The effects of combined static and dynamic stretching of anti-gravitational muscles on body flexibility and standing balance: A preliminary study of healthy young participants.

INTRODUCTION: Falling is a leading cause of injury-related death. Previous studies reported that an impairment of standing balance is one of the causative factors associated with falling. The combined use of static and dynamic stretching has been reported as a treatment method for improving standing balance. As one of the combined methods, stretching based on Mézières' concept, which has an efficacy on the improvement of body flexibility, has been used. However, it is not fully clear whether stretching based on Mézières' concept can improve standing balance. This study aimed to examine the effects of combined method of static and dynamic stretching of anti-gravitational muscles based on Mézières' concept on body flexibility and standing balance. METHODS: This study employed a quasi-randomized controlled trial design. Thirteen subjects were assigned randomly to one of two groups: stretching or control. A sit and reach test (SRT), functional reach test (FRT), and total trajectory length of center of pressure (COP) during static standing were assessed at pre- and post-intervention. An independent t-test was used to compare the rate of improvement between both groups at each assessment. RESULTS: The stretching group demonstrated a significantly larger rate of improvement in the total trajectory length of COP compared to the control group. In the SRT and FRT, the stretching group showed a trend toward improvement compared to the control group, but did not achieve statistical significance. CONCLUSIONS: The combined use of static and dynamic stretching of anti-gravitational muscles might have the potential to improve the standing balance.

The serum amyloid A3 promoter-driven luciferase reporter mice is a valuable tool to image early renal fibrosis development and shows the therapeutic effect of glucosyl-hesperidin treatment.

Tubulointerstitial fibrosis is a progressive process affecting the kidneys, causing renal failure that can be life-threatening. Thus, renal fibrosis has become a serious concern in the ageing population; however, fibrotic development cannot be diagnosed early and assessed noninvasively in both patients and experimental animal models. Here, we found that serum amyloid A3 (Saa3) expression is a potent indicator of early renal fibrosis; we also established in vivo Saa3/C/EBPß-promoter bioluminescence imaging as a sensitive and specific tool for early detection and visualization of tubulointerstitial fibrosis. Saa3 promoter activity is specifically upregulated in parallel with tumor necrosis factor α (TNF-α) and fibrotic marker collagen I in injured kidneys. C/EBPß, upregulated in injured kidneys and expressed in tubular epithelial cells, is essential for the increased Saa3 promoter activity in response to TNF-α, suggesting that C/EBPß plays a crucial role in renal fibrosis development. Our model successfully enabled visualization of the suppressive effects of a citrus flavonoid derivative, glucosyl-hesperidin, on inflammation and fibrosis in kidney disease, indicating that this model could be widely used in exploring therapeutic agents for fibrotic diseases.

Discovery of a sugar-based nanoparticle universally existing in boiling herbal water extracts and their immunostimulant effect.

Herbal medicine is mainly prepared from boiling herbal water extracts. Many epoch-making immunosuppressant drugs, such as glycyrrhizic acid (old example) and FTY720 (current example), were developed from herbal secondary metabolites in the boiling water extract by partition with organic solvents. However, few immunostimulants have been discovered by this method. Instead of the usual method, we aimed to find a novel immunostimulant component by two unique methods in the research of herbal medicine: ultracentrifugation and electron microscopy. The immunostimulant was not a secondary metabolite, as expected, but the structure was a nanoparticle formed by a polysaccharide. In addition, we clarified the immune effect of the nanoparticle. Intake of the nanoparticle by phagocytosis resulted in immunostimulant effects by increasing the genes and proteins of inflammatory cytokines in macrophage cells. The immunostimulant effects were inhibited by a phagocytosis inhibitor, cytochalasin D. To the best of our knowledge, this study is the first to describe the discovery of a nanoparticle in boiling herbal water extracts and its immunostimulant properties. This study will provide additional understanding of the efficacy of herbal medicine, in that the immunostimulant nanoparticle universally exists in boiling herbal water extracts. Thus, traditional herbal medicine may be an oldest known nanomedicine. Furthermore, this study suggests that the immunostimulant nanoparticle simply can be obtained from herbal medicine only by ultracentrifugation. We hope that this simple strategy will substantially contribute to drug development, including vaccine adjuvant, in the future.

Anti-enterovirus 71 activities of Melissa officinalis extract and its biologically active constituent rosmarinic acid.

