Alleviate COPD using Liquorice and Asafoetida-enriched Foods by Combating AGE-RAGE Axis
Dr. Sharadendu Bali¹, Dr. Randhir Singh², Asfia Khan³
¹ Professor General Surgery, Adesh Medical College and Hospital, Shahbad Markanda, Kurukshetra, Haryana
² Associate Professor, Department of Pharmacology, Central University of Punjab, Bathinda
³ M.Phil, Hamdard University, Karachi
Healthcare Bulletin UK | Open Access Research Article
Abstract
Research ArticleAdvanced Glycation End Products (AGEs) are formed in the lungs either spontaneously or as a result of the insult due to cigarette smoke. These AGEs have deleterious effects due to their pro-oxidant and inflammatory actions. The AGEs can interact with the receptor for AGE, called RAGE, triggering various kinase pathways that activate transcription factor NF-κB (nuclear factor kappa B). This, in turn, leads to the production of several inflammatory substances and promoters. Impeding the formation of AGEs and inhibiting the AGE-RAGE axis can prove beneficial in down-regulating the inflammatory process, leading to favourable outcomes. Asafoetida and liquorice are two such herbs that can significantly impede the AGE-RAGE-NF-κB axis, which plays a key role in the pathogenesis of chronic obstructive pulmonary disease (COPD). These herbs have the potential to improve symptoms and lung function in patients suffering from this condition.
1. Introduction & Glycation Chemistry
Glycyrrhiza glabra (Liquorice, Mulethi in Hindi) has been extensively utilized in diverse traditional medicinal systems due to its wide-ranging therapeutic properties including ulcer protection, demulcent, expectorant, and antitussive actions. Asafoetida (Heeng in Hindi), extracted from Ferula species, is an oleo-gum resin valued in Indian, Pakistani, Afghan, and Iranian medicine for expectorant and antispasmodic benefits in respiratory diseases.
Glycation is a non-enzymatic reaction between reducing sugars and free amine groups on macromolecules, producing Schiff bases, Amadori products, and reactive α-dicarbonyls (glyoxal, methylglyoxal) culminating in Advanced Glycation End Products (AGEs). Membrane-bound RAGE is highly expressed in pulmonary tissue and immune cells (neutrophils, macrophages), acting as a primary mediator of chronic inflammation.
2. Traditional Use of Mulethi (Glycyrrhiza glabra) and Heeng (Asafoetida)
In Ayurveda and Siddha, licorice roots aid in reducing upper respiratory tract congestion and enhancing tracheal mucus secretion. Active compounds like Glycyrrhizic acid (GA) and isoliquiritin show anti-asthmatic, anti-allergic, and anti-inflammatory activity.
Ayurvedic medicine administers hot water extracts of dried asafoetida resin for chronic bronchitis, whooping cough, and asthma. Traditional practices in India, Thailand, and Pakistan involve hanging a pouch of asafoetida around a sick child's neck or arm as a protective shield against airborne respiratory infections.
Blocks the formation of AGEs at several stages (Schiff base & dicarbonyl cross-linking).
Binds HMGB1, preventing HMGB1 from interacting with RAGE and TLR4 receptors, blocking NF-κB inflammatory cascade.
Figure 1: Shows the AGE-RAGE axis and the points of inhibition by asafoetida and liquorice. While asafoetida acts by blocking the formation of AGEs at several stages, glycyrrhizin in liquorice acts by binding to HMGB1 which prevents the interaction of HMGB1 with the RAGE and TLR4 receptors.
3. Advanced Glycation Endproducts (AGEs) & RAGE Signaling
Accumulation of AGEs activates RAGE receptors, triggering intracellular pathways such as ERK/MAPK, JAK/STAT, and NF-κB. This leads to massive production of reactive oxygen species (ROS), pro-inflammatory cytokines (IL, TNF), endoplasmic reticulum stress, and bronchial cell death.
4. Pathological Role of AGEs in COPD
Cigarette smoke delivers toxic glycotoxins directly to alveolar spaces. Patients with COPD exhibit elevated skin autofluorescence (AFR) and increased staining of AGEs/RAGE in bronchial walls, accompanied by a decline in protective soluble RAGE (sRAGE).
Figure 2: The structure of the HMGB1 protein. Glycyrrhizin in liquorice acts as a natural HMGB1 antagonist, binding this protein and suppressing airway inflammation.
5. Blockade of AGE-RAGE Interaction & HMGB1 Antagonism
Extracellular HMGB1 binds RAGE (residues 150-183) and TLR4 (residues 89-108), driving severe pulmonary inflammation in COPD. Glycyrrhizin in licorice acts as a direct natural HMGB1 antagonist, forming a glycyrrhizin-HMGB1 complex that blocks HMGB1 interaction with RAGE and TLR4.
6. Asafoetida (Heeng) Chemistry & Antiglycation Activity
Ferula narthex resin yields sesquiterpenecoumarins such as Ligupersin A, 8'-O-acetyl-asacoumarin A, umbelliprenin, and umbelliferone. Ligupersin A demonstrates potent antiglycation activity in BSA-glucose assays, outperforming standard aminoguanidine inhibitors.
Hingu-Pippali Yoga Clinical Trial: In a randomized clinical trial of Hingu-Pippali Yoga (250 mg bid for 28 days), patients with pollution and smoke-induced respiratory dysfunction showed significant improvements in spirometric lung capacity, marked reduction in cough, dyspnea, eosinophil counts, and ESR.
7. Licorice (Glycyrrhiza glabra) Actions & Nrf2 Pathway
Isoliquiritigenin from licorice attenuates cigarette smoke-induced COPD by regulating Nrf2 antioxidant and NF-κB inflammatory pathways. Glycyrrhizic acid (GA) induces autophagy via PI3K/AKT/mTOR signaling, downregulating TNF-α, IL-1β, and TGF-β1/Smad tissue fibrosis pathways.
8. Culinary Science & Recommended Dishes for Heeng and Mulethi
Heeng is a staple in savory Indian curries, lentils, and pickles, acting as a potent digestive Vata-alleviating spice. Mulethi (Yastimadhu), being 30-50 times sweeter than sucrose, serves as a natural sweetening flavor in puddings, mousses, and herbal teas, or can be sucked raw as a throat lozenge.
9. Discussion & Conclusion
COPD is a highly prevalent respiratory disorder worldwide. Incorporating asafoetida and liquorice into daily dietary meals offers a safe, palatable, and potent natural intervention to combat the AGE-RAGE axis, suppress inflammatory cytokines, and improve lung function in COPD patients.
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