Ligustrazine-Oleanolic Acid Glycine Derivative, G-TOA, Selectively Inhibited the Proliferation and Induced Apoptosis of Activated HSC-T6 Cells

Siling, Bi; Chu, Fuxiang; Wang, Mina; Bi, Li; Mao, Pei; Zhang, Huazheng; Wang, Penglong; Guo, Wenbo; Xu, Liang; Ren, Liwei; Zhang, Yu-Zhong

doi:10.3390/molecules21111599

Cited by 15 publications

(11 citation statements)

References 62 publications

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“…The apoptosis of activated HSCs is important to control hepatic fibrosis. Several studies have been conducted to elucidate the molecular mechanisms and the central elements of HSC apoptotic pathways (Duval et al, ; Best et al, ; Bi et al, ), providing grounds for innovative research (Cheng and Pan, ; Huang et al, ; Xu et al, ). For those studies, different drugs and/or molecules became the focus of investigation for the activation of apoptosis in HSC (Figure ).…”

Section: Cellular Apoptosis and Its Correlation With Hepatic Fibrosismentioning

confidence: 99%

Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis

Silva

Ramos

Moraes

2017

Cell Biology International

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Liver fibrosis is a pathophysiological process correlated with intense repair and cicatrization mechanisms in injured liver, and over the past few years, the characterization of the fine-tuning of molecular interconnections that support the development of liver fibrosis has been investigated. In this cellular process, the hepatic stellate cells (HSCs) support the organ fibrogenesis. The HSCs are found in two distinct morpho-physiological states: quiescent and activated. In normal liver, most HSCs are found in quiescent state, presenting a considerable amount of lipid droplets in the cytoplasm, while in injured liver, the activated phenotype of HSCs is a myofibroblast, that secrete extracellular matrix elements and contribute to the establishment of the fibrotic process. Studies on the molecular mechanisms by which HSCs try to restore their quiescent state have been performed; however, no effective treatment to reverse fibrosis has been so far prescribed. Therefore, the elucidation of the cellular and molecular mechanisms of apoptosis, senescence, and the cell reversion phenotype process from activate to quiescent state will certainly contribute to the development of effective therapies to treat hepatic fibrosis. In this context, this review aimed to address central elements of apoptosis, senescence, and reversal of HSC phenotype in the control of hepatic fibrogenesis, as a guide to future development of therapeutic strategies.

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Section: Cellular Apoptosis and Its Correlation With Hepatic Fibrosismentioning

confidence: 99%

Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis

Silva

Ramos

Moraes

2017

Cell Biology International

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“…Unlike the effects of ANA, OA did not show a direct influence on the activated HSCs due to the absence of TGR5 expression. On the contrary, it was recently reported that OA-derivatives inhibit the proliferation and induce apoptosis of HSC-T6 cells [44]. However, the molecular mechanisms underlying these phenomena remain unclear.…”

Section: Discussionmentioning

confidence: 99%

TGR5 Activation Modulates an Inhibitory Effect on Liver Fibrosis Development Mediated by Anagliptin in Diabetic Rats

Kaya

Kaji

Tsuji

et al. 2019

Cells

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Hyperglycemia and hyperinsulinemia activate the proliferative potential of hepatic stellate cells (HSCs) and promote hepatic fibrosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic agents, reportedly inhibit the HSC proliferation. Additionally, Takeda G protein-coupled receptor 5 (TGR5) agonists induce the systemic release of glucagon-like peptides from intestinal L cells, which maintains glycemic homeostasis. This study assessed the combined effect of TGR5 agonist and DPP-4 inhibitor on diabetes-based liver fibrosis development. Male diabetic rats received intraperitoneal injection of porcine serum (PS) to induce liver fibrosis, and they were orally administered the following agents: oleanolic acid (OA) as a TGR5 agonist, anagliptin (ANA) as a DPP-4 inhibitor, and a combination of both agents. Treatment with OA or ANA significantly improved glycemic status and attenuated intrahepatic steatosis and lipid peroxidation in diabetic rats. PS-induced liver fibrosis development was also drastically suppressed by treatment with either agent, and the combination of both reciprocally enhanced the antifibrotic effect. Fecal microbiome demonstrated that both agents inhibited the increase in the Firmicutes/Bacteroidetes ratio, an indicator of dysbiosis related to metabolic syndromes. Furthermore, ANA directly inhibited in vitro HSC proliferative and profibrogenic activities. Collectively, TGR5 agonist and DPP-4 inhibitor appears to be a novel strategy against liver fibrosis under diabetic conditions.

