## 2 Phytonutrients
### Graviola
#### 2.4.3. Biomedical Effects  
Anticancer  
Graviola anticancer activity has been extensively studied, and the cytotoxicity of graviola has been reported for several cancer types e.g., breast, colorectal, skin, head and neck, lung, liver, pancreatic, prostate cancer, and leukemia [178, 192, 193, 194]. Most of the antiproliferative properties of the extracts are suggested to be mediated by the graviola acetogenins. The acetogenins exert an inhibitory activity on the NADPH mitochondrial complex 1, a component of the energy transport chain, which is crucial to the synthesis of high quantities of ATP in cancer cells [195, 196, 196]. Acetogenins have also been shown to target several critical cancer metabolic pathways by inhibiting the Na\({}^{+}\)/K\({}^{+}\) ATPase pump and the hypoxic and glycolytic pathways, inducing apoptosis and cell cycle arrest [196, 197, 198]. Antioxidant  
Studies conducted in vitro and in vivo suggest that graviola contains antioxidant compounds that act as free-radical scavengers and increase the activity of the antioxidant enzymes superoxide dismutase and catalase and downregulate the function of mitochondrial NADPH oxidase complex I [199, 200, 201]. The leaf and the fruit pulp of graviola are the parts of the tree with the highest antioxidant properties [182]. The antioxidant activity of graviola is believed to be mediated by the following phenolic phytochemicals: quercetin, gallic acid, and graviola leaf polysaccharides [202, 203]. Antimicrobial
* Antiviral  
It has been suggested that the phytochemicals polyphenols in graviola exert some antiviral activity against RNA and DNA viruses [189; 204]. A study by [PERSON] et al. showed that pretreating monkey kidney epithelial cells with a graviola leaf extract 24 h prior to infecting them with the dengue virus serotype 2 inhibited the virus replication. The treatment also increased the survival of the dengue-infected cells [205]. A recent clinical study conducted by [PERSON] et al. investigated the antiviral properties of graviola on human papillomavirus (HPV)-infected patients who were supplemented with ellagic acid and graviola extract twice a day for six months. Results showed a 74% HPV clearance in treated patients compared to the 25% clearance for the placebo group [206]. Furthermore, recent in silico studies suggest that rutin, a phytoontrient abundant in graviola, could act as strong ligands and inhibit the function of proteins of the SARS-CoV and SARS-CoV-2 virus, thus suggesting potential therapeutic benefits against the COVID-19 infection [207; 208]. * Antibacterial  
Graviola leaf extracts have been shown to exert in vitro antibacterial activity against oral pathogenic strains such as _S. mutans_, _S. mitis_, _P. gingivalis_, _P. intermedia_, _P. intermedia_, and _C. albicans_[209; 210]. An in vivo study conducted in albino rats demonstrated the efficiency of graviola unripe fruit extracts to inhibit the growth of _S. typhi_[211]. Furthermore, aqueous leaf extract and fruit-skin ethanolic graviola extracts showed a strong antibacterial effect against _K. pneumoniae_, _S. aureus_, and _P. aeruginosa_ bacteria, i.e., the pathogens responsible for respiratory infections in the human immunodeficiency virus (HIV/AIDS) patients [212]. * Antifungal  
We did not find studies testing the antifungal activity of any graviola extract. However, we found studies evaluating this property in some of graviola's phytochemicals. In 2017, a research group found that gallic acid has in vitro antifungal activity against dermatophyte strains (between 43.75 and 83.33 \(\upmu\)g/mL), and Candida strains (_C. albicans_ MIC = 12.5 \(\upmu\)g/mL, and _Trichophyton rubrum_ MIC = 43.75 \(\upmu\)g/mL) by inhibiting the ergosterol synthesis. They also confirmed this activity after in vivo studies administrating 80 mg/kg d of gallic acid [213]. In another study, researchers found that quercetin induces apoptosis in _Candida albicans_ through mitochondrial dysfunction by increasing intracellular magnesium [214].