# Xanthone Derivatives and Their Potential Usage in the Treatment of Telangiectasia and Rosacea
## 2 Xanthone Derivatives and Their Vascular Activity
### Sealing Blood Vessel Activity
#### 2.1.2 Endothelial and Mitochondrial Dysfunction  
Mitochondrial dysfunction arises from disruptions in mitochondrial HK-II activity. Mangiferin (Figure 4) effectively preserves mitochondrial HK-II, thereby safeguarding overall mitochondrial function. In endothelial cells, palmitic acid (PA) stimulation induces oxidative stress, as evidenced by heightened ROS production, which is mitigated by mangiferin at concentrations of 1.0 and 10 \(\upmu\)M. Considering the vital role of mitochondria in energy production and cell survival, mangiferin's ability to promote HK-II binding to mitochondria through protein kinase B (Akt) activation becomes crucial. This mechanism not only protects mitochondrial function in vessel endothelial cells but also suggests a potential therapeutic avenue for mitigating endothelial dysfunction by preserving mitochondrial HK-II via pharmacological Akt activation. Akt activation stimulates downstream responses and promotes cell survival by mediating the cellular growth factors and blocking apoptosis through the inactivation of pro-apoptotic proteins. Consequently, mangiferin reduces caspase-3 expression and safeguards a vessel's endothelial integrity by modulating ROS  
Figure 3: Structure of \(\alpha\)-mangostin (1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-yl)-xanthone). Figure 2: Structure of gambogic acid: (Z)-4-((15,3a,85,11R,14 aS)-8-hydroxy-2,2,11-trimethyl-13-(3-methylbut-2-en-1-yl)-11-(4-methylpent-3-en-1-yl)-4,7-diox-1,2,5,7-tetrahydro-11H-1,5-methan-ofuro[3,2-glyyrano[3,2-b]xanthen-3a(4H)-yl)-2-methylbut-2-enoic acid). generation and enhancing NO production, as demonstrated in vivo. This study further underscores the significance of mitochondrial HK-II for maintaining mitochondrial functional integrity in vessel endothelial cells. Through Akt activation, mangiferin fosters HK-II binding to mitochondria, thus ameliorating mitochondrial dysregulation and promoting endothelial cell survival [29]. In native, healthy endothelial cells, a number of stimuli (e.g., serotonin from aggregating platelets, sphingosine 1-phosphate, and thrombin) activate eNOS, causing the release of NO, which relaxes the vascular smooth muscle that surrounds them. NO, in synergy with prostacyclin, further inhibits platelet aggregation [30]. It has been reported that endothelial dysfunction is associated with cell apoptosis, migration, and then inflammation [31]. It has been shown that endothelium-dependent vasodilation is attenuated in many risk factors of atherosclerosis, such as hypercholesterolemia, hypertension, and diabetes mellitus, and endothelial dysfunction is recognized as an early event in the pathogenesis of atherosclerosis which can be visible on the skin, such as xanthomas. Xanthomas are yellowish or orange bumps or nodules that develop under the skin due to the deposition of cholesterol-rich material [32]. Nitric oxide (NO), synthesized from \(L\)-arginine by NO synthase (NOS) in endothelial cells, has been thought to play a key role in the maintenance of vascular tone and structure. NO possesses complex cardiovascular actions such as protection of endothelial cells and decreasing the endothelial adhesiveness and inhibition of the adhesion of monocytes to endothelial cells, and it is generally described as an \"endogenous antiatherosclerotic molecule\". Recently, it has been found that \(L\)-arginine analogues such as asymmetric dimethylarginine (ADMA), which is present in the blood of both humans and animals, can inhibit NOS in vivo and in vitro. ADMA, depending on its concentration, has been shown to inhibit vasodilitor responses to acetylcholine in isolated aortic rings, upregulate the expression of monocyte chemoattractant protein-1 (MCP-1), and enhance the adhesion of monocytes in cultured endothelial cells. There is growing evidence that endothelial dysfunction in some cardiovascular diseases, such as hypercholesterolemia, heart failure, and hypertension, is associated with elevated ADMA levels, and its levels could predict endothelial dysfunction [33].