The American Journal of Chinese Medicine

Tai Chi has frequently been used as a preventive measure against falling in at-risk populations. However, studies have yielded contradictory results, and literature reviews have considered only a small number of trials and have not addressed some key aspects, such as sources of heterogeneity and publication bias. This study includes 13 controlled trials published before June 2015 that analyzed the effectiveness of Tai Chi in fall prevention in populations of frail and at-risk adults. The effect measure used in this meta-analysis was absolute risk reduction (ARR) with a 95% confidence interval (CI). According to our findings, practice of Tai Chi significantly prevents the risk of falling (ARR, $-0.10$; 95% CI: $-0.06$, $-0.15$). The heterogeneity of results across the trials was low, with a reduced risk of publication bias, and no significant effect differences were observed between studies comparing Tai Chi with other interventions or non-treatment. We therefore conclude that Tai Chi is more effective than other measures, or no intervention, for fall prevention in at-risk populations. Further research is warranted to analyze the consequences of falls and to study the episodes rather than the cases of falls.

The rhizome of Coptis chinensis is commonly used in traditional Chinese medicine alone or in combination with other herbs to treat diseases characterized by causing oxidative stress including inflammatory diseases, diabetes mellitus and neurodegenerative diseases. In particular, there is emerging evidence that Coptis chinensis is effective in the treatment of neurodegenerative diseases associated with oxidative stress. Hence, the aim of this study was to investigate the neuroprotective effect of Coptis chinensis in vitro and in vivo using MPP${}^{+}$ and MPTP models of Parkinson’s disease. MPP${}^{+}$ treated human SH-SY5Y neuroblastoma cells were used as a cell model of Parkinson’s disease. A 24h pre-treatment of the cells with the watery extract of Coptis chinensis significantly increased cell viability, as well as the intracellular ATP concentration and attenuated apoptosis compared to the MPP${}^{+}$ control. Further experiments with the main alkaloids of Coptidis chinensis, berberine, coptisine, jaterorrhizine and palmatine revealed that berberine and coptisine were the main active compounds responsible for the observed neuroprotective effect. However, the full extract of Coptis chinensis was more effective than the tested single alkaloids. In the MPTP-induced animal model of Parkinson’s disease, Coptis chinensis dose-dependently improved motor functions and increased tyrosine hydroxylase-positive neurons in the substantia nigra compared to the MPTP control. Based on the results of this work, Coptis chinensis and its main alkaloids could be considered potential candidates for the development of new treatment options for Parkinson’s disease.

Berberine exerts neuroprotective and modulates hypoxia inducible factor-1-alpha (HIF-1$\alpha )$. Based on the role of HIF-1$\alpha$ in hypoxia preconditioning and association between HIF-1$\alpha$ and sphingosine-1-phosphate (S1P), we hypothesized that berberine preconditioning (BP) would ameliorate the cerebral injury induced by ischemia through activating the system of HIF-1$\alpha$ and S1P. Adult male rats with middle cerebral artery occlusion (MCAO) and rat primary cortical neurons treated with oxygen and glucose deprivation (OGD) with BP at 24h (40mg/kg) and 2h (10${}^{-6}$mol/L), respectively, were used to determine the neuroprotective effects. The HIF-1$\alpha$ accumulation, and S1P metabolism were assayed in the berberine-preconditioned neurons, and the HIF-1$\alpha$-mediated transcriptional modulation of sphingosine kinases (Sphk) 1 and 2 was analyzed using chromatin immunoprecipitation and real-time polymerase chain reaction. BP significantly prevented cerebral ischemic injury in the MCAO rats at 24h and 72h following ischemia/reperfusion. In OGD-treated neurons, BP enhanced HIF-1$\alpha$ accumulation with activation of PI3K/Akt, and induced S1P production by activating Sphk2 via the promotion of HIF-1$\alpha$-mediated Sphk2 transcription. In conclusion, BP activated endogenous neuroprotective mechanisms associated with the S1P/HIF-1 pathway and helped protect neuronal cells against hypoxia/ischemia.

Interest in the health benefits of flavonoids, particularly their effects on neurodegenerative disease, is increasing. This study evaluated the role of baicalein, a flavonoid compound isolated from the traditional Chinese medicine Scutellaria baicalensis, in glutamate release and glutamate neurotoxicity in the rat hippocampus. In the rat hippocampal nerve terminals (synaptosomes), baicalein inhibits depolarization-induced glutamate release, and this phenomenon is prevented by chelating the extracellular Ca${}^{2+}$ ions and blocking presynaptic Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel activity. In slice preparations, whole cell patch-clamp experiments revealed that baicalein reduced the frequency of miniature excitatory postsynaptic currents, without affecting their amplitude. In a kainic acid rat model, intraperitoneally administering baicalein to rats before the kainic acid intraperitoneal injection substantially attenuated kainic acid-induced neuronal cell death, c-Fos expression, and the activation of the mammalian target of rapamycin in the hippocampus. This study is the first to demonstrate that the natural compound baicalein inhibits glutamate release from hippocampal nerve terminals, and executes a protective action against kainic acid-induced excitotoxicity in vivo. The findings enhance the understanding of baicalein’s action in the brain, and suggest that this natural compound is valuable for treating brain disorders related to glutamate excitotoxicity.

Baizhu, the dried rhizome of Atractylodes Macrocephala Koidz (Compositae), is one of the most important traditional Chinese herbal medicines. Baizhu is generally used to treat digestive disorders and diabetes in Asian countries. This study investigates the activity of two sesquiterpenes isolated from Baizhu, atractylenolide I (AT-I) and atractylenolide II (AT-II), for their effects on glucose uptake in mouse skeletal muscle C2C12 cells, and the corresponding mechanism. These compounds show a significant stimulatory effect on glucose uptake in C2C12 myotubes. Both AT-I and AT-II significantly increased GLUT4 but not GLUT1 protein levels, and promoted GLUT4 translocation to the plasma membrane. The increased glucose uptake induced by these compounds is associated with activation of AMP-activated protein kinase (AMPK) and PI3K/Akt pathways in these cells. Further studies have indicated that AT-I and AT-II ameliorate TNF-$\alpha$-induced insulin resistance in C2C12 myotubes. In summary, our findings highlight the insulin mimetic activity of Baizhu in myotubes, and provide insights into the action mechanism underlying these effects. Our findings may also prove highly relevant to the development of novel therapeutic applications for these compounds.

In North America, a high proportion of pregnant women use herbal medications including North American ginseng. This medicinal plant contains high amounts of triterpene saponins (ginsenosides), which are the main bioactive compounds. It is important to assess ginseng’s impact on all reproductive functions to ensure the safety of pregnant women and fetuses. In this study, we defined the concentration-responsive effects of North American alcoholic and aqueous ginseng extracts on preimplantation development in vitro and on pregnancy and post-partum development in the mouse. Two-cell mouse embryos were cultured with 5 different concentrations of whole ginseng root extracts, or ginsenosides Rb1, Rg1 and Re alone, a combinatorial ginsenoside solution and a crude polysaccharide fraction solution. Embryonic development and recovery from each treatment was assessed. To investigate the in vivo effects of ginseng extracts, female mice were gavaged with 50mg/kg/day, 500mg/kg/day or 2000mg/kg/day of either extract (treatment) or water (sham) for 2 weeks prior to mating and throughout gestation. Gestation period, litter size, pup growth and pup sex ratio were evaluated. Oral ginseng consumption did not significantly affect fertility or pregnancy in the mouse. High doses of ginseng (2000mg/kg/day) decreased maternal weight gain. Direct treatment of preimplantation embryos in vitro demonstrated that ALC and AQ extract treatment reduced development in a concentration responsive manner, while only ALC extract effects were largely reversible. Treatments with individual or combinatorial ginsenosides, or the polysaccharide fraction solution alone did not impair preimplantation development, in vitro. In conclusion, maternal oral consumption of ginseng has little negative impact on pregnancy in the mouse, however, direct exposure to ginseng extract during mouse preimplantation development in vitro is detrimental.

