Potential applications of components of aged garlic extract in mitigating pro-inflammatory gene expression linked to human diseases (Review)

Abstract

In the present review, simple approaches for the screening and characterization of natural compound agents that alter pro-inflammatory gene expression are described, with a particular focus on aged garlic extract (AGE), which has been the subject of several investigations that have supported its potential application as an anti-inflammatory agent. Additionally, evidence regarding the possible effects and mechanisms of action of two major AGE components, S-allyl cysteine (SAC) and S-1-propenyl-l-cysteine (S1PC), is reviewed. The proposed molecular targets of SAC and S1PC are IKKβ kinase, the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 complex, peroxisome proliferator-activated receptor-γ, histone deacetylase and toll-like receptor 4 (TLR4). Targeting these molecules causes a marked reduction in NF-κB activity accompanied by a notable decrease in the transcription of NF-κB-regulated genes. Another main objective of the present review was to discuss the possibility that AGE and its bioactive components could be employed in the treatment of several human pathologies that are characterized by a hyperinflammatory state resulting from dysregulation of the TLR4 and NF-κB pathways. SAC is of interest in the treatment of lung pathologies, neurological diseases, osteoarthritis, muscular atrophy, cardiovascular diseases, diabetes and cancer. Additionally, the anti-oxidative activities of AGE, SAC and S1PC are compatible with their employment in the treatment of diseases characterized by oxidative stress, such as sickle cell disease and β-thalassemia.

Keywords: AGE; IL-8; NF-κB; TLR4; inflammation.

Figure 1

Examples of experimental approaches for the screening and characterization of anti-inflammatory agents to be proposed for the experimental therapy of respiratory diseases, such as cystic fibrosis, asthma, COPD, COVID-19, PASC and long-COVID. The experimental model systems described are based on IB3-1 human bronchial epithelial cells (A) infected with PAO, or exposed to (B) TNF-α, (C) SARS-CoV-2 spike protein and (D) the COVID-19 BNT162b2 vaccine. The image of IB3-1 cells was modified from Gasparello et al (45) (copyright can be found at https://doi.org/10.3390/molecules29245938). AGE, aged garlic extract; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease-2019; PAO, Pseudomonas aeruginosa; PASC, post-acute sequelae of SARS-CoV-2 infection; S1PC, S-1-propenyl-l-cysteine; SAC, S-allyl cysteine; SARS-CoV-2, severe acute respiratory syndrome corona virus 2.

Figure 2

Proposed effects of SAC on the TLR4/NF-κB pathway. (A) Docking experiments showing the interaction between SAC and the Toll/interleukin-1 receptor domain of TLR4(45). Inhibitory effects of SAC (B) on MAP kinases, IKKβ, PPARγ and HDAC (62-64) and (C) on ROS and TLR4 dimerization are shown. HDAC, histone deacetylase; MyD88, myeloid differentiation primary response 88; P, phosphorylated; PPARγ, peroxisome proliferator-activated receptor-γ; ROS, reactive oxygen species; S1PC, S-1-propenyl-l-cysteine; SAC, S-allyl cysteine; TLR4, toll-like receptor 4; Ub, ubiquitinated.

Figure 3

Inhibitory effects of AGE, SAC and S1PC on the NF-κB-associated expression of pro-inflammatory genes in human diseases. AGE, aged garlic extract; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease-2019; S1PC, S-1-propenyl-l-cysteine; SAC, S-allyl cysteine; SARS-CoV-2, severe acute respiratory syndrome corona virus 2; TLR4, toll-like receptor 4.