Pharmacological activity and clinical application analysis of traditional Chinese medicine ginger from the perspective of one source and multiple substances.

All types of ginger have common fundamental components, although they possess distinct strengths and inclinations when it comes to effectiveness and medicinal applications. Fresh ginger possesses the ability to effectively stimulate movement within the body, alleviate the act of vomiting, induce sweating, and provide relief for external syndromes. Dried ginger possesses both defensive and stimulant characteristics, which effectively raise the internal temperature and enhance the Yang energy. Fresh ginger is more hydrating than dried ginger, highly skilled at heating the Middle-jiao, alleviating pain, halting bleeding, and managing diarrhea. Dried ginger possesses the ability to alleviate coldness when consumed in a heated form, as well as to alleviate diarrhea when consumed in a heated form. It thrives in warm conditions and has a tendency to revert back to its warm nature. The moisture content of baked ginger is inferior to that of dried ginger, but it is highly effective in alleviating pain, bleeding, and diarrhea by warming the Middle-jiao. Ginger charcoal and stir-fried charcoal, produced through carbonization, have excellent heat retention properties and are effective in warming meridians and stopping bleeding. The potency and ability to spread of roasted ginger is less intense compared to fresh ginger, and its moisture content is not as low as that of dried ginger. The medicinal characteristics of this substance are gentle, making it beneficial for alleviating vomiting in patients who are physically frail. Its primary mode of action is on the Middle-jiao. Nevertheless, the main chemical compositions of various traditional Chinese medicines are nearly identical due to their shared base element. Ginger, in particular, possesses a range of pharmacological activities including antioxidant, anti-inflammatory, anti-tumor, anti-bacterial, and anticoagulant properties. However, modern pharmacological research has not fully acknowledged the clinical medicinal value of ginger and consequently, fails to provide accurate guidance for clinical medication. This situation has a negative impact on the contemporary advancement of traditional Chinese medicine (TCM). The research on modernizing ginger is conducted by analyzing and considering the prospects. It is based on Traditional Chinese Medicine (TCM) theory and incorporates the comprehensive perspective of TCM philosophy. In order to modernize ginger, it is essential to have a proper knowledge of the concepts of "recognizing nature by efficacy, homology, and mutual expression of nature and efficacy" and "rationally utilizing modern drug research technology". By applying these principles, we can construct a bridge towards the advancement of ginger.

Par3L, a polarity protein, promotes M1 macrophage polarization and aggravates atherosclerosis in mice via p65 and ERK activation.

Proinflammatory M1 macrophages are critical for the progression of atherosclerosis. The Par3-like protein (Par3L) is a homolog of the Par3 family involved in cell polarity establishment. Par3L has been shown to maintain the stemness of mammary stem cells and promote the survival of colorectal cancer cells. In this study, we investigated the roles of the polar protein Par3L in M1 macrophage polarization and atherosclerosis. To induce atherosclerosis, Apoe-/- mice were fed with an atherosclerotic Western diet for 8 or 16 weeks. We showed that Par3L expression was significantly increased in human and mouse atherosclerotic plaques. In primary mouse macrophages, oxidized low-density lipoprotein (oxLDL, 50 µg/mL) time-dependently increased Par3L expression. In Apoe-/- mice, adenovirus-mediated Par3L overexpression aggravated atherosclerotic plaque formation accompanied by increased M1 macrophages in atherosclerotic plaques and bone marrow. In mouse bone marrow-derived macrophages (BMDMs) or peritoneal macrophages (PMs), we revealed that Par3L overexpression promoted LPS and IFNγ-induced M1 macrophage polarization by activating p65 and extracellular signal-regulated kinase (ERK) rather than p38 and JNK signaling. Our results uncover a previously unidentified role for the polarity protein Par3L in aggravating atherosclerosis and favoring M1 macrophage polarization, suggesting that Par3L may serve as a potential therapeutic target for atherosclerosis.

Cocrystallization of Gefitinib Potentiate Single-Dose Oral Administration for Lung Tumor Eradication via Unbalancing the DNA Damage/Repair.

