# Plant Extracellular Vesicles: Investigating Their Utilization as Beneficial Nutrients in Diet
## 4 P-EV Biological Properties and Therapeutic Applications
This finding was confirmed by intratumoral administration of lemon-derived exosomes in mice with chronic myeloid leukemia. Tumor growth was suppressed by regulating apoptosis and by inhibiting angiogenesis [60]. Recently, [PERSON] et al. [61] demonstrated that EVs purified from ginseng roots induce apoptosis of murine melanoma cells by inducing the formation of ROS. This result suggests that plant EVs may participate as a crucial modulator in the mammalian immune response. It was also proven that P-EVs may exhibit synergistic effects with anticancer therapies [56]. Co-administration of bitter-melon-derived vesicles with the chemotherapeutic agent 5-fluorouracilacil in oral squamous cell carcinoma treatment showed increased antiproliferative and cytotoxic effects [35]. The effects of plant vesicles on in vitro skin regeneration have been studied, suggesting new potential applications. Wheatgrass-derived EVs have been shown to induce cell regeneration in wound healing, by triggering the proliferation and migration of epithelial, endothelial, and dermal fibroblast in a dose-dependent manner and by stimulating type I collagen expression [62]. The regenerative functions of grape-derived vesicles were investigated in mice with induced colitis. In this study, it was reported that these vesicles can penetrate the intestinal barrier and stimulate stem cell proliferation, by inducing the expression of genes responsible for pluripotency (SOX2, Oct4, Klf4), thus resulting in a strong acceleration of mucosal epithelial renewal [63]. Therefore, the proliferation of intestinal stem cells mediated by grape vesicles could potentially be used for the treatment of patients with intestinal epithelial injuries. A summary of the anticancer, anti-inflammatory and regenerative properties of plant-derived vesicles evaluated through in vitro and in vivo experiments is shown in Figure 2 and Table 4.  
Figure 2: Summary of biological functions and applications of plant-derived EVs. \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Source** & **Therapeutic Activity** & **In Vitro Effect** & **In Vivo Effect** & **Ref.** \\ \hline \multirow{4}{*}{Bitter melon} & \multirow{4}{*}{Anticancer} & Antiproliferation, apoptosis induction, & \multirow{4}{*}{Enhancement of the cytotoxic effect} \\  & & ROS generation induction on oral & & of 5-FU in \\  & & squamous cell carcinoma CAL27 and & & \\  & & WSU-HN6 cells & & female BALB/c nude mice \\ \multirow{4}{*}{Grapefruit} & \multirow{4}{*}{Anticancer} & Cell cycle arrest at G2/M checkpoint, & \multirow{4}{*}{Enhancement of the cytotoxic effect} \\  & & reduction of cyclins B1 and B2 expression & & \\  & & levels, upregulation of cell cycle inhibitor & & \\  & & p21 in A375 human melanoma cells & & \\  & & Suppression of pro-inflammatory & & \\  & & Suppression of pro-inflammatory & & \\  & & Anti-inflammatory & cytokine & \\  & & cytokine and chemokyne expression and & & \\  & & increment in anti-inflammatory cytokine & & \\  & & expression in Raw 264.7 macrophages & & \\  & & Increment of cell viability and migration & & \\  & & of keratinocyte HaCaT cells & & \\  & & Regenerative & Upregulation of wound-healing genes & \\  & & Promotion of tube formation ability of & & \\  & & & HUVEC cells & \\  & & & Inhibition of cancer cell proliferation in & \\  & & chronic myeloid leukemia LAMA84 cells, & & \\ Lemon & Anticancer & human colorectal adenocarcinoma SW480 & & \\  & & cells, human lung carcinoma A549 cells & & \\  & & Cell cycle S-phase arrest and induction of & & \\  & & apoptosis in BGC-823 and SGC-7901 & & \\  & & gastric cancer cells & & \\  & & & & \\  & & & & \\  & & & & \\  & & & & \\  & & & & \\ \end{tabular}
\end{table} 
Table 4: Activity of different sources of P-EVs in in vitro and in vivo models.