PMID: 

Gene. 2019 Jul 1 ;712:143956. Epub 2019 Jul 1. PMID: 31271843

Abstract Title: 

Oleanolic acid reduces aerobic glycolysis-associated proliferation by inhibiting yes-associated protein in gastric cancer cells.

Abstract: 

Gastric cancer represents a common malignancy of digestive tract with high incidence and mortality. Increasing evidence suggests that the growth of gastric tumor cells relies largely on aerobic glycolysis. Currently, many potential anti-cancer candidates are derived from natural products. Here, we evaluated the effects of oleanolic acid (OA), a triterpenoid component widely found in the plants of Oleaceae family, on aerobic glycolysis and proliferation in human MKN-45 and SGC-7901 gastric cancer cells. Our results demonstrated that OA reduced the viability and proliferation of gastric cancer cells and inhibited the expression of cyclin A and cyclin-dependent kinase 2. OA blocked glycolysis in these cells evidenced by decreases in the uptake and consumption of glucose, intracellular lactate levels and extracellular acidification rate. Glycolysis inhibitor 2-deoxy-d-glucose, similar to OA, suppressed gastric cancer cell proliferation. OA also decreased the expression and intracellular activities of glycolysis rate-limiting enzymes hexokinase 2 (HK2) and phosphofructokinase 1 (PFK1). Moreover, OA downregulated the expression of hypoxia inducible factor-1α (HIF-1α) and decreased its nuclear abundance. Upregulation of HIF-1α by deferoxamine rescued OA-inhibited HK2 and PFK1. Furthermore, OA reduced the nuclear abundance of yes-associated protein (YAP) in gastric tumor cells. YAP inhibitor verteporfin, similar to OA, downregulated the expression ofHIF-1α and glycolytic enzymes in gastric cancer cells; whereas overexpression of YAP abrogated all these effects of OA. Collectively, inhibition of YAP was responsible for OA blockade of HIF-1α-mediated aerobic glycolysis and proliferation in human gastric tumor cells. OA could be developed as apromising candidate for gastric cancer treatment.

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PMID: 

Molecules. 2019 Apr 22 ;24(8). Epub 2019 Apr 22. PMID: 31013661

Abstract Title: 

Tuscan Varieties of Sweet Cherry Are Rich Sources of Ursolic and Oleanolic Acid: Protein Modeling Coupled to Targeted Gene Expression and Metabolite Analyses.

Abstract: 

The potential of six ancient Tuscan sweet cherry (L.) varieties as a source of health-promoting pentacyclic triterpenes is here evaluated by means of a targeted gene expression and metabolite analysis. By using a sequence homology criterion, we identify five oxidosqualene cyclase genes (s) and three cytochrome P450s (s) that are putatively involved in the triterpene production pathway in sweet cherries. We performed 3D structure prediction and induced-fit docking using cation intermediates and reaction products for some OSCs to predict their function. We show that the Tuscan varieties have different amounts of ursolic and oleanolic acids and that these variations are related to different gene expression profiles. This study stresses the interest of valorizing ancient fruits as alternative sources of functional molecules with nutraceutical value. It also provides information on sweet cherry triterpene biosynthetic genes, which could be the object of follow-up functional studies.

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PMID: 

Anticancer Drugs. 2019 Mar 14. Epub 2019 Mar 14. PMID: 30882397

Abstract Title: 

Oleanolic acid inhibits cell proliferation migration and invasion and induces SW579 thyroid cancer cell line apoptosis by targeting forkhead transcription factor A.

Abstract: 

