Repurposing Metabolic Inhibitors in the Treatment of Colon Adenocarcinoma Patient-Derived Models.

The effect of agonists on AMP-activated protein kinase (AMPK), mainly metformin and phenformin, has been appreciated in the treatment of multiple types of tumors. Specifically, the antitumor activity of phenformin has been demonstrated in melanomas containing the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) activating mutation. In this report, we elucidated the synergistic antitumor effects of biguanides with metabolism inhibitors on colon tumors.

Mistletoe Extract Targets the STAT3-FOXM1 Pathway to Induce Apoptosis and Inhibits Metastasis in Breast Cancer Cells.

Mistletoe extracts ( L.) have been widely used as complementary and alternative medicines for the treatment of cancer, and their cytotoxic effects have been reported on various types of cancer. However, the molecular targets of mistletoe extracts have not been well studied.

Lotus (Nelumbo nucifera) seedpod extract inhibits cell proliferation and induces apoptosis in non-small cell lung cancer cells via downregulation of Axl.

Non-small-cell lung cancer (NSCLC) is the most frequent cause of cancer-related death. In this study, we found the anticancer activity of lotus seedpod extract (LSPE) in NSCLC cells, since LSPE treatment inhibited cell proliferation of A549 and H460 cells in a dose-dependent manner and the clonogenic activities of LSPE-treated cells were also reduced. In LSPE-treated cells, the cleavage of poly (ADP-ribose) polymerase (PARP) and phosphorylation of H2X, were also observed, indicating the pro-apoptotic effect of LSPE.

Bufalin down-regulates Axl expression to inhibit cell proliferation and induce apoptosis in non-small-cell lung cancer cells.

Axl, a member of the TAM (Tyro3, AXL, Mer) receptor tyrosine kinase family, plays critical roles in cell growth, proliferation, apoptosis, and migration. In the present study, we demonstrated that the anti-cancer activity of bufalin, a major bioactive component of the Chinese traditional medicine Chan Su, is mediated by the down-regulation of Axl in non-small-cell lung cancer (NSCLC) cells. We observed the inhibitory effect of bufalin on the proliferation of A549 and H460 NSCLC cells and the clonogenicity of these cells was reduced by bufalin treatment in a dose-dependent manner.

Taxotere Induces Dephosphorylation of MET in Patient-derived Tumor Models.

Background/aim: Although molecular targeting therapy is an attractive treatment for cancer, resistance eventually develops in most cases. Here, we evaluated chemotherapeutic efficacy on non-small cell lung cancer (NSCLC) with acquired resistance to epidermal growth factor receptor inhibitors mechanistically.

Materials And Methods: Antitumor effects of taxotere were evaluated using multiple models, including xenograft, and patient-derived models developed from adenocarcinoma cancer patients.

Mistletoe (Viscum album) extract targets Axl to suppress cell proliferation and overcome cisplatin- and erlotinib-resistance in non-small cell lung cancer cells.

Background: Mistletoe extract of Visucm album extract (VAE) contains many biologically active components and has been reported to be not only a complementary and alternative medicine, but also a potent therapeutic agent for many types of cancer.

Purpose: In this study, we examined the effect of VAE on expression and activation of Axl and scrutinized the involvement of Axl in the anti-cancer activity of VAE in parental and chemo-resistant non-small cell lung cancer (NSCLC) cells.

Methods: The levels of Axl protein and mRNA were determined by Western blot analysis and RT-PCR, respectively.

Development and validation of a subject-specific finite element model of the functional spinal unit to predict vertebral strength.

Finite element models of an isolated vertebral body cannot accurately predict compressive strength of the spinal column because, in life, compressive load is variably distributed across the vertebral body and neural arch. The purpose of this study was to develop and validate a patient-specific finite element model of a functional spinal unit, and then use the model to predict vertebral strength from medical images. A total of 16 cadaveric functional spinal units were scanned and then tested mechanically in bending and compression to generate a vertebral wedge fracture.

Suppression of the metastatic spread of breast cancer by DN10764 (AZD7762)-mediated inhibition of AXL signaling.

Breast cancer is the most common malignant disease occurring in women and represents a substantial proportion of the global cancer burden. In these patients, metastasis but not the primary tumor is the main cause of breast cancer-related deaths. Here, we report the novel finding that DN10764 (AZD7762, a selective inhibitor of checkpoint kinases 1 and 2) can suppress breast cancer metastasis.

Suppression of gain-of-function mutant p53 with metabolic inhibitors reduces tumor growth in vivo.

Mutation of p53 occasionally results in a gain of function, which promotes tumor growth. We asked whether destabilizing the gain-of-function protein would kill tumor cells. Downregulation of the gene reduced cell proliferation in p53-mutant cells, but not in p53-null cells, indicating that the former depended on the mutant protein for survival.

Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation.

Background: Laminar flow protects from atherosclerosis in endothelium.

Results: Laminar flow induces Nrf2 activation dependent on ERK5 activation, leading to up-regulation of downstream genes of Nrf2.

Conclusion: ERK5 requires Nrf2 activation to exert cytoprotective effect on HUVEC.

Toll-like receptor 9-mediated inhibition of apoptosis occurs through suppression of FoxO3a activity and induction of FLIP expression.

Synthetic oligodeoxynucleotides (ODN) with a CpG-motif are recognized by Toll-like receptor 9 (TLR9) and pleiotropic immune responses are elicited. Stimulation of macrophages with TLR9 agonist prevented apoptosis induced by serum deprivation through increased expression of FLICE-like inhibitory protein (FLIP). CpG ODN-mediated anti-apoptosis depended on the TLR9-Akt-FoxO3a signaling pathway.

Glycogen synthase kinase 3beta and beta-catenin pathway is involved in toll-like receptor 4-mediated NADPH oxidase 1 expression in macrophages.

Macrophage activation contributes to the pathogenesis of atherosclerosis. In the vascular system, the major source of reactive oxygen species is the NADPH oxidase (Nox) family. Nox1 is induced by lipopolysaccharide (LPS) in macrophages, but the expression mechanism is not fully understood.

Calcium-independent phospholipase A2beta-Akt signaling is involved in lipopolysaccharide-induced NADPH oxidase 1 expression and foam cell formation.

Foam cell formation is the most important process in atherosclerosis, and low density lipoprotein oxidation by reactive oxygen species (ROS) is the key step in the conversion of macrophages to foam cells. This study reveals the control mechanism of the gene for NADPH oxidase 1 (Nox1), which produces ROS in the formation of foam cells by stimulating TLR4. Treatment of macrophages by the TLR4 agonist LPS stimulated ROS production and ROS-mediated macrophage to foam cell conversion.

Induction of cellular senescence by secretory phospholipase A2 in human dermal fibroblasts through an ROS-mediated p53 pathway.

Secretory phospholipase A(2) (sPLA(2)) is involved in various cellular physiological and pathological responses, especially in inflammatory responses. Accumulating evidence suggests that inflammation is an underlying basis for the molecular alterations that link aging and age-related pathological processes. However, the involvement of sPLA(2) in cellular senescence is not clear.

Cortical effect and functional recovery by the electromyography-triggered neuromuscular stimulation in chronic stroke patients.

We investigated the effect of electromyography (EMG)-triggered neuromuscular electrical stimulation (NMES; EMG-stim) on functional recovery of the hemiparetic hand and the related cortical activation pattern in chronic stroke patients. We enrolled 14 stroke patients, who were randomly assigned to the EMG-stim (n=7) or the control groups (n=7). The EMG-stim was applied to the wrist extensor of the EMG-stim group for two sessions (30 min/session) a day, five times per week for 10 weeks.

Brain activation pattern according to exercise complexity: a functional MRI study.

The aim of this study was to compare the areas of brain activation between complex and simple exercises in a unimanual hand and to assess the possibility of an exercise task for paretic hands following stroke. The subjects included 11 healthy right-handed volunteers. The complex exercise was a wooden ball rotation task with the unimanual hand and the simple exercise was a hand grasp task performed during a functional MRI scan.

Effect of constraint-induced movement therapy with modified opposition restriction orthosis in chronic hemiparetic patients with stroke.

Objectives: Constraint-induced movement therapy (CIMT) has been demonstrated to be effective in improving hemiparetic upper extremity function in stroke patients, but few studies have been performed to assess orthosis modification. We investigated the effect of the newly designed small orthosis named modified opposition restriction orthosis (MORO) in chronic hemiparetic patients with stroke.