Enterovirus 71 (EV71) infection is endemic in the Asia-Pacific region. No specific antiviral drug has been available to treat EV71 infection. Melissa officinalis (MO) is a medicinal plant with long history of usage in the European and Middle East. We investigated whether an aqueous solution of concentrated methanolic extract (MOM) possesses antiviral activity. MOM inhibited plaque formation, cytopathic effect, and viral protein synthesis in EV71-infected cells. Using spectral techniques, we identified rosmarinic acid (RA) as a biologically active constituent of MOM. RA reduced viral attachment and entry; cleavage of eukaryotic translation initiation factor 4 G (eIF4G); reactive oxygen species (ROS) generation; and translocation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) from nucleus to cytoplasm. It alleviated EV71-induced hyperphosphorylation of p38 kinase and EPS15. RA is likely to suppress ROS-mediated p38 kinase activation, and such downstream molecular events as hnRNP A1 translocation and EPS15-regulated membrane trafficking in EV71-infected cells. These findings suggest that MO and its constituent RA possess anti-EV71 activities, and may serve as a candidate drug for therapeutic and prophylactic uses against EV71 infection.

Antiviral activities of Schizonepeta tenuifolia Briq. against enterovirus 71 in vitro and in vivo.

No effective drug is currently available for treatment of enterovirus 71 (EV71) infection. Schizonepeta tenuifolia Briq. (ST) has been used as a herbal constituent of traditional Chinese medicine. We studied whether the aqueous extract of Schizonepeta tenuifolia Briq (STE) has antiviral activity. STE inhibited replication of EV71, as evident by its ability to diminish plaque formation and cytopathic effect induced by EV71, and to inhibit the synthesis of viral RNA and protein. Moreover, daily single-dose STE treatment significantly improved the survival of EV71-infected mice, and ameliorated the symptoms. Mechanistically, STE exerts multiple effects on enteroviral infection. Treatment with STE reduced viral attachment and entry; the cleavage of eukaryotic translation initiation factor 4 G (eIF4G) by EV71 protease, 2Apro; virus-induced reactive oxygen species (ROS) formation; and relocation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) from the nucleus to the cytoplasm. It was accompanied by a decline in EV71-associated hyperphosphorylation of p38 kinase and EPS15. It is plausible that STE may inhibit ROS-induced p38 kinase activation, and subsequent hnRNP A1 relocation and EPS15-mediated membrane trafficking in infected cells. These findings suggest that STE possesses anti-EV71 activities, and may serve as health food or candidate antiviral drug for protection against EV71.

Ethanolic extract of Thevetia peruviana flowers enhances TNF-α and TRAIL-induced apoptosis of human cervical cancer cells via intrinsic and extrinsic pathways.

Tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) are promising candidates for cancer treatment due to their ability to induce apoptosis through death receptor stimulation. However, their usage may be limited due to the resistance of cancer cells to TNF-α- and TRAIL-induced apoptosis. Currently, there is interest in screening for natural products that can sensitize cancer cells to TNF-α- and TRAIL-induced apoptosis for their use in combination with TNF-α or TRAIL. It was previously reported that the bark extract of Thevetia peruviana showed a reversal effect on TRAIL-resistance in human gastric adenocarcinoma cell lines. In the present study, the effects of the ethanolic extract of T. peruviana flowers on TNF-α- and TRAIL-induced apoptosis of human cervical cancer HeLa cells were investigated in vitro by determining cell viability and apoptosis using a WST-1 cell proliferation assay and immunoblot analysis, respectively. The ethanolic extract of T. peruviana flowers promoted TNF-α and TRAIL-mediated cell death through the activation of the caspase cascade, poly(ADP-ribose) polymerase and BH3-interacting domain death agonist cleavage. Combined treatment using the extract plus TNF-α resulted in downregulation of anti-apoptotic protein, including myeloid cell leukemia sequence-1, B-cell lymphoma-extra large (Bcl-XL), X-linked inhibitor of apoptosis protein and survivin, while the combined treatment with TRAIL downregulated Bcl-XL. Thus, the ethanolic extract of T. peruviana flowers has potential in sensitizing the TNF-α- and TRAIL-induced apoptosis of HeLa cells via the intrinsic and extrinsic pathways.

Influence of transcutaneous electrical nerve stimulation conditions on disynaptic reciprocal Ia inhibition and presynaptic inhibition in healthy adults.