Oleanolic acid (OA) is a naturally occurring triterpenoid that possesses antitumor activity against several tumor cell lines. However, the potential mechanism underlying OA-induced thyroid carcinoma cell death is poorly understood. We investigated the biological functions of OA by performing migration, invasion, colony formation, and apoptosis assays on SW579 cells. Forkhead box A1 (FOXA1) expression was used to predict poor prognosis in patients with thyroid carcinoma among the TCGA samples from the UALCAN and gene expression profiling interactive analysis databases. Western blot was used to detect protein expression level. Results revealed that OA inhibited the migration, colony formation, and invasion of thyroid carcinoma cells in a dose-dependent manner. Further investigation verified that OA treatment induced significant apoptosis of thyroid carcinoma cells. Moreover, high FOXA1 expression predicted the poor prognosis of patients with thyroid cancer. The proliferation, migration, and invasion of thyroid carcinoma cells were significantly decreased when FOXA1 was silenced. OA significantly increased Akt phosphorylation and reduced FOXA1 expression in SW579 cells, but only PI3K/Akt inhibitor LY294002 attenuated OA-induced FOXA1 downregulation. Furthermore, Akt overexpression suppressed the FOXA1 expression in SW579 cells. In addition, molecular docking assay revealed that OA possessed high affinity toward FOXA1 with a low binding energy. OA may be a potential chemotherapeutic agent against thyroid carcinoma cells.

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PMID: 

Molecules. 2019 Jan 18 ;24(2). Epub 2019 Jan 18. PMID: 30669379

Abstract Title: 

Plant-Derived Oleanolic Acid (OA) Ameliorates Risk Factors of Cardiovascular Diseases in a Diet-Induced Pre-Diabetic Rat Model: Effects on Selected Cardiovascular Risk Factors.

Abstract: 

The pathogenesis of prediabetes is associated with risk factors such as chronic consumption of an unhealthy diet. Recent studies have reported that diet-induced pre-diabetes is also associated with risk factors of cardiovascular complications, hence this study was aimed at evaluating the effects of oleanolic acid (OA) on pre-diabetes rats. Pre-diabetes was induced by chronic exposure of Sprague Dawley rats (SD) to high-fat high-carbohydrate diet (20 weeks), whereas the non-pre-diabetes control (NC) was given standard rat chow. Pre-diabetes animals were grouped into five groups namely prediabetes control (PC), metformin treated (Met), metformin with diet intervention (Met + DI), oleanolic acid treated (OA), and oleanolic acid with diet intervention (OA + DI) then treated for 12 weeks. At the end of treatment, all animals were sacrificed where organs and tissues were harvested for biochemical analysis and histological studies. The results showed that PC had a significantly higher triglycerides (TGs), low density lipoprotein cholesterol (LDL-C, interleukin-6(IL-6), tumor necrosis factor alpha (TNFα), C-reactive protein (CRP), mean arterial pressure (MAP) and hearts weights in comparison to NC (

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PMID: 

Cell Death Discov. 2018 ;4:48. Epub 2018 Oct 15. PMID: 30345079

Abstract Title: 

Oleanolic acid enhances neural stem cell migration, proliferation, and differentiation in vitro by inhibiting GSK3β activity.

Abstract: 

Oleanolic acid (OA), one of the bioactive ingredients in ginseng, has been reported to have neuroprotective activities. However, the effects and its mechanism on neural stem cell (NSC) induction are not entirely clear. In the present study, we investigated the effects of OA on promoting the migration, proliferation, and differentiation of neural stem cells (NSCs). Migration and proliferation were investigated by using neural-specific markers, neurosphere assay, and Cell Counting Kit-8, respectively. We found OA remarkably promoted neural migration and proliferation of NSCs in a time- and dose-dependent manner. Differentiation was analyzed by western blotting and immunofluorescence staining, which found MAP2 expression was remarkably increased, whereas Nestin was dramatically decreased. In addition, OA increased phosphorylation of GSK3β at Ser9 and expression of active forms of β-catenin. Furthermore, NSCs with constitutively active GSK3β (S9A) significantly suppressed the OA-induced proliferation and neural differentiation. These results showed that OA could stimulate NSC proliferation and neural differentiation in vitro viasuppressing the activity of GSK3β. Our findings may have significant implications for the treatment of neurodegenerative diseases.

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PMID: 

Mol Cancer Ther. 2019 01 ;18(1):62-74. Epub 2018 Oct 8. PMID: 30297361

Abstract Title: 

Oleanolic Acid Inhibits Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma by Promoting iNOS Dimerization.

Abstract: 

Oleanolic acid exhibits extensive pharmacologic activities and takes significant antitumor effects. Its pharmacologic mechanism, however, still remained to be further clarified. In this study, we demonstrated that oleanolic acid attenuated the migration and invasion abilities, resulting in the suppression of the epithelial-mesenchymal transition (EMT) process in liver cancer cells, and inhibited the tumor growth of the peritoneal lymphocytes-bearing mice. We further proved that inducible nitric oxide synthase (iNOS) may be the potential target of oleanolic acid. We confirmed that oleanolic acid could promote the dimerization of iNOS, activating it, and subsequently increasing the production of nitric oxide. Further experiments indicated that oleanolic acid promoted the nitration of specific proteins and consequently suppressed their EMT-related biological functions. Furthermore, it has been confirmed that oleanolic acid enhanced the antitumor effects of regorafenib in liver cancer treatment. These results deepened our understanding of the pharmacologic mechanism of the antitumor effect oleanolic acid, and the importance of nitric oxide synthetase as a therapeutic target for liver cancer treatment.

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PMID: 

Int J Antimicrob Agents. 2019 Jul 26. Epub 2019 Jul 26. PMID: 31356859

Abstract Title: 

URSOLIC ACID: A NOVEL ANTIVIRAL COMPOUND INHIBITING ROTAVIRUS INFECTION IN VITRO.

Abstract: 

Rotavirus is one of the leading causes of severe acute gastroenteritis in children under five years of age, mainly affecting developing countries. Once the disease is acquired, no specific treatment is available; thus the development of new pharmacological drugs for effective anti-Rotaviral therapies becomes critical. Ursolic acid is a pentacyclic triterpenoid which antiviral activity has been extensively studied in vitro and in vivo. To study the potential anti-Rotaviral activity of ursolic acid, we first analyzed its toxic potential over both, the viral particles (virucidal effect) and the cultured cells (cytotoxicity). We observed no virion infectivity affectation with treatments of up to 40µM ursolic acid, while incipient cytotoxicity started to be evident with 20 µM ursolic acid. Next, we evaluated the antiviral potential of ursolic acid in in vitro Rotavirus infections, demonstrating that 10 µM ursolic acid inhibits Rotavirus replication, observed by a decrease in the viral titerand the level of the main viral proteins and an impact of ursolic acid on viral particles maturation, a process associated to the endoplasmic reticulum 15 h post infection. Interestingly, we determined that ursolic acid also hampers the early stages of the viral replication cycle, since a significant reduction in the number and size of viroplasms, consistent with a decrease in VP6 and NSP2 viral proteins was observed after 4 h of infection. Thus, our observations demonstrate that ursolic acid exhibits antiviral activity suggesting that this chemical could be potentially used as a new anti-Rotavirus therapeutic compound.

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PMID: 

Cytokine. 2019 Jul 11 ;123:154726. Epub 2019 Jul 11. PMID: 31302461

Abstract Title: 

Ursolic acid exhibits anti-inflammatory effects through blocking TLR4-MyD88 pathway mediated by autophagy.

Abstract: 

There is an urgent need for effective treatments to reduce the large and growing burden of acute kidney injury (AKI) and its consequences. Inflammation is believed to play a vital role in the pathophysiology of AKI. Macrophage autophagy is considered protective against inflammation. Previous study discovered that ursolic acid (UA), a natural pentacyclic triterpene carboxylic acid found in many plants as apples, bilberries, cranberries and so on, promoted cancer cell autophagy. In the present study, we aimed to explore the effect of UA on ameliorating AKI and the role of macrophage autophagy in the context of inflammation. The data from in vivo experiments showed that pretreatment of mice with UA significantly suppressed xylene-induced ear oedema as well as protected against LPS-induced AKI. Related mechanisms were further studied through in vitro experiment. As expected, UA decreased inflammatory factors TNF-α, IL-6 and IL-1β secretion in macrophages in response to lipopolysaccharide (LPS) stimulation. Furthermore, UA blocked LPS-induced TLR4/MyD88 pathway. More importantly, enhanced autophagy of macrophages by UA through increasing the expression of both LC3B and Beclin-1 led to alter macrophage function. What is more, similar to UA, autophagy inhibitor 3-MA obviously decreased inflammation factors releases hinting the vital role of autophagy in regulating inflammation. In all, above study suggested that UA is a potential anti-inflammatory natural compound for treating AKI by inducing autophagy.

