Borapetoside A

Network pharmacology integrated molecular dynamics reveals the bioactive compounds and potential targets of Tinospora crispa Linn. as insulin sensitizer.[Pubmed:35737707]

PLoS One. 2022 Jun 23;17(6):e0251837.

Insulin resistance is a metabolic disorder characterized by the decreased response to insulin in muscle, liver, and adipose cells. This condition remains a complex phenomenon that involves several genetic defects and environmental stresses. In the present study, we investigated the mechanism of known phytochemical constituents of Tinospora crispa and its interaction with insulin-resistant target proteins by using network pharmacology, molecular docking, and molecular dynamics (MD) simulation. Tinoscorside A, Makisterone C, Borapetoside A and B, and beta sitosterol consider the main phytoconstituents of Tinospora crispa by its binding with active sites of main protein targets of insulin resistance potential therapy. Moreover, Tinoscorside A was revealed from the docking analysis as the ligand that binds most strongly to the target protein, PI3K. This finding was strengthened by the results of MD simulation, which stated that the conformational stability of the ligand-protein complex was achieved at 15 ns and the formation of hydrogen bonds at the active site. In conclusion, Tinospora crispa is one of the promising therapeutic agent in type 2 diabetes mellitus management. Regulation in glucose homeostasis, adipolysis, cell proliferation, and antiapoptosis are predicted to be the critical mechanism of Tinospora crispa as an insulin sensitizer.

Computational study and in vitro alpha-glucosidase inhibitory effects of medicinal plants from a Thai folk remedy.[Pubmed:34632145]

Heliyon. 2021 Sep 29;7(9):e08078.

The number of patients with type 2 diabetes mellitus (T2DM) has increased worldwide. Although an instant cure was achieved with the standard treatment acabose, unsatisfactory symptoms associated with cardiovascular disease after acabose administration have been reported. Therefore, it is important to explore new treatments. A Thai folk recipe has long been used for T2DM treatment, and it effectively decreases blood glucose. However, the mechanism of this recipe has never been proven. Therefore, the potential anti-T2DM effect of this recipe, which is used in Thai hospitals, was determined to involve alpha-glucosidase (AG) inhibition with a half maximal inhibitory concentration (IC(50)). In vitro experiments showed that crude Cinnamomum verum extract (IC(50) = 0.35 +/- 0.12 mg/mL) offered excellent inhibitory activity, followed by extracts from Tinospora crispa (IC(50) = 0.69 +/- 0.39 mg/mL), Stephania suberosa (IC(50) = 1.50 +/- 0.17 mg/mL), Andrographis paniculate (IC(50) = 1.78 +/- 0.35 mg/mL), and Thunbergia laurifolia (IC(50) = 4.66 +/- 0.27 mg/mL). However, the potencies of these extracts were lower than that of acabose (IC(50) = 0.55 +/- 0.11 mg/mL). Therefore, this study investigated and developed a formulation of this recipe using computational docking. Among 61 compounds, 7 effectively inhibited AG, including chlorogenic acid (IC(50) = 819.07 pM) through 5 hydrogen bonds (HBs) and 2 hydrophobic interactions (HIs); beta-sitosterol (IC(50) = 4.46 nM, 6 HIs); ergosterol peroxide (IC(50) = 4.18 nM, 6 HIs); borapetoside D (IC(50) = 508.63 pM, 7 HBs and 2 HIs); Borapetoside A (IC(50) = 1.09 nM, 2 HBs and 2 His), stephasubimine (IC(50) = 285.37 pM, 6 HIs); and stephasubine (IC(50) = 1.09 nM, 3 HBs and 4 HIs). These compounds bind with high affinity to different binding pockets, leading to additive effects. Moreover, the pharmacokinetics of six of these seven compounds (except ergosterol peroxide) showed poor absorption in the gastrointestinal tract, which would allow for competitive binding to AG in the small intestine. These results indicate that the development of these 6 compounds into oral antidiabetic agents is promising.

Crude extract and purified components isolated from the stems of Tinospora crispa exhibit positive inotropic effects on the isolated left atrium of rats.[Pubmed:23778316]

J Ethnopharmacol. 2013 Aug 26;149(1):123-32.

