Obtusifolin

J Agric Food Chem. 2014 Dec 10;62(49):11933-40.

Obtusifolin suppresses phthalate esters-induced breast cancer bone metastasis by targeting parathyroid hormone-related protein.[Pubmed: 25415928]

This study is the first to demonstrate that parathyroid hormone-related protein (PTHrP), produced by human breast cancer cells after exposure to phthalate esters, contributes to bone metastasis by increasing osteoclastogenesis.
METHODS AND RESULTS:
This is also the first to reveal that Obtusifolin reverses phthalate esters-mediated bone resorption. Human breast cancer cells were treated with dibutyl phthalate (DBP), harvested in conditioned medium, and cultured to osteoblasts or osteoclasts. Cultures of osteoblasts with DBP-MDA-MB-231-CM increased the osteoclastogenesis activator RANKL (receptor activator of nuclear factor κ-B ligand) and M-CSF (macrophage colony-stimulating factor). PTHrP was secreted in MDA-MB-231 cells. DBP-MDA-MB-231-CM reduced osteoblasts to produce osteoprotegerin, an osteoclastogenesis inhibitor, while DBP mediated PTHrP up-regulation, increasing IL-8 secretion in MDA-MB-231 and contributing to breast cancer-mediated osteoclast differentiation and bone resorption. Obtusifolin, a major bioactive compound present in Cassia tora L., suppressed phthalate esters-mediated bone resorption.
CONCLUSIONS:
Therefore, Obtusifolin may be a novel anti-breast-cancer bone metastasis agent.

Phytother Res . 2019 Apr;33(4):919-928.

Obtusifolin isolated from the seeds of Cassia obtusifolia regulates the gene expression and production of MUC5AC mucin in airway epithelial cells via affecting NF-κB pathway[Pubmed: 30632219]

Abstract We investigated whether obtusin, Obtusifolin, and cassiaside isolated from the seeds of Cassia obtusifolia inhibit the gene expression and production of airway mucin 5AC (MUC5AC). Confluent NCI-H292 cells were pretreated with obtusin, Obtusifolin, or cassiaside for 30 min and then stimulated with epidermal growth factor (EGF), phorbol 12-myristate 13-acetate (PMA), or tumor necrosis factor-α (TNF-α) for 24 hr. The MUC5AC mucin gene expression was measured by reverse transcription-polymerase chain reaction. Production of MUC5AC mucin protein was measured by enzyme-linked immunosorbent assay. To elucidate the action mechanism of Obtusifolin, effect of Obtusifolin on PMA-induced nuclear factor kappa B (NF-κB) signaling pathway was investigated by western blot analysis. Obtusin, Obtusifolin, or cassiaside inhibited the expression of MUC5AC mucin gene and the production of MUC5AC mucin protein, induced by EGF, PMA, or TNF-α. Obtusifolin inhibited PMA-induced activation (phosphorylation) of inhibitory kappa B kinase, and thus phosphorylation and degradation of inhibitory kappa B alpha. Obtusifolin inhibited PMA-induced nuclear translocation of NF-κB p65. These results suggest that Obtusifolin can regulate the production and gene expression of mucin by acting on airway epithelial cells through regulation of NF-κB signaling pathway. Keywords: airway; mucin; Obtusifolin.

Cell Biochem Biophys. 2014 Dec;70(3):1655-61.

Effect of obtusifolin administration on retinal capillary cell death and the development of retinopathy in diabetic rats.[Pubmed: 25030406]

Oxidative stress is increased in the retina in diabetes, and it is considered to play an important role in the development of retinopathy. Findings indicate that Obtusifolin has antioxidant properties. The purpose of this study was to examine the effect of Obtusifolin on retinal capillary cell apoptosis and the development of pathology in diabetes.
METHODS AND RESULTS:
Retina was used from streptozotocin-induced diabetic rats receiving diets supplemented with or without Obtusifolin (100, 200, and 400 mg/kg) for 11 months of diabetes. Capillary cell apoptosis (by terminal transferase-mediated dUTP nick-end labeling) and formation of acellular capillaries were investigated in the trypsin-digested retinal microvessels. The effect of Obtusifolin administration on retinal 8-hydroxy-2'deoxyguanosine (8-OHdG) and nitrotyrosine levels was determined by enzyme-linked immunosorbent assay. Obtusifolin administration for the entire duration of diabetes inhibited capillary cell apoptosis and the number of acellular capillaries in the retina, despite similar severity of hyperglycemia in the four diabetic groups (with and without Obtusifolin). Retinal 8-OHdG and nitrotyrosine levels were significantly increased, respectively, in diabetes, and Obtusifolin administration inhibited these increases.
CONCLUSIONS:
Our results demonstrate that the long-term administration of Obtusifolin has beneficial effects on the development of diabetic retinopathy via inhibition of accumulation of oxidatively modified DNA and nitrotyrosine in the retina. Obtusifolin represents an achievable adjunct therapy to help prevent vision loss in diabetic patients.

Biol Pharm Bull. 2014;37(10):1606-16.

