Combined Effects of Fangchinoline from Stephania Tetrandra Radix and Formononetin and Calycosin from Astragalus membranaceus Radix on Hyperglycemia and Hypoinsulinemia in Streptozotocin-Diabetic Mice

Abstract

Boi-ogi-to (Fang-ji-huang-qi-tang) is a traditional prescription in Kampo medicine and consists of Stephania tetrandra Radix (Stephania), Astragalus membranaceus BUNGE Radix (Astragali), Atractylodes Lancea Rhizoma, Glycyrrhizae Radix, Zingiberis Rhizoma and Zizyphi Fructus. Boi-ogi-to has long been used clinically in the treatment of arthritis and edema in China and Japan. It also improves abnormal glucose and lipid metabolism in obese diabetic patients. 1) We have reported that Boi-ogi-to increases blood insulin and decreases blood glucose levels in streptozotocin (STZ)-diabetic mice. The anti-hyperglycemic and anti-hypoinsulinemic actions of Boi-ogi-to depend on the combination of Stephania and Astragali.2) Astragali does not have a direct anti-hyperglycemic effect, but potentiates the actions of Stephania on blood levels of both glucose and insulin in STZ-induced diabetes. 3,4) In addition, Stephania suppresses abnormal choroidal and retinal neovascularization in STZ-induced diabetes in vitro and in vivo. 5)Stephania contains many bis-benzylisoquinoline-type constituents, such as tetrandrine and fangchinoline.6,7) Fangchinoline significantly improves hyperglycemia of STZ-diabetic mice.4) Tetrandrine inhibits precapillary formation of vascular endothelial cells and neovascularization of cultured choroidal explants in STZ-diabetic rats, 8,9) but does not affect hyperglycemia in diabetic mice.4) Fangchinoline and tetrandrine show different anti-inflammatory actions via inhibition of cyclooxygenase and interleukin-5 activities.10) In other studies, fangchinoline and tetrandrine were found to have similar inhibitory activities on both angiotensin I converting enzyme, 6,7) and induction of proinflammatory cytokines, interleukin-1 and tumor necrosis factor-alpha by Staphylococcus aureus Cowan 1-stimulated human peripheral blood mononuclear cells. 11)Astragali contains many isoflavones and isoflavonoids, such as formononetin, calycosin and ononin, and many saponins, such as astragaloside IV, astragaloside II, astragaloside I, and acetylastragaloside I.12) Formononetin significantly reduces arachidonic acid release and production of nitric oxide in lipopolysaccharide activated RAW 264.7 macrophages.13) It also shows estrogen receptor agonistic activity in human breast cell line MCF-7.14,15) Formononetin and calycosin activate the peroxisome proliferator-activated receptors (PPAR) alpha and gamma. The action of formononetin is more potent than that of calycosin.16) Calycosin is a vasorelaxant and is a noncompetitive Ca 2ϩ channel blocker, whose action is endothelium-independent and unrelated to intracellular Ca 2ϩ release. The effect of calycosin on Ca 2ϩ channel blockade may be different from that of dihydropyridines.17) In addition, formononetin, calycosin and ononin all inhibit glutamate-induced cell damage by increasing endogenous antioxidant and stabilizing cell membrane structures. 18)In the present study, the combined effects of fangchinoline with formononetin, calycosin and ononin on the blood levels of glucos...

The effective fraction isolated from Radix Astragali alleviates glucose intolerance, insulin resistance and hypertriglyceridemia in db/db diabetic mice through its anti-inflammatory activity

“…It should be noted that PPAR-γ is highly expressed in the adipose tissue where it regulates insulin sensitivity, adipocyte differentiation and lipid storage, and is responsible for regulating the alternative activation of macrophages [41]. Formononetin and calycosin have also been reported to potentiate the anti-hyperglycemic action of fangchinoline [42] and inhibit the LPS-induced production of TNF-α, nitric oxide and superoxide in mesencephalic neuron glia culture [43]. On the other hand, calycosin has a protective effect in endothelial cells against hypoxia-induced barrier impairment [44], while calycosin-7-O-β-D-glucoside and ononin have been reported to be free radicals scavenging anti-oxidants [45].…”

Study of the Hypoglycemic Activity of Derivatives of Isoflavones from Cicer arietinum L.

“…This may be due to the chemical structure of this isoflavone and phenolic hydroxyl moiety, which is responsible for its low bioavailability. The study of formononetin has been focused on its role in auxiliary hypoglycemic drugs, and it does not appear as the main active ingredients in any hypoglycemic drug [11]. There were a few reports of the hypoglycemic activity of biochanin A, and its hypoglycemic activity was not strong [12].…”

Vasorelaxant and antihypertensive effects of formononetin through endothelium-dependent and -independent mechanisms

“…Some isoflavones have been reported for treatment of hypertension, coronary heart diseases and cardiac infarct [11][12][13][14] through dilating arteries and increasing blood flow [15,16] . Formononetin, an O-methylated isoflavone, is contained in the roots of Astragalus membranaceus [17,18] , liquorice [19] , black cohosh [20,21] and Trifolium pratense L [22] . Medicinal herbs containing formononetin have been used to treat cardiovascular diseases including hypertension in Asia for centuries [23] .…”