Zhao X., Zhang Y. Two new and effective food-extracted immunomodulatory agents exhibit anti-inflammatory response activity in the hACE2 acute lung injury murine model of COVID-19. Frontiers in Immunology. 2024;15:1374541.
    101. Cai W., Wen H., Zhou Q., Wu L., Chen Y., Zhou H. 14-Deoxy-11,12-didehydroandrographolide inhibits apoptosis in influenza A (H5N1) virus-infected human lung epithelial cells via the caspase-9-dependent intrinsic apoptotic pathway which contributes to its antiviral activity. Antiviral Research. 2020;181:104885.
    102. Huang X., Zou L., Yu X., Chen M., Guo R., Cai H. Salidroside attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2A receptor-related mitochondria-dependent apoptosis pathway. Journal of Molecular and Cellular Cardiology. 2015;82:153–166.
    103. Farhadi F., Jahanpour S., Hazem K., Aghbali A., Baradran B., Vahid Pakdel S.M. Garlic (Allium sativum) fresh juice induces apoptosis in human oral squamous cell carcinoma: The involvement of caspase-3, Bax and Bcl-2. Journal of Dental Research, Dental Clinics, Dental Prospects. 2015;9:267–273.
    104. Yildiz Gulhan P., Eroz R., Ataoglu O., İnce N., Davran F., Öztürk C.E. The evaluation of both the expression and serum protein levels of caspase-3 gene in patients with different degrees of SARS-CoV-2 infection. Journal of Medical Virology. 2022;94:897–905.
    105. Fodor R., Georgescu A.M., Grigorescu B.L., Cioc A.D., Veres M., Cotoi O.S. Caspase-3 expression and plasma level of Fas ligand as apoptosis biomarkers in inflammatory endotoxemic lung injury. Romanian Journal of Morphology and Embryology. 2016;57:951–957.
    106. Damarla M., Parniani A.R., Johnston L., Maredia H., Serebreni L., Hamdan O. Mitogen-activated protein kinase-activated protein kinase 2 mediates apoptosis during lung vascular permeability by regulating movement of cleaved caspase-3. American Journal of Respiratory Cell and Molecular Biology. 2014;50:932–941.
    107. Yapasert R., Khaw-On P., Banjerdpongchai R. Coronavirus infection-associated cell death signaling and potential therapeutic targets. Molecules. 2021;26:7459.
    108. Ashley S.L., Sisson T.H., Wheaton A.K., Kim K.K., Wilke C.A., Ajayi I.O. Targeting inhibitor of apoptosis proteins protects from bleomycin-induced lung fibrosis. American Journal of Respiratory Cell and Molecular Biology. 2016;54:482–492.
    109. Muniyan R., Gurunathan J. Lauric acid and myristic acid from Allium sativum inhibit the growth of Mycobacterium tuberculosis H37Ra: In silico analysis reveals possible binding to protein kinase B. Pharmaceutical Biology. 2016;54:2814–2821.
    110. Vaz de Paula C.B., Nagashima S., Liberalesso V., Collete M., da Silva F.P.G., Oricil A.G.G. COVID-19: Immunohistochemical analysis of TGF-β signaling pathways in pulmonary fibrosis. International Journal of Molecular Sciences. 2022;23:168.
    111. Pelzl L., Singh A., Funk J., Witzemann A., Marini I., Zlamal J. Antibody-mediated procoagulant platelet formation in COVID-19 is AKT-dependent. Journal of Thrombosis and Haemostasis. 2022;20:387–398.
    112. Ma L., Brown M., Kogut P., Serban K., Li X., McConville J. Akt activation induces hypertrophy without contractile phenotypic maturation in airway smooth muscle. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2011;300:L701–L709.
    113. Casalino-Matsuda S.M., Chen F., Gonzalez-Gonzalez F.J., Nair A., Dib S., Yemelyanov A. Hypercapnia suppresses macrophage antiviral activity and increases mortality of influenza A infection via Akt1. Journal of Immunology. 2020;205:489–501.
    114. Fan Z., Li C., Qin C., Xie L., Wang X., Gao Z. Role of the PI3K/Akt pathway in modulating cytoskeleton rearrangements and phenotype switching in rat pulmonary arterial vascular smooth muscle cells. DNA and Cell Biology. 2014;33:12–19.
    115. Chen Y., Cui L., Wang J., Liu C., Guo J. Ameliorative effects and mechanism of Buyang Huanwu decoction on pulmonary vascular remodeling: Network and experimental analyses. Oxidative Medicine and Cellular Longevity. 2021;2021:4576071.
    116. Abdalla M., Sabbineni H., Prakash R., Ergul A., Fagan S.C., Somanath P.R. The Akt inhibitor, triciribine, ameliorates chronic hypoxia-induced vascular pruning and TGFβ-induced pulmonary fibrosis. British Journal of Pharmacology. 2015;172:4173–4188.
    117. Zhang L., Cui M., Chen S. Identification of the molecular mechanisms of Peimine in the treatment of cough using computational target fishing. Molecules. 2020;25:1105.
    118. Mehrabi A., Mahmoudi R., Khedmati Morasa H., Mosavi S., Kazeminia M., Attaran Rezaei F., Shahsavari S. Study of chemical composition, antibacterial and antioxidant activity of thyme leaves and stems essential oil. Journal of Medicinal Plants and By-products. 2022;11(2):253–263.
    119. Fah L., Klotoé J.R., Agbodjento E., Dougnon V.T., Kitchey A., Sintondji K., Déguénon E., Atègbo J.M. Evaluation of the anti-inflammatory and immunomodulatory properties of Jatropha multifida stem sap. Journal of Medicinal Plants and By-products. 2024;13(3):680–690.
    120. Bahrampour Juybari K., Mahmoudi M., Bayat S., Noorian P., Rostami Ghadi F., Goudarzi M., Houshmand G. Gallic acid mitigates carrageenan-induced acute paw edema in rats through antioxidant activity and modulation of NF-κB, COX-2, and proinflammatory cytokines. Journal of Medicinal Plants and By-products. 2026;15(3):376–382.
    121. Arabjafari S., Golkar P., Tarkesh Esfahani M., Taghizadeh M. Secondary metabolites and antioxidant activity in different Iranian accessions of Dorema ammoniacum D. Don and Dorema aucheri Boiss. Journal of Medicinal Plants and By-products. 2023;12(4):459–468.
    122. Gupta J., Sharma S.S., Kabra N.R. Phytochemicals enriched in spices: A source of natural epigenetic therapy. Archives of Pharmacal Research. 2020;43:171–186.
    123. Bauer D., Redmon N., Mazzio E., Taka E., Reuben J.S., Day A. Diallyl disulfide inhibits TNFα-induced CCL2 release through MAPK/ERK and NF-κB signaling. Cytokine. 2015;75:117–126.
    124. Bauer D., Mazzio E., Soliman K.F., Taka E., Oriaku E., Womble T. Diallyl disulfide inhibits TNFα-induced CCL2 release by MDA-MB-231 cells. Anticancer Research. 2014;34:2763–2770.
    125. Suzuki J.I., Miki S., Ushijima M., Kodera Y. Regulation of immune response by S-1-propenylcysteine through autophagy-mediated protein degradation. Experimental and Therapeutic Medicine. 2020;19:1570–1573.
    126. Roy N., Nazeem P.A., Babu T.D., Abida P.S., Narayanankutty A., Valsalan R. EGFR gene regulation in colorectal cancer cells by garlic phytocompounds with special emphasis on S-allyl-L-cysteine sulfoxide. Interdisciplinary Sciences: Computational Life Sciences. 2018;10:686–693.
    127. Wallace G.C., Haar C.P., Vandergrift W.A., Giglio P., Dixon-Mah Y.N., Varma A.K. Multi-targeted DATS prevents tumor progression and promotes apoptosis in ectopic glioblastoma xenografts in SCID mice via HDAC inhibition. Journal of Neuro-Oncology. 2013;114:43–50.
    128. El-Saadony M.T., Saad A.M., Korma S.A., Salem H.M., Abd El-Mageed T.A., Alkafaas S.S., Elsalahaty M.I., Elkafas S.S., Mosa W.F.A., Ahmed A.E., Mathew B.T., Albastaki N.A., Alkuwaiti A.A., El-Tarabily M.K., AbuQamar S.F., El-Tarabily K.A., Ibrahim S.A. Garlic bioactive substances and their therapeutic applications for improving human health: A comprehensive review. Frontiers in Immunology. 2024;15:1277074.