Gefitinib (GEF) is a clinical medication for the treatment of lung cancer targeting the epidermal growth factor receptor (EGFR). However, its efficacy is remarkably limited by low solubility and dissolution rates. In this study, two cocrystals of GEF with co-formers were successfully synthesized using the recrystallization method characterized via Powder X-ray Diffraction, Fourier Transform Infrared Spectroscopy, and 2D Nuclear Overhauser Effect Spectroscopy. The solubility and dissolution rates of cocrystals were found to be two times higher than those of free GEF. In vitro cytotoxicity studies revealed that the cocrystals enhanced the inhibition of cell proliferation and apoptosis in A549 and H1299 cells compared to free GEF. In mouse models, GEF@TSBO demonstrated targeted, safe, and effective antitumor activity with only one-dose administration. Mechanistically, the GEF cocrystals were shown to increase the cellular levels of damaged DNA, while potentially downregulating PARP, thereby impairing the DNA repair machinery and leading to an imbalance between DNA damage and restoration. These findings suggest that the cocrystallization of GEF could serve as a promising adjunct to significantly enhance the physicochemical and biopharmaceutical performance for lung cancer treatment, providing a facial strategy to improve GEF anticancer efficiency with high bioavailability that can be orally administrated with only one dose.

Fibronectin leucine-rich transmembrane protein 2 drives monocyte differentiation into macrophages via the UNC5B-Akt/mTOR axis.

Upon migrating into the tissues, hematopoietic stem cell (HSC)-derived monocytes differentiate into macrophages, playing a crucial role in determining innate immune responses towards external pathogens and internal stimuli. However, the regulatory mechanisms underlying monocyte-to-macrophage differentiation remain largely unexplored. Here we divulge a previously uncharacterized but essential role for an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), in monocyte-to-macrophage maturation. FLRT2 is almost undetectable in human monocytic cell lines, human peripheral blood mononuclear cells (PBMCs), and mouse primary monocytes but significantly increases in fully differentiated macrophages. Myeloid-specific deletion of FLRT2 (Flrt2ΔMyel ) contributes to decreased peritoneal monocyte-to-macrophage generation in mice in vivo, accompanied by impaired macrophage functions. Gain- and loss-of-function studies support the promoting effect of FLRT2 on THP-1 cell and human PBMC differentiation into macrophages. Mechanistically, FLRT2 directly interacts with Unc-5 netrin receptor B (UNC5B) via its extracellular domain (ECD) and activates Akt/mTOR signaling. In vivo administration of mTOR agonist MYH1485 reverses the impaired phenotypes observed in Flrt2ΔMyel mice. Together, these results identify FLRT2 as a novel pivotal endogenous regulator of monocyte differentiation into macrophages. Targeting the FLRT2/UNC5B-Akt/mTOR axis may provide potential therapeutic strategies directly relevant to human diseases associated with aberrant monocyte/macrophage differentiation.

Kazinol B protects H9c2 cardiomyocytes from hypoxia/reoxygenation-induced cardiac injury by modulating the AKT/AMPK/Nrf2 signalling pathway.

CONTEXT: Kazinol B (KB), an isoprenylated flavan derived from Broussonetia kazinoki Sieb. (Moraceae) root, has long been used in folk medicine. OBJECTIVE: This study examines the protective effects of KB and its underlying mechanisms in hypoxia and reoxygenation (H/R)-induced cardiac injury in H9c2 rat cardiac myoblasts. MATERIALS AND METHODS: H9c2 cells were incubated with various concentrations of KB (0, 0.3, 1, 3, 10 and 30 µM) for 2 h and then subjected to H/R insults. The protective effects of KB and its underlying mechanisms were explored. RESULTS: KB significantly elevated cell viability (1 µM, 1.21-fold; 3 µM, 1.36-fold, and 10 µM, 1.47-fold) and suppressed LDH release (1 µM, 0.77-fold; 3 µM, 0.68-fold, and 10 µM, 0.59-fold) in H/R-induced H9c2 cells. Further, 10 µM KB blocked apoptotic cascades, as shown by the Annexin-V/PI (0.41-fold), DNA fragmentation (0.51-fold), caspase-3 (0.52-fold), PARP activation (0.27-fold) and Bax/Bcl-2 expression (0.28-fold) assays. KB (10 µM) downregulated reactive oxygen species production (0.51-fold) and lipid peroxidation (0.48-fold); it upregulated the activities of GSH-Px (2.08-fold) and SOD (1.72-fold). KB (10 µM) induced Nrf2 nuclear accumulation (1.94-fold) and increased ARE promoter activity (2.15-fold), HO-1 expression (3.07-fold), AKT (3.07-fold) and AMPK (3.07-fold) phosphorylation. Nrf2 knockdown via using Nrf2 siRNA abrogated KB-mediated protective effects against H/R insults. Moreover, pharmacological inhibitors of AKT and AMPK also abrogated KB-induced Nrf2 activation and its protective function. DISCUSSION AND CONCLUSIONS: KB prevented H/R-induced cardiomyocyte injury via modulating the AKT and AMPK-mediated Nrf2 induction. KB might be a promising drug candidate for managing ischemic cardiac disorders.

Antiatherosclerotic effect of dehydrocorydaline on ApoE-/- mice: inhibition of macrophage inflammation.

Despite improvements in cardiovascular disease (CVD) outcomes by cholesterol-lowering statin therapy, the high rate of CVD is still a great concern worldwide. Dehydrocorydaline (DHC) is an alkaloidal compound isolated from the traditional Chinese herb Corydalis yanhusuo. Emerging evidence shows that DHC has anti-inflammatory and antithrombotic benefits, but whether DHC exerts any antiatherosclerotic effects remains unclear. Our study revealed that intraperitoneal (i.p.) injection of DHC in apolipoprotein E-deficient (ApoE-/-) mice not only inhibited atherosclerosis development but also improved aortic compliance and increased plaque stability. In addition, DHC attenuated systemic and vascular inflammation in ApoE-/- mice. As macrophage inflammation plays an essential role in the pathogenesis of atherosclerosis, we next examined the direct effects of DHC on bone marrow-derived macrophages (BMDMs) in vitro. Our RNA-seq data revealed that DHC dramatically decreased the levels of proinflammatory gene clusters. We verified that DHC significantly downregulated proinflammatory interleukin (IL)-1ß and IL-18 mRNA levels in a time- and concentration-dependent manner. Furthermore, DHC decreased lipopolysaccharide (LPS)-induced inflammation in BMDMs, as evidenced by the reduced protein levels of CD80, iNOS, NLRP3, IL-1ß, and IL-18. Importantly, DHC attenuated LPS-induced activation of p65 and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Thus, we conclude that DHC ameliorates atherosclerosis in ApoE-/- mice by inhibiting inflammation, likely by targeting macrophage p65- and ERK1/2-mediated pathways.

Curcumin prevents As3+-induced carcinogenesis through regulation of GSK3ß/Nrf2.

BACKGROUND: Arsenic (As3+) is a carcinogen with considerable environmental and occupational relevancy. Its mechanism of action and methods of prevention remain to be investigated. Previous studies have demonstrated that ROS is responsible for As3+-induced cell transformation, which is considered as the first stage of As3+ carcinogenesis. The NF-E2 p45-related factor-2 (Nrf2) signaling pathway regulates the cellular antioxidant response, and activation of Nrf2 has recently been shown to limit oxidative damage following exposure to As3+ METHODS AND RESULTS: In this study, molecular docking was used to virtually screen natural antioxidant chemical databases and identify molecules that interact with the ligand-binding site of Keap1 (PDB code 4L7B). The cell-based assays and molecular docking findings revealed that curcumin has the best inhibitory activity against Keap1-4L7B. Co-immunoprecipitation (Co-IP) results indicated that curcumin is a potent Keap1 Kelch domain-dependent Nrf2 activator that stabilizes Nrf2 by hindering its ubiquitination. The increased activation of Nrf2 and its target antioxidant genes by curcumin could significantly decrease As3+-generated ROS. Moreover, curcumin induced autophagy in As3+-treated BEAS-2B via inducing autophagy by the formation of a p62/LC-3 complex and increasing autophagic flux by promoting transcription factor EB (TFEB) and lysosome-associated membrane protein 1 (LAMP1) expression. Knockdown of Nrf2 abolished curcumin-induced autophagy and downregulated ROS. Further studies showed that inhibition of autophagosome and lysosome fusion with bafilomycin a1 (BafA1) could block curcumin and prevented As3+-induced cell transformation. These results demonstrated that curcumin prevents As3+-induced cell transformation by inducing autophagy via the activation of the Nrf2 signaling pathway in BEAS-2B cells. However, overexpression of Keap-1 showed a constitutively high level of Nrf2 in As3+-transformed BEAS-2B cells (AsT) is Keap1-independent regulation. Overexpression of Nrf2 in AsT demonstrated that curcumin increased ROS levels and induced cell apoptosis via the downregulation of Nrf2. Further studies showed that curcumin decreased the Nrf2 level in AsT by activating GSK-3ß to inhibit the activation of PI3K/AKT. Co-IP assay results showed that curcumin promoted the interaction of Nrf2 with the GSK-3ß/ß-TrCP axis and ubiquitin. Moreover, the inhibition of GSK-3ß reversed Nrf2 expression in curcumin-treated AsT, indicating that the decrease in Nrf2 is due to activation of the GSK-3ß/ß-TrCP ubiquitination pathway. Furthermore, in vitro and in vivo results showed that curcumin induced cell apoptosis, and had anti-angiogenesis and anti-tumorigenesis effects as a result of activating the GSK-3ß/ß-TrCP ubiquitination pathway and subsequent decrease in Nrf2. CONCLUSIONS: Taken together, in the first stage, curcumin activated Nrf2, decreased ROS, and induced autophagy in normal cells to prevent As3+-induced cell transformation. In the second stage, curcumin promoted ROS and apoptosis and inhibited angiogenesis via inhibition of constitutive expression of Nrf2 in AsT to prevent tumorigenesis. Our results suggest that antioxidant natural compounds such as curcumin can be evaluated as potential candidates for complementary therapies in the treatment of As3+-induced carcinogenesis.

Synergistic Therapy Using Doxorubicin-Loading and Nitric Oxide-Generating Hollow Prussian Blue Nanoparticles with Photoacoustic Imaging Potential Against Breast Cancer.

INTRODUCTION: Traditional antitumor chemotherapy faces great challenges, such as multi-drug resistance (MDR) and poor penetration into tumor tissues. The newly emerging nitric oxide (NO)-based gas therapy has been recognized to reduce MDR and has improved permeation into tumor tissue. METHODS: In this study, NO-generating prodrug sodium nitroprusside (SNP) was doped to hollow mesoporous Prussian blue (PB) nanoparticles to fabricate NO-generating nanoparticles (NO-PB), which was further loaded with doxorubicin (DOX). RESULTS: DOX loaded NO-PB (DOX-NO-PB) was released quicker at pH 6 compared with neutral pH, suggesting NO-PB may facilitate the release of loaded drug in acidic tumor tissue. The capacity of NO production by NO-PB was measured, and the results showed the presence of NO in the culture medium from 4T1 cells incubated with NO-PB and inside the cells. NP-PB could be detected by photoacoustic imaging (PAI) in tumor tissue in 4T1 tumor bearing mice, suggesting this nanoparticle may serve as contrast agent for the noninvasive diagnosis of tumor tissues. NO-PB suppressed the growth of tissues in 4T1 tumor bearing mice. DOX-NO-PB showed more potent anti-tumor effects in 4T1 cells and tumor bearing mice compared with free DOX and NO-PB alone, indicating that the combination of DOX and NO-PB exhibited synergistic effects on tumor suppression. CONCLUSION: This study provides a novel nanocarrier for gas therapy with additional PAI imaging capacity. This nanocarrier can be utilized for combination therapy of NO and chemotherapeutics which may serve as theranostic agents.

Pinocembrin-7-Methylether Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Neurotoxicity via Modulating Nrf2 Induction Through AKT and ERK Pathways.