This study investigated the influence of stimulus conditions of transcutaneous electrical nerve stimulation (TENS) on disynaptic reciprocal Ia inhibition (RI) and presynaptic inhibition (D1 inhibition) in healthy adults. Eight healthy participants received TENS (stimulus frequencies of 50, 100, and 200 Hz) over the deep peroneal nerve and tibialis anterior (TA) muscle in the resting condition for 30 min. At pre- and post-intervention, the RI from the TA to the soleus (SOL) and D1 inhibition of the SOL alpha motor neuron were assessed by evoked electromyography. The results showed that RI was not changed by TENS at any stimulus frequency condition. Conversely, D1 inhibition was significantly changed by TENS regardless of the stimulus frequency. The present results and previous studies pertaining to RI suggest that the resting condition might strongly influence the lack of pre- vs. post-intervention change in the RI. Regarding the D1 inhibition, the present results suggest that the effect of TENS might be caused by post-tetanic potentiation. The knowledge gained from the present study might contribute to a better understanding of fundamental studies of TENS in healthy adults and its clinical application for stroke survivors.

Enhancement of hyperthermia-induced apoptosis by 5Z-7-oxozeaenol, a TAK1 inhibitor, in A549 cells.

KRAS mutant lung cancers have long been considered as untreatable with drugs. Transforming growth factor-ß-activated kinase 1 (TAK1) appears to play an anti-apoptotic role in response to multiple stresses and has been reported to be a responsive kinase that regulates cell survival in KRAS-dependent cells. In this study, in order to find a useful approach to treat KRAS mutant lung cancer, we focused on the combined effects of 5Z-7-oxozeaenol, a TAK1 inhibitor, with hyperthermia (HT) in KRAS mutant lung cancer cell line A549. Annexin V-FITC/PI assay, cell cycle analysis, and colony formation assay revealed a significant enhancement in apoptosis induced by HT treatment, when the cells were pre-incubated with 5Z-7-oxozeaenol in a dose-dependent manner. The enhanced apoptosis by 5Z-7-oxozeaenol was accompanied by a significant increase in reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential (MMP). In addition, western blot showed that 5Z-7-oxozeaenol enhanced HT-induced expressions of cleaved caspase-3, cleaved caspase-8, and HSP70 and decreased HT-induced expressions of Bcl-2, p-p38, p-JNK, and LC3. Moreover, 5Z-7-oxozeaenol pre-treatment resulted in a marked elevation of intracellular calcium level which might be associated with endoplasmic reticulum (ER) stress-related pathway. Taken together, our data provides further insights of the mechanism of action of 5Z-7-oxozeaenol and HT treatment, and their potential application as a novel approache to treat patients with KRAS mutant lung cancer.

Modulation of spinal inhibitory reflexes depends on the frequency of transcutaneous electrical nerve stimulation in spastic stroke survivors.

Neurophysiological studies in healthy subjects suggest that increased spinal inhibitory reflexes from the tibialis anterior (TA) muscle to the soleus (SOL) muscle might contribute to decreased spasticity. While 50 Hz is an effective frequency for transcutaneous electrical nerve stimulation (TENS) in healthy subjects, in stroke survivors, the effects of TENS on spinal reflex circuits and its appropriate frequency are not well known. We examined the effects of different frequencies of TENS on spinal inhibitory reflexes from the TA to SOL muscle in stroke survivors. Twenty chronic stroke survivors with ankle plantar flexor spasticity received 50-, 100-, or 200-Hz TENS over the deep peroneal nerve (DPN) of the affected lower limb for 30 min. Before and immediately after TENS, reciprocal Ia inhibition (RI) and presynaptic inhibition of the SOL alpha motor neuron (D1 inhibition) were assessed by adjusting the unconditioned H-reflex amplitude. Furthermore, during TENS, the time courses of spinal excitability and spinal inhibitory reflexes were assessed via the H-reflex, RI, and D1 inhibition. None of the TENS protocols affected mean RI, whereas D1 inhibition improved significantly following 200-Hz TENS. In a time-series comparison during TENS, repeated stimulation did not produce significant changes in the H-reflex, RI, or D1 inhibition regardless of frequency. These results suggest that the frequency-dependent effect of TENS on spinal reflexes only becomes apparent when RI and D1 inhibition are measured by adjusting the amplitude of the unconditioned H-reflex. However, 200-Hz TENS led to plasticity of synaptic transmission from the antagonist to spastic muscles in stroke survivors.

Inhibition of p38 mitogen-activated protein kinase potentiates the apoptotic effect of berberine/tumor necrosis factor-related apoptosis-inducing ligand combination therapy.

It was previously reported that berberine (BBR) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) exhibited a synergistic apoptotic effect on triple negative breast cancer (TNBC) cells. In addition, the BBR/TRAIL combination treatment sensitized TRAIL-resistant TNBC cells to TRAIL. The aim of the present study was to investigate a novel pathway for enhancing the apoptotic effect of BBR/TRAIL through mitogen-activated protein kinases (MAPKs). Selective inhibitors and small interfering RNAs were utilized to understand the role of p38 MAPK in this pathway. The results demonstrated that p38 MAPK was activated in response to the combination therapy in TRAIL-resistant TNBC cells. In addition, it was revealed that the inhibition of p38 enhanced apoptosis in epidermal growth factor receptor (EGFR)-overexpressing MDA-MB-468 TNBC cells and EGFR-mutant PC-9 non-small-cell lung carcinoma cells, which was associated with the downregulation of EGFR serine phosphorylation. Viability assays for these two cell lines also confirmed the significant reduction of cell viability following p38 inhibition in BBR/TRAIL-treated cells. In conclusion, the present study provided novel evidence for the role of p38 in suppressing BBR/TRAIL-mediated apoptosis and its association with EGFR, which may explain the mechanism of treatment resistance in certain types of cancer.

Analysis of chemical properties of edible and medicinal ginger by metabolomics approach.

In traditional herbal medicine, comprehensive understanding of bioactive constituent is important in order to analyze its true medicinal function. We investigated the chemical properties of medicinal and edible ginger cultivars using a liquid-chromatography mass spectrometry (LC-MS) approach. Our PCA results indicate the importance of acetylated derivatives of gingerol, not gingerol or shogaol, as the medicinal indicator. A newly developed ginger cultivar, Z. officinale cv. Ogawa Umare or "Ogawa Umare" (OG), contains more active ingredients, showing properties as a new resource for the production of herbal medicines derived from ginger in terms of its chemical constituents and rhizome yield.

Immune adjuvant effect of Juzentaihoto, a Japanese traditional herbal medicine, on tumor vaccine therapy in a mouse model.

Japanese traditional herbal medicine (Kampo) have been used to improve the general physical condition after surgery and to mitigate the side effects of radiation and chemotherapy in tumor patients. Juzentaihoto (JTT) consists of ten medical herbs, and is also called Shi-Quan-Da-Bu-Tang in Chinese herbal medicine. Among Kampo medicines, JTT has especially gained attention as a biological response modifier. Currently, clinical trials of various tumor vaccine therapies are being performed world-wide. However, tumor antigens that are inoculated as vaccines do not have high immunogenicity; thus, it is difficult to obtain an effective therapeutic effect. Thus, it is necessary to develop a tumor vaccine adjuvant that is more potent and very safe. In the present study, we examined the efficacy of JTT as an oral adjuvant when given together with tumor vaccines. As a result, JTT enhanced the phagocytic ability of OVA antigen and the presentation ability of OVA antigen in dendritic cells in vitro. Furthermore, tumor growth was markedly decreased, and the survival period was significantly prolonged in mice inoculated with mouse lymphoma, which is expressed with tumor model antigen. In conclusion, these findings suggest that JTT can be used with tumor vaccines as an immune adjuvant.

Inhibitory effect of Moutan Cortex aqueous fraction on mast cell-mediated allergic inflammation.

Moutan Cortex and its major compounds have been shown to possess various biological activities, including anti-inflammatory properties. However, the effects of Moutan Cortex aqueous fraction (MCA) and its molecular mechanisms have yet to be elucidated. In this study, we attempted to evaluate the effects of MCA on mast cell-mediated allergy inflammation in vitro and in vivo compared with major Moutan Cortex compounds. Thus, we examined the anti-inflammatory effects of a water extract of Moutan Cortex by comparing the inhibition of ß-hexosaminadase and tumor necrosis factor-α (TNF-α) release in an aqueous fraction with other major compounds of Moutan Cortex. The inhibitory mechanism of MCA was investigated by western blotting in IgE-mediated DNP-BSA-stimulated RBL-2H3 cells. We confirmed the pharmacological effects of MCA on compound 48/80-induced allergic reactions in a mouse model by assessing scratching behavior and passive cutaneous anaphylaxis (PCA)-like reaction. Consequently, MCA inhibited IgE-mediated DNP-BSA-induced ß-hexosaminadase and TNF-α release via inactivation of p38, ERK, Akt, and NF-κB in RBL-2H3 cells. MCA reduced compound 48/80-induced PCA reaction and scratching behavior in mice. This inhibitory effect of MCA is more potent than major compounds of Moutan Cortex. In conclusion, our results suggest that MCA has more potential in the treatment of allergic inflammatory diseases compared to other major compounds of Moutan Cortex.

