• Humans
• Molecular Docking Simulation
• Salvia/chemistry
• MCF-7 Cells
• Triterpenes/pharmacology
• Triterpenes/isolation & purification
• Triterpenes/chemistry
• Antineoplastic Agents, Phytogenic/pharmacology
• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/isolation & purification
• Molecular Structure
• NF-kappa B/metabolism
• Plant Extracts/pharmacology
• Plant Extracts/chemistry
• Plant Components, Aerial/chemistry

• Breast cancer
• Chemotherapy
• Colorectal cancer
• Electrospun polymer nanofibers
• Localized drug release
• Tyramine-maslinic acid

• Chaenomeles genus
• Pharmacological activities
• Phytochemistry

• Rosaceae
• Plant Extracts/pharmacology
• Flavonoids
• Antioxidants
• Phenols
• Phytochemicals/pharmacology
• Ethnopharmacology
• Phytotherapy

• 32270424 National Natural Science Foundation of China
• 2021194 Horizontal cooperation topic
• 2022xkjT045 Scientific Research Platform Improvement Project of Anhui Medical University

• biological effects
• derivatives
• drug delivery system
• triterpenoids
• ursolic acid

• Anticancer
• Cancer hallmarks
• Maslinic acid
• Mechanism of action
• Signaling pathways
• Systematic review

• Humans
• Antineoplastic Agents/pharmacology
• Neoplasms/drug therapy
• Oleanolic Acid/pharmacology
• Triterpenes/pharmacology

• Maslinic acid
• biological activity
• extraction
• identification
• pharmacokinetics
• purification
• treatment of multiple organ diseases

• Humans
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Antioxidants/pharmacology
• Antioxidants/therapeutic use
• Olea
• Oleanolic Acid/pharmacology
• Oleanolic Acid/therapeutic use
• Triterpenes/therapeutic use
• Triterpenes/pharmacokinetics

• 82074151 National Natural Science Foundation of China

Despite the extensive knowledge on cancer nature acquired over the last years, the high incidence of this disease evidences a need for new approaches that complement the clinical intervention of tumors. Interestingly, many types of cancer are closely related to dietary habits associated with the Western lifestyle, such as low fruit and vegetable intake. Recent advances around the old-conceived term of chemoprevention highlight the important role of phytochemicals as good candidates for the prevention or treatment of cancer. The potential to inhibit angiogenesis exhibited by many natural compounds constituent of plant foods makes them especially interesting for their use as chemopreventive agents. Here, we review the antitumoral potential, with a focus on the antiangiogenic effects, of phenolic and polyphenolic compounds, such as quercetin or myricetin; terpenoids, such as ursolic acid or kahweol; and anthraquinones from Aloe vera, in different in vitro and in vivo assays, and the available clinical data. Although clinical trials have failed to assess the preventive role of many of these compounds, encouraging preclinical data support the efficacy of phytochemicals constituent of diet in the prevention and treatment of cancer, but a deeper understanding of their mechanisms of action and better designed clinical trials are urgently needed.

• antiproliferative
• molecular docking
• network pharmacology
• triple-negative breast cancer
• ursolic acid

• Angiogenesis
• Apoptotic pathways
• Derivatives
• Metastasis
• Oleanolic acid
• Systematic -analysis review

Ursolic acid (UA) is a well-studied natural pentacyclic triterpenoid found in herbs, fruit and a number of traditional Chinese medicinal plants. UA has a broad range of biological activities and numerous potential health benefits. In this review, we summarize the current data on the bioavailability and pharmacokinetics of UA and review the literature on the biological activities of UA and its closest analogues in the context of inflammation, metabolic diseases, including liver and kidney diseases, obesity and diabetes, cardiovascular diseases, cancer, and neurological disorders. We end with a brief overview of UA’s main analogues with a special focus on a newly discovered naturally occurring analogue with intriguing biological properties and potential health benefits, 23-hydroxy ursolic acid.

• antioxidants
• atherosclerosis
• botanicals
• cancer
• inflammation
• metabolic diseases
• nutraceutical

• Cissus incisa
• Vitaceae
• cytotoxicity
• extracts
• network pharmacology
• untargeted metabolomics

• 04-093765-FAR-11/250-FCQ-UANL Universidad Autónoma de Nuevo León
• LANEM Project Universidad Autónoma del Estado de Morelos

Background: Ursolic acid (UA) is a natural pentacyclic triterpene derived from fruit, herb, and other plants. UA can act on molecular targets of various signaling pathways, inhibit the growth of cancer cells, promote cycle stagnation, and induce apoptosis, thereby exerting anticancer activity. However, its poor water-solubility, low intestinal mucosal absorption, and low bioavailability restrict its clinical application. In order to overcome these deficiencies, nanotechnology, has been applied to the pharmacological study of UA.

Objective: In this review, we focused on the absorption, distribution, and elimination pharmacokinetics of UA in vivo, as well as on the research progress in various UA nanoformulations, in the hope of providing reference information for the research on the anticancer activity of UA.

Methods: Relevant research articles on Pubmed and Web of Science in recent years were searched selectively by using the keywords and subheadings, and were summarized systematically.

Key finding: The improvement of the antitumor ability of the UA nanoformulations is mainly due to the improvement of the bioavailability and the enhancement of the targeting ability of the UA molecules. UA nanoformulations can even be combined with computational imaging technology for monitoring or diagnosis.

Conclusion: Currently, a variety of UA nanoformulations, such as micelles, liposomes, and nanoparticles, which can increase the solubility and bioactivity of UA, while promoting the accumulation of UA in tumor tissues, have been prepared. Although the research of UA in the nanofield has made great progress, there is still a long way to go before the clinical application of UA nanoformulations.

• cancer
• nanoformulations
• natural molecule
• pharmacokinetics
• ursolic acid

• NFKB, SP1
• herbal medicine
• intestinal cancer
• reactive oxygen species
• ursolic acid

• Biocompatibility
• Glycyrrhiza glabra
• Nanocarriers
• Olea europaea
• Self-assembly
• Terminalia arjuna

Inflammation is considered as one of the hallmarks of cancer development and progression. Ursolic acid (UA) showed strong effects as an anti-inflammatory and antioxidant. However, the anti-cancer effects of ursolic acid require further study.

This study aimed to investigate the role of ursolic acid in a lipopolysaccharide (LPS)-treated gastric tumour mouse model and in a human gastric carcinoma cell line (BGC-823 cells). This study also aimed to confirm whether ursolic acid can protect against proliferation and the inflammatory response induced by LPS, by inhibiting the activation of the NLRP3 inflammasome via the NF-κB pathway.

The present study demonstrated that ursolic acid significantly attenuated LPS-treated proliferation in a gastric tumour mouse model and the human gastric carcinoma BGC-823 cell line, reduced the expression of the NLRP3 inflammasome and suppressed the release of pro-inflammatory cytokines. In addition, ursolic acid inhibited the LPS-induced activation of NF-κB. Furthermore, the NF-κB pathway regulated the activation of the NLRP3 inflammasome.

In conclusion, these results demonstrated that ursolic acid could suppress proliferation and the inflammatory response in an LPS-induced mouse gastric tumour model and human BGC-823 cells by inhibiting the activation of the NLRP3 inflammasome via the NF-κB pathway. This indicates that ursolic acid can be a potential therapeutic agent for the treatment of gastric cancer.

• NF-κB pathway
• NLRP3 inflammasome
• gastric carcinoma
• inflammatory
• proliferation
• ursolic acid

• Anti-tumor effect
• Chinese herbal medicines
• Liposomes
• Targeting strategies
• Tumor microenvironment

• Animals
• Antineoplastic Agents, Phytogenic/administration & dosage
• Drugs, Chinese Herbal/administration & dosage
• Humans
• Liposomes
• Medicine, Chinese Traditional
• Neoplasms/drug therapy
• Phytotherapy
• Tumor Microenvironment/drug effects

• U54 CA198999 NCI NIH HHS

Adipose-derived stem cell (ADSC) transplantation is a promising strategy to promote wound healing because of the paracrine function of stem cells. However, glucose-associated effects on stem cell paracrine function and survival contribute to impaired wound closure in patients with diabetes, limiting the efficacy of ADSC transplantation. Hypoxia-inducible factor (HIF)1α plays important roles in wound healing, and in this study, we investigated the effects of HIF1α overexpression on ADSCs in high glucose and low oxygen conditions.

