Abstract
The study elucidates the effect of ɑ-linolenic acid (ALA) on mitochondrial stress, hypoxic cancer microenvironment, and intervention of cholinergic anti-inflammatory pathway using N-methyl-N-nitrosourea (MNU) induced estrogen receptor (ER+) mammary gland carcinoma and Caenorhabditis elegans model, respectively. The efficacy of ALA was scrutinized in vivo and in vitro using various experiments like hemodynamic studies, morphological analysis, antioxidants parameters, immunoblotting, and quantitative reverse transcription polymerase chain reaction. The effect of ALA was also validated using C. elegans worms. ALA administration had a positive effect on tissue architecture of the malignancy when scrutinized through the whole mount carmine staining, hematoxylin and eosin staining, and scanning electron microscopy. The proteomic and genomic checkpoint revealed the participation of mitochondrial dysfunction, alteration of hypoxic microenvironment, and involvement of cholinergic anti-inflammatory response after treatment with ALA. ALA treatment has also increased the level of synaptic acetylcholine and acetylcholine esterase with a significant decrease in lipid content. It was concluded that ALA persuaded the mitochondrial stress, activation of downstream cholinergic anti-inflammatory markers, and favorable regulation of hypoxia microenvironment through inhibition of fatty acid synthase and sterol regulatory element-binding protein.
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Key Findings
Major components of the cell membrane integrity and cell fluidity are polyunsaturated fatty acids (PUFAs). The nematode model of Caenorhabditis elegans is a well established model for studying the physiology of unsaturated fatty acids. The current study was performed to validate the anticancer effect of ALA on mammary gland carcinoma and elucidate its mechanism of action. The underlying mechanism for the effects of ALA was perceived to be mitochondrial‐mediated death apoptosis pathway, activation of cholinergic anti‐inflammatory pathway, and favorable regulation of hypoxia‐mediated downstream markers for FASN. Oxidative stress is an imbalance between the systemic manifestation of ROS and the ability of the biological system to detoxify the reactive intermediates or repair the cellular damage. ALA administration curtailed the levels of TBARs with restoration of enzymatic antioxidant defense of SOD, catalase, and GSH. ALA treatment increased the process of apoptosis through the decreased expression of several enzymes. It was concluded that ALA has a marked positive effect on morphological, biochemical, and associated biological parameter for mammary gland chemoprevention. On the basis of mechanistic insight, ALA effected mitochondrial stress, activation of cholinergic anti‐inflammatory pathway in C. elegans and had favorable regulation of hypoxia‐mediated downstream markers for the inhibition of palmitic acid synthesis. The study also validates the need for clinical evaluation of ALA for its future use as potential chemo adjuvant.