**Author details**

Harumi Jyonouchi1,2\* and Lee Geng1

1 Department of Pediatrics, Saint Peter's University Hospital (SPUH), New Brunswick, NJ, United States

2 Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States

\*Address all correspondence to<EMAIL_ADDRESS>
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**5. Conclusions**

Despite the promising antiangiogenic activity of flavonoids presented in many literature studies, no flavonoids have reached clinical trials for this application. This systematic review and meta-analysis therefore aimed to provide further insight into this area by evaluating the in vivo antiangiogenic activity of flavonoids as determined by the widely reported, clinically relevant CAM assay. A comprehensive overview of the antiangiogenic activities of flavonoids with regards to the class of flavonoids, pathology and assays used was presented. Results have shown that the biggest fraction of studies focused on the flavone subclass, cancer related angiogenesis, and in vitro assays. Furthermore, an overall evaluation of the in vivo antiangiogenic activity of flavonoids was offered focusing on SAR and mechanistic considerations. Isoflavones, flavonols and flavones were found to be the most active classes of flavonoids where antiangiogenic activity was dose dependent. Several structural features were considered, from which it was concluded that the position of the hydroxyl substituents and the degree of unsaturation are key for high activity. Even though there were some limitations such as the miscellany of the studied flavonoids and the high heterogeneity, this study provided substantial information that will underpin further investigations by addressing current gaps in the literature regarding the antiangiogenic activity of flavonoids, and highlighting their future prospective as potentially clinically active antiangiogenic agents.

**Supplementary Materials:** The following are available online, Table S1: Study characteristics of Section 1, Tables S2–S4: Sensitivity analysis, Tables S5 and S6: Database search results, Table S7: PRISMA checklist.

**Author Contributions:** M.K., F.G. and H.M.I.O. designed the study. The literature search, documentation, data extraction and analysis were carried out by M.K. and supervised by F.G. and H.M.I.O. M.K. wrote the first draft of the manuscript. M.K., F.G. and H.M.I.O. edited and revised the manuscript and approved the final version. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Newton-Mosharafa Fund, through a scholarship to MK.

**Acknowledgments:** We are grateful to the Newton-Mosharafa Fund for a scholarship that has funded MK's PhD studies.

**Conflicts of Interest:** The authors declare no conflict of interest.

### **References**

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*<IP_ADDRESS>. Pathway of homolactic and heterolactic acid fermentation in LAB*

LAB are able to live in the presence of oxygen; however, they obtain their energy by substratelevel phosphorylation. These bacteria do not present a functional respiratory system, as they lack the ability to synthesize cytochromes and porphyrins, key components of respiratory chains [45, 46]. Therefore, an important parameter used in the differentiation of the LAB species is the type of lactate fermentations: homofermentative and heterofermentative [35]. As a general rule, homofermentative lactic acid bacteria use the Embden–Meyerhof–Parnas pathway (EMP pathway or glycolysis) to produce pyruvate, while heterofermentative lactic acid bacteria use the pentose phosphate pathway (PPP). However, a third pathway, the Bifidum pathway, presents distinct reactions (Figure 4) [45, 46].

In the homofermentative lactate fermentation, as the name implies, the major end product generated is lactate. Initially, two ATP molecules are produced per mole of glucose via the oxidation of phosphoglyceraldehyde. In a second stage, NADH molecules resulting from the previous oxidative stage are used to reduce the pyruvate, forming lactate [45, 46]. The overall reaction is as follows: