• COL1A1
• ERK
• MAPK
• NR4A1
• drug‐induced gingival enlargement
• n‐butylidenephthalide

• Animals
• Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
• Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
• Mice
• Humans
• Phthalic Anhydrides/pharmacology
• MAP Kinase Signaling System/drug effects
• Fibroblasts/drug effects
• Fibroblasts/metabolism
• Gingiva/drug effects
• Gingiva/metabolism
• Gingiva/pathology
• Male
• Gingival Overgrowth/chemically induced
• Gingival Overgrowth/metabolism
• Gingival Overgrowth/pathology
• Up-Regulation/drug effects
• Interleukin-1beta/genetics
• Interleukin-1beta/metabolism
• Female
• Cyclosporine/pharmacology
• Cyclosporine/adverse effects
• Disease Models, Animal
• Mice, Inbred C57BL
• Phenytoin/pharmacology
• Phenytoin/adverse effects

• 20K23111 Japan Society for the Promotion of Science
• JPMJSP2132 Japan Science and Technology Agency
• Japan Society for the Promotion of Science
• Japan Science and Technology Agency

• Cancer
• Metastasis
• Natural compounds
• Nuclear receptors
• Signaling molecules

• Humans
• Receptors, Cytoplasmic and Nuclear
• Transcription Factors
• Neoplasms/drug therapy
• Signal Transduction

• Nur77
• prognosis
• prostate cancer
• target

The coincident downregulation of NR4A1 and NR4A3 has been implicated in myeloid leukemogenesis, but it remains unknown how these two genes function in myeloid cells and how their combined downregulation promotes myeloid leukemogenesis. Since NR4A1 abrogation is thought to confer a survival and proliferation advantage to myeloid cells, we hypothesized that downregulation of NR4A3 may have a complementary effect on myeloid cell differentiation. First, we tested the association between differentiation status of leukemic cells and NR4A3 expression using two large clinical datasets from patients with different acute myeloid leukemia (AML) subtypes. The analysis revealed a close association between differentiation status and different subtypes of AML Then, we probed the effects of differentiation-inducing treatments on NR4A3 expression and NR4A3 knockdown on cell differentiation using two myeloid leukemia cell lines. Differentiation-inducing treatments caused upregulation of NR4A3, while NR4A3 knockdown prevented differentiation in both cell lines. The cell culture findings were validated using samples from chronic myeloid leukemia (CML) patients at chronic, accelerated and blastic phases, and in acute promyelocytic leukemia (APL) patients before and after all trans-retinoic acid (ATRA)-based differentiation therapy. Progressive NR4A3 downregulation was coincident with impairments in differentiation in patients during progression to blastic phase of CML, and NR4A3 expression was increased in APL patients treated with ATRA-based differentiating therapy. Together, our findings demonstrate a tight association between impaired differentiation status and NR4A3 downregulation in myeloid leukemias, providing a plausible mechanistic explanation of how myeloid leukemogenesis might occur upon concurrent downregulation of NR4A1 and NR4A3.

• Acute myeloid leukemia
• Differentiation
• NR4A3
• Orphan receptor

• Cancer
• Edible and medicinal plants
• Immunometabolism
• Traditional Chinese medicinal herb

• AMP-activated protein kinase (AMPK)
• Angelica sinensis
• Metabolism
• Obesity
• Thermogenesis
• Traditional Chinese medicines (TCMs)

• Binding site evaluation
• Inflammation
• Nur77
• Virtual Screening

High-grade serous ovarian cancer (HGSOC) constitutes 80% of ovarian cancer. Cancer stem cells (CSCs) are responsible for most of the tumor metastasis and chemoresistance. n-Butylidenephthalide (BP) is a potential anti-tumor agent for treating a variety of cancers. The aim of this study was to evaluate the effect of BP on CSCs of HGSOC. CSCs were isolated using the CSC marker (ALDH; aldehyde dehydrogenase) from KURAMOCHI and OVSAHO cells (HGSOC cell lines). The cell proliferation, IC50 (the half-maximal inhibitory concentration), cell migration and invasion, TUNEL (terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling) assay, western blot of ovarian CSC were evaluated. The animal xenograft studies were evaluated on an immunodeficient mouse model. The results showed the proliferation of ALDH+ cells was greater than that of ALDH- cells. The dosage of IC50 of BP was higher in ALDH+ cells than in mixed cancer cells (317.2 vs. 206.5 μg/ml) in KURAMOCHI cells, but not in OVSAHO cells (61.1 vs. 48.5 μg/ml). BP could inhibit the migration and invasion of both cancer stem cells. BP treatment could activate apoptosis signaling, as indicated by the TUNEL assay and the increased expression of cleaved caspase-3, -7, and -9 but not cleaved caspase-8. A low dose of BP (20 and 25 μg/mL) treatment could increase the toxicity of taxol and cisplatin. In the animal model, BP (200 mg/kg) treatment also decreased the KURAMOCHI and OVSAHO tumor growth rate and induced tumor apoptosis. In conclusion, BP could kill ALDH+ CSCs of HGSOC in vitro and in vivo by inducing apoptosis. BP may provide a new therapeutic approach for HGSOC.

• ALDH, apoptosis.
• Butylidenephthalide
• cancer stem cell
• high grade serous ovarian cancer

Hepatocellular carcinoma (HCC) is the second and sixth leading cause of cancer death in men and woman in 185 countries statistics, respectively. n-Butylidenephthalide (BP) has shown anti-HCC activity, but it also has an unstable structure that decreases its potential antitumor activity. The aim of this study was to investigate the cell uptake, activity protection, and antitumor mechanism of BP encapsulated in the novel liposome LPPC in HCC cells. BP/LPPC exhibited higher cell uptake and cytotoxicity than BP alone, and combined with clinical drug etoposide (VP-16), BP/LPPC showed a synergistic effect against HCC cells. Additionally, BP/LPPC increased cell cycle regulators (p53, p-p53, and p21) and decreased cell cycle-related proteins (Rb, p-Rb, CDK4, and cyclin D1), leading to cell cycle arrest at the G₀/G₁ phase in HCC cells. BP/LPPC induced cell apoptosis through activation of both the extrinsic (Fas-L and Caspase-8) and intrinsic (Bax and Caspase-9) apoptosis pathways and activated the caspase cascade to trigger HCC cell death. In conclusion, the LPPC complex improved the antitumor activity of BP in terms of cytotoxicity, cell cycle regulation and cell apoptosis, and BP/LPPC synergistically inhibited cell growth during combination treatment with VP-16 in HCC cells. Therefore, BP/LPPC is potentially a good candidate for clinical drug development or for use as an adjuvant for clinical drugs as a combination therapy for hepatocellular carcinoma.

• cancer
• nuclear receptor
• nuclear translocation
• cell signaling
• apoptosis

• Apoptosis
• Humans
• Neoplasms/genetics
• Orphan Nuclear Receptors/metabolism
• Signal Transduction
• Transcription Factors/metabolism

• P30 ES023512 NIEHS NIH HHS
• P30 ES029067 NIEHS NIH HHS
• T32 ES026568 NIEHS NIH HHS

• Cell apoptosis
• Cell cycle
• Polycationic liposome containing PEI and polyethylene glycol complex (LPPC)
• Synergistic effect
• n-Butylidenephthalide (BP)

• Cell apoptosis
• Cell cycle
• Leukemia
• Polycationic liposome containing PEI and polyethylene glycol complex (LPPC)
• n-Butylidenephthalide (BP)

• Chinese herbal medicine
• Hepatocellular carcinoma
• Molecular mechanism
• Network pharmacology
• Traditional Chinese medicine

Colorectal cancer (CRC) is the third most common type of cancer and the second most common cause of cancer-related death in the world. N-Butylidenephthalide (BP), a natural compound, inhibits several cancers, such as hepatoma, brain tumor and colon cancer. However, due to the unstable structure, the activity of BP is quickly lost after dissolution in an aqueous solution. A polycationic liposomal polyethylenimine and polyethylene glycol complex (LPPC), a new drug carrier, encapsulates both hydrophobic and hydrophilic compounds, maintains the activity of the compound, and increases uptake of cancer cells. The purpose of this study is to investigate the antitumor effects and protection of BP encapsulated in LPPC in CRC cells. The LPPC encapsulation protected BP activity, increased the cytotoxicity of BP and enhanced cell uptake through clathrin-mediated endocytosis. Moreover, the BP/LPPC-regulated the expression of the p21 protein and cell cycle-related proteins (CDK4, Cyclin B1 and Cyclin D1), resulting in an increase in the population of cells in the G₀/G₁ and subG₁ phases. BP/LPPC induced cell apoptosis by activating the extrinsic (Fas, Fas-L and Caspase-8) and intrinsic (Bax and Caspase-9) apoptosis pathways. Additionally, BP/LPPC combined with 5-FU synergistically inhibited the growth of HT-29 cells. In conclusion, LPPC enhanced the antitumor activity and cellular uptake of BP, and the BP/LPPC complex induced cell cycle arrest and apoptosis, thereby causing death. These findings suggest the putative use of BP/LPPC as an adjuvant cytotoxic agent for colorectal cancer.

