α-Mangostin Alleviated HIF-1α-Mediated Angiogenesis in Rats With Adjuvant-Induced Arthritis by Suppressing Aerobic Glycolysis

A previously validated anti-rheumatic compound α-mangostin (MAN) shows significant metabolism regulatory effects. The current study aimed to clarify whether this property contributed to its inhibition on synovial angiogenesis. Male wistar rats with adjuvant-induced arthritis (AIA) were orally treated by MAN for 32 days. Afterwards, biochemical parameters and cytokines in plasma were determined by corresponding kits, and glycometabolism-related metabolites were further accurately quantified by LC-MS method. Anti-angiogenic effects of MAN were preliminarily assessed by joints based-immunohistochemical examination and matrigel plug assay. Obtained results were then validated by experiments in vitro. AIA-caused increase in circulating transforming growth factor beta, interleukin 6, hypoxia inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in blood and local HIF-1α/VEGF expression in joints was abrogated by MAN treatment, and pannus formation within matrigel plugs implanted in AIA rats was inhibited too. Scratch and transwell assays revealed the inhibitory effects of MAN on human umbilical vein endothelial cells (HUVECs) migration. Furthermore, MAN inhibited tubule formation capability of HUVECs and growth potential of rat arterial ring-derived endothelial cells in vitro. Meanwhile, MAN eased oxidative stress, and altered glucose metabolism in vivo. Glycolysis-related metabolites including glucose 6-phosphate, fructose 6-phosphate, 3-phosphoglyceric acid and phosphoenolpyruvic acid in AIA rats were decreased by MAN, while the impaired pyruvate-synthesizing capability of lactate dehydrogenase (LDH) was recovered. Consistently, MAN restored lipopolysaccharide-elicited changes on levels of glucose and LDH in HUVECs culture system, and exerted similar effects with LDH inhibitor stiripentol on glycometabolism and VEGF production as well as tubule formation capability of HUVECs. These evidences show that MAN treatment inhibited aerobic glycolysis in AIA rats, which consequently eased inflammation-related hypoxia, and hampered pathological neovascularization.

Antiarthritic Activities of Herbal Isolates: A Comprehensive Review

Numerous plant isolates with therapeutic properties, such as antimicrobial, antiinflammatory, antiviral, antimalarial, antiarthritic (AA), hepatoprotective, cardiotonic, and so forth, are reported in the literature. Usually, medicinal plants are widely used, and assumed to be safe and cheaper alternatives to chemically synthesized drugs. However, they are not regulated for potency and purity, and thus care must be taken for their safe use. In this review, we aimed to compile all of the herbal isolates possessing AA properties, including alkaloids (montanine, 3-acetylaconitine, sanguinarine, jatrorrhizine hydrochloride, and piperine), terpenoids (eugenol, nimbolide, bartogenic acid, cannabidiol, and curcumin), and flavonoids (quercetin, resveratrol, kaempferol, chebulanin, ellagic acid, rosmarinic acid, gallic acid, chlorogenic acid, ferulic acid, and brazilin). These isolates act through numerous pharmacological mechanisms such as inhibiting cytokines, chemokines, or matrix metalloproteinase, etc., to demonstrate AA activity. Animal models utilized for assessing the AA properties of these isolates, including adjuvant-induced arthritis mouse models, are also discussed. Furthermore, nanotechnology-based approaches to deliver these isolates are also reviewed, which have shown improved therapeutic efficacy of isolated compounds.