Renoprotective Effect of Pediococcus acidilactici GKA4 on Cisplatin-Induced Acute Kidney Injury by Mitigating Inflammation and Oxidative Stress and Regulating the MAPK, AMPK/SIRT1/NF-κB, and PI3K/AKT Pathways.

Acute kidney injury (AKI) describes a sudden loss of kidney function and is associated with a high mortality. Pediococcus acidilactici is a potent producer of bacteriocin and inhibits the growth of pathogens during fermentation and food storage; it has been used in the food industry for many years. In this study, the potential of P. acidilactici GKA4 (GKA4) to ameliorate AKI was investigated using a cisplatin-induced animal model. First, mice were given oral GKA4 for ten days and intraperitoneally injected with cisplatin on the seventh day to create an AKI mode. GKA4 attenuated renal histopathological alterations, serum biomarkers, the levels of inflammatory mediators, and lipid oxidation in cisplatin-induced nephrotoxicity. Moreover, GKA4 significantly decreased the expression of inflammation-related proteins and mitogen-activated protein kinase (MAPK) in kidney tissues. Eventually, GKA4 also increased the levels of related antioxidant enzymes and pathways. Consistently, sirtuin 1 (SIRT1) upregulated the level of autophagy-related proteins (LC3B, p62, and Beclin1). Further studies are needed to check our results and advance our knowledge of the mechanism whereby PI3K inhibition (wortmannin) reverses the effect of GKA4 on cisplatin-treated AKI. Taken together, GKA4 provides a therapeutic target with promising clinical potential after cisplatin treatment by reducing oxidative stress and inflammation via the MAPK, AMP-activated protein kinase (AMPK)/SIRT1/nuclear factor kappa B (NF-κB), and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) axes.

Lactobacillus plantarum GKM3 and Lactobacillus paracasei GKS6 Supplementation Ameliorates Bone Loss in Ovariectomized Mice by Promoting Osteoblast Differentiation and Inhibiting Osteoclast Formation.

Osteoporosis, an imbalance in the bone-forming process mediated by osteoblasts and the bone-resorbing function mediated by osteoclasts, is a bone degenerative disease prevalent among the aged population. Due to deleterious side effects of currently available medications, probiotics as a potential treatment of osteoporosis is an appealing approach. Hence, this study aims to evaluate the beneficial effects of two novel Lactobacilli strain probiotics on bone health in ovariectomized (OVX) induced osteoporotic mice model and its underlying mechanisms. Forty-five 9-week-old Institute of Cancer Research (ICR) mice underwent either a sham-operation (n = 9) or OVX (n = 36). Four days after the operation, OVX mice were further divided into four groups and received either saline alone, Lactobacillus plantarum GKM3, Lactobacillus paracasei GKS6 or alendronate per day for 28 days. After sacrifice by decapitation, right distal femur diaphysis was imaged via micro-computed tomography (MCT) and parameters including bone volume/tissue volume ratio (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), and bone mineral density (BMD) were measured. Moreover, GKM3 and GKS6 on RANKL-induced osteoclast formation and osteoblast differentiation using in vitro cultures were also investigated. The results showed that both probiotics strains inhibited osteoporosis in the OVX mice model, with L. paracasei GKS6 outperforming L. plantarum GKM3. Besides this, both GKS6 and GKM3 promoted osteoblast differentiation and inhibited RANKL-induced osteoclast differentiation via the Bone Morphogenetic Proteins (BMP) and RANKL pathways, respectively. These findings suggested that both strains of Lactobacilli may be pursued as potential candidates for the treatment and management of osteoporosis, particularly in postmenopausal osteoporosis.

Jdp2-deficient granule cell progenitors in the cerebellum are resistant to ROS-mediated apoptosis through xCT/Slc7a11 activation.

The Jun dimerization protein 2 (Jdp2) is expressed predominantly in granule cell progenitors (GCPs) in the cerebellum, as was shown in Jdp2-promoter-Cre transgenic mice. Cerebellum of Jdp2-knockout (KO) mice contains lower number of Atoh-1 positive GCPs than WT. Primary cultures of GCPs from Jdp2-KO mice at postnatal day 5 were more resistant to apoptosis than GCPs from wild-type mice. In Jdp2-KO GCPs, the levels of both the glutamate‒cystine exchanger Sc7a11 and glutathione were increased; by contrast, the activity of reactive oxygen species (ROS) was decreased; these changes confer resistance to ROS-mediated apoptosis. In the absence of Jdp2, a complex of the cyclin-dependent kinase inhibitor 1 (p21Cip1) and Nrf2 bound to antioxidant response elements of the Slc7a11 promoter and provide redox control to block ROS-mediated apoptosis. These findings suggest that an interplay between Jdp2, Nrf2, and p21Cip1 regulates the GCP apoptosis, which is one of critical events for normal development of the cerebellum.

Genetic Association Analysis of Cell Cycle Regulators Reveals YWHAZ Has Prognostic Significance in Prostate Cancer.

BACKGROUND/AIM: This study aimed to identify the genes that cause biochemical recurrence (BCR) following radical prostatectomy (RP) in men with localized prostate cancer. PATIENTS AND METHODS: A two-stage genetic association study of 19 single-nucleotide polymorphisms in 11 key cell cycle regulation genes was carried out. BCR-free survival after RP was evaluated in a discovery cohort of 458 patients with prostate cancer, and replication was investigated in another cohort of 185 patients. RESULTS: A consistent association was found between BCR and rs2290291 (discovery: p=0.008; replication: p=0.029). rs2290291 is located in the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), and was predicted to possess a regulatory function that affected YWHAZ expression. Furthermore, YWHAZ expression was frequently up-regulated in advanced tumours, and associated with poorer survival in patients with prostate cancer. CONCLUSION: YWHAZ rs2290291 was found to be associated with BCR. YWHAZ may function as a putative oncogene during prostate cancer progression.

Prognostic Value of CD1B in Localised Prostate Cancer.

Cluster of differentiation (CD) antigens are cell surface markers used to differentiate haematopoietic cell types. These antigens are present in various malignancies and are reportedly linked to patient prognosis; however, they have not been implemented as prostate cancer progression markers. Here, we aimed to assess the impact of genetic variation in haematopoietic cell CD markers on clinical outcomes in patients with prostate cancer. An association study of 458 patients with prostate cancer was conducted to identify single-nucleotide polymorphisms in 11 candidate CD marker genes associated with biochemical recurrence (BCR) after radical prostatectomy. Identified predictors were further evaluated in an additional cohort of 185 patients. Joint population analyses showed that CD1B rs3181082 is associated with BCR (adjusted hazard ratio 1.42, 95% confidence interval 1.09-1.85, p = 0.010). In addition, rs3181082 overlapped with predicted transcriptional regulatory elements and affected CD1B expression. Furthermore, low CD1B expression correlated with poorer BCR-free survival. Our results indicated that CD1B rs3181082 confers prostate cancer progression and may help improve clinical prognostic stratification.

Cordyceps cicadae mycelia and its active compound HEA exert beneficial effects on blood glucose in type 2 diabetic db/db mice.

BACKGROUND: This is the first study to investigate the therapeutic effects of Cordyceps cicadae (C. cicadae) mycelia and its active compound N6 -(2-hydroxyethyl)adenosine (HEA) on blood glucose in genetically diabetic mice. RESULTS: Forty mice, 9 weeks of age, were divided into normal control, diabetic control, and three C. cicadae mycelia treated diabetic groups. After 9 weeks of continuous supplementation, the oral glucose tolerance test (OGTT) and homeostasis model of assessment-insulin resistance index showed significant glucose tolerance with C. cicadae mycelia. Furthermore, the effect of HEA is similar to that of C. cicadae mycelia in an OGTT, suggesting that HEA could be the major factor responsible for the functional properties of C. cicadae mycelia. CONCLUSION: Based on these findings, it is suggested that the therapeutic effect of C. cicadae mycelia may be driven by one of its active components, HEA, which could alleviate many diabetes complications in genetically obese mice and may offer promise as a supplement for diabetes management. © 2018 Society of Chemical Industry.

Design and synthesis of BPR1K653 derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition.

Twenty five novel chemical analogs of the previously reported Aurora kinase inhibitor BPR1K653 (1-(4-(2-((5-chloro-6-phenylfuro[2,3-d]pyrimidin-4-yl)amino)ethyl)phenyl)-3-(2-((dimethylamino)methyl)phenyl)urea) have been designed, synthesized, and evaluated by Aurora-A and Aurora-B enzymatic kinase activity assays. Similar to BPR1K653, analogs 3b-3h bear alkyl or tertiary amino group at the ortho position of the phenylurea, and showed equal or better inhibition activity for Aurora-B over Aurora-A. Conversely, preferential Aurora-A inhibition activity was observed when the same functional group was moved to the meta position of the phenylurea. Compounds 3m and 3n, both of which harbor a tertiary amino group at the meta position of the phenylurea, showed 10-16 fold inhibition selectivity for Aurora-A over Aurora-B. The in vitro kinase inhibition results were verified by Western blot analysis, and indicated that compounds 3m and 3n were more than 75-fold superior in inhibiting T-loop autophosphorylation of Aurora-A (Thr288), compared to Aurora-B (Thr232) in HCT116 colon carcinoma cells. The computational docking analysis suggested that the tertiary amine at the meta position of the phenylurea formed a more stable interaction with residues in the back pocket of Aurora-A than in Aurora-B, a possible explanation for the observed discrepancy in the selectivity. These results support an alternative small molecule design strategy targeting the back pocket of Aurora kinases for selective isoform inhibition.

Erinacine A-Enriched Hericium erinaceus Mycelium Produces Antidepressant-Like Effects through Modulating BDNF/PI3K/Akt/GSK-3ß Signaling in Mice.

Antidepressant-like effects of ethanolic extract of Hericium erinaceus (HE) mycelium enriched in erinacine A on depressive mice challenged by repeated restraint stress (RS) were examined. HE at 100, 200 or 400 mg/kg body weight/day was orally given to mice for four weeks. After two weeks of HE administration, all mice except the control group went through with 14 days of RS protocol. Stressed mice exhibited various behavioral alterations, such as extending immobility time in the tail suspension test (TST) and forced swimming test (FST), and increasing the number of entries in open arm (POAE) and the time spent in the open arm (PTOA). Moreover, the levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were decreased in the stressed mice, while the levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were increased. These changes were significantly inverted by the administration of HE, especially at the dose of 200 or 400 mg/kg body weight/day. Additionally, HE was shown to activate the BDNF/TrkB/PI3K/Akt/GSK-3ß pathways and block the NF-κB signals in mice. Taken together, erinacine A-enriched HE mycelium could reverse the depressive-like behavior caused by RS and was accompanied by the modulation of monoamine neurotransmitters as well as pro-inflammatory cytokines, and regulation of BDNF pathways. Therefore, erinacine A-enriched HE mycelium could be an attractive agent for the treatment of depressive disorders.

Cancer cell reprogramming to identify the genes competent for generating liver cancer stem cells.

The cancer stem cell (CSC) hypothesis postulates that cancer originates from the malignant transformation of stem/progenitor cells and is considered to apply to many cancers, including liver cancer. Identification that CSCs are responsible for drug resistance, metastasis, and secondary tumor appearance suggests that these populations are novel obligatory targets for the treatment of cancer. Here, we describe our new method for identifying potential CSC candidates. The reprogramming of cancer cells via induced pluripotent stem cell (iPSC) technology is a novel therapy for the treatment and for the study of CSC-related genes. This technology has advantages for studying the interactions between CSC-related genes and the cancer niche microenvironment. This technology may also provide a useful platform for studying the genes involved in the generation of CSCs before and after reprogramming, and for elucidating the mechanisms underlying cancer initiation and progression. The present review summarizes the current understanding of transcription factors involved in the generation of liver CSCs from liver cancer cell-derived iPSCs and how these contribute to oncogenesis, and discusses the modeling of liver cancer development.

Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells.

Reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) is a compelling idea for inhibiting oncogenesis, especially through modulation of homeobox proteins in this reprogramming process. We examined the role of various long noncoding RNAs (lncRNAs)-homeobox protein HOXA13 axis on the switching of the oncogenic function of bone morphogenetic protein 7 (BMP7), which is significantly lost in the gastric cancer cell derived iPS-like cells (iPSLCs). BMP7 promoter activation occurred through the corecruitment of HOXA13, mixed-lineage leukemia 1 lysine N-methyltransferase, WD repeat-containing protein 5, and lncRNA HoxA transcript at the distal tip (HOTTIP) to commit the epigenetic changes to the trimethylation of lysine 4 on histone H3 in cancer cells. By contrast, HOXA13 inhibited BMP7 expression in iPSLCs via the corecruitment of HOXA13, enhancer of zeste homolog 2, Jumonji and AT rich interactive domain 2, and lncRNA HoxA transcript antisense RNA (HOTAIR) to various cis-element of the BMP7 promoter. Knockdown experiments demonstrated that HOTTIP contributed positively, but HOTAIR regulated negatively to HOXA13-mediated BMP7 expression in cancer cells and iPSLCs, respectively. These findings indicate that the recruitment of HOXA13-HOTTIP and HOXA13-HOTAIR to different sites in the BMP7 promoter is crucial for the oncogenic fate of human gastric cells. Reprogramming with octamer-binding protein 4 and Jun dimerization protein 2 can inhibit tumorigenesis by switching off BMP7. Stem Cells 2017;35:2115-2128.

Application of Cancer Cell Reprogramming Technology to Human Cancer Research.

The cancer stem cell (CSC) hypothesis is an evolving concept of oncogenesis that has recently gained wide acceptance. By definition, CSCs exhibit continuous proliferation and self-renewal, and they have been proposed to play significant roles in oncogenesis, tumor growth, metastasis, chemoresistance, and cancer recurrence. The reprogramming of cancer cells using induced pluripotent stem cell (iPSC) technology is a potential strategy for the identification of CSC-related oncogenes and tumor-suppressor genes. This technology has some advantages for studying the interactions between CSC-related genes and the cancer microenvironment. This approach may also provide a useful platform for studying the mechanisms of CSCs underlying cancer initiation and progression. The present review summarizes the recent advances in cancer cell reprogramming using iPSC technology and discusses its potential clinical use and related drug screening.

The Roles of 4ß-Hydroxywithanolide E from Physalis peruviana on the Nrf2-Anti-Oxidant System and the Cell Cycle in Breast Cancer Cells.

4[Formula: see text]-Hydroxywithanolide E is an active component of the extract of Physalis peruviana that has been reported to exhibit antitumor effects. Although the involvement of reactive oxygen species (ROS) production and the ataxia-telangiectasia mutated protein (ATM)-dependent DNA damage signaling pathway in 4[Formula: see text]-hydroxywithanolide E-induced apoptosis of breast cancer MCF-7 cells was demonstrated in our previous study, the relationship between ROS production and the cellular defense system response in 4[Formula: see text]-hydroxywithanolide E-induced cell death requires further verification. The present study suggests that ROS play an important role in 4[Formula: see text]-hydroxywithanolide E-induced MCF-7 cell death in which anti-oxidants, such as glutathione or N-acetylcysteine, can resist the 4[Formula: see text]-hydroxywithanolide E-induced accumulation of ROS and cell death. Furthermore, N-acetylcysteine or glutathione can reverse the 4[Formula: see text]-hydroxywithanolide E-induced changes in the cell cycle distribution and the expression of cell cycle regulators. We found that the 4[Formula: see text]-hydroxywithanolide E-induced ROS accumulation was correlated with the upregulation of Nrf2 and Nrf2-downstream genes, such as antioxidative defense enzymes. In general, the activity of Nrf2 is regulated by the Ras signalling pathway. However, we demonstrated that Nrf2 was activated during 4[Formula: see text]-hydroxywithanolide E-induced MCF-7 cell death in spite of the 4[Formula: see text]-hydroxywithanolide E-induced inhibition of the Ras/Raf/ERK pathway. The activity and protein expression of superoxide dismutase and catalase were involved in the 4[Formula: see text]-hydroxywithanolide E-induced ROS production in MCF-7 cells. Furthermore, 4[Formula: see text]-hydroxywithanolide E was demonstrated to significantly reduce the sizes of the tumor nodules in the human breast cancer MDA-MB231 xenograft tumor model.

K20E, an oxidative-coupling compound of methyl caffeate, exhibits anti-angiogenic activities through down-regulations of VEGF and VEGF receptor-2.

Anti-angiogenesis is one of the most popular clinical interventions for cancer chemotherapy. A series of synthesized derivative of methyl caffeate were used to evaluate the anti-angiogenic activity and to investigate possible pharmacological mechanisms in the present study. The most potent anti-angiogenic compound was evaluated in the experiments of murine allograft tumor model and Matrigel plug assay as well as cell models in the human umbilical vascular endothelial cells (HUVECs) and the LLC1 lung cancer cells. Our results suggested that K20E suppressed the tumor growth in the allograft tumor model and exhibited anti-angiogenic activity in Matrigel plug assay. Besides, HUVEC viability was found to be significantly reduced by arresting cell cycle at G2/M phase and apoptosis. Cell migration, invasion, and tube formation of the HUVECs were also markedly suppressed by K20E treatment. K20E largely down-regulated the intracellular and secreted vascular endothelial growth factor (VEGF) in the LLC1 cancer cells. Besides, VEGF receptor-2 (VEGFR-2) and its downstream signaling cascades (AKT-mTOR and MEK1/2-ERK1/2) as well as gelatinases were all evidently reduced in the HUVECs treated with K20E. Inversely, K20E can up-regulate the expression levels of p53 and p21 proteins in the HUVECs. Based on these results, our study suggested that K20E possessed inhibiting angiogenesis through regulation of VEGF/VEGFR-2 and its downstream signaling cascades in the vascular endothelial cells (VECs).

Dysregulated interactions between lamin A and SUN1 induce abnormalities in the nuclear envelope and endoplasmic reticulum in progeric laminopathies.

Hutchinson-Gilford progeria syndrome (HGPS) is a human progeroid disease caused by a point mutation on the LMNA gene. We reported previously that the accumulation of the nuclear envelope protein SUN1 contributes to HGPS nuclear aberrancies. However, the mechanism by which interactions between mutant lamin A (also known as progerin or LAΔ50) and SUN1 produce HGPS cellular phenotypes requires further elucidation. Using light and electron microscopy, this study demonstrated that SUN1 contributes to progerin-elicited structural changes in the nuclear envelope and the endoplasmic reticulum (ER) network. We further identified two domains through which full-length lamin A associates with SUN1, and determined that the farnesylated cysteine within the CaaX motif of lamin A has a stronger affinity for SUN1 than does the lamin A region containing amino acids 607 to 656. Farnesylation of progerin enhanced its interaction with SUN1 and reduced SUN1 mobility, thereby promoting the aberrant recruitment of progerin to the ER membrane during postmitotic assembly of the nuclear envelope, resulting in the accumulation of SUN1 over consecutive cellular divisions. These results indicate that the dysregulated interaction of SUN1 and progerin in the ER during nuclear envelope reformation determines the progression of HGPS.

NSC746364, a G-quadruplex-stabilizing agent, suppresses cell growth of A549 human lung cancer cells through activation of the ATR/Chk1-dependent pathway.

The telomere is considered to be a potential target for cancer therapy. NSC746364, a novel G-quadruplex-stabilizing agent, has been found to have cytotoxic effects on various cancer cells. To date, its pharmacological mechanisms are still unknown. The goal of this study was to investigate the molecular mechanisms of NSC746364 on the A549 human lung adenocarcinoma cell line. For this, we used a wide variety of in vitro assays. The intracellular signaling pathways including DNA damage sensing and response proteins, cell cycle regulatory proteins, and some key executors involved in apoptosis were evaluated in this study. Our study suggested that NSC746364 induced cell cycle arrest at the G2/M phase and triggers programming cell death on A549 human lung cancer cells, whose effects are modulated through the activation of the ATR/Chk1 pathway, the downregulation of cyclin B1 expression, and the activation of caspase-3. Consequently, our results indicated that NSC746364 may have therapeutic potential as a chemotherapy for non-small-cell lung cancers.

Deep sea water modulates blood pressure and exhibits hypolipidemic effects via the AMPK-ACC pathway: an in vivo study.

Deep sea water (DSW), originally pumped from the Pacific Rim off the coast of Hualien County (Taiwan), and its mineral constituents, were concentrated by a low-temperature vacuum evaporation system to produce a hardness of approximately 400,000 mg/L of seawater mineral concentrate. The primary composition of this seawater mineral concentrate was ionic magnesium (Mg²âº), which was approximately 96,000 mg/L. Referring to the human recommended daily allowance (RDA) of magnesium, we diluted the mineral concentrate to three different dosages: 0.1 × DSW (equivalent to 3.75 mg Mg²âº/kg DSW); 1 × DSW (equivalent to 37.5 mg Mg²âº/kg DSW); and 2 × DSW (equivalent to 75 mg Mg²âº/kg DSW). Additionally, a magnesium chloride treatment was conducted for comparison with the DSW supplement. The study indicated that 0.1 × DSW, 1 × DSW and 2 × DSW decreased the systolic and diastolic pressures in spontaneous hypertensive rats in an eight-week experiment. DSW has been shown to reduce serum lipids and prevent atherogenesis in a hypercholesterolemic rabbit model. Our results demonstrated that 1 × DSW and 2 × DSW significantly suppressed the serum cholesterol levels, reduced the lipid accumulation in liver tissues, and limited aortic fatty streaks. These findings indicated that the antiatherogenic effects of DSW are associated with 5'-adenosine monophosphate-activated protein kinase (AMPK) stimulation and the consequent inhibition of phosphorylation of acetyl-CoA carboxylase (ACC) in atherosclerotic rabbits. We hypothesize that DSW could potentially be used as drinking water because it modulates blood pressure, reduces lipids, and prevents atherogenesis.

Aurora kinase inhibitors reveal mechanisms of HURP in nucleation of centrosomal and kinetochore microtubules.

The overexpression of Aurora kinases in multiple tumors makes these kinases appealing targets for the development of anticancer therapies. This study identified two small molecules with a furanopyrimidine core, IBPR001 and IBPR002, that target Aurora kinases and induce a DFG conformation change at the ATP site of Aurora A. Our results demonstrate the high potency of the IBPR compounds in reducing tumorigenesis in a colorectal cancer xenograft model in athymic nude mice. Human hepatoma up-regulated protein (HURP) is a substrate of Aurora kinase A, which plays a crucial role in the stabilization of kinetochore fibers. This study used the IBPR compounds as well as MLN8237, a proven Aurora A inhibitor, as chemical probes to investigate the molecular role of HURP in mitotic spindle formation. These compounds effectively eliminated HURP phosphorylation, thereby revealing the coexistence and continuous cycling of HURP between unphosphorylated and phosphorylated forms that are associated, respectively, with microtubules emanating from centrosomes and kinetochores. Furthermore, these compounds demonstrate a spatial hierarchical preference for HURP in the attachment of microtubules extending from the mother to the daughter centrosome. The finding of inequality in the centrosomal microtubules revealed by these small molecules provides a versatile tool for the discovery of new cell-division molecules for the development of antitumor drugs.

Elucidating the inhibitory mechanisms of the ethanolic extract of the fruiting body of the mushroom Antrodia cinnamomea on the proliferation and migration of murine leukemia WEHI-3 cells and their tumorigenicity in a BALB/c allograft tumor model.

The aim of this study was to explore whether the ethanolic extract of Antrodia cinnamomea (EEAC), a medical mushroom form Taiwan, could affect the proliferation and migration of WEHI-3 cells in vitro and to explore the antitumor effects of EEAC in BALB/c mice engrafted with WEHI-3 cells. The results showed that EEAC inhibited the proliferation of WEHI-3 cells, resulting in the accumulation of cell in G0/G1 and G2/M phases, as determined by flow cytometry. Moreover, EEAC markedly reduced the migration of WEHI-3 cells, as determined by a transwell assay. Treatment of WEHI-3 cells with EEAC also decreased MMP-9 protein expression and enzyme activity. The protein levels of p-Akt, p-ERK1/2 were also decreased, whereas the expression of p21 and p27 was increased. Furthermore, in an in vivo model, EEAC treatment reduced the infiltration of WEHI-3 cells into the liver and spleens and decreased tumor growth. Other bioactive compounds, such as cordycepin and zhankuic acid A, have been demonstrated to reduce the expression of MMP-9, cyclin E, cyclin D1 and to increase the expression of p21, p27. This is the first study to investigate that the mechanisms by which EEAC reduce the proliferation and migration of WEHI-3 cells in vitro, as well as the ability of EEAC to reduced infiltration of WEHI-3 cells into the liver and spleen in vivo. The results suggest that EEAC may prove to be useful in future antileukemic therapies.

A Chinese herbal formula "Gan-Lu-Yin" suppresses vascular smooth muscle cell migration by inhibiting matrix metalloproteinase-2/9 through the PI3K/AKT and ERK signaling pathways.

BACKGROUND: This study was to explore the effects of Gan-Lu-Yin (GLY) on the migration of vascular smooth muscle cells (VSMCs) induced by fetal bovine serum and on neointima formation in a rat model of carotid artery balloon injury. METHODS: VSMCs were treated with different concentrations of GLY, and then analyzed with Flow cytometric analysis, zymography, transwell, and western blotting. SD rats received balloon-injury were analyzed with H&E staining. RESULTS: Our results showed that GLY significantly decreased the thickness of neointima. The inhibition by non-cytoxic doses of GLY of VSMCs migration was through its negative regulatory effects on phosphorylated ERK1/2, PI3K/AKT, and FAK. The data showed that GLY can inhibit the migration of VSMCs cells, and might block injury-induced neointima hyperplasia via the inhibition of VSMCs migration, without inducing apoptosis. CONCLUSIONS: These observations provide a mechanism of GLY in attenuating cell migration, thus as a potential intervention for restenosis.

Anti-inflammatory effects of Calophyllum inophyllum L. in RAW264.7 cells.

Calophyllum inophyllum L. has been used as folk medicine in the treatment of ocular burn and it has demonstrated potential to be an anti-inflammatory agent. The aim of this study was to explore the anti-inflammatory activities of an acetone extract of C. inophyllum L. leaves (CIL). The CIL extract was tested on lipopolysaccharide (LPS)-induced RAW 264.7 cells to evaluate the effect of CIL extract on the expression of nitric oxide (NO) and inducible nitric oxide synthase (iNOS). Results showed that the CIL extract markedly suppressed the LPS-induced production of nitric oxide, as well as the expression of iNOS, cyclooxygenase (COX)-2 and nuclear factor-kappaB (NF-κB) in a dose-dependent manner. LPS-induced microRNA (miR)-146a expression was inhibited by CIL extract, while miR-155 and miR-424 expression was not affected as demonstrated using quantitative RT-PCR analysis. Taken together, these observations show that CIL extract has anti-inflammatory effect, which extends the potential application for prevention of inflammatory diseases, and its mechanism may be partially associated with blocking COX-2 and iNOS of RAW 264.7 cells.