• LPPC nanoparticle
• N-butylidenephthalide
• antitumor
• colorectal cancer
• cytotoxicity

• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Cycle Checkpoints/drug effects
• Cell Proliferation/drug effects
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/pathology
• HT29 Cells
• Humans
• Liposomes/chemistry
• Liposomes/pharmacology
• Phthalic Anhydrides/chemistry
• Phthalic Anhydrides/pharmacology

n-Butylidenephthalide (BP) has anti-tumor effects on glioblastoma. However, the limitation of BP for clinical application is its unstable structure. A polycationic liposomal polyethylenimine (PEI) and polyethylene glycol (PEG) complex (LPPC) has been developed to encapsulate BP for drug structure protection. The purpose of this study was to investigate the anti-cancer effects of the BP/LPPC complex on glioblastoma in vitro and in vivo.

DBTRG-05MG tumor bearing xenograft mice were treated with BP and BP/LPPC and then their tumor sizes, survival, drug biodistribution were measured. RG2 tumor bearing F344 rats also treated with BP and BP/LPPC and then their tumor sizes by magnetic resonance imaging for evaluation blood–brain barrier (BBB) across and drug therapeutic effects. After treated with BP/LPPC in vitro, cell uptake, cell cycle and apoptotic regulators were analyzed for evaluation the therapeutic mechanism.

In athymic mice, BP/LPPC could efficiently suppress tumor growth and prolong survival. In F334 rats, BP/LPPC crossed the BBB and led to tumor shrinkage. BP/LPPC promoted cell cycle arrest at the G₀/G₁ phase and triggered the extrinsic and intrinsic cell apoptosis pathways resulting cell death. BP/LPPC also efficiently suppressed VEGF, VEGFR1, VEGFR2, MMP2 and MMP9 expression.

BP/LPPC was rapidly and efficiently transported to the tumor area across the BBB and induced cell apoptosis, anti-angiogenetic and anti-metastatic effects in vitro and in vivo.

• blood–brain barrier
• drug delivery
• glioblastoma
• n-butylidenephthalide

Due to a lack of evidence from large-scale epidemiological studies by far on this issue, whether there is a link between Angelica sinensis exposure and breast cancer risk remained inconclusive.

We conducted a population-based case-control study using Taiwan’s National Health Insurance claim data, in which all breast cancer patients newly diagnosed between 2005 and 2008 were employed as the case group (n = 34,262) and a random sample of non-breast cancer individuals selected from 1-million beneficiaries registered in 2005 was served as the control group. For fair comparability, we employed the time density sampling method to select controls who were matched to case on date of breast cancer diagnosis and age with a case/control ratio of 1/3 (n = 102,786).

We found that the use of Angelica sinensis presents a weakly but significantly protective effect on breast cancer (adjusted odds ratio (aOR) 0.95, 95% confidence interval (CI) 0.93–0.98), with a significant dose-gradient relationship. We also noted a stronger association with breast cancer with initial use of Angelica sinensis at a longer time before breast cancer diagnosis, and found that the seemingly protective effect of Angelica sinensis was more obvious among women who had initial use at 47–55 years (aOR 0.93, 95% CI 0.88–0.98).

This population-based case-control study revealed that exposure to Angelica sinensis showed a weakly but significantly protective effect on breast cancer risk, which could ease people’s concern over the potential carcinogenic effect from exposure to Angelica sinensis.

•

Angelica sinensis was associated with a weakly protective effect on breast cancer.

• Angelica sinensis
• Breast cancer
• CI, confidence interval
• Herbal medicine
• ICD-9-CM, International Classification of Disease 9th version Clinical Modification
• NHIRD, national health insurance research database
• OR, odds ratio
• Phytomedicine
• TCM, traditional Chinese medicine
• Traditional Chinese medicine
• aOR, adjusted odds ratio

Oral submucous fibrosis (OSF) is characterized by abnormal collagen deposition. It is a precancerous disorder and transforms into a malignant tumor in 1.5–15% of all cases. Symptoms include submucous fibrosis, ulceration, xerostomia, a burning sensation, and restricted mouth opening. All of these greatly interfere with patient quality of life. The present review introduces OSF from a molecular perspective and summarizes what is known about its underlying mechanisms, diagnostic biomarkers, and therapeutic interventions. In addition to the aggressive treatment of OSF, its prevention is also important. Future research should, therefore, focus on improving the oral health literacy of the patients susceptible to OSF.