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“…Now, there are large number of oleanolic acid derivatives that have been synthesized and hopefully developed into clinical liver protection drug [ 20 ]. In our previous report, a variety of OA’s derivatives were designed, synthesized, and evaluated according to bio-activity, and a series of hepatoprotective lead compounds with high efficiency and low toxicity were screened out [ 16 , 18 , 19 , 25 ]. In this report, a series of OA-amino acid derivatives were designed and synthesized to improve biological activity and hydrophilicity.…”

Section: Discussionmentioning

confidence: 99%

“…[ 12 ]. Due to its favorable properties, OA is considered as a base molecule for further synthetic modifications to develop lead compounds for hepatoprotective agents in our reported studies and others [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ], and some of these derivatives have been therapeutic candidates in clinical trials [ 20 ]. However, there are some shortcomings in poor water-solubility, low bioavailability, and weak bioactivity, which seriously restrict their further clinical application.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous study, different polarity amino acids or dipeptides were introduced into 3-hydroxyl o Oleanolic acid-ligustrazine derivative (TOA) and Betulinic acid-ligustrazine derivative (TBA), the anticancer lead compound [ 28 , 29 , 30 ]. It was found that small molecule amino acids or dipeptides could improve their hydrophilic and bioactivity [ 18 , 23 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Oleanolic Acid-amino Acids Derivatives: Design, Synthesis, and Hepatoprotective Evaluation In Vitro and In Vivo

et al. 2018

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Activated hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)-producing cells in the injured liver and the key mediators of liver fibrosis; they also promote the progression of hepatocellular carcinoma (HCC). In the acidic extracellular microenvironment of HCC, HSCs are activated to promote the migration of HCC cells. It is worth attempting to alter the weak acidic microenvironment to promote activated HSC apoptosis to treat liver fibrosis and liver cancer. In the present study, a series of novel OA-amino acids analogues were designed and synthesized to introduce different amino acids in the 3-hydroxyl of OA using the ester condensation reaction to enhance hydrophilicity, alkalinity, and biological activity. We found that OA-lysine derivative (3g) could improve the hydrophilic of OA and induce HSCs apoptosis via inducing MMP depolarization and increasing intracellular Ca2+ levels. Additionally, 3g displayed a better hepatoprotective effect than OA (20 mg/kg, intragastric administration) against the acute liver injury induced by carbon tetrachloride (CCl4) in mice. The results suggested that basic amino acids (lysine) could effectively enhance OA’s hydrophilicity, alkalinity, and hepatoprotective activity in vitro and in vivo, which might be likely associated with increasing bioavailability and altering an extracellular weak acidic microenvironment with further verification. Therefore, the OA-lysine derivative (3g) has the potential to be developed as an agent with hepatoprotective activity.

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Ligustrazine-Oleanolic Acid Glycine Derivative, G-TOA, Selectively Inhibited the Proliferation and Induced Apoptosis of Activated HSC-T6 Cells

Cited by 15 publications

References 62 publications

Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis

Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis

TGR5 Activation Modulates an Inhibitory Effect on Liver Fibrosis Development Mediated by Anagliptin in Diabetic Rats

Oleanolic Acid-amino Acids Derivatives: Design, Synthesis, and Hepatoprotective Evaluation In Vitro and In Vivo

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