Since primitive societies plants herbs and seeds

Since primitive societies, plants, herbs and seeds, rich in phytochemicals, were used due to their benefits in human health. These molecules were shown to present a diverse array of action mechanisms, including antioxidant activity, enzyme stimulation, hormones mimicking and by interfering with DNA replication [115]. Phytochemicals have thus demonstrated positive effects in health, especially in cancer prevention [118]. Thereby, secondary plant metabolites have been considered as potential candidates for inhibition of pathological angiogenesis [47], [119], [120]. In some situations, in order to increase the benefits/properties of plants, extractions are conducted. Extractions allow the isolation of active ingredients, which may subsequently be administered at higher dosage, in order to obtain higher therapeutic effects [47]. Also, extracts may contain various phenolic compounds in natural proportions that, through synergistic interactions between them, complement each other's biological activity [19].
Future challenges Due to their remarkable chemical variety, natural compounds have attracted considerable attention as potential candidates for therapeutic use against different pathologies. Special attention has been payed to naturally occurring anticancer agents, and respective derivatives, and in the study of the multiple pathways involved in cancer development [167]. Angiogenesis is an essential process involved in several diseases, including tumor-associated angiogenesis. Although angiogenesis is considered a relevant target for the prevention and treatment of many disorders, the bulk of the research done so far is focused on tumor angiogenesis, and, as a consequence, clinically available antiangiogenic drugs are all targeted to tumor angiogenesis [47], [168]. Current antiangiogenic drugs are limited in number, expensive and have shown to induce serious side effects (Table 1 and Fig. 2). The search for natural products and natural molecules as potential antiangiogenics, with less toxicity and at competitive prices, is thus the obvious next step in antiangiogenic therapy [115]. This review describes a wide variety of natural extracts and molecules (Table 2, Table 3, Table 4 and Fig. 3, Fig. 4, Fig. 5, Fig. 6) with angiogenic modulation ability and, when relevant information is available, the molecular mechanisms underlying the respective activity are discussed. When comparing the small number of proteins targeted by current antiangiogenic drugs, with the large number of molecular pathways involved in the complex mechanism of angiogenesis, it is clear to draw the conclusion that there is still considerable work to be done in order to find better and more diverse antiangiogenic drugs, and natural sources urge to be explored due to their chemical azd2014 synthesis [47]. The main advantage of natural products, relies on their ability to be more acceptable to patients, thus more adequate to be administered orally. As shown in Table 2, Table 3, Table 4, natural compounds present various mechanisms in order to target angiogenesis. Furthermore, these natural molecules exhibit antiangiogenic activity identical to the synthetically drugs currently in clinical use [47]. In this sense, Chatterjee & Bhattacharjee [167] compared the performance of epigallocatechin gallate and the drug pazopanib, as VEGFR-2 inhibitors. The results showed similar effectiveness of the two compounds. Furthermore, the use of phenolic compounds individually, or combined, has shown to diminish synthetic drugs resistance and may have therapeutic potential for a broader range of tumor diseases [47]. In spite of the current context, there are still problems that need to be overcome, to generalize the use of natural compounds in clinical practice against different pathologies [115]. The main problems are related to bioavailability, bioefficacy and biostability issues, since many natural compounds exhibit low solubility and low absorption rates. Therefore, only a small amount of the ingested dose reaches the circulation and the desired target location [115]. Microencapsulation constitutes a possible technique that may help to surpass these constraints, ensuring a better deliver of natural compounds to the desired tissue target. Through microencapsulation, natural compounds are incorporated into polymer matrices enabling better protection [169]. Such processes help to guarantee the activity of the natural compounds, and to improve targeting to the desired location [170]. Several studies, conducted to microencapsulate phenolic compounds, showed enhanced antiangiogenic effects of these forms [170], [171], [172]. Another strategy to increase the bioavailability, efficacy and stability is discussed by Wang et al. [47] and Lu et al. [115] consisting on chemical derivatization. Chemical derivatization also called as chemical modification correspond at a transformation of chemical compound in another compound by changing one or more functional groups in order to modify the specific characteristics. In this sense, the main objective is altering reactivity or properties such as solubility, thermal stability, among others. Thus, with this approach, functional groups are added or removed to the phenolic compounds, improving its pharmacokinetic profile [47]. The principal objective of these modifications is increasing the bioactivity of the phenolic compounds and consequently problems, such as absorption, can be overcome and thus favoring their interaction with the specific molecules of pathological angiogenesis blocking the reaction chain. However, these technologies such as microencapsulation or chemical derivations applied in natural compounds require further studies in order to optimize the antiangiogenic effect.