The present study aimed to evaluate the neuroprotective effects and underlying mechanisms of pinocembrin-7-methylether (PME), a natural bioflavonoid, in 6-hydroxydopamine (6-OHDA)-induced models of Parkinson's disease in vivo and in vitro. First, we found that PME decreased apoptosis in 6-OHDA-intoxicated SH-SY5Y cells. PME also blocked several 6-OHDA-induced mitochondrial apoptotic cascades, including loss of mitochondrial membrane potential, caspase 3 and PARP activation, and a decrease in the Bcl-2/Bax ratio. Also, PME suppressed 6-OHDA-induced oxidative stress while increasing antioxidant enzymatic activity. Further investigations indicated that PME significantly enhanced nuclear accumulation of Nrf2, improved ARE promoter activity, and upregulated HO-1 and NQO1 expression levels. In addition, siRNA-mediated Nrf2 knockdown abolished PME-induced anti-oxidative and anti-apoptotic effects. Interestingly, we found that PME promoted phosphorylation of AKT and ERK, whereas pharmacological inhibition of AKT or ERK pathways diminished PME-induced Nrf2 activation and protective actions. Moreover, PME attenuated 6-OHDA-induced loss of dopaminergic neurons and ameliorated locomotor deficiency in zebrafish, supporting the neuroprotective actions of PME in vivo. In summary, we found that PME conferred neuroprotection against 6-OHDA-induced neurotoxicity in PD models in vivo and in vitro. Taken together, our findings suggest that activation of Nrf2/ARE/HO-1 signaling cascades contributes to PME-induced anti-oxidative and neuroprotective actions, which are at least partially mediated by AKT and ERK pathways.

The microneedles carrying cisplatin and IR820 to perform synergistic chemo-photodynamic therapy against breast cancer.

BACKGROUNDS: Surgical resection and adjunct chemotherapy or radio-therapy has been applied for the therapy of superficial malignant tumor in clinics. Whereas, there are still some problems limit its clinical use, such as severe pains and side effect. Thus, it is urgent need to develop effective, minimally invasive and low toxicity therapy stagey for superficial malignant tumor. Topical drug administration such as microneedle patches shows the advantages of reduced systemic toxicity and nimble application and, as a result, a great potential to treat superficial tumors. METHODS: In this study, microneedle (MN) patches were fabricated to deliver photosensitizer IR820 and chemotherapy agent cisplatin (CDDP) for synergistic chemo-photodynamic therapy against breast cancer. RESULTS: The MN could be completely inserted into the skin and the compounds carrying tips could be embedded within the target issue for locoregional cancer treatment. The photodynamic therapeutic effects can be precisely controlled and switched on and off on demand simply by adjusting laser. The used base material vinylpyrrolidone-vinyl acetate copolymer (PVPVA) is soluble in both ethanol and water, facilitating the load of both water-soluble and water-insoluble drugs. CONCLUSIONS: Thus, the developed MN patch offers an effective, user-friendly, controllable and low-toxicity option for patients requiring long-term and repeated cancer treatments.

Bismuth chelate as a contrast agent for X-ray computed tomography.

BACKGROUNDS: Due to the unexpected side effects of the iodinated contrast agents, novel contrast agents for X-ray computed tomography (CT) imaging are urgently needed. Nanoparticles made by heavy metal elements are often employed, such as gold and bismuth. These nanoparticles have the advantages of long in vivo circulation time and tumor targeted ability. However, due to the long residence time in vivo, these nanoparticles may bring unexpected toxicity and, the preparation methods of these nanoparticles are complicated and time-consuming. METHODS: In this investigation, a small molecular bismuth chelate using diethylenetriaminepentaacetic acid (DPTA) as the chelating agent was proposed to be an ideal CT contrast agent. RESULTS: The preparation method is easy and cost-effective. Moreover, the bismuth agent show better CT imaging for kidney than iohexol in the aspect of improved CT values. Up to 500 µM, the bismuth agent show negligible toxicity to L02 cells and negligible hemolysis. And, the bismuth agent did not induce detectable morphology changes to the main organs of the mice after intravenously repeated administration at a high dose of 250 mg/kg. The pharmacokinetics of the bismuth agent follows the first-order elimination kinetics and, it has a short half-life time of 0.602 h. The rapid clearance from the body promised its excellent biocompatibility. CONCLUSIONS: This bismuth agent may serve as a potential candidate for developing novel contrast agent for CT imaging in clinical applications.

Formononetin promotes angiogenesis through the estrogen receptor alpha-enhanced ROCK pathway.

Formononetin is an isoflavone that has been shown to display estrogenic properties and induce angiogenesis activities. However, the interrelationship between the estrogenic properties and angiogenesis activities of formononetin are not well defined. In the present study, docking and enzymatic assay demonstrated that formononetin displayed direct binding to the ligand-binding domain (LBD) of estrogen receptor alpha (ERα) with an agonistic property. Results from Human Umbilical Vein Endothelial Cells (HUVEC) by using real-time migration xCELLigence system, immunofluorescence and western blotting provided strong evidences of formononetin induced endothelial cell migration and dramatic actin cytoskeleton spatial modification through ERα-enhanced-ROCK-II/MMP2/9 signaling pathways. In addition, results from co-immunoprecipitation suggested formononetin induced cell migration via recruiting of ERα/ROCK-II activated complex formation. More interestingly, in zebrafish embryo we observed that formononetin significantly promoted angiogenic sproutings in the subintestinal vessels (SIVs) that could be completely abolished by ROCK inhibitor. In this study, we elucidated the underlying mechanisms that formononetin produced proangiogenesis effects through an ERα-enhanced ROCK-II signaling pathways. Results from the present study also expand our knowledge about the enigmatic underlying mechanisms of phytoestrogenic compounds in the promotion of angiogenesis in relation to ERα and ROCK interaction in endothelial cells and their relationship with actin assembly and cell migration.

Effects of furanodiene on 95-D lung cancer cells: apoptosis, autophagy and G1 phase cell cycle arrest.

Furanodiene (FUR) is a natural terpenoid isolated from Rhizoma curcumae, a well-known Chinese medicinal herb that presents anti-proliferative activities in several cancer cell lines. Herein, we systematically investigated the effects of FUR on the significant processes of tumor progression with the relatively low concentrations in 95-D lung cancer cells. FUR concentration-dependently inhibited cell proliferation and blocked the cell cycle progressions in G1 phase by down-regulating the protein levels of cyclin D1 and CDK6, and up-regulating those of p21 and p27 in 95-D cells. FUR also affected the signaling molecules that regulate apoptosis in 95-D cells revealed by the down-regulation of the protein levels of full PARP, pro-caspase-7, survivin, and Bcl-2, and the up-regulation of cleaved PARP. Further studies showed that FUR enhanced the expression of light chain 3-II (LC3-II) in the protein level, indicating that autophagy is involved in this process. Besides, the adhesion ability of 95-D cells to matrigel and fibronectin was slightly inhibited after FUR treatment for 1 h in our experimental condition. FUR also slightly suppressed cell migration and invasion in 95-D cells according to the data from wound healing and Transwell assays, respectively. Taken together, FUR activated the signal molecules regulating G1 cell cycle arrest, apoptosis and autophagy, while slightly affecting the key steps of cell metastasis in 95-D lung cancer cells in the relatively low concentrations.

Furanodiene presents synergistic anti-proliferative activity with paclitaxel via altering cell cycle and integrin signaling in 95-D lung cancer cells.

Furanodiene (FUR) is a natural terpenoid isolated from Rhizoma Curcumae, a well-known Chinese medicinal herb that presents anti-proliferative activities in several cancer cell lines. Recently, we found that the combined treatment of FUR with paclitaxel (TAX) showed synergetic anti-proliferative activities in 95-D lung cancer cells. Herein, we showed that FUR reduced the cell numbers distributed in mitosis phase induced by TAX while increased those in G1 phase. The protein levels of cyclin D1, cyclin B1, CDK6 and c-Myc were all down-regulated in the group of combined treatment. The dramatically down-regulated expression of integrin ß4, focal adhesion kinase and paxillin might partially contribute to the synergic effect. Though FUR alone obviously induced endoplasmic reticulum stress, this signaling pathway may not contribute to the synergetic anti-proliferative effect as the protein expression of CHOP and BIP was similar in FUR alone and combined treatment group.