Adipose samples were obtained from BALB/C mice, and ADSCs were cultured in vitro by digestion. Control and HIF1α-overexpressing ADSCs were induced by transduction. The mRNA and protein levels of angiogenic growth factors in control and HIF1α-overexpressing ADSCs under high glucose and low oxygen conditions were analyzed by quantitative reverse transcription-polymerase chain reaction and western blotting. The effects of ADSC HIF1α overexpression on the proliferation and migration of mouse aortic endothelial cells (MAECs) under high glucose were evaluated using an in vitro coculture model. Intracellular reactive oxygen species (ROS) and 8-hydroxydeoxyguanosine (8-OHdG) levels in ADSCs were observed using 2,7-dichlorodihydrofluorescein diacetate staining and enzyme-linked immunosorbent assays, respectively. Apoptosis and cell cycle analysis assays were performed by flow cytometry. An in vivo full-thickness skin defect mouse model was used to evaluate the effects of transplanted ADSCs on diabetic wound closure.

In vitro, HIF1α overexpression in ADSCs significantly increased the expression of vascular endothelial growth factor A, fibroblast growth factor 2, and C-X-C motif chemokine ligand 12, which were inhibited by high glucose. HIF1α overexpression in ADSCs alleviated high glucose-induced defects in MAEC proliferation and migration and significantly suppressed ADSC ROS and 8-OHdG levels, thereby decreasing apoptosis and enhancing survival. In vivo, HIF1α overexpression in ADSCs prior to transplantation significantly enhanced angiogenic growth factor expression, promoting wound closure in diabetic mice.

HIF1α overexpression in ADSCs efficiently alleviates high glucose-induced paracrine dysfunction, decreases oxidative stress and subsequent DNA damage, improves viability, and enhances the therapeutic effects of ADSCs on diabetic wound healing.

• Adipose-derived stem cells
• High glucose
• Hypoxia-inducible factor 1α
• Mice
• Reactive oxygen species
• Stem cell transplantation
• Wound healing

• Bioactive compounds
• Cancer
• Chinese herbal medicine
• Natural products
• Traditional Chinese medicine

• the Macao Science and Technology Development Fund
• the Research Committee of the University of Macau

• Cancer
• chemoprevention
• cranberries
• nutraceuticals
• quercetin
• ursolic acid.

Maslinic acid is a pentacyclic triterpene with a plethora of biological activities, including anti-inflammatory, antioxidant, antimicrobial, cardioprotective, and antitumor effects. New derivatives with improved properties and broad-spectrum activity can be obtained following structural changes of the compound. The present study was aimed to characterize a benzylamide derivative of maslinic acid—benzyl (2α, 3β) 2,3-diacetoxy-olean⁻12-en-28-amide (EM2)—with respect to the anti-angiogenic and anti-inflammatory effects in two in vivo experimental models. Consequently, the compound showed good tolerability and lack of irritation in the chorioallantoic membrane assay with no impairment of the normal angiogenic process during the tested stages of development. In the acute ear inflammation murine model, application of EM2 induced a mild anti-inflammatory effect that was potentiated by the association with zinc chloride (ZnCl₂). A decrease in dermal thickness of mice ears was observed when EM2 and ZnCl₂ were applied separately or in combination. Moreover, hyalinization of the dermis appeared only when EM2 was associated with ZnCl₂, strongly suggesting the role of their combination in wound healing.

• EM2, benzylamide derivative
• angiogenesis
• inflammation
• maslinic acid
• zinc chloride

• Angiogenesis Inhibitors/administration & dosage
• Angiogenesis Inhibitors/adverse effects
• Angiogenesis Inhibitors/therapeutic use
• Animals
• Anti-Inflammatory Agents/administration & dosage
• Anti-Inflammatory Agents/adverse effects
• Anti-Inflammatory Agents/therapeutic use
• Chick Embryo
• Chlorides/administration & dosage
• Chlorides/therapeutic use
• Chorioallantoic Membrane/drug effects
• Drug Therapy, Combination
• Female
• Mice
• Otitis/drug therapy
• Triterpenes/administration & dosage
• Triterpenes/adverse effects
• Triterpenes/therapeutic use
• Zinc Compounds/administration & dosage
• Zinc Compounds/therapeutic use

Maslinic acid triggers compelling antiproliferative and pro-apoptotic effects in different human cancer cell lines. Hence, the chemopreventive activity was investigated on early stages of carcinogenesis induced by 1,2-dimethylhydrazine (DMH) which is a model that mimics human sporadic colorectal cancer. Male Sprague-Dawley rats were orally administered either maslinic acid at 5, 10 or 25 mg/kg dissolved in (2-hydroxypropyl)-β-cyclodextrin 20% (w/v) or the solvent for 49 days. After one week of treatment, animals received three weekly intraperitoneal injections of DMH at the dose of 20 mg/kg. Maslinic acid reduced the preneoplastic biomarkers, aberrant crypt foci (ACF) and mucin-depleted foci (MDF), already at 5 mg/kg in a 15% and 27%, respectively. The decline was significant at 25 mg/kg with decreases of 33% and 51%, respectively. Correlation analysis showed a significant association between the concentrations of maslinic acid found in the colon and the reduction of ACF (r = 0.999, p = 0.019) and MDF (r = 0.997, p = 0.049). The present findings demonstrate that maslinic acid induced an inhibition of the initiation stages of carcinogenesis. The assessment of this pentacyclic triterpene at the colon sheds light for designing diets with foods rich in maslinic acid to exert a chemopreventive activity in colorectal cancer.

• aberrant crypt foci
• colon cancer
• dimethylhydrazine
• maslinic acid
• mucin depleted foci

From several decades ago to now, cancer continues to be the leading cause of death worldwide, and metastasis is the major cause of cancer-related deaths. For health benefits, there is a great desire to use non-chemical therapy such as nutraceutical supplementation to prevent pathology development. Over 10,000 different natural bioactives or phytochemicals have been known that possessing potential preventive or supplementary effects for various diseases including cancer. Previously, the in vitro and in vivo anti-invasive and anti-metastatic activities of phenolic acids, monophenol, polyphenol and their derivatives and flavonoids and their derivatives have been reviewed. However, a vast number of natural dietary compounds other than phenolics have been demonstrated to potentially possess the ability to inhibit the invasion and metastasis of various cancers. In this review, we summarize the studies in recent decade on in vitro and in vivo effects and molecular mechanisms of natural bioactives, excluding the phenolics in food, in cancer invasion and metastasis. By combining this review of non-phenolics with the previous phenolics reviews, the puzzle for the contribution of natural dietary bioactives on cancer invasive or/and metastatic progress will be almost complete and more clear.

• Angiogenesis
• Invasion
• Metastasis
• Natural dietary bioactives

Background/Aim: MK615 extracted from Prunus mume was reported to have anti-inflammatory effects. In this article, we examined the in vivo antitumor effect of MK615 (an extract from Japanese apricot) using mouse tumor xenografts and focusing on the downregulation of PD-L1 (programmed death-ligand 1), a ligand of programmed cell death-1, a surface protein of activated T cells. Materials and Methods: B16/BL6 melanoma cells were injected into C57BL/6 or BALB/c-nu/nu mice to establish lung metastasis. BALB/c-nu/nu mice (nude mice) were used as a T cell–deficient model. The mice were given MK615 or saline orally every other day for approximately 8 weeks, and their survival was observed. NF-κB (nuclear factor-κB) and PD-L1 expressions of metastatic lung tissues were also examined. Results: The survival rate was improved only in the MK615-treated C57BL/6 mice (P < .05), not in the saline-given control mice or BALB/c-nu/nu mice. The downregulations of NF-κB and PD-L1 were observed in both MK615-treated C57BL/6 and BALB/c-nu/nu mice. These results suggest that the antitumor effects of MK615 are associated with T cell–mediated immunity activated by MK-615-induced PD-L1 downregulation in tumor cells. Conclusion: MK615 is beneficial for a prolonged host survival time in the B16/BL6 melanoma xenograft model associated with T cell–mediated antitumor immunity.

