Semisynthesis and Biological Evaluation of Oleanolic Acid 3-O-β-d-Glucuronopyranoside Derivatives for Protecting H9c2 Cardiomyoblasts against H₂O₂-Induced Injury.
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ABSTRACT:
SUBMITTER: Tian Y
PROVIDER: S-EPMC5943939 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Modulation of apoptosis is therapeutically effective in cardiomyocytes damage. Calenduloside E (CE), a naturally occurring triterpenoid saponin, is a potent anti-apoptotic agent. However, little is known about its synthetic analogues on the protective effects in apoptosis of cardiomyocytes. The present research was performed to investigate the potential protective effect of CE analogues against H2O2-induced apoptosis in H9c2 cardiomyocytes and the underlying mechanisms. Sixteen novel CE anologues have been designed, synthesized and biological evaluation. Among the 16 CE anologues, as well as the positive control CE tested, compound 5d was the most effective in improving cardiomyocytes viability. Pretreatment with anologue 5d inhibited ROS generation, maintained the mitochondrial membrane potential and reduced apoptotic cardiomyocytes. Moreover, exposure to H2O2 significantly increased the levels of Bax, cleaved caspase-3, and cleaved PARP, and decreased the level of Bcl-2, resulting in cell apoptosis. Pretreatment with anologue 5d (0.02-0.5 ?g/mL) dose-dependently upregulated antiapoptotic proteins and downregulated proapoptotic proteins mentioned above during H2O2-induced apoptosis. These results suggested that CE analogues provide protection to H9c2 cardiomyocytes against H2O2-induced oxidative stress and apoptosis, most likely via anti-apoptotic mechanism, and provided the basis for the further optimization of the CE analogues.
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Project description:Mitochondrial dysfunction and excessive lipid accumulation in non-adipose tissues have been proposed widely as the roots for comorbidities generated by the growing epidemia of type 2 diabetes mellitus. Mouse models of lipotoxic cardiomyopathy have underlined this detrimental situation, but so far the proteins involved in diabetic patients’s induced mitochondrial dysfunction remain unknown. Apolipoprotein O (ApoO), originally found overexpressed in human diabetics hearts (Lamant et al. JBC 2006), is a candidate that was investigated here at the transcriptome level using H9c2 cardiomyoblasts after stable integration of an expression vector (pTT-ApoO) constitutively expressing ApoO.
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Project description:AimChlorogenic acid has shown protective effect on cardiomyocytes against oxidative stress-induced damage. Herein, we evaluated nine caffeoylquinic acid analogues (1-9) isolated from the leaves of Gynura nepalensis for their protective effect against H2O2-induced H9c2 cardiomyoblast damage and explored the underlying mechanisms.MethodsH9c2 cardiomyoblasts were exposed to H2O2 (0.3 mmol/L) for 3 h, and cell viability was detected with MTT assay. Hoechst 33342 staining was performed to evaluate cell apoptosis. MMPs (mitochondrial membrane potentials) were measured using a JC-1 assay kit, and ROS (reactive oxygen species) generation was measured using CM-H2 DCFDA. The expression levels of relevant proteins were detected using Western blot analysis.ResultsExposure to H2O2 markedly decreased the viability of H9c2 cells and catalase activity, and increased LDH release and intracellular ROS production; accompanied by a loss of MMP and increased apoptotic rate. Among the 9 chlorogenic acid analogues as well as the positive control drug epigallocatechin gallate (EGCG) tested, compound 6 (3,5-dicaffeoylquinic acid ethyl ester) was the most effective in protecting H9c2 cells from H2O2-induced cell death. Pretreatment with compound 6 (1.56-100 ?mol/L) dose-dependently alleviated all the H2O2-induced detrimental effects. Moreover, exposure to H2O2 significantly increased the levels of Bax, p53, cleaved caspase-8, and cleaved caspase-9, and decreased the level of Bcl-2, resulting in cell apoptosis. Exposure to H2O2 also significantly increased the phosphorylation of p38, JNK and ERK in the H9c2 cells. Pretreatment with compound 6 (12.5 and 25 ?mol/L) dose-dependently inhibited the H2O2-induced increase in the level of cleaved caspase-9 but not of cleaved caspase-8. It also dose-dependently suppressed the H2O2-induced phosphorylation of JNK and ERK but not that of p38.ConclusionCompound 6 isolated from the leaves of Gynura nepalensis potently protects H9c2 cardiomyoblasts against H2O2-induced apoptosis, possibly by inhibiting intrinsic apoptosis and the ERK/JNK pathway.