• collagen deposition
• diagnostic biomarkers
• oral submucous fibrosis (OSF)
• precancerous disorder
• therapeutic interventions
• underlying mechanisms

• -Butylidenephthalide
• anticancer
• drug delivery
• iron oxide magnetic nanoparticles
• riboflavin

Advanced melanoma can metastasize to distal organs from the skin and yield an aggressive disease and poor prognosis even after treatment with chemotherapeutic agents. The compound n-Butylidenephthalide (BP) is isolated from Angelica sinensis, which is used to treat anemia and gynecological dysfunction in traditional Chinese medicine. Studies have indicated that BP can inhibit cancers, including brain, lung, prostate, liver, and colon cancers. However, because BP is a natural hydrophobic compound, it is quickly metabolized by the liver within 24 h, and thus has limited potential for development in cancer therapy. This study investigated the anticancer mechanisms of BP through encapsulation with a novel polycationic liposome containing polyethylenimine (PEI) and polyethylene glycol complex (LPPC) in melanoma cells. The results demonstrated that BP/LPPC had higher cytotoxicity than BP alone and induced cell cycle arrest at the G₀/G₁ phase in B16/F10 melanoma cells. The BP/LPPC-treated cell indicated an increase in subG₁ percentage and TUNEL positive apoptotic morphology through induction of extrinsic and intrinsic apoptosis pathways. The combination of BP and LPPC and clinical drug 5-Fluorouracil had a greater synergistic inhibition effect than did a single drug. Moreover, LPPC encapsulation improved the uptake of BP values through enhancement of cell endocytosis and maintained BP cytotoxicity activity within 24 h. In conclusion, BP/LPPC can inhibit growth of melanoma cells and induce cell arrest and apoptosis, indicating that BP/LPPC has great potential for development of melanoma therapy agents.

• melanoma
• n-Butylidenephthalide
• polycationic liposome containing PEI and polyethylene glycol complex (LPPC)

• Chinese herbal medicine
• Colorectal cancer
• Machine learning
• Neural network analysis
• Traditional Chinese medicine

• arecoline
• butylidenephthalide
• myofibroblast
• oral submucous fibrosis

• Angelica sinensis
• Cell Movement/drug effects
• Cell Transdifferentiation/drug effects
• Cells, Cultured
• Down-Regulation/drug effects
• Fibroblasts/drug effects
• Fibroblasts/pathology
• Humans
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/physiology
• Mouth Mucosa/drug effects
• Mouth Mucosa/pathology
• Myofibroblasts/drug effects
• Myofibroblasts/physiology
• Oral Submucous Fibrosis/pathology
• Phthalic Anhydrides/pharmacology
• Precancerous Conditions/pathology

• Non-small cell lung cancer
• Radiosensitivity
• Sanyang Xuedai (SYKT)
• iNOS/NO

• Apoptosis/drug effects
• Apoptosis/radiation effects
• CDC2 Protein Kinase/metabolism
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/radiotherapy
• Cell Cycle Checkpoints/drug effects
• Cell Cycle Checkpoints/radiation effects
• Cell Line, Tumor
• Combined Modality Therapy
• Cyclin B1/metabolism
• Drugs, Chinese Herbal/pharmacology
• Drugs, Chinese Herbal/therapeutic use
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/metabolism
• Lung Neoplasms/radiotherapy
• Nitric Oxide/biosynthesis
• Nitric Oxide Synthase Type II/metabolism
• Radiation Tolerance/drug effects
• Radiation Tolerance/radiation effects
• Radiation, Ionizing
• Radiation-Sensitizing Agents/pharmacology
• Radiation-Sensitizing Agents/therapeutic use

Dysregulated expression of long non-coding RNAs (lncRNAs) has been reported in the pathogenesis and progression of multiple cancers, including hepatocellular carcinoma (HCC). LncRNA CTD-2547G23.4 is a novel lncRNA, and its role in HCC is still unknown. Here, we aimed to clarify the expression pattern and clinical value of CTD-2547G23.4 and to investigate the prospective regulatory mechanism via bioinformatics analysis in HCC.

To identify differentially expressed lncRNAs in HCC, we downloaded RNA-Seq data for HCC and adjacent non-tumour tissues via The Cancer Genome Atlas (TCGA). CTD-2547G23.4 was selected by using the R language and receiver operating characteristic curve analysis. Furthermore, we validated the differential expression of CTD-2547G23.4 via Gene Expression Omnibus (GEO), ArrayExpress, Oncomine databases and quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between the CTD-2547G23.4 level and clinic pathological parameters was also assessed. To further probe the role of CTD-2547G23.4 in HCC cell cycle, lentivirus-mediated small interfering RNA was applied to silence CTD-2547G23.4 expression in Huh-7 cell line. In addition, the related genes of CTD-2547G23.4 gathered from The Atlas of Noncoding RNAs in Cancer (TANRIC) database and Multi Experiment Matrix (MEM) were assessed with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes, Protein Analysis Through Evolutionary Relationships and protein–protein interaction (PPI) networks.