Design: Twenty-one stroke patients were randomly assigned to the CIMT group or control group.

Primary motor cortex activation by transcranial direct current stimulation in the human brain.

Transcranial direct current stimulation (tDCS) can modulate motor cortex excitability in the human brain. We attempted to demonstrate the cortical stimulation effect of tDCS on the primary motor cortex (M1) using functional MRI (fMRI). An fMRI study was performed for 11 right-handed healthy subjects at 1.

Motor outcome according to the integrity of the corticospinal tract determined by diffusion tensor tractography in the early stage of corona radiata infarct.

Diffusion tensor tractography (DTT) is useful for exploring the state of the corticospinal tract (CST). An accurate estimation of the integrity of the CST in the early stage of a cerebral infarct would enable a determination of motor recovery. DTT was performed to classify CST integrity following a corona radiata infarct to evaluate if the procedure could characterize the motor outcome of the affected hand.

Motor recovery via the peri-infarct area in patients with corona radiata infarct.

Objectives: Diffusion tensor image tracography (DTT) could be useful for exploration of the state of the corticospinal tract at the subcortical white matter level. We investigated the neural pathway associated with motor recovery in the patients with corona radiata infarct (CR) using DTT.

Design: Three hemiparetic patients who showed severe weakness of the affected upper extremity at stroke onset, were recruited.

Cortical activation changes induced by visual biofeedback tracking training in chronic stroke patients.

Objectives: We tried to examine whether visual biofeedback tracking training (VBTT) can improve both the gait performance and cortical activation pattern in chronic stroke patients.

Design: We enrolled 10 chronic hemiparetic patients with stroke(mean age 46.3 +/- 5.

Motor outcome according to diffusion tensor tractography findings in the early stage of intracerebral hemorrhage.

We tried to investigate the motor outcome according to diffusion tensor tractography (DTT) findings for the corticospinal tract (CST) in the early stage for hemiparetic patients with intracerebral hemorrhage (ICH). Forty patients with severe paralysis of the affected side were enrolled. DTT was obtained in the early stage of the stroke (7-30 days) and was classified into four groups: type A, the CST originating from primary motor cortex was preserved around the hematoma; type B, the CST was similar to type A except the fiber originated from the adjacent areas to the primary motor cortex; type C, the CST was interrupted at or around the hematoma; and type D, the CST did not reach the hematoma due to degeneration (Fig.

Toll-like receptor 9 dependent activation of MAPK and NF-kB is required for the CpG ODN-induced matrix metalloproteinase-9 expression.

Unmethylated CpG oligodeoxynucleotides (CpG ODNs) activate immune cells to produce immune mediators. This study demonstrates that in murine macrophage RAW 264.7 cells, CpG ODN-mediated matrix metalloproteinase-9 (MMP-9) expression is regulated at transcriptional level and requires de novo protein synthesis.

Activation of toll-like receptor-9 induces matrix metalloproteinase-9 expression through Akt and tumor necrosis factor-alpha signaling.

CpG oligodeoxunucleotide (ODN) plays an important role in immune cell function. The present study examined whether temporal control of toll-like receptor (TLR)-9 by CpG ODN can regulate the expression of matrix metalloproteinase-9 (MMP-9). CpG ODN induced the release of tumor necrosis factor (TNF)-alpha and the expression of TNF receptor (TNFR)-II, but not of TNFR-I, in a time-dependent manner and stimulated significant, though delayed, MMP-9 expression.

Effect of ethanol extract of dried Chinese yam (Dioscorea batatas) flour containing dioscin on gastrointestinal function in rat model.

In this study, a 40% ethanol extract of Chinese yam flour (Dioscoreae rhizoma), containing 177 +/- 58 microg/mL of dioscin, was tested in order to evaluate its pharmacological effects on the gastrointestinal tracts of Sprague-Dawley rats. Via the ingestion of the Chinese yam extract, the secretion of gastric acid was suppressed in the rats, and gastrointestinal motility increased by as much as 10%. The fecal quantity of rats fed on the Chinese yam extract also increased, by more than 40% as compared with that of the controls.