Furanodiene induces endoplasmic reticulum stress and presents antiproliferative activities in lung cancer cells.

Furanodiene (FUR) is a natural terpenoid isolated from Curcumae Rhizoma, a well-known Chinese medicinal herb that presents antiproliferation activities in several cancer cell lines. In this study, we demonstrated that FUR concentration dependently inhibits the cell proliferation of A549, NIH-H1299, and 95-D lung cancer cells. ß-elemene, another terpenoid isolated from Curcumae Rhizoma, exhibited weaker antiproliferative effects in A549 and NIH-H1299 cells and activities similar to FUR in 95-D cells. FUR significantly inhibited colony formation in A549 and 95-D cells and upregulated both the mRNA and protein expression levels of binding immunoglobulin protein (BIP) and C/EBP homologous protein (CHOP), indicating that endoplasmic reticulum (ER) stress is induced. FUR treatment led to the accumulation of CHOP in the nucleus, which further confirms induction of ER stress. Furthermore, combined treatment of FUR with paclitaxel showed significant synergetic activities in NIH-H1299 and 95-D cells, suggesting its potential roles in combination therapy. These findings provide a basis for the further study of the anticancer effects in vivo and the internal mechanisms of FUR.

Furanodiene, a natural product, inhibits breast cancer growth both in vitro and in vivo.

PURPOSE: Previous studies have reported that the Curcuma wenyujin Y.H. Chen et C. Ling extract, which has a high furanodiene content, showed anti-cancer effects in breast cancer cells in vitro. The present study was designed to evaluate the in vitro and in vivo anti-cancer activity of furanodiene. METHODS: The in vitro effects of furanodiene were examined on two human breast cancer cell lines, MCF-7 and MDA-MB-231 cells. Assays of proliferation, LDH release, mitochondrial membrane potential (ΔΨm), cell cycle distribution, apoptosis and relevant signaling pathways were performed. The in vivo effect was determined with MCF7 tumor xenograft model in nude mice. RESULTS: Furanodiene significantly inhibited the proliferation and increased the LDH release in both cell lines in a dose-dependent manner. ΔΨm depolarization, chromatin condensation, and DNA fragmentation were also observed after furanodiene treatment. Furanodiene dose-dependently induced cell cycle arrest at the G0/G1 phase. The protein expressions of p-cyclin D1, total cyclin D1, p-CDK2, total CDK2, p-Rb, total Rb, Bcl-xL, and Akt were significantly inhibited by furanodiene, whereas the protein expressions of Bad and Bax, and the proteolytic cleavage of caspase-9, caspase-7, and poly-ADP-ribose polymerase (PARP) were dramatically increased. Furthermore, the z-VAD-fmk markedly reversed the furanodiene-induced cell cytotoxicity, the proteolytic cleavage of caspase-9, and DNA fragmentation but did not affect the proteolytic cleavage of PARP, whereas the Akt inhibitor VIII increased the furanodiene-induced cytotoxicity and PARP cleavage. In addition, furanodiene dose-dependently suppressed the tumor growth in vivo, achieving 32% and 54% inhibition rates after intraperitoneal injection of 15 mg/kg and 30 mg/kg, respectively. CONCLUSIONS: Taken together, we concluded that furanodiene suppresses breast cancer cell growth both in vitro and in vivo and could be a new lead compound for breast cancer chemotherapy.

Anti-cancer properties of terpenoids isolated from Rhizoma Curcumae--a review.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhizoma Curcumae is a popular type of traditional Chinese medicine whose essential oils are widely used in the treatment of cancer in China. This review aims to systematically summarize and analyze the anti-cancer properties of terpenoids, the main components of essential oils in Rhizoma Curcumae, and thus enable the development of new anti-cancer drugs. MATERIALS AND METHODS: Information on the recent progress of anti-cancer studies on terpenoids isolated from Rhizoma Curcumae, including ß-elemene, δ-elemene, furanodiene, furanodienone, curcumol, and germacrone, was gathered and analyzed. RESULTS: Among these terpenoids, ß-elemene is the most widely studied, whereas δ-elemene, furanodiene, furanodienone, curcumol, and germacrone have just recently attracted the attention of researchers. The anti-cancer effects of these terpenoids are related to the retardation of cell cycle arrest, the induction of apoptosis, and the inhibition of metastasis or tissue invasion, among others. CONCLUSIONS: Most studies have focused on the in vitro data, and in vivo data is urgently needed. Further insight into the anti-cancer activity and the molecular basis of these compounds, combined with efforts in pharmaceutical chemistry and/or pharmaceutics, will potentially enable the development of new anti-cancer agents.

