The American Journal of Chinese Medicine

Alzheimer’s disease (AD) is associated with the unprecedented aging tendency in our world population and has become a significant health issue. The use of Traditional Chinese Medicine to treat AD has been increasing in recent years. The objective of this meta-analysis is to evaluate the effectiveness of combining acupuncture with herbal medicine to treat AD. Randomized controlled trials (RCTs) of acupuncture plus herbals versus treatment with western drugs for AD were retrieved from 11 databases. The data were extracted by two authors; dichotomous data were expressed as odds ratio (ORs) and 95% confidence intervals (CIs), while continuous data were calculated by mean differences (MDs) with 95% CIs. Although the combined analysis of the score of Activity of Daily Life (ADL) scale MD was $-$3.59 (95% CI $-$7.18–0.01, $p=0.05$), which indicates there was no statistically significant difference between the two treatments at reducing the ADL scale score, the pooled results of 12 trials indicated that acupuncture plus Chinese herbal medicine was better than western drugs at improving the effectiveness rate (OR 2.24, 95% CI 1.40–3.56), the combined evidence of 11 articles showed that acupuncture plus Chinese herbal medicine was more effective than western drugs at improving the scores for the Mini Mental State Examination (MMSE) scale (2.10, 95% CI 0.69–3.51, $p=0.004$) and the traditional Chinese medicine symptom (MD 5.07, 95% CI 3.90–6.25, $p<0.0001$). From the current research results, acupuncture plus herbal medicine may have advantages over western drugs for treating AD. Nevertheless, well-designed RCTs with a larger sample size are required in the future.

Large-scale natural disasters, such as earthquakes, tsunamis, volcanic eruptions, and typhoons, occur worldwide. After the Great East Japan earthquake and tsunami, our medical support operation’s experiences suggested that traditional medicine might be useful for treating the various symptoms of the survivors. However, little information is available regarding herbal medicine treatment in such situations. Considering that further disasters will occur, we performed a literature review and summarized the traditional medicine approaches for treatment after large-scale disasters. We searched PubMed and Cochrane Library for articles written in English, and Ichushi for those written in Japanese. Articles published before 31 March 2016 were included. Keywords “disaster” and “herbal medicine” were used in our search. Among studies involving herbal medicine after a disaster, we found two randomized controlled trials investigating post-traumatic stress disorder (PTSD), three retrospective investigations of trauma or common diseases, and seven case series or case reports of dizziness, pain, and psychosomatic symptoms. In conclusion, herbal medicine has been used to treat trauma, PTSD, and other symptoms after disasters. However, few articles have been published, likely due to the difficulty in designing high quality studies in such situations. Further study will be needed to clarify the usefulness of herbal medicine after disasters.

Estrogen, a steroid hormone, is associated with several human activities, including environmental, industrial, agricultural, pharmaceutical and medical fields. In this review paper, estrogenic activity associated with traditional Chinese medicines (TCMs) is discussed first by focusing on the assays needed to detect estrogenic activity (animal test, cell assay, ligand-binding assay, protein assay, reporter-gene assay, transcription assay and yeast two-hybrid assay), and then, their sources, the nature of activities (estrogenic or anti-estrogenic, or other types), and pathways/functions, along with the assay used to detect the activity, which is followed by a summary of effective chemicals found in or associated with TCM. Applications of estrogens in TCM are then discussed by a comprehensive search of the literature, which include basic study/pathway analysis, cell functions, diseases/symptoms and medicine/supplements. Discrepancies and conflicting cases about estrogenicity of TCM among assays or between TCM and their effective chemicals, are focused on to enlarge estrogenic potentials of TCM by referring to omic knowledge such as transcriptome, proteome, glycome, chemome, cellome, ligandome, interactome and effectome.

Autophagy is an evolutionarily conserved degradation process which eliminates dysfunctional proteins and cytoplasmic components to maintain homeostasis for cell survival. Increasing evidence has demonstrated the modulatory role of autophagy in ischemic heart diseases (IHDs). Traditionally, this process has been recognized as having protective functions, such as inhibiting atherosclerosis progression and reducing cell death during the ischemic phase. However, recent studies have suggested its dual roles in myocardial ischemia/reperfusion (MIR) injury. Excessive autophagy may play a deleterious role in cