## 4 Discussion  
PPARs exert an important impact regarding the control of cell metabolism, growth and proliferation, and are also implicated in several pathophysiological conditions. The recent literature has demonstrated that natural compounds and/or their synthetic derivatives can behave as ligands of PPARs, stimulating their transcriptional activity and enabling their use as therapeutic agents for diverse non-communicable diseases and cancer. Natural compounds seem to have more appropriate drug-like properties, exhibiting minor side effects compared to their synthetic bioactive derivatives. The 38 natural compounds examined in the present review, all with lipophilic chemical profiles, including saponins, flavonoids, polyphenols, triterpenenes, and polyunsaturated and saturated acids, act as potential PPAR ligands, mainly as activators or modulators of PPAR-\(\gamma\). Rimethoxylagic acid, kaempferol 3-O-rutinoside, \(\beta\)-sitosterol glycoside and geraniol, farnesol, geranylgeraniol Huangkui, and dehydrodiabetic acid showed dual binding properties by binding to and stimulating both PPAR-\(\alpha\) and PPAR-\(\gamma\). Remarkably, these double PPAR-\(\alpha/\gamma\) agonists manifested properties associated with lipid metabolism, insulin resistance, cytotoxicity against cancer cells, liver steatosis, nephropathy, and treatment of neurodegenerative pathological states. On the other hand, synthetic dual PPAR\(\alpha/\gamma\) agonists are used for the drug synthesis targeting management of the previously mentioned health issues. Nevertheless, their clinical use has been determined to be unsafe because of side effects like edema, hyperplasia, cardiac and kidney disorders, and increased body weight (e.g., glitazone and raagglitazar) [99]. Indicatively, naveglitazar, a \(\gamma\)-dominant PPAR-\(\alpha/\gamma\) dual agonist, was assessed for its anti-anti-cancer properties in F344 rats in a two-year follow-up survey [100]. This study showed that naveglitazar resulted in hypertrophic and proliferative outcomes on the urothel; however, no alterations in the urinary parameters were found [100]. Accordingly, muraglitazar, another PPAR-\(\alpha/\gamma\) ligand, promoted, in a dose-dependent manner, urinary bladder cancer in male Harlan Sprague-Dawley rats at concentrations of 5, 30, or 50 mg/kg/day for almost two years [101]. Regarding PPAR-\(\gamma\) agonists, the research is more extended. PPAR-\(\gamma\) modulates gene expression associated with glucose and fat metabolism. Glitazonees are synthetic PPAR-\(\gamma\) agonists, exhibiting hypoglycemic and anti-lipid actions. While they are a part of diabetes management, they have also demonstrated serious side effects, such as myocardial infarction (rosiglitazone) [92]. On the contrary, natural PPAR-\(\gamma\) ligands show the same action as synthetic analogues. Notably, triggering of PPAR-\(\gamma\) by naturally occurring agonists like PUFAs (docosahexaenoic acid and eicosapentaenoic acid) increased the renal catalase activity and PPAR-\(\gamma\) gene expression, providing anti-inflammatory properties and increasing insulin sensitivity [97]. Notably, lysophosphatidylcholine decreases free fatty acid synthesis and thus can manage metabolic syndrome, avoiding implications [95]. Neuropathetic pain is generally faced through non-steroidal anti-inflammatory drugs (NSAID), exhibiting side effects like hypertension and gastrointestinal bleeding [102; 103]. Palmitoylethanolamide, a natural N-acyl-ethanolamine (NAE) fatty acid amide and a PPAR-\(\alpha\) ligand, has been implemented for decreasing neuropathic inflammation and joint pain, anxiety, and sleep disorders without causing any serious side effects [102; 104]. In contrast, studies on PPAR-\(\beta/\delta\) activation remain extremely limited. Although PPAR-\(\beta/\delta\) is found in all the tissues of the human body, activating lipid oxidation and causing a thermogenic effect [105], when overexpressed, it raises health concerns because of possible carcinogenesis effects [106].