International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 342-354 http://medscipublisher.com/index.php/ijmms 347 conditions, Nrf2 is bound to its inhibitor, Keap1 (Kelch-like ECH-associated protein 1), in the cytoplasm, where it is targeted for degradation. However, upon oxidative stress or exposure to LBPs, Keap1 is inactivated, allowing Nrf2 to translocate into the nucleus, where it binds to AREs and activates the transcription of various antioxidant and cytoprotective genes such as heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and glutathione peroxidase (GPx). Studies have demonstrated that LBP treatment significantly enhances the nuclear translocation of Nrf2 and increases the expression of these antioxidant enzymes, leading to an elevated cellular defense against oxidative stress-induced damage (Wang et al., 2020). In various models of oxidative stress, such as alcohol-induced liver injury, UV-induced skin damage, and hyperoxia-induced lung injury, LBPs have been shown to robustly activate the Nrf2/ARE signaling pathway. For instance, in alcohol-exposed liver cells, LBPs enhanced the expression of Nrf2 and its downstream target HO-1, reducing oxidative damage and preventing apoptosis by modulating the balance between pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins (Wei et al., 2021). Similarly, in UV-damaged skin fibroblasts, LBPs activated Nrf2, leading to increased levels of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), which reduced ROS accumulation and lipid peroxidation (Liang et al., 2018). Importantly, the protective effects of LBPs were significantly diminished in cells where Nrf2 was silenced, highlighting the central role of the Nrf2 pathway in LBP-mediated antioxidant defense. These findings underscore the therapeutic potential of LBPs in preventing oxidative damage in various tissues and highlight Nrf2 as a key target for antioxidant therapies. 4 Immunomodulatory Effects of Lycium Barbarum Polysaccharides 4.1 Macrophage activation and cytokine modulation Macrophages are vital components of the immune system, playing a central role in both innate and adaptive immune responses by engulfing pathogens and dead cells and releasing cytokines to coordinate immune reactions. Lycium barbarum polysaccharides (LBPs) have been shown to significantly enhance the activity of macrophages, thereby boosting the immune system's ability to fight infections and maintain homeostasis. Studies demonstrate that LBPs stimulate macrophages through the activation of specific signaling pathways, such as the toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) pathways, which are critical in immune cell activation. For example, LBP-treated macrophages exhibit increased phagocytic activity, which enhances their capacity to engulf and destroy pathogens and apoptotic cells. This effect is accompanied by the release of reactive nitrogen species (RNS) and reactive oxygen species (ROS), further aiding in pathogen clearance (Liu et al., 2021). In addition to enhancing macrophage activity, LBPs modulate the production of pro- and anti-inflammatory cytokines, which are critical in orchestrating immune responses. LBPs have been shown to upregulate the secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) in macrophages, which are essential for mounting an effective defense against infections. At the same time, LBPs can increase the levels of anti-inflammatory cytokines such as interleukin-10 (IL-10), helping to regulate the immune response and prevent excessive inflammation, which can cause tissue damage. This dual role—promoting a strong initial immune response while also regulating inflammation—indicates the immune-balancing properties of LBPs. Studies also show that LBP-induced macrophage polarization can shift towards the M1 phenotype, which is associated with pro-inflammatory responses and pathogen killing, while balancing this with anti-inflammatory actions to ensure proper immune regulation (Feng et al., 2020). This modulation of cytokine production by LBPs provides a potential therapeutic mechanism for enhancing immune defense in various diseases while preventing excessive immune responses that can lead to chronic inflammation. 4.2 T-Cell and Immune Response Modulation Lycium barbarum polysaccharides (LBPs) play a crucial role in modulating T-cell responses, particularly in restoring immune function in immunocompromised conditions. Research has shown that LBPs regulate the balance of T-helper (Th) cell subsets, especially Th1 and Th2 cells, which are responsible for mediating cellular and humoral immunity, respectively. In studies involving cyclophosphamide-induced immunosuppression models, LBPs were observed to restore the population of CD4+ T-helper cells and CD8+ cytotoxic T lymphocytes (CTLs),
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