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Project description:The increasing demand for natural products as an alternative therapy for chronic diseases has encouraged research into the pharmacological importance of bioactive compounds from plants. Recently, there has been a surge of interest in the therapeutic potential of oleanolic acid (OA) in the prevention and management of chronic diseases. Oleanolic acid is a pentacyclic triterpenoid widely found in plants, including fruits and vegetables with different techniques and chromatography platforms being employed in its extraction and isolation. Several studies have demonstrated the potential therapeutic effects of OA on different diseases and their symptoms. Furthermore, oleanolic acid also serves as a framework for the development of novel semi-synthetic triterpenoids that could prove vital in finding therapeutic modalities for various ailments. There are recent advances in the design and synthesis of chemical derivatives of OA to enhance its solubility, bioavailability and potency. Some of these derivatives have also been therapeutic candidates in a number of clinical trials. This review consolidates and expands on recent reports on the biological effects of oleanolic acid from different plant sources and its synthetic derivatives as well as their mechanisms of action in in vitro and in vivo study models. This review suggests that oleanolic acid and its derivatives are important candidates in the search for alternative therapy in the treatment and management of chronic diseases.
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Project description:Necroptosis, a form of necrosis, and alterations in mitochondrial dynamics, a coordinated process of mitochondrial fission and fusion, have been implicated in the pathogenesis of cardiovascular diseases. This study aimed to determine the role of mitochondrial morphology in canonical necroptosis induced by a combination of TNFα and zVAD (TNF/zVAD) in H9c2 cells, rat cardiomyoblasts. Time-course analyses of mitochondrial morphology showed that mitochondria were initially shortened after the addition of TNF/zVAD and then their length was restored, and the proportion of cells with elongated mitochondria at 12 h was larger in TNF/zVAD-treated cells than in non-treated cells (16.3 ± 0.9% vs. 8.0 ± 1.2%). The knockdown of dynamin-related protein 1 (Drp1) and fission 1, fission promoters, and treatment with Mdivi-1, a Drp-1 inhibitor, had no effect on TNF/zVAD-induced necroptosis. In contrast, TNF/zVAD-induced necroptosis was attenuated by the knockdown of mitofusin 1/2 (Mfn1/2) and optic atrophy-1 (Opa1), proteins that are indispensable for mitochondrial fusion, and the attenuation of necroptosis was not canceled by treatment with Mdivi-1. The expression of TGFβ-activated kinase (TAK1), a negative regulator of RIP1 activity, was upregulated and the TNF/zVAD-induced RIP1-Ser166 phosphorylation, an index of RIP1 activity, was mitigated by the knockdown of Mfn1/2 or Opa1. Pharmacological TAK1 inhibition attenuated the protection afforded by Mfn1/2 and Opa1 knockdown. In conclusion, the inhibition of mitochondrial fusion increases TAK1 expression, leading to the attenuation of canonical necroptosis through the suppression of RIP1 activity.
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Project description:Oleanolic acid (OA) is a natural cosmeceutical compound with various skin beneficial activities including inhibitory effect on hyaluronidase but the anti-hyaluronidase activity and mechanisms of action of its synthetic analogues remain unclear. Herein, a series of OA derivatives were synthesised and evaluated for their inhibitory effects on hyaluronidase. Compared to OA, an induction of fluorinated (6c) and chlorinated (6g) indole moieties led to enhanced anti-hyaluronidase activity (IC50 = 80.3 vs. 9.97 and 9.57 µg/mL, respectively). Furthermore, spectroscopic and computational studies revealed that 6c and 6g can bind to hyaluronidase protein and alter its secondary structure leading to reduced enzyme activity. In addition, OA indole derivatives showed feasible skin permeability in a slightly acidic environment (pH = 6.5) and 6c exerted skin protective effect by reducing cellular reactive oxygen species in human skin keratinocytes. Findings from the current study support that OA indole derivatives are potential cosmeceuticals with anti-hyaluronidase activity.
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