CTD-2547G23.4 expression was remarkably higher in 370 HCC tissue samples than that in adjacent non-tumour liver tissues (48.762 ± 27.270 vs. 14.511 ± 8.341, P < 0.001) from TCGA dataset. The relative expression level of CTD-2547G23.4 in HCC was consistently higher than that in adjacent non-cancerous tissues (2.464 ± 0.833 vs. 1.813 ± 0.784, P = 0.001) as assessed by real time RT-qPCR. The area under the curve of the summary receiver operating characteristic curve was 0.8720 based on TCGA, qRT-PCR and GEO data. Further analysis indicated that the increased expression levels of CTD-2547G23.4 were associated with the neoplasm histologic grade and vascular tumour cell type. The expression of CTD-2547G23.4 was significantly downregulated in CTD-2547G23.4 knockdown cells. Moreover, cell cycle analysis revealed that CTD-2547G23.4 depletion in Huh-7 cell line led to S phase arrest. Furthermore, 314 related genes identified by TANRIC and MEM databases were processed with a pathway analysis. The bioinformatics analysis indicated that CTD-2547G23.4 might play a key role in the progress of HCC through four hub genes, SRC, CREBBP, ADCY8 and PPARA.

Collectively, we put forward the hypothesis that the novel lncRNA CTD-2547G23.4 may act as an exceptional clinical index and promote the HCC tumourigenesis and progression via various related genes.

The online version of this article (10.1186/s12935-018-0566-3) contains supplementary material, which is available to authorized users.

• Bioinformatic analysis
• CTD-2547G23.4
• GEO
• Hepatocellular carcinoma (HCC)
• TCGA
• qRT-PCR

Glioblastoma multiforme (GBM) is one of the most aggressive and malignant forms of brain tumors. Despite recent advances in operative and postoperative treatments, it is almost impossible to perform complete resection of these tumors owing to their invasive and diffuse nature. Several natural plant-derived products, however, have been demonstrated to have promising therapeutic effects, such that they may serve as resources for anticancer drug discovery. The therapeutic effects of one such plant product, n-butylidenephthalide (BP), are wide-ranging in nature, including impacts on cancer cell apoptosis, cell cycle arrest, and cancer cell senescence. The compound also exhibits a relatively high level of penetration through the blood-brain barrier (BBB). Taken together, its actions have been shown to have anti-proliferative, anti-chemoresistance, anti-invasion, anti-migration, and anti-dissemination effects against GBM. In addition, a local drug delivery system for the subcutaneous and intracranial implantation of BP wafers that significantly reduce tumor size in xenograft models, as well as orthotopic and spontaneous brain tumors in animal models, has been developed. Isochaihulactone (ICL), another kind of plant product, possesses a broad spectrum of pharmacological activities, including impacts on cancer cell apoptosis and cell cycle arrest, as well as anti-proliferative and anti-chemoresistance effects. Furthermore, these actions have been specifically shown to have cancer-fighting effects on GBM. In short, the results of various studies reviewed herein have provided substantial evidence indicating that BP and ICH are promising novel anticancer compounds with good potential for clinical applications.

• O-6-methylguanine-DNA methyltransferase (MGMT)
• blood-brain barrier (BBB)
• glioblastoma multiforme (GBM)
• isochaihulactone (ICL)
• n-butylidenephthalide (BP)
• protein kinase C (PKC)
• retinoblastoma protein (Rb)
• temozolomide (TMZ)

N-butylidenephthalide (BP) isolated from Radix Angelica Sinensis (Danggui) exhibits anti-tumorigenic effect in various cancer cells both in vivo and in vitro. The effect of BP in bladder cancer treatment is still unclear and worth for further investigate.

Changes of patients with bladder cancer after Angelica Sinensis exposure were evaluated by analysis of Taiwan’s National Health Insurance Research Database (NHIRD) database. The anti-proliferative effect of BP on human bladder cancer cells was investigated and their cell cycle profiles after BP treatment were determined by flow cytometry. BP-induced apoptosis was demonstrated by Annexin V-FITC staining and TUNEL assay, while the expressions of apoptosis-related proteins were determined by western blot. The migration inhibitory effect of BP on human bladder cancer cells were shown by trans-well and wound healing assays. Tumor model in NOD-SCID mice were induced by injection of BFTC human bladder cancer cells.

The correlation of taking Angelica sinensis and the incidence of bladder cancer in NHIRD imply that this herbal product is worth for further investigation. BP caused bladder cancer cell death in a time- and dose- dependent manner and induced apoptosis via the activation of caspase-9 and caspase-3. BP also suppressed the migration of bladder cancer cells as revealed by the trans-well and wound healing assays. Up-regulation of E-cadherin and down-regulation of N-cadherin were evidenced by real-time RT-PCR analysis after BP treatment in vitro. Besides, in combination with BP, the sensitivity of these bladder cancer cells to cisplatin increased significantly. BP also suppressed BFTC xenograft tumor growth, and caused 44.2% reduction of tumor volume after treatment for 26 days.

BP caused bladder cancer cell death through activation of mitochondria-intrinsic pathway. BP also suppressed the migration and invasion of these cells, probably by modulating EMT-related genes. Furthermore, combination therapy of BP with a lower dose of cisplatin significantly inhibited the growth of these bladder cancer cell lines. The incidence of bladder cancer decreased in patients who were exposed to Angelica sinensis, suggesting that BP could serve as a potential adjuvant in bladder cancer therapy regimen.

The online version of this article (10.1186/s12906-017-2034-3) contains supplementary material, which is available to authorized users.

• Apoptosis
• Bladder cancer
• Combination therapy
• Metastasis
• NHIRD
• n-butylidenephthalide

• Adipose-derived stem cells
• Arrhythmia
• Butylidenephthalide
• Glycogen synthase kinase-3β
• Preconditioned
• Sympathetic hyperinnervation

• Chinese herbal compound
• hepatocellular carcinoma
• phytopharmacology
• prevention
• treatment

• Antineoplastic Agents/chemistry
• Antineoplastic Agents/therapeutic use
• Apoptosis
• Autophagy
• Carcinoma, Hepatocellular/drug therapy
• Cell Cycle/drug effects
• Cell Proliferation/drug effects
• Cellular Senescence
• Drugs, Chinese Herbal/chemistry
• Drugs, Chinese Herbal/therapeutic use
• Epithelial-Mesenchymal Transition/drug effects
• Humans
• Liver Neoplasms/drug therapy

Butylidenephthalide (Bdph), a main constituent of Ligusticum chuanxiong Hort., was reported to have selective antianginal effect without changing blood pressure in conscious rat. Recently, we have observed that Bdph antagonized cromakalim, an ATP-dependent K⁺ channel opener, in guinea-pig trachea. Thus, we were interested in investigating whether Bdph at the dose without changing blood pressure antagonized cromakalim-induced systolic pressure reduction in conscious rats.

Systolic arterial pressures of conscious rats were determined by using the indirect tail-cuff method.

Bdph (30 mg/kg, i.p.) did not affect baseline systolic pressure in conscious normotensive and spontaneous hypertensive rats. Bdph (30 mg/kg, i.p.) also did not affect log dose–response curves of prazosin, clonidine and Bay K 8644, a Ca²⁺ channel activator, in normotensive rats. However, Bdph (30 mg/kg, i.p.) similar to 4-aminopyridine (4-AP, 0.4 mg/kg, i.p.), a K⁺ channel blocker, non-parallelly but surmountably, and partially similar to glibenclamide (GBC, 10 mg/kg, i.v.), an ATP-sensitive K⁺ channel blocker, surmountably but not parallelly rightward shifted the log dose-systolic pressure reduction curve of cromakalim, an ATP-sensitive K⁺ channel opener, in normotensive rats, respectively.

The antagonistic effect of Bdph against cromakalim was similar to that of 4-AP, a K+ channel blocker of Kv1 family, and partially similar to that of GBC, an ATP-sensitive K+ channel blocker. Thus, Bdph may be a kind of K+ channel blockers, which have been reviewed to have a potential clinical use for Alzheimer disease. Indeed, Bdph has also been reported to reverse the deficits of inhibitory avoidance performance and improve memory in rats. Recently, 4-AP was reported to treat Episodic ataxia type 2 (EA2) which is a form of hereditary neurological disorder. Consistently, Bdph was recently reported to have antihyperglycemic activity in mice, since GBC is a powerful oral hypoglycemic drug.

Bdph similar to 4-AP and partially similar to GBC may block K_v1 family and ATP-sensitive K⁺ channels in conscious normotensive rats.

The natural compound n-butylidenephthalide (BP) can pass through the blood–brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo.

The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery.

To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC). Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections.