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PMID: 

Evid Based Complement Alternat Med. 2019 ;2019:2474805. Epub 2019 Jun 9. PMID: 31281396

Abstract Title: 

Ursolic Acid Inhibits Epithelial-Mesenchymal Transition through the Axl/NF-B Pathway in Gastric Cancer Cells.

Abstract: 

Background: Ursolic acid (UA) is an antitumor component derived from Chinese herbal medicine; this study is to observe the effects of UA on epithelial-mesenchymal transition (EMT) in gastric cancer.Methods: (1)experiments: 25mol/L and 50mol/L UA were applied to BGC-823, AGS, MGC-803, and HGC-27 cells; MTT staining, Transwell assay, and flow cytometry were used to assess cell proliferation, cell migration, and apoptosis, respectively. Western blot was performed to detect the expressions of N-Cadherin, Vimentin, Snail, Twist, Axl, p-Axl, IKK, p-IKK, NF-B, and p-NF-B. (2)experiments: Ten BALB/c-nu mice were used to establish gastric cancer xenograft model. Five were orally given UA for 4 weeks and five were given normal saline. Expressions of N-Cadherin and Snail were examined by immunohistochemical assay; expressions of N-Cadherin, Snail, Twist, Axl, p-Axl, IKK, and p-IKK were detected by Western blot.Results: (1) UA inhibited cell proliferation in BGC-823 and HGC-27 cells in dose-dependent manners. (2) UA inhibited cell migration in BGC-823, AGS, and MGC-803 cells while inducing apoptosis in BGC-823 cells. (3) UA significantly decreased the expressions of N-Cadherin, Vimentin, Snail, Twist p-Axl, p-IKK/, and p-NF-B in BGC-823 and MGC-803 cells. (4) UA distinctly decreased the expressions of N-Cadherin, Snail, p-Axl, and p-IKK/in gastric cancer xenograft model rats.Conclusion: UA can effectively inhibit the proliferation and migration and induce apoptosis of gastric cancer cells. The antitumor effect of UA is conducted by EMT inhibition, which may be associated with the regulation of Axl/NF-B signaling pathway.

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PMID: 

Front Pharmacol. 2019 ;10:700. Epub 2019 Jun 20. PMID: 31281258

Abstract Title: 

Ursolic Acid Protected Lung of Rats From Damage Induced by Cigarette Smoke Extract.

Abstract: 

We found previously that ursolic acid (UA) administration could alleviate cigarette smoke-induced emphysema in rats partly through the unfolded protein response (UPR) PERK-CHOP and Nrf2 pathways, thus alleviating endoplasmic reticulum stress (ERS)-associated oxidative stress and cell apoptosis. We hypothesized that other UPR pathways may play similar roles in cigarette smoke extract (CSE)-induced emphysema. So, we sought to investigate the dynamic changes and effects of UPR and the downstream apoptotic pathways. Further, we investigated whether UA could alleviate CSE-induced emphysema and airway remodelling in rats, whether and when it exerts its effects through UPR pathways as well as Smads pathways.One hundred eight Sprague Dawley (SD) rats were randomly divided into three groups: Sham group, CSE group, and UA group, and each group was further divided into three subgroups, administered CSE (vehicle) for 2, 3, or 4 weeks; each subgroup had 12 rats. We examined pathological changes, analyzed the three UPR signaling pathways and subsequent ERS, intrinsic and extrinsic apoptotic pathway indicators, as well as activation of Smad2,3 molecules in rat lungs.Exposure to CSE for 3 or 4 weeks could apparently induce emphysema and airway remodeling in rats, including gross and microscopic changes, alteration of mean alveolar number (MAN), mean linear intercept (MLI), and mean airway thickness in lung tissue sections. UA intervention could significantly alleviate CSE-induced emphysema and airway remodeling in rats. UA exerted its effects through ameliorating apoptosis by down regulating UPR signalling pathways and subsequent apoptosis pathways, as well as, downregulating p-Smad2 and p-Smad3 molecules.UA attenuated CSE-induced emphysema and airway remodeling, exerting its effects partly through regulation of three UPR pathways, amelioration downstream apoptotic pathways, and alleviating activation of Smad2 and Smad3.

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