NMES with rTMS for moderate to severe dysfunction after stroke.

BACKGROUND: Motor dysfunction after stroke might be improved by neuromuscular electrical stimulation (NMES) combined with 1 Hz repetitive transcranial magnetic stimulation (rTMS) in patients with moderate and severe motor dysfunction. OBJECTIVE: This preliminary study tested the effect of this treatment combination. METHODS: Fifteen patients (60.5 ± 10.3 years old) participated in the study. All patients had been affected by cerebral artery infarction or hemorrhage and had moderate or severe motor dysfunction in their affected hand. The patients received NMES at paretic wrist extensor muscles combined with rTMS over the unaffected M1 hemisphere twice a day, six days/week over two weeks. All participants underwent the following battery of tests to evaluate the motor function of the affected hand: Upper limb Fugl-Meyer Assessment (UFMA), Wolf Motor Function Test (WMFT), and Box and Block Test (BBT). RESULTS: UFMA, WMFT, and BBT scores improved significantly after the study. CONCLUSIONS: These results suggest that NMES combined with rTMS could be useful for recovery of moderate and severe motor function after stroke.

The long-term effects of a kampo medicine, juzentaihoto, on maintenance of antibody titer in elderly people after influenza vaccination.

We have performed a broad-ranging analysis of the adjuvant effect of a Kampo medicine, juzentaihoto (JTT), on influenza vaccination in a multicenter randomized controlled trial. In this study, the enhancing effect of JTT on antibody titer after influenza vaccination was studied for 28 weeks in elderly people who were in the high-risk group for influenza infection. In total, 91 subjects over 65 years old were recruited from four long-term-care facilities located in Chiba, Gunma, and Toyama prefectures in Japan. Participants were randomly assigned to the JTT and the control groups. Blood samples were taken at 4 weeks before vaccination, at the time of vaccination, and then at 4, 8, 12, and 24 weeks after vaccination. The hemagglutination inhibition (HI) titers against A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 were then manually measured. A significant increase in HI titer against H3N2 was observed at week 8 after vaccination in the JTT group compared with the control group (P = 0.0229), and the HI titer of the JTT group significantly increased from 4 to 24 weeks (P = 0.0468), compared with the control group. In conclusion, our results indicated that JTT increased and prolonged antibody production against A/Victoria/210/2009 (H3N2), in particular, after influenza vaccination.

Procyanidin C1 from Cinnamomi Cortex inhibits TGF-ß-induced epithelial-to-mesenchymal transition in the A549 lung cancer cell line.

Cancer metastasis is one of the most critical events in cancer patients, and the median overall survival of stage IIIb or IV patients with metastatic lung cancer in the TNM classification is only 8 or 5 months, respectively. We previously demonstrated that Juzentaihoto, a Japanese traditional medicine, can inhibit cancer metastasis through the activation of macrophages and T cells in mouse cancer metastatic models; however, the mechanism(s) through which Juzentaihoto directly affects tumor cells during the metastasis process and which herbal components from Juzentaihoto inhibit the metastatic potential have not been elucidated. In this study, we focused on the epithelial-to-mesenchymal transition (EMT), which plays an important role in the formation of cancer metastasis. We newly determined that only the Cinnamomi Cortex (CC) extract, one of 10 herbal components of Juzentaihoto, inhibits TGF-ß-induced EMT. Moreover, the contents of catechin trimer in CC extracts were significantly correlated with the efficacy of inhibiting TGF-ß-induced EMT. Finally, the structure of the catechin trimer from CC extract was chemically identified as procyanidin C1 and the compound showed inhibitory activity against TGF-ß-induced EMT. This illustrates that procyanidin C1 is the main active compound in the CC extract responsible for EMT inhibition and that procyanidin C1 could be useful as a lead compound to develop inhibitors of cancer metastasis and other diseases related to EMT.

Cytotoxic cardiac glycosides from the roots of Streptocaulon juventas.

Chemical investigation on the 75% ethanol extract of the roots of Streptocaulon juventas afforded two new cardiac glycosides, digitoxigenin 3-O-[O-ß-D-glucopyranosyl-(1 → 4)-2-O-acetyl-ß-D-digitalopyranoside] (1) and periplogenin 3-O-[O-ß-D-glucopyranosyl-(1 → 4)-O-ß-D-glucopyranosyl-(1 → 4)-ß-D-cymaropyranoside] (2), and thirteen known cardenolides. Structures were elucidated by spectral methods. This is the first report of the isolation of compounds 3, 10, 14, and 15 from plants of the Streptocaulon genus, while 4, 11, and 12 are hitherto unreported from Streptocaulon juventas. All the compounds were in vitro evaluated for their cytotoxic activities against the A549 cell line, and seven effective cardiac glycosides were screened against the PC-9 cell line by WST assay, which also showed strong antiproliferation activities. Moreover, the characteristic morphological changes in PC-9 cells treated with cardenolides indicated cell inhibition due to apoptosis. These results revealed that these compounds possessed potential antitumor activities.

Gomisin A enhances tumor necrosis factor-α-induced G1 cell cycle arrest via signal transducer and activator of transcription 1-mediated phosphorylation of retinoblastoma protein.

Gomisin A, a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra chinensis, has been reported as an anti-cancer substance. In this study, we investigated the effects of gomisin A on cancer cell proliferation and cell cycle arrest in HeLa cells. Gomisin A significantly inhibited cell proliferation in a dose-dependent manner after 72 h treatment, especially in the presence of tumor necrosis factor-α (TNF-α), due to cell cycle arrest in the G1 phase with the downregulation of cyclin D1 expression and Retinoblastoma (RB) phosphorylation. In addition, gomisin A in combination with TNF-α strongly suppressed the expression of signal transducer and activator of transcription 1 (STAT1). Inhibition of STAT1 pathways by a small-interfering RNA against STAT1 and AG490 Janus kinase (JAK) kinase inhibitor AG490 reduced the cyclin D1 expression and RB phosphorylation, indicating that JAK-mediated STAT1 activation is involved in gomisin A-induced G1 cell cycle arrest.

Effect of Hachimijiogan against Renal Dysfunction and Involvement of Hypoxia-Inducible Factor-1α in the Remnant Kidney Model.

In chronic renal failure, hypoxia of renal tissue is thought to be the common final pathway leading to end-stage renal failure. In this study the effects of hachimijiogan, a Kampo formula, were studied with respect to hypoxia-inducible factor (HIF). Using remnant kidney rats, we studied the effects of hachimijiogan on renal function in comparison with angiotensin II receptor blocker. The result showed that oral administration of hachimijiogan for seven days suppressed urinary protein excretion and urinary 8-OHdG, a marker of antioxidant activity, equally as well as oral administration of candesartan cilexetil. In contrast, the protein volume of HIF-1α in the renal cortex was not increased in the candesartan cilexetil group, but that in the hachimijiogan group was increased. In immunohistochemical studies as well, the expression of HIF-1α of the high-dose hachimijiogan group increased compared to that of the control group. Vascular endothelial growth factor and glucose transporter 1, target genes of HIF-1α, were also increased in the hachimijiogan group. These results suggest that hachimijiogan produces a protective effect by a mechanism different from that of candesartan cilexetil.

Gomisin N enhances TNF-α-induced apoptosis via inhibition of the NF-κB and EGFR survival pathways.

Tumor necrosis factor (TNF-α) is a pleiotropic cytokine that plays an important role in the control of cell proliferation, differentiation, and apoptosis. TNF-α-induced apoptosis is limited by TAK1-mediated activation of NF-κB (mainly p65-p50 hetrodimer) signaling pathway. We have recently reported that TAK1 regulates phosphorylation of EGFR at Ser-1046/7 through p38 MAPK, which cooperates with NF-κB in TNF-α-induced apoptosis. The present study investigated the effect of gomisins A and N, dibenzocyclooctadiene lignans isolated from the fruit of Schisandra chinensis, on TNF-α-induced apoptosis in HeLa cells. Gomisins A and N strongly promoted TNF-α-induced cleavage of caspase-3 and PARP-1, which are key markers of apoptosis. We found that gomisin N, but not gomisin A, inhibited the TNF-α-induced activation of NF-κB by suppressing the activation of IKKα. Gomisin N also inhibited p38-mediated phosphorylation of the EGFR at Ser-1046/7 and subsequent endocytosis of EGFR, another prosurvival pathway. The findings suggested that gomisin N enhanced TNF-α-induced apoptosis by suppressing of NF-κB and EGFR signaling pathways.