Isocalophyllic acid

Diastereomeric Mixture of Calophyllic and Isocalophyllic Acid Ameliorates Scopolamine-Induced Memory Impairment in Mice: Involvement of Antioxidant Defense and Cholinergic Systems.[Pubmed:31656017]

Neurotox Res. 2020 Jan;37(1):58-66.

Dementia of Alzheimer disease type (AD) and type 2 diabetes mellitus (T2D) are two most common diseases of aging which has reached epidemic proportions. Moreover, there is a shared mechanism of pathogenesis between metabolic disorders and AD. Hence, the need for discivery of effective prevention and treatment strategies. Diastereomeric mixture of calophyllic acid and Isocalophyllic acid (ISO) has been shown to stimulate glucose uptake through GLUT4- translocation. In this study, an attempt was made to investigate the effect of ISO on scopolamine-induced memory deficit in mice. ISO (5, 25 or 50 mg/kg, p.o.) or vehicle (10 ml/kg, p.o.) was administered for 3 consecutive days. One hour post-treatment on day 3, scopolamine (3 mg/kg, i.p.) was given before the animals were subjected to Y-maze, open field, novel object recognition (NOR) or Morris water maze (MWM; 5 consecutive days) paradigms. The mice were sacrificed 45 min after MWM test on day 8. The hippocampus and prefrontal cortex were rapidly isolated on ice for assay of biochemical markers of oxidative stress and acetylcholinesterase activity. Scopolamine reduced the percentage alternation behaviour in the Y-maze and discrimination index in NOR tests with no significant change in escape latency time in MWM task suggestive of deficit in learning and memory. However, the pretreatment of mice with ISO produced a dose-dependent improvement in learning and memory. Moreover, ISO administration attenuated scopolamine-induced increase in malondialdehyde/nitrite generation and acetylcholinesterase activity and deficit in antioxidant enzyme activity in the hippocampus and prefrontal cortex. Findings from this study showed that the diastereomeric mixture of calophyllic acid and Isocalophyllic acid possesses anti-amnesic effect through enhancement of antioxidant defense and cholinergic signaling pathway.

Free fatty acid induced impairment of insulin signaling is prevented by the diastereomeric mixture of calophyllic acid and isocalophyllic acid in skeletal muscle cells.[Pubmed:25445050]

Eur J Pharmacol. 2015 Jan 5;746:70-7.

Elevated fatty acid levels play a pathogenic role in the development of insulin resistance, associated with type 2 diabetes. Interventions with ability to ameliorate fatty acid-induced insulin resistance might be useful for the management of diabetes. Here, we explored the effect of the diastereomeric mixture of calophyllic acid and Isocalophyllic acid (F015) on palmitate-induced insulin resistance in skeletal muscle cells. An incubation of L6 myotubes with palmitate inhibited insulin-stimulated glucose uptake and translocation of GLUT4 to cell surface. Addition of F015 strongly prevented these inhibitions. Furthermore, F015 effectively inhibited the ability of palmitate to reduce insulin-stimulated phosphorylation of IRS-1, AKT and GSK-3beta in L6 myotubes. F015 presented a strong inhibition on palmitate-induced production of reactive oxygen species and associated inflammation, as the activation JNK, ERK1/2 and p38 MAPK were greatly reduced. F015 also inhibited inflammation-stimulated IRS-1 serine phosphorylation and restored insulin-stimulated IRS-1 tyrosine phosphorylation in presence of palmitate, resulted in enhanced insulin sensitivity. Results suggest that F015 inhibits palmitate-induced, reactive oxygen species-associated MAPK kinase activation and restored insulin sensitivity through regulating IRS-1 function. All these indicate F015 to be a potentially therapeutic candidate for insulin resistance and type 2 diabetes.

Diastereomeric mixture of calophyllic acid and isocalophyllic acid stimulates glucose uptake in skeletal muscle cells: involvement of PI-3-kinase- and ERK1/2-dependent pathways.[Pubmed:23428406]

Mol Cell Endocrinol. 2013 May 6;370(1-2):11-9.

