*3.12. Other Mechanisms*

The e ffects of EGCG have been also reported in many other signaling pathways and other diseases other than cancer could be involved in the benefit of the catechin. For example, EGCG treatment inhibited VEGF signaling, leading to a reduction in mitogenesis of human umbelical arterial cells [217]. Mitogenesis is key process for cell energy and its modulation can impact the survival, growth, and replication. As already reported in paragraphs 3.8 and 3.10, the inhibition of some components of MMP family by EGCG could reduce tumor invasion and metastasis. For instance, MMP-2 and MMP-9 are both inhibited by EGCG in the prostate of transgenic adenocarcinoma of mouse prostate (TRAMP) model, as mentioned before [89], as well in endothelial cells [218]. In addition, the anticancer properties of EGCG may be dependent on the inhibition of the protease urokinase-plasminogen activator (uPA), which is often overexpressed in human tumors and whose activity is involved in the regulation of apoptosis, cell replication, migration, and adhesion [219]. EGCG was also studied in the amyloid aggregation and neurotoxicity model. The catechin e ffects were examined in relation to misfolded or misassembled proteins in human islet amyloid polypeptide (hIAPP) transgenic mice, an animal model for investigating the formation of amyloid fibrils and, thus, pancreas dysfunction and diabetes [220]. EGCG was administered at 60 mg/kg in drinking water for three weeks and revealed potential benefit in reducing amyloid fibril formation. Another work explored the e ffect of EGCG on the aggregation process and toxicity of the expanded ataxin-3 (AT3), the polyglutamine (polyQ)-containing protein responsible for spinocerebellar ataxia type 3 (SCA3) [221]. EGCG interfered with fibril aggregation and blocked mature fibrils formation of both the cell and animal model. Indeed, in fibroblast-like cells (COS-7), co-incubation of EGCG and AT3 diminished the toxicity of protein aggregates, as also demonstrated in in vivo model (*Caenorhabditis elegans* simplified SCA3), whereas EGCG increased motility of a ffected worms. In Alzheimer disease, amyloid β (Aβ) accumulates in the brain, leading to neuronal cell death. EGCG reduced the inflammation and neurotoxicity in EOC 13.31 mouse cell line, with a mechanism suppressing TNF α, IL-1β, IL-6, iNOS, NF-κB, JNK, p38, ERK, and restoring Nrf2/HO-1 antioxidant signaling in neuroinflammatory responses of Aβ -stimulated microglia [222]. Moreover, the e ffect of EGCG on cAMP activated protein kinase (PKA) is currently under investigation: pioneeristic studies were considering a possible role of EGCG in the regulation of glucose homeostasis via PKA inhibition downregulation of FoxO1. The proposed model needs further confirmation, but opens a new door for EGCG [223].