Dehydrocorydaline inhibits breast cancer cells proliferation by inducing apoptosis in MCF-7 cells.

Dehydrocorydaline is an alkaloid isolated from traditional Chinese herb Corydalis yanhusuo W.T. Wang. We discovered that it possessed anti-tumor potential during screening of anti-tumor natural products from Chinese medicine. In this study, its anti-tumor potential was investigated with breast cancer line cells MCF-7 in vitro. The anti-proliferative effect of dehydrocorydaline was determined by MTT assay and the mitochondrial membrane potential (Δ Ψ m) was monitored by JC-1 staining. DNA fragments were visualized by Hoechst 33342 staining and DNA ladder assay. Apoptotic related protein expressions were measured by Western blotting. Dehydrocorydaline significantly inhibited MCF-7 cell proliferation in a dose- dependent manner, which could be reversed by a caspase-8 inhibitor, Z-IETD-FMK. Dehydrocorydaline increased DNA fragments without affecting ΔΨm. Western blotting assay showed that dehydrocorydaline dose-dependently increased Bax protein expression and decreased Bcl-2 protein expression. Furthermore, dehydrocorydaline induced activation of caspase-7,-8 and the cleavage of PARP without affecting caspase-9. These results showed that dehydrocorydaline inhibits MCF-7 cell proliferation by inducing apoptosis mediated by regulating Bax/Bcl-2, activating caspases as well as cleaving PARP.

Ganoderic acid DM, a natural triterpenoid, induces DNA damage, G1 cell cycle arrest and apoptosis in human breast cancer cells.

Ganoderic acid DM (GADM) is a triterpenoid isolated from Ganoderma lucidum, a well-known edible medicinal mushroom. In the present study, we found that GADM effectively inhibited cell proliferation and colony formation in MCF-7 human breast cancer cells, which was much stronger than that of MDA-MB-231 breast cancer cells. GADM both concentration- and time-dependently mediated G1 cell cycle arrest and significantly decreased the protein level of CDK2, CDK6, cycle D1, p-Rb and c-Myc in MCF-7 cells. Moreover, GADM obviously induced DNA fragmentation and cleavage of PARP which are the characteristics of apoptosis and decreased the mitochondrial membrane potential in MCF-7 cells. Besides, we also showed that GADM elicited DNA damage as measured by comet assay which is a sensitive method for DNA damage detection. γ-H2AX, a marker of DNA damage, was also slightly up-regulated after treated with GADM for 6h, suggesting that the G1 cell cycle arrest and apoptosis induced by GADM may be partially resulted from GADM-induced DNA damage. These results have advanced our current understandings of the anti-cancer mechanisms of GADM.

Anti-cancer natural products isolated from chinese medicinal herbs.

In recent years, a number of natural products isolated from Chinese herbs have been found to inhibit proliferation, induce apoptosis, suppress angiogenesis, retard metastasis and enhance chemotherapy, exhibiting anti-cancer potential both in vitro and in vivo. This article summarizes recent advances in in vitro and in vivo research on the anti-cancer effects and related mechanisms of some promising natural products. These natural products are also reviewed for their therapeutic potentials, including flavonoids (gambogic acid, curcumin, wogonin and silibinin), alkaloids (berberine), terpenes (artemisinin, ß-elemene, oridonin, triptolide, and ursolic acid), quinones (shikonin and emodin) and saponins (ginsenoside Rg3), which are isolated from Chinese medicinal herbs. In particular, the discovery of the new use of artemisinin derivatives as excellent anti-cancer drugs is also reviewed.