When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than that of free BP (~4.5- to 8.5-fold). This increased cytotoxic activity of BP/LPPC is attributable to its rapid transport across the cell membrane. In an animal study, a subcutaneously xenografted glioblastoma multiforme mouse that was treated with BP by intratumoral and intravenous administration showed inhibited tumor growth. The same dose of BP/LPPC was significantly more effective in terms of tumor inhibition.

LPPC encapsulation technology is able to protect BP’s structural stability and enhance its antitumor effects, thus providing a better tool for use in cancer therapy.

• antitumor
• glioblastoma multiforme
• lipo-PEG-PEI complex
• n-butylidenephthalide

Traditional Chinese medicine (TCM) has played a positive role in the management of hepatocarcinoma. Hepatocarcinoma patients may present Qi-stagnation, damp-heat, blood stasis, Qi-deficiency, Yin-deficiency and other TCM syndromes (Zheng). Modern treatments such as surgery, transarterial chemoembolization (TACE) and high intensity focus ultrasound treatment would influence the manifestation of TCM syndromes. Herbs with traditional efficacy of tonifying Qi, blood and Yin, soothing liver-Qi stagnation, clearing heat and detoxifying and dissolving stasis, have been demonstrated to be potent to prevent hepatocarcinogenesis. TCM has been widely used in all aspects of integrative therapy in hepatocarcinoma, including surgical resection, liver transplantation, TACE, local ablative therapies and even as monotherapy for middle-advanced stage hepatocarcinoma. Clinical practices have confirmed that TCM is effective to alleviate clinical symptoms, improve quality of life and immune function, prevent recurrence and metastasis, delay tumor progression, and prolong survival time in hepatocarcinoma patients. The effective mechanism of TCM against hepatocarcinoma is related to inducing apoptosis, autophagy, anoikis and cell senescence, arresting cell cycle, regulating immune function, inhibiting metastasis and angiogenesis, reversing drug resistance and enhancing effects of chemotherapy. Along with the progress of research in this field, TCM will contribute more to the prevention and treatment of hepatocarcinoma.

• Hepatocarcinoma
• Traditional Chinese medicine
• Prevention
• Treatment
• Traditional Chinese medicine syndrome (Zheng)
• Therapeutic principle
• Chinese herbal formula
• Chinese herb

• Agonist
• Antagonist
• Nuclear receptor
• Pharmacology
• Traditional Chinese medicine

• Drugs, Chinese Herbal/pharmacology
• Gene Expression Regulation/drug effects
• Humans
• Medicine, Chinese Traditional
• Phytoestrogens/pharmacology
• Receptors, Cytoplasmic and Nuclear/metabolism
• Receptors, Steroid/metabolism

• Chemical constituents
• Clinical applications
• Interactions
• Pharmacological effect
• Radix Angelica Sinensis
• Toxicity

• Angelica sinensis/chemistry
• Animals
• Antiparkinson Agents/pharmacology
• Caenorhabditis elegans/drug effects
• Caenorhabditis elegans/genetics
• Caenorhabditis elegans/metabolism
• Caenorhabditis elegans Proteins/agonists
• Caenorhabditis elegans Proteins/antagonists & inhibitors
• Caenorhabditis elegans Proteins/genetics
• Caenorhabditis elegans Proteins/metabolism
• Disease Models, Animal
• Dopamine/metabolism
• Dopaminergic Neurons/drug effects
• Dopaminergic Neurons/metabolism
• Dopaminergic Neurons/pathology
• Drugs, Chinese Herbal/chemistry
• Gene Expression Regulation
• Humans
• Longevity/drug effects
• Muscle Cells/drug effects
• Muscle Cells/metabolism
• Muscle Cells/pathology
• Oxidopamine/pharmacology
• Parkinson Disease/drug therapy
• Parkinson Disease/genetics
• Parkinson Disease/metabolism
• Parkinson Disease/pathology
• Phthalic Anhydrides/pharmacology
• Proteasome Endopeptidase Complex/drug effects
• Proteasome Endopeptidase Complex/genetics
• Proteasome Endopeptidase Complex/metabolism
• Repressor Proteins/antagonists & inhibitors
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• Transgenes
• alpha-Synuclein/antagonists & inhibitors
• alpha-Synuclein/biosynthesis
• alpha-Synuclein/genetics

• Cancer
• Cell death
• Cell survival
• Clinical therapy
• Signal pathway
• TR3/Nur77/NGFI-B

In 2006, induced pluripotent stem (iPS) cells were generated from somatic cells by introducing Oct4, Sox2, c-Myc and Klf4. The original process was inefficient; maintaining the pluripotency of embryonic stem (ES) and iPS cell cultures required an expensive reagent–leukemia induced factor (LIF). Our goal is to find a pure compound that not only maintains ES and iPS cell pluripotency, but also increases iPS cell generation efficiency. From 15 candidate compounds we determined that 10 µg/ml n-Butylidenephthalide (BP), an Angelica sinensis extract, triggers the up-regulation of Oct4 and Sox2 gene expression levels in MEF cells. We used ES and iPS cells treated with different concentrations of BP to test its usefulness for maintaining stem cell pluripotency. Results indicate higher expression levels of several stem cell markers in BP-treated ES and iPS cells compared to controls that did not contain LIF, including alkaline phosphatase, SSEA1, and Nanog. Embryoid body formation and differentiation results confirm that BP containing medium culture was capable of maintaining ES cell pluripotency after six time passage. Microarray analysis data identified PPAR, ECM, and Jak-Stat signaling as the top three deregulated pathways. We subsequently determined that phosphorylated Jak2 and phosphorylated Stat3 protein levels increased following BP treatment and suppressed with the Jak2 inhibitor, AG490. The gene expression levels of cytokines associated with the Jak2-Stat3 pathway were also up-regulated. Last, we used pou5f1-GFP MEF cells to test iPS generation efficiency following BP treatment. Our data demonstrate the ability of BP to maintain stem cell pluripotency via the Jak2-Stat3 pathway by inducing cytokine expression levels, at the same time improving iPS generation efficiency.

• Animals
• Biomarkers/metabolism
• Cell Differentiation/drug effects
• Cell Differentiation/genetics
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Cell Survival/genetics
• Cytokines/metabolism
• Databases, Genetic
• Embryo, Mammalian/cytology
• Embryoid Bodies/cytology
• Embryoid Bodies/drug effects
• Embryoid Bodies/metabolism
• Fibroblasts/cytology
• Fibroblasts/drug effects
• Fibroblasts/metabolism
• Gene Expression Regulation/drug effects
• Induced Pluripotent Stem Cells/cytology
• Induced Pluripotent Stem Cells/drug effects
• Induced Pluripotent Stem Cells/metabolism
• Janus Kinase 2/metabolism
• Kruppel-Like Factor 4
• Mice
• Octamer Transcription Factor-3/genetics
• Octamer Transcription Factor-3/metabolism
• Oligonucleotide Array Sequence Analysis
• Phosphorylation/drug effects
• Phthalic Anhydrides/pharmacology
• Pluripotent Stem Cells/cytology
• Pluripotent Stem Cells/drug effects
• Pluripotent Stem Cells/enzymology
• SOXB1 Transcription Factors/genetics
• SOXB1 Transcription Factors/metabolism
• STAT3 Transcription Factor/metabolism
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Staining and Labeling

• Animals
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p16/metabolism
• Cyclin-Dependent Kinase Inhibitor p21/metabolism
• Cyclin-Dependent Kinase Inhibitor p27/metabolism
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress/drug effects
• Endoribonucleases/antagonists & inhibitors
• Endoribonucleases/genetics
• Endoribonucleases/metabolism
• G1 Phase Cell Cycle Checkpoints
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Mitogen-Activated Protein Kinase 8/antagonists & inhibitors
• Mitogen-Activated Protein Kinase 8/genetics
• Mitogen-Activated Protein Kinase 8/metabolism
• Mitogen-Activated Protein Kinase 9/antagonists & inhibitors
• Mitogen-Activated Protein Kinase 9/genetics
• Mitogen-Activated Protein Kinase 9/metabolism
• Phthalic Anhydrides/pharmacology
• Prostatic Neoplasms
• Protein Serine-Threonine Kinases/antagonists & inhibitors
• Protein Serine-Threonine Kinases/genetics
• Protein Serine-Threonine Kinases/metabolism
• RNA Interference
• RNA, Small Interfering/metabolism
• Signal Transduction
• Transcription Factor CHOP/antagonists & inhibitors
• Transcription Factor CHOP/genetics
• Transcription Factor CHOP/metabolism
• Transplantation, Heterologous

• Animals
• Apoptosis/drug effects
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Blotting, Western
• Cell Line, Tumor
• Cell Nucleus/drug effects
• Cell Nucleus/metabolism
• Cell Proliferation/drug effects
• Gene Expression Profiling
• Humans
• Immunoenzyme Techniques
• Indoles/chemistry
• Indoles/pharmacology
• Male
• Mice
• Mice, Nude
• Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
• Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
• Oligonucleotide Array Sequence Analysis
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/pathology
• RNA, Messenger/genetics
• Reverse Transcriptase Polymerase Chain Reaction
• Xenograft Model Antitumor Assays

• R01 CA124998 NCI NIH HHS
• R01CA124998 NCI NIH HHS