Hypoxia-inducible factor-1 (HIF-1) is an $\alpha ∕\beta$ dimeric transcription factor. Because HIF-1$\alpha$ is instable with oxygen, HIF-1 is scarce in normal mammalian cells. However, HIF-1$\alpha$ is expressed in pathological conditions such as cancer and obesity. Inhibiting HIF-1$\alpha$ may be of therapeutic value for these pathologies. Here, we investigated whether emodin, derived from the herb of Rheum palmatum L, which is also known as Chinese rhubarb, and is native to China, regulates HIF-1$\alpha$ expression. Male C57BL/6 mice without or with diet-induced obesity were treated with emodin for two weeks, while control mice were treated with vehicle. HIF-1$\alpha$ expression was determined by Western blot. We found that emodin inhibited obesity-induced HIF-1$\alpha$ expression in liver and skeletal muscle but did not regulate HIF-1$\alpha$ expression in the kidneys or in intra-abdominal fat. In vitro, emodin inhibited HIF-1$\alpha$ expression in human HepG2 hepatic cells and Y1 adrenocortical cells. Further, we investigated the mechanisms of HIF-1$\alpha$ expression in emodin-treated HepG2 cells. First, we found that HIF-1$\alpha$ had normal stability in the presence of emodin. Thus, emodin did not decrease HIF-1$\alpha$ by stimulating its degradation. Importantly, emodin decreased the activity of the signaling pathways that led to HIF-1$\alpha$ biosynthesis. Interestingly, emodin increased HIF-1$\alpha$ mRNA in HepG2 cells. This may be a result of feedback in response to the emodin-induced decrease in the protein of HIF-1$\alpha$. In conclusion, emodin decreases hepatic HIF-1$\alpha$ by inhibiting its biosynthesis.

An effective method for activating macrophages and deriving a Th1 immune response could be used to improve the defenses of hosts. In this study, we investigated the immunomodulation effect and the related signaling mechanism of $\beta$-(1,3)-glucan, isolated from the Agrobacterium species. Here, we found that $\beta$-(1,3)-glucan predominantly induced the tumor necrosis factor (TNF)-$\alpha$, interleukin (IL)-1$\beta$, IL-6, IL-12p70, and nitric oxide, which was dependent on mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-$\kappa$B signaling. Additionally, $\beta$-(1,3)-glucan treatment significantly up-regulated the expression of the co-stimulatory molecules CD80 and CD86, and also significantly increased the expression of iNOS and Dectin-1, which is a transmembrane protein that binds $\beta$-glucan and associates with macrophage activation. Importantly, the splenic T cells co-cultured with $\beta$-(1,3)-glucan-treated macrophages produced the a Th1 cytokine profile that includes high levels of IFN-$\gamma$, but not IL-4 (Th2 cytokine), indicating that $\beta$-(1,3)-glucan contributes to Th1 polarization of the immune response. Taken together, our results suggest that $\beta$-(1,3)-glucan isolated from Agrobacterium species can induce macrophage activation through the MAPK and NF-$\kappa$B signaling pathway, as well as Th1 polarization.

Inhaled corticosteroids (ICS) are widely used to manage chronic obstructive pulmonary disease (COPD). However, withdrawal of ICS generally causes various adverse effects, warranting careful management of the ICS withdrawal. Pinellia ternata, a traditional Chinese herbal medicine, has been used to treat respiratory diseases in China for centuries. Here, we investigated its role in antagonizing ICS withdrawal-induced side effects, and explored the underlying mechanisms. The rat COPD model was established using a combination of passive cigarette smoking and intratracheal instillation of lipopolysaccharide (LPS). COPD rats were treated with saline or budesonide inhalation, or with budesonide inhalation followed by saline inhalation or Pinellia ternata gavage. The number of goblet cells and the level of mucin 5AC (MUC5AC) were enhanced by budesonide withdrawal. Pinellia ternata treatment significantly blocked these effects. Further, Pinellia ternata treatment reversed budesonide withdrawal-induced increase of interleukin 1$\beta$ (IL-1$\beta )$ and tumor necrosis factor $\alpha$ (TNF-$\alpha$) levels in bronchoalveolar lavage fluid (BALF). Extracellular signal-regulated kinase (ERK), but neither p38 nor c-Jun N-terminal kinase (JNK), was activated by budesonide withdrawal, and the activation was blocked by Pinellia ternata treatment. The MUC5AC expression was positively correlated with goblet cell number, IL-1$\beta$ and TNF-$\alpha$ levels, and ERK activity. Pinellia ternata treatment protected the airway from ICS withdrawal-induced mucus hypersecretion and airway inflammation by inhibiting ERK activation. Pinellia ternata treatment may represent a novel therapeutic strategy to prevent ICS withdrawal-induced side effects in COPD patients.

