Protective Effects Of Oleanolic Acid Research Articles

Effects of oleanolic acid administration on renal NF-kB, IL-18, IL-6, YKL-40, and KIM-1 in experimental diabetic rats.

Neuropathy, retinopathy, and nephropathy, known as the triopathy of diabetes, are the consequences of microvascular complications of diabetes. The present study aimed to investigate the potential protective effects of oleanolic acid (OA) administration against diabetic nephropathy considering biochemical and histopathological parameters. The rats with fasting blood glucose levels of 200 mg/dl and above were considered diabetic after induction of diabetes via injecting STZ. The other half of the rats were not injected with STZ (healthy rats). Both healthy and diabetic rats were then divided randomly into two subgroups to be administered with either OA (5 mg/kg) with 1 ml tap water by oral gavage or 1 ml tap water in the same route for 21 days. Serum urea-N, Ca, P, and Mg as well as renal tissue MDA, SOD, NF-κB, IL-6, IL-18, AMPK, YKL-40, and KIM-1 levels were measured. OA administration partially decreased levels of serum urea-N and P, as well as levels of renal tissue MDA and inflammation markers (NF-κB, IL-6, IL-18, YKL-40, and KIM-1) in the diabetic rats. It also partially increased serum Ca and renal tissue AMPK levels in diabetic rats. These positive effects were also seen in renal tissue histopathology. OA treatment partially alleviated renal damage inflammatory and oxidative profiles in diabetic rats.

Oleanolic acid inhibits mouse spinal cord injury through suppressing inflammation and apoptosis via the blockage of p38 and JNK MAPKs

Spinal cord injury (SCI) is reported as a devastating disease, leading to tissue loss and neurologic dysfunction. However, there is no effective therapeutic strategy for SCI treatment. Oleanolic acid (OA), as a triterpenoid, has anti-oxidant, anti-inflammatory, and anti-apoptotic activities. However, its regulatory effects on SCI have little to be elucidated, as well as the underlying molecular mechanisms. In this study, we attempted to explore the role of OA in SCI progression. Behavior tests suggested that OA treatments markedly alleviated motor function in SCI mice. Evans blue contents up-regulated in spinal cords of SCI mice were significantly reduced by OA in a dose-dependent manner, demonstrating the improved blood-spinal cord barrier. Moreover, we found that OA treatments significantly reduced the apoptotic cell death in spinal cord samples of SCI mice through decreasing the expression of cleaved Caspase-3. In addition, pro-inflammatory response in SCI mice was significantly attenuated by OA treatments. Furthermore, SCI mice exhibited higher activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signaling pathways, but these effects were clearly blocked in SCI mice with OA treatments, as evidenced by the down-regulated phosphorylation of p38, c-Jun-NH 2 terminal kinase (JNK), IκB kinase α (IKKα), inhibitor of nuclear factor κB-α (IκBα) and NF-κB. The protective effects of OA against SCI were confirmed in lipopolysaccharide (LPS)-stimulated mouse neurons mainly through the suppression of apoptosis and inflammatory response, which were tightly associated with the blockage of p38 and JNK activation. Together, our data demonstrated that OA treatments could dose-dependently ameliorate spinal cord damage through impeding p38- and JNK-regulated apoptosis and inflammation, and therefore OA might be served as an effective therapeutic agent for SCI treatment.

Protective effects of oleanolic acid on oxidative stress and the expression of cytokines and collagen by the AKT/NF‑κB pathway in silicotic rats.

