Potential Valorization of Edible Nuts By-Products: Exploring the Immune-Modulatory and Antioxidants Effects of Selected Nut Shells Extracts in Relation to Their Metabolic Profiles

The immune system is a potent army that defends our body against various infections and diseases through innate and adaptive immunity. Herbal medicine is one of the essential sources for enhancing immunity because of affordability, availability, minor side effects, and consumers’ preferences. Hazelnuts, walnuts, almonds, and peanuts are among the most widespread edible nuts that are rich in phenolics, fats, fibers, vitamins, proteins, and minerals. The potential of nut shells in phytoremediation has attracted increasing attention as a sustainable solution for waste recycling. Here, we determined the in vitro immune-modulatory activity as well as the metabolite profile of the four nut shell extracts. The addition of the extracts to LPS-stimulated macrophages, especially peanut and walnut shells, has downregulated the gene expression of AP-1, TNF-α, IL-8, iNOS, and COX-2 expression levels. Significant antioxidant capabilities and immune-modulatory effects have been traced for peanut shells. UPLC-MS metabolic profiling of the four nut shell extracts allowed the detection of a relatively high level of phenolic compounds in peanut shells. Intriguingly, a significant correlation between the antioxidant capacity and the total phenolic content was found, indicating the contribution of the phenolic compounds to the antioxidant properties and hence the immune-modulatory activity. Furthermore, molecular docking and structure–activity relationship (SAR) studies revealed kaempferol rutinoside and proanthocyanidin A5’ as potential iNOS inhibitors.