Forsythiae Fructus, the fruits of Forsythia suspensa (Thunb.) Vahl, Lianqiao in Chinese, is one of the most fundamental herbs in traditional Chinese medicine (TCM). It is a typical heat-clearing and detoxicating herb, according to TCM theory. In this study, we investigated the antitumor effect of Forsythiae Fructus aqueous extract (FAE) on B16-F10 melanoma cells in vivo. The transplanted B16-F10 melanoma in C57BL/6 mice was established and used for the evaluation of the in vivo antitumor effect of FAE. FAE strongly inhibited the growth of B16-F10 cells in vitro and the tumor in vivo. The survival time of tumor-bearing mice was significantly prolonged by FAE. FAE inhibited cancer cell proliferation and angiogenesis in the tumor, as indicated by the decreased expressions of Ki67 and CD31. The levels of ROS, MDA, TNF-$\alpha$ and IL-6 decreased, while GSH increased in the FAE treatment group, indicating FAE possesses strong anti-oxidative and anti-inflammatory activity. The expression of anti-oxidant proteins Nrf-2 and HO-1, tumor suppressors P53 and p-PTEN, and the MAPK pathways in tumor tissues were upregulated by FAE treatment. These data demonstrated that FAE exhibited strong antitumor activity against B16-F10 murine melanoma both in vitro and in vivo. The antitumor effect of FAE involved decreases in oxidative stress and inflammation in the tumor, which is closely related to the heat-clearing and detoxicating properties of FAE.

Most cancer cells predominantly produce ATP by maintaining a high rate of lactate fermentation, rather than by maintaining a comparatively low rate of tricarboxylic acid cycle, i.e., Warburg’s effect. In the pathway, the pyruvate produced by glycolysis is converted to lactic acid by lactate dehydrogenase (LDH). Here, we demonstrated that water extracts from the seeds of Myristica fragrans Houtt. (MF) inhibit the in vitro enzymatic activity of LDH. MF effectively suppressed cell growth and the overall Warburg effect in HT29 human colon cancer cells. Although the expression of LDH-A was not changed by MF, both lactate production and LDH activity were decreased in MF-treated cells under both normoxic and hypoxic conditions. In addition, intracellular ATP levels were also decreased by MF treatment, and the uptake of glucose was also reduced by MF treatment. Furthermore, the experiment on tumor growth in the in vivo mice model revealed that MF effectively reduced the growth of allotransplanted Lewis lung carcinoma cells. Taken together, these results suggest that MF effectively inhibits cancer growth and metabolism by inhibiting the activity of LDH, a major enzyme responsible for regulating cancer metabolism. These results implicate MF as a potential candidate for development into a novel drug against cancer through inhibition of LDH activity.

Urokinase receptor (uPAR) is enhanced in many human cancer cells and is frequently an indicator of poor prognosis. Activation of $\alpha 5\beta$1-integrin requires caveolin-1 and is regulated by uPAR. However, the underlying molecular mechanism responsible for the interaction between uPAR and $\alpha 5\beta$1-integrin remains obscure. We found that modified regular Panax ginseng extract (MRGX) had a negative modulating effect on the uPAR/$\alpha 5\beta$1-integrin interaction, disrupted the uPAR/integrin interaction by modulating caveoline-1, and caused early apoptosis in cancer cells. Additionally, we found that siRNA-mediated caveoline-1 downregulation inhibited uPAR-mediated $\alpha 5\beta$1-integrin signaling, whereas caveoline-1 up-regulation stimulated the signaling, which suppressed p53 expression, thereby indicating negative crosstalk exists between the integrin $\alpha 5\beta$1 and the p53 pathways. Thus, these findings identify a novel mechanism whereby the inhibition of $\alpha 5\beta$1 integrin and the activation of p53 modulate the expression of the anti-apoptotic proteins that are crucially involved in inducing apoptosis in A549 lung cancer cells. Furthermore, MRGX causes changes in the expressions of members of the Bcl-2 family (Bax and Bcl-2) in a pro-apoptotic manner. In addition, MGRX-mediated inhibition of $\alpha 5\beta$1 integrin attenuates ERK phosphorylation (p-ERK), which up-regulates caspase-8 and Bax. Therefore, ERK may affect mitochondria through a negative regulation of caspase-8 and Bax. Taken together, these findings reveal that MRGX is involved in uPAR-$\alpha 5\beta$1-integrin signaling by modulating caveolin-1 signaling to induce early apoptosis in A549 lung-cancer cells and strongly indicate that MRGX might be useful as a herbal medicine and may lead to the development of new herbal medicine that would suppress the growth of lung-cancer cells.