Oleanolic acid (OA), a natural pentacyclic triterpenoid, has been reported to have several benefits and medicinal properties. However, its protective effects against silica‑induced lung injury and fibrosis remain to be elucidated. The aim of the present study was to investigate the effects of OA on oxidative stress, and the expression of cytokines and collagen in silicotic rats. Male rats were induced by intratracheal instillation of silicosis (250mg/kg), with the exception of the control group (NS). The rats in the OA group were intragastrically administered with OA (60mg/kg/d). The rats in the solvent control group were gavaged daily with 0.6% sodium carboxymethyl cellulose (10ml/kg) solution for 56 consecutive days. The data showed that OA significantly attenuated the extent of silicosis fibrosis by histopathologic analysis of the lung tissues. In addition, oxidative stress activated by silica exposure, as evidenced by increasing of malondialdehyde content, and activities of superoxide dismutase and glutathione peroxidase in the lung, was regulated by treatment with OA. Furthermore, enzyme‑linked immunosorbent assay analysis showed that OA significantly decreased the levels of tumor necrosis factor‑α and transforming growth factor‑β1. Immunohistochemistry analysis showed that OA significantly decreased collagen types I and III. In investigating the mechanisms underlying the action of OA, it was found that OA decreased the level of phosphorylated AKT1, which in turn inactivated the transcriptional of nuclear factor (NF)‑κB in the development and progress of silicosis. In conclusion, these results suggested that the protective effects of OA were due, at least in part, to its anti‑oxidant activity and its ability to decrease the expression of cytokines and collagen by modulating the AKT/NF‑κB pathway.

Protective effects of oleanolic acid on cerebral ischemic damage in vivo and H2O2-induced injury in vitro

Context: Oleanolic acid (OA), a triterpenoid compound, exists in many plants. It has numerous bioactivities and has been used to treat hepatitis in China. However, few studies have reported its effect on the central nervous system, especially in ischemic stroke.Objective: To explore the protective effects of OA on cerebral ischemic injury for the first time.Materials and methods: Survival time was tested in mice injured by bilateral common carotid artery ligation (BCCAL). Neurological function, infarct area, cerebral edema, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) were estimated in rats operated by middle cerebral artery occlusion (MCAO). Cell survival, lactate dehydrogenase (LDH), SOD, reduced glutathione (GSH), MDA, mitochondrial membrane potential (MMP) and succinic dehydrogenase (SDH) were detected in H2O2-injured PC12 cells.Results: Pre-administration with OA significantly prolonged survival time in mice at 50 and 25 mg/kg, alleviated neurological function, infarct area and cerebral edema, increased SOD and GSH-Px activities and decreased MDA level in rats at 25 and 12.5 mg/kg. Pre-treatment with OA at 10 and 1 μM remarkably improved cell survival, enhanced SOD activity and GSH content, reduced LDH and MDA levels and reversed the lowering of MMP and SDH activity.Discussion and conclusion: These results demonstrate that oleanolic acid effectively alleviates cerebral ischemic damage in vivo and oxidative injury in vitro, which may be in part due to the modulation of endogenous antioxidants and the improvement of mitochondrial function. Oleanolic acid may be a potential medicine for attenuating ischemic stroke.

Protective effects of ursolic acid and oleanolic acid in leukemic cells

Ursolic acid (UA) and oleanolic acid (OA) have similar chemical structures but differ in the position of one methyl group on the ring E. We investigated protective effects of these two triterpenoic acids against H 2O 2-induced DNA damage in leukemic L1210, K562 and HL-60 cells using single-cell gel electrophoresis (SCGE). We compared their protective effects (antioxidant activities) with respect to the different position of the methyl group in their chemical structures. After 24 h pre-treatment of cells both compounds investigated inhibited significantly the incidence of DNA single strand breaks induced by H 2O 2. The concentration range of UA and OA was in all experiments 2.5–10 μmol/l. The antioxidant activity of OA determined by SCGE was significantly higher compared to UA in L1210 ( + P < 0.05) and K562 cells ( +++ P < 0.001). Significant difference of the antioxidant activities of the two compounds was evidently connected with the different position of the methyl group. The protective effect of OA was in HL-60 cells slightly lower compared to the activity of UA, but the difference between the protective effects of UA and OA was not significant. In conclusion we can say that both natural pentacyclic triterpenoic acids investigated, UA and OA, manifested potent antioxidant effects. The different position of one methyl group in their chemical structures caused moderately different biological activities of these compounds on three leukemic cell lines. To explore their mechanisms of action further investigation seems to be therefore worthwhile.