The diastereomeric mixture of calophyllic acid and Isocalophyllic acid (F015) isolated from the leaves of Calophyllum inophyllum was investigated for the metabolic effect on glucose transport in skeletal muscle cells. In L6 myotubes, F015 dose-dependently stimulated glucose uptake by increasing translocation of glucose transporter4 (GLUT4) to plasma membrane without affecting their gene expression. The effects on glucose uptake were additive to insulin. Inhibitors analyses revealed that F015-induced glucose uptake was dependent on the activation of phosphatidylinositol-3-kinase (PI-3-K) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), while independent to the activation of 5'AMP-activated kinase (AMPK). F015 significantly increased the phosphorylation of AKT, AS160 and ERK1/2, account for the augmented glucose transport capacity in L6 myotubes. Furthermore, F015 improved glucose tolerance and enhanced insulin sensitivity in skeletal muscle of dexamethasone-induced insulin resistant mice. Our findings demonstrate that F015 activates glucose uptake in skeletal muscle cells through PI-3-K- and EKR1/2-dependent mechanisms and can be a potential lead for the management of diabetes and obesity.

A fast and efficient HPLC-PDA-MS method for detection and identification of pyranochromanone acids in Calophyllum species.[Pubmed:23333683]

J Pharm Biomed Anal. 2013 Mar 25;76:157-63.

Pyranochromanone acids isolated from Calophyllum species have shown a variety of biological potentialities including antioxidant, antiulcer, anticancer and anti-Helicobacter pylori activities. These compounds seem to be the main constituents of Cuban Calophyllum species together xanthones and biflavonoids. Recently, the pyranochromanone acids calophyllic acid, Isocalophyllic acid, apetalic acid, calolongic acid, isoapetalic acid, pinetoric acid I, pinetoric acid II, were isolated from Calophyllum pinetorum, a Cuban endemic species. The objective of the present work was the development of a rapid and efficient HPLC-DAD-MS method for fast screening of pyranochromanones in the leaves and resins of different endemic Calophyllum spp of Cuba, without clean-up procedures. For this purpose, a generalized fragmentation pathway was proposed and used to characterize, by HPLC-DAD-MS, the pyranochromanone acids in leaves and resins of different Calophyllum species. The developed method enables to detect also minor compounds in Calophyllum spp. The structures proposed by MS data for these compounds were unambiguous confirmed by 1D and 2D-NMR analysis and three new pyranochromanone acids, isocalolongic acid, pinetoric acid III and isopinetoric acid III, were reported here for the first time.

Antidyslipidemic and antioxidant activity of the constituents isolated from the leaves of Calophyllum inophyllum.[Pubmed:23083817]

Phytomedicine. 2012 Nov 15;19(14):1245-9.

In continuation of our drug discovery program on Indian medicinal plants, we isolated bioactive compounds (1-5) from the leaves of Calophyllum inophyllum and evaluated their antidyslipidemic activity in triton induced hyperlipidemia model. The calophyllic acid (1A) and Isocalophyllic acid (1B) mixture, canophyllic acid (4) and amentoflavone (5) showed dose dependent lipid lowering activity in in vivo experiments. The compounds 1A+1B mixture and 3 also showed good in vitro antioxidant activity.

Constituents of the Cuban endemic species Calophyllum pinetorum.[Pubmed:18553925]

J Nat Prod. 2008 Jul;71(7):1283-6.

A new prenylated xanthone, pinetoxanthone (1), and two new pyranochromanones, pinetoric acid I (2) and pinetoric acid II (3), together with 10 known compounds, namely, the triterpenes friedelin and canophyllol, the xanthone macluraxanthone, the pyranochromanone derivatives calophyllic acid, Isocalophyllic acid, calolongic acid, apetalic acid, and isoapetalic acid, and the flavonoids amentoflavone and apigenin, were isolated from the stem bark and leaves of Calophyllum pinetorum, an endemic species in Cuba. The structures of 1-3 were elucidated by spectroscopic methods including 1D and 2D NMR experiments as well as HRESIMS analysis.