Anti-allodynic effects of obtusifolin and gluco-obtusifolin against inflammatory and neuropathic pain.[Pubmed: 25070277 ]

Inflammatory pain and neuropathic pain are major health issues that represent considerable social and economic burden worldwide.
METHODS AND RESULTS:
In this study we investigated the potential of Obtusifolin and gluco-Obtusifolin, two anthraquinones found in the seeds of the widely used traditional Chinese medical botanical Cassia obtusifolia, to reduce neuropathic and inflammatory pain. The potential analgesic effects of Obtusifolin and gluco-Obtusifolin were evaluated by mice formalin test and complete Freund's adjuvant (CFA)-induced nociceptive behaviors in rats. Chronic constriction injury (CCI), L5 spinal nerve ligation (L5 SNL), diabetes, and chemotherapeutics inducing allodynia were used to test whether repeated treatment with Obtusifolin and gluco-Obtusifolin ameliorated neuropathic pain. Finally, we explored whether Obtusifolin and gluco-Obtusifolin altered the degree of neuroinflammation in rat spinal cord after CFA administration and CCI induction. Obtusifolin and gluco-Obtusifolin (0.25, 0.5, 1, and 2 mg/kg) reduced licking/biting time in dose-dependent manner in phase 2 of formalin-induced behavior in mice. Furthermore, repeated administration of Obtusifolin and gluco-Obtusifolin (0.25, 0.5, 1, and 2 mg/kg) reversed mechanical allodynia induced by CFA, CCI, L5 SNL, diabetes, and oxaliplatin in a dose-dependent manner in rats. Levels of activated nuclear factor-kappa B (NF-κB) and proinflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α)) in lumbar spinal cord were elevated in rats following CFA treatment and CCI induction, and Obtusifolin and gluco-Obtusifolin significantly inhibited these effects.
CONCLUSIONS:
Our results demonstrate that Obtusifolin and gluco-Obtusifolin produce significant antinociceptive action in rodent behavioral models of inflammatory/neuropathic pain, and that this activity is associated with modulation of neuroinflammation in spinal cord.

Cell Biochem Biophys. 2014 Dec;70(3):1751-7.

Obtusifolin treatment improves hyperlipidemia and hyperglycemia: possible mechanism involving oxidative stress.[Pubmed: 25015065]

Clinical research has confirmed the efficacy of several plant extracts in the modulation of oxidative stress associated with hyperlipidemia and hyperglycemia induced by obesity and diabetes. Findings indicate that Obtusifolin has antioxidant properties. The aim of this study was to evaluate the possible protective effects of Obtusifolin against oxidative damage in diabetic hyperlipidemia and hyperglycemia.
METHODS AND RESULTS:
In this study, the rats were divided into the following groups with eight animals in each: control, untreated diabetic, three Obtusifolin (10, 30, and 90 mg/kg/day)-treated diabetic groups. Diabetes was induced by streptozotocin (STZ) in rats. STZ was injected intraperitoneally at a single dose of 60 mg/kg for diabetes induction. Obtusifolin (intraperitoneal injection) was administered 3 days after STZ administration; these injections were continued to the end of the study (4 weeks). At the end of the 4-week period, blood was drawn for biochemical assays. In order to determine the changes of cellular antioxidant defense systems, antioxidant enzymes including glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities were measured in serum. Moreover, we also measured serum nitric oxide (NO) and serum malondialdehyde (MDA) levels, markers of lipid peroxidation. STZ-induced diabetes caused an elevation (P < 0.001) of blood glucose, MDA, NO, total lipids, triglycerides and cholesterol, with reduction of GSH level and CAT and SOD activities. The results indicated that the significant elevation in the blood glucose, MDA, NO, total lipids, triglycerides and cholesterol; also the reduction of glutathione level and CAT and SOD activity were ameliorated in the Obtusifolin-treated diabetic groups compared with the untreated groups, in a dose-dependent manner (P < 0.05, P < 0.01, P < 0.001).
CONCLUSIONS:
These results suggest that Obtusifolin has antioxidant properties and improves chemically induced diabetes and its complications by modulation of oxidative stress.

J Pharmacol Sci. 2009 Oct;111(2):110-6.

Gluco-obtusifolin and its aglycon, obtusifolin, attenuate scopolamine-induced memory impairment.[Pubmed: 19834282]

METHODS AND RESULTS:
In the present study, we assessed the effects of gluco-Obtusifolin, isolated from the seeds of Cassia obtusifolia L., and its aglycone, Obtusifolin, on the learning and memory impairments induced by scopolamine using the passive avoidance and the Morris water maze tasks in mice. Gluco-Obtusifolin (1, 2, and 4 mg/kg, p.o.) and Obtusifolin (0.25, 0.5, 1, and 2 mg/kg, p.o.) significantly reversed scopolamine-induced cognitive impairments in the passive avoidance test (P<0.05). Moreover, gluco-Obtusifolin (2 mg/kg, p.o.) and Obtusifolin (0.5 mg/kg, p.o.) improved escape latencies, swimming times in the target quadrant, and crossing numbers in the zone where the platform previously existed in the Morris water maze test. In the acetylcholinesterase assay, gluco-Obtusifolin and Obtusifolin were found to inhibit acetylcholinesterase activity in vitro (IC(50) = 37.2 and 18.5 microM, respectively) and ex vivo.
CONCLUSIONS:
These results suggest that gluco-Obtusifolin and its aglycone may be useful for the treatment of cognitive impairment, and that its beneficial effects are mediated, in part, by the enhancement of cholinergic signaling.