Hepatoprotection of Oleanolic Acid is Related to Its Inhibition on Mitochondrial Permeability Transition

The protective effects of oleanolic acid (OA) on carbon tetrachloride (CCl4)-induced liver mitochondrial damage and the possible mechanisms were investigated. Pretreatment with OA prior to the administration of CCl4 significantly suppressed the increases of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (4.2- and 19.9-fold, respectively) in a dose-dependent manner in mice. The dissipation of mitochondrial membrane potential (14.8%) and intra-mitochondrial Ca2+ overload (2.1-fold) in livers of CCl4-insulted mice were also dose-dependently prevented by pretreatment with 20, 50 or 100 mg/kg OA. In addition, the effects of OA on liver mitochondria permeability transition (MPT) induced by Ca2+ were assessed by measuring the change in mitochondrial membrane potential, release of matrix Ca2+ and mitochondrial swelling in vitro. The results showed that preincubation with 50 or 100 microg/ml OA obviously inhibited the Ca2+-induced mitochondrial swelling, mitochondrial membrane depolarization and intra-mitochondrial Ca2+ release. It could be concluded that OA has protective effects on liver mitochondria and the mechanisms underlying its protection may be related to its inhibitory action on MPT.

Inhibition of cytochrome P450 2E1 expression by oleanolic acid: hepatoprotective effects against carbon tetrachloride-induced hepatic injury

The protective effects of oleanolic acid on carbon tetrachloride-induced hepatotoxicities and the possible mechanisms involved in this protection were investigated in mice. Pretreatment with oleanolic acid prior to the administration of carbon tetrachloride significantly prevented the increase in serum alanine aminotransferase and lactate dehydrogenase activity and liver lipid peroxidation in a dose-dependent manner. Hepatic glutathione levels and glutathione- S-transferase activities were not affected by treatment with oleanolic acid alone but pretreatment with oleanolic acid protects carbon tetrachloride-induced depletion of hepatic glutathione levels. The effects of oleanolic acid on the cytochrome P450 (P450) 2E1, the major isozyme involved in carbon tetrachloride bioactivation were investigated. Treatment of mice with oleanolic acid resulted in a significant decrease of P450 2E1-dependent p-nitrophenol and aniline hydroxylation in a dose-dependent manner. Consistent with these observations, the P450 2E1 expressions were also decreased, as determined by immunoblot analysis. These results show that the protective effects of oleanolic acid against the carbon tetrachloride-induced hepatotoxicity may, at least in part, be due to its ability to block bioactivation of carbon tetrachloride mainly by the inhibition of expression and activities of P450 2E1.

Protection against carbon tetrachloride hepatotoxicity by oleanolic acid is not mediated through metallothionein

Oleanolic acid is a triterpenoid compound that has been shown to protect against liver injury produced by some hepatotoxicants. This study was designed to characterize the protective effects of oleanolic acid on carbon tetrachloride-induced hepatotoxicity, and the role of metallothionein in the protection. Oleanolic acid pretreatment (100–400 μmol/kg, sc) protected Sprague–Dawley rats and mice from carbon tetrachloride-induced liver injury in a dose- and time-dependent manner, as evidenced by serum alanine aminotransferase and sorbitol dehydrogenase activities, as well as by histopathology. The protection against carbon tetrachloride hepatotoxicity was not evident until animals were pretreated with oleanolic acid 12 h, and lasted for 72 h after a single injection. This suggests that the protection might be due to induction of some adaptive mechanisms. Metallothionein (MT), an acute-phase protein proposed to decrease carbon tetrachloride-induced liver injury, was dramatically induced following oleanolic acid treatment. To examine whether oleanolic acid protection is mediated through MT, MT-I and II knock-out (MT-null) mice were utilized. Oleanolic acid pretreatment increased MT levels in control mice (20-fold), but not in MT-null mice, however, it protected equally against carbon tetrachloride-induced hepatotoxicity in both control and MT-null mice. These data indicate that oleanolic acid is effective in protecting rats and mice from the hepatotoxicity produced by carbon tetrachloride, and the protection is not mediated through induction of MT.