ETHNOPHARMACOLOGICAL RELEVANCE: Tinospora crispa has been used in folkloric medicine for the control of blood pressure. We previously found that an extract of Tinospora crispa and its constituents effect the heart rate and blood pressure in anesthetized rats. AIM OF THE STUDY: The aim was to investigate the effects and mechanisms of the Tinospora crispa extract and bioactive components on the rat isolated left atria. MATERIALS AND METHODS: Air-dried stems of Tinospora crispa were extracted with water, followed by partitioning with chloroform, ethyl acetate, and finally by n-butanol. The n-butanol soluble material was concentrated and dried under reduced pressure and lyophilized to obtain a crude powder (Tinospora crispa extract). The active components of Tinospora crispa extract were separated by column chromatography and preparative HPLC. The effects and mechanisms of the n-butanol extract and the bioactive purified components (adenine, uridine, adenosine, salsolinol, tyramine, higenamine, syringin, (-)-litcubinine, Borapetoside A, borapetoside B, borapetoside D and borapetoside E) were studied in isolated left atria from normal and reserpinized rats. RESULTS: Tinospora crispa extract caused an increase in the force of contraction of the electrical field stimulated left atrium. This effect was inhibited by propranolol, atenolol, ICI-118,551, phentolamine and atropine. The positive inotropic effect on the reserpenized isolated left atrium of the Tinospora crispa extract was significantly inhibited by propranolol, atenolol and ICI-118,551. Phentolamine, on the other hand, caused potentiation and the effect was inhibited when propranolol was also added. Higenamine caused an increase in the force of contraction of the electrical field stimulated left atrium and this effect was significantly inhibited by ICI-118,551 and atenolol but not by phentolamine. Reserpine did not significantly shift the concentration-response curve (C-R curve) of the inotropic effect of the higenamine. ICI-118,551 and atenolol caused a parallel shift of the C-R curve to the right of about 8 and 33 fold, respectively. At low concentrations salsolinol caused a slight increase in the force of contraction of the left atrium, but at higher concentrations a decrease was observed. The negative inotropic effect of salsolinol was significantly inhibited by propranolol and atropine. In the reserpinized isolated left atrium, the negative inotropic effect of salsolinol was potentiated and again this effect was significantly inhibited by propranolol and atropine. Tyramine caused a positive inotropic effect, and this effect was inhibited by propranolol or by pretreatment of the rat with reserpine. Adenosine caused a negative inotropic effect, while uridine caused a slight positive inotropic effect on the left atrium. This effect was significantly inhibited by DPCPX. CONCLUSIONS: Crude extract of Tinospora crispa exert a positive inotropic effect on the electrical field stimulated isolated left atria that results from the concerted action of 5 bioactive compounds: higenamine, salsolinol, tyramine, adenosine and uridine. Higenamine, salsolinol (at low concentration) and tyramine acted via the adrenergic receptors to increase the force of the atrial contraction, whereas a high concentration of salsolinol acted indirectly by stimulating the release of acetylcholine. Adenosine and uridine acted via the purinergic pathways to cause negative inotropic effects on the isolated left atria.

Hypoglycemic action of borapetoside A from the plant Tinospora crispa in mice.[Pubmed:23523259]

Phytomedicine. 2013 Jun 15;20(8-9):667-75.

AIM: This study explores the hypoglycemic effects of Borapetoside A, the most active principle among three major diterpenoids (borapetosides A, B, and C) isolated from ethanol extract of Tinospora crispa vines. METHODS: We employed mouse mitogenic C2C12 and hepatocellular carcinoma Hep3B cells in this study. Furthermore, the mice were divided into three groups, including streptozotocin-induced type 1 diabetes mellitus, diet-induced type 2 diabetes mellitus, and normal control. The mice in each group were treated with assigned vehicle control, Borapetoside A, or other active agents. RESULTS: Borapetoside A was shown to increase the glycogen content and decrease the plasma glucose concentration in a concentration or dose-dependent manner in vitro and in vivo. The hypoglycemic effects in the normal mice and the mice with type 2 diabetes mellitus were associated with the increases of the plasma insulin levels; whereas, the insulin levels remained unchanged in the mice with type 1 diabetes mellitus. Borapetoside A not only attenuated the elevation of plasma glucose induced by an intraperitoneal glucose tolerance test, but also increased the glycogen synthesis of IL-6 treated C2C12 cells. Moreover, the elevated protein expression levels of phosphoenolpyruvate carboxykinase were reversed after Borapetoside A treatment twice a day for 7 days. CONCLUSIONS: The hypoglycemic effects of Borapetoside A were mediated through both the insulin-dependent and the insulin-independent pathways. Furthermore, Borapetoside A was shown to increase the glucose utilization in peripheral tissues, to reduce the hepatic gluconeogenesis, and to activate the insulin signaling pathway; they thereby contributed to the lowering of the plasma glucose. Comparison of the structures of three borapetosides suggests clearly that the C-8 stereochemistry plays a key role in hypoglycemic effect since the active Borapetoside A and C possess 8R-chirality but the inactive borapetoside B possess 8S-chirality. The location of glycoside at C-3 for Borapetoside A but C-6 for borapetoside C and the formation of lactone between C-4 and C-6 for Borapetoside A, could account for the different potency in hypoglycemic action for these two compounds.

cis-Clerodane-type furanoditerpenoids from Tinospora crispa.[Pubmed:20356064]

J Nat Prod. 2010 Apr 23;73(4):541-7.

Phytochemical and cytotoxicity investigations on organic solvent extracts of the aerial parts of Tinospora crispa have led to the isolation of 15 cis-clerodane-type furanoditerpenoids. Of these, nine compounds (1-9) were found to be new. Spectroscopic assignments of a previously reported compound, Borapetoside A (13), were revised on the basis of HMQC and HMBC correlations. No discernible activity was observed when compounds 10-13 were subjected to evaluation in cytotoxicity assays against human prostate cancer (PC-3) and the normal mouse fibroblast (3T3) cell lines.