• MK615
• NF-κB
• PD-L1
• mume
• triterpenoid

A large number of terpenoids exhibit potential geroprotector and anti-cancer properties. Here, we studied whole transcriptomic effects of Abisil, the extract of fir (Abies sibirica) terpenes, on normal and cancer cell lines. We used early passaged and senescent none-immortalized fibroblasts as cellular aging models. It was revealed that in normal fibroblasts, terpenes induced genes of stress response, apoptosis regulation and tissue regeneration. The restoration of the expression level of some prolongevity genes after fir extract treatment was shown in old cells. In Caco-2 and AsPC-1 cancer cell lines, Abisil induced expression of both onco-suppressors (members of GADD45, DUSP, and DDIT gene families), and proto-oncogenes (c-Myc, c-Jun, EGR and others). Thus, the study demonstrates the potential anti-aging and anti-cancer effects of Abisil on senescent and cancer cell lines.

• Abies sibirica
• anti-aging effects
• anti-cancer effects
• plant extract
• terpenoids

• oleanolic acid
• ursolic acid
• anti-invasive
• anti-angiogenic
• melanoma

• Angiogenesis Inhibitors/pharmacology
• Animals
• Cell Adhesion/drug effects
• Cell Cycle/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Chick Embryo
• Chorioallantoic Membrane/blood supply
• Chorioallantoic Membrane/drug effects
• Humans
• Melanoma/blood supply
• Melanoma/drug therapy
• Melanoma/pathology
• Neovascularization, Physiologic/drug effects
• Oleanolic Acid/pharmacology
• Skin Neoplasms/blood supply
• Skin Neoplasms/drug therapy
• Skin Neoplasms/pathology
• Triterpenes/pharmacology
• Ursolic Acid

• oleanolic acid
• oxidized LDL
• proliferation
• signaling pathway
• uncoupling protein 2
• vascular smooth muscle cell

• Animals
• Antineoplastic Agents, Phytogenic/administration & dosage
• Antineoplastic Agents, Phytogenic/therapeutic use
• Apoptosis/drug effects
• Biocompatible Materials/chemistry
• Caspases/metabolism
• Cell Proliferation/drug effects
• Drug Carriers/chemistry
• Female
• Gold/chemistry
• HeLa Cells
• Humans
• Injections, Intraperitoneal
• Male
• Mice, Nude
• Nanoparticles/chemistry
• Polyglactin 910/chemistry
• Triterpenes/administration & dosage
• Triterpenes/therapeutic use
• Tumor Suppressor Protein p53/metabolism
• Uterine Cervical Neoplasms/drug therapy
• Xenograft Model Antitumor Assays
• Ursolic Acid

Despite the introduction of many novel therapeutics in clinical practice, metastatic renal cell carcinoma (RCC) remains a treatment-resistant cancer. As red and processed meat are considered risk factors for RCC, and a vegetable-rich diet is thought to reduce this risk, research into plant-based therapeutics may provide valuable complementary or alternative therapeutics for the management of RCC. Herein, we present the antiproliferative and antiangiogenic effects of maslinic acid, which occurs naturally in edible plants, particularly in olive fruits, and also in a variety of medicinal plants. Human RCC cell lines (ACHN, Caki-1, and SN12K1), endothelial cells (human umbilical vein endothelial cell line [HUVEC]), and primary cultures of kidney proximal tubular epithelial cells (PTEC) were treated with maslinic acid. Maslinic acid was relatively less toxic to PTEC when compared with RCC under similar experimental conditions. In RCC cell lines, maslinic acid induced a significant reduction in proliferation, proliferating cell nuclear antigen, and colony formation. In HUVEC, maslinic acid induced a significant reduction in capillary tube formation in vitro and vascular endothelial growth factor. This study provides a rationale for incorporating a maslinic acid–rich diet either to reduce the risk of developing kidney cancer or as an adjunct to existing antiangiogenic therapy to improve efficacy.

• angiogenesis
• maslinic acid
• proliferating cell nuclear antigen
• renal cell carcinoma
• vascular endothelial growth factor

• Angiogenesis Inhibitors/chemical synthesis
• Angiogenesis Inhibitors/pharmacology
• Animals
• Anticoagulants/chemistry
• Body Size/drug effects
• Collagen/chemistry
• Drug Combinations
• Female
• Glycoconjugates/chemical synthesis
• Glycoconjugates/pharmacology
• Heparin, Low-Molecular-Weight/chemistry
• Human Umbilical Vein Endothelial Cells
• Humans
• Injections, Intravenous
• Laminin/chemistry
• Melanoma, Experimental/drug therapy
• Melanoma, Experimental/pathology
• Mice
• Mice, Inbred C57BL
• Micelles
• Nanoparticles/administration & dosage
• Nanoparticles/chemistry
• Neovascularization, Pathologic/pathology
• Neovascularization, Pathologic/prevention & control
• Particle Size
• Proteoglycans/chemistry
• Surface-Active Agents/chemical synthesis
• Surface-Active Agents/pharmacology
• Triterpenes/chemistry
• Tumor Burden/drug effects
• Ursolic Acid

It is well known that the naturally occurring modified triterpenes in plants have a wide diversity of chemical structures and biological functions. The lupane-, oleanane-, and ursane-type triterpenes are the three major members of natural triterpenes with a wide range of biological properties. A systematic approach is necessary to review their structures and biological activities according to the backbones and the different substituents.

Thirty lupane-(L1-7), oleanane-(O1-14), and ursane-type (U1-9) triterpenes with structural diversity were examined to evaluate their cytotoxic activities against two cancer cell lines, human hepatocellular carcinoma (HepG2) and AGS cells.

They were isolated from Hedera helix, Juglans sinensis, and Pulsatilla koreana using a series of column chromatography methods and were treated to evaluate their cytotoxic activities against HepG2 and AGS human gastric adenocarcinoma cell. Further, two triterpenes showing the most potent activities were subjected to the apoptotic screening assay using flow cytometry.

The polar groups, such as an oxo group at C-1, a free hydroxyl at C-2, C-3, or C-23, and a carboxylic moiety at C-28, as well as the type of backbone, explicitly increased the cytotoxic activity on two cancer cells. O5 and U5 showed significantly the potent cytotoxic activity in comparison to other glycosidic triterpenes. In annexin-V/propidium iodide (PI) staining assay, the percentage of late apoptosis (annexin-V+/PI+) 12 and 24 h after treatment with O5 and U5 at 25 μM increased from 14.5% to 93.1% and from 46.4% to 49.1%, respectively, in AGS cells. The cytotoxicity induced by O5 showed a significant difference compared to U5 for 12 and 24 h.

In the study, we can suggest the potent moieties which influence their cytotoxic activities against two cancer cells. The polar groups at C-1, C-2, C-3, C-23, and C-28 and the linkage of sugar moieties influenced the different cytotoxic activities.

Thirty naturally occurring oleanane-, ursane-, and lupane-type triterpenes were isolated from Hedera helix, Juglans sinensis, and Pulsatilla koreana

• Flow cytometry
• lupane
• oleanane
• triterpene
• ursane

• glutathione
• hypoxia inducible factor-1α
• non-small cell lung cancer
• radiosensitization
• ursolic acid

• HCC
• mechanisms
• structural modification
• structure activity relationship

• Animals
• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/isolation & purification
• Antineoplastic Agents, Phytogenic/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/metabolism
• Cell Line, Tumor
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/metabolism
• Plant Extracts/chemistry
• Plant Extracts/isolation & purification
• Plant Extracts/therapeutic use
• Triterpenes/chemistry
• Triterpenes/isolation & purification
• Triterpenes/therapeutic use
• Ursolic Acid

• Intestinal metabolism
• Maslinic acid
• Olives
• Phase I metabolites
• Rat

• Anti-inflammatory
• Anti-metastasis
• Anti-oxidant
• Apoptosis
• Derivatives
• Ursolic acid

• Animals
• Antineoplastic Agents, Phytogenic/adverse effects
• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/therapeutic use
• Humans
• Neoplasms/drug therapy
• Neoplasms/pathology
• Triterpenes/adverse effects
• Triterpenes/chemistry
• Triterpenes/therapeutic use
• Ursolic Acid

• anti-inflammatory
• antibacterial
• anticancer
• triterpene
• ursolic acid

• Animals
• Anti-Infective Agents/chemistry
• Anti-Infective Agents/pharmacology
• Anti-Inflammatory Agents/chemistry
• Anti-Inflammatory Agents/pharmacology
• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/pharmacology
• Brain/drug effects
• Heart/drug effects
• Humans
• Liver/drug effects
• Plant Extracts/biosynthesis
• Plant Extracts/chemistry
• Plant Extracts/pharmacology
• Triterpenes/chemistry
• Triterpenes/pharmacology
• Ursolic Acid

Maslinic acid (MA) is a pentacyclic triterpene acid that is present in numerous dietary plants. Although certain studies have demonstrated that MA has anti-cancer properties in different cell types, the effect of MA on lung cancer cell proliferation and apoptosis and the potential underlying mechanisms remain to be elucidated. In the present study, A549 lung cancer cells were treated with different doses of MA and it was found that MA significantly inhibited A549 cell growth in a dose-dependent manner. In addition, Annexin V/propidium iodide flow cytometric analysis demonstrated that MA induced apoptosis of A549 cells. The present study also confirmed that MA induced apoptosis by observing morphological alterations. In addition, the effect of MA treatment on the levels of apoptosis-associated proteins was examined. The results demonstrated that MA treatment suppressed the expression of caspase-3, -8 and -9, and increased the expression of cleaved caspase-3, -8 and -9 in a dose-dependent manner. The level of inhibitors of apoptosis (IAPs) and Smac, which are possible upstream factors of caspase proteins, were also examined. It was found that MA treatment increased the protein expression of Smac and decreased the protein levels of c-IAP1, c-IAP2, X-linked inhibitor of apoptosis protein (XIAP) and Survivin in a dose-dependent manner. These results suggested that MA inhibited proliferation and induced apoptosis of A549 cells through regulation of caspase cleavage as well as Smac, c-IAP1, c-IAP2, XIAP and Survivin.

AIM: To investigate the relationship between contrast-enhanced ultrasound (CEUS), basic fibroblast growth factor (bFGF), endothelin-1 (ET-1), and hepatocellular carcinoma (HCC) recurrence after ablation.

METHODS: A total of 51 HCC patients (38 males and 13 females) who received radiofrequency ablation in our hospital from June 2012 to July 2014 were enrolled in this study. The patients were divided into two groups: recurrence group and non-recurrence group. Routine abdominal examination was first performed in the horizontal position. Then the patients underwent CEUS and immunohistochemical staining before receiving radiofrequency ablation. All patients were followed-up every three months for one year. The results of CEUS and serum tumor marker levels were evaluated and combined together to estimate HCC recurrence and metastasis. Patients were divided into two groups: recurrence group and non-recurrence group. Quantitative parameters of CEUS and tumor expression levels of bFGF and ET-1 were compared between the two groups, respectively. Binary logistic regression analysis was used to analyze the relationship between CEUS quantitative parameters, expression levels of ET-1 and bFGF, and HCC recurrence after ablation.

RESULTS: Based on the quantitative parameters of CEUS before patients received radiofrequency ablation, the levels of tumor rise time (tRT), tumor time to peak (tTTP), tumor peak intensity (tPI) and tumor-parenchymal peak intensity (t-pPI) in the recurrence group were significantly lower than those in the non-recurrence group (16.6 ± 6.1 vs 23.2 ± 7.0, P = 0.000; 41.2 ± 10.2 vs 59.6 ± 14.2, P = 0.000; 23.8 ± 6.7 vs 31.4 ± 6.4, P = 0.000; 7.1 ± 3.4 vs 14.6 ± 7.4, P = 0.000; respectively). The expression levels of bFGF in the recurrence group were significantly higher than those in the non-recurrence group (P < 0.05). Levels of tTTP showed a significant inverse correlation with the level of bFGF in tumors (r = -0.312, P = 0.037). The Binary logistic regression analysis results revealed that the levels of tRT, tTTP, tPI and the level of bFGF were associated with HCC recurrence after radiofrequency ablation (P < 0.05).

CONCLUSION: CEUS is a noninvasive and effective method for evaluating the angiogenesis of HCC, and predicting its recurrence and prognosis.

• Contrast-enhanced ultrasonography
• Hepatocellular carcinoma
• Radiofrequency ablation

• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/blood
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/chemistry
• Carcinoma, Hepatocellular/diagnostic imaging
• Carcinoma, Hepatocellular/secondary
• Carcinoma, Hepatocellular/surgery
• Catheter Ablation
• Contrast Media
• Female
• Humans
• Immunohistochemistry
• Liver Neoplasms/blood
• Liver Neoplasms/chemistry
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/pathology
• Liver Neoplasms/surgery
• Logistic Models
• Male
• Middle Aged
• Neoplasm Recurrence, Local
• Phospholipids
• Predictive Value of Tests
• Risk Factors
• Sulfur Hexafluoride
• Time Factors
• Treatment Outcome
• Ultrasonography

• LC−MS
• maslinic acid
• metabolism
• pentacyclic triterpenes
• rat plasma

• (−)-Citronellal
• Calcium
• Hepatocellular carcinoma
• Olfactory receptor
• Proliferation
• p38 MAPK

The apoptotic effects of maslinic acid (MA) at 4, 8, 16, 32 and 64 μmol/L on human lung cancer A549 cells under normoxic and hypoxic conditions were examined. MA at 4–64 and 16–64 μmol/L lowered Bcl-2 expression under normoxic and hypoxic conditions, respectively (p < 0.05). This agent at 4–64 μmol/L decreased Na⁺-K⁺-ATPase activity and increased caspase-3 expression under normoxic conditions, but at 8–64 μmol/L it caused these changes under hypoxic conditions (p < 0.05). MA up-regulated caspase-8, cytochrome c and apoptosis-inducing factor expression under normoxic and hypoxic conditions at 8–64 μmol/L and 32–64 μmol/L, respectively (p < 0.05). MA down-regulated hypoxia-inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF), survivin and inducible nitric oxide synthase (iNOS) expression under normoxic and hypoxic conditions at 8–64 and 16–64 μmol/L, respectively (p < 0.05). After cells were pre-treated with YC-1, an inhibitor of HIF-1α, MA failed to affect the protein expression of HIF-1α, VEGF, survivin and iNOS (p > 0.05). MA at 8-64 and 32-64 μmol/L reduced reactive oxygen species and nitric oxide levels under both conditions (p < 0.05). These findings suggest that maslinic acid, a pentacyclic triterpenic acid, exerted its cytotoxic activities toward A549 cells by mediating mitochondrial apoptosis and the HIF-1α pathway.

Reactive oxygen species (ROS) take part in diverse biological processes like cell growth, programmed cell death, cell senescence, and maintenance of the transformed state through regulation of signal transduction. Cancer cells adapt to new higher ROS circumstance. Sometimes, ROS induce cancer cell proliferation. Meanwhile, elevated ROS render cancer cells vulnerable to oxidative stress-induced cell death. However, this prominent character of cancer cells allows acquiring a resistance to oxidative stress conditions relative to normal cells. Activated signaling pathways that increase the level of intracellular ROS in cancer cells not only render up-regulation of several genes involved in cellular proliferation and evasion of apoptosis but also cause cancer cells and cancer stem cells to develop a high metabolic rate. In over the past several decades, many studies have indicated that ROS play a critical role as the secondary messenger of tumorigenesis and metastasis in cancer from both in vitro and in vivo. Here we summarize the role of ROS and anti-oxidants in contributing to or preventing cancer. In addition, we review the activated signaling pathways that make cancer cells susceptible to death.

• Oxidative stress
• Reactive oxygen species
• Carcinogenesis
• Apoptosis
• Signal transduction
• Antioxidants

Metastasis is a major cause of cancer-related mortality in patients with gastric cancer. Ursolic acid, a pentacyclic triterpenoid compound derived from medicinal herbs, has been demonstrated to exert anticancer effects in various cancer cell systems. However, to the best of our knowledge, the inhibitory effect of ursolic acid on the invasive phenotype of gastric cancer cells has yet to be reported. Therefore, the aim of the present study was to investigate the effect of ursolic acid on the invasiveness of SNU-484 human gastric cancer cells. Ursolic acid efficiently induced apoptosis, possibly via the downregulation of B-cell lymphoma 2 (Bcl-2), the upregulation of Bcl-2-associated X protein and the proteolytic activation of caspase-3. Furthermore, the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase was increased by the administration of ursolic acid. In addition, ursolic acid significantly suppressed the invasive phenotype of the SNU-484 cells and significantly decreased the expression of matrix metalloproteinase (MMP)-2, indicating that MMP-2 may be responsible for the anti-invasive activity of ursolic acid. Taken together, the results of the present study demonstrate that ursolic acid induces apoptosis and inhibits the invasive phenotype of gastric cancer cells; therefore, ursolic acid may have a potential application as a chemopreventive agent to prevent the metastasis of gastric cancer or to alleviate the process of metastasis.

• cell invasion
• matrix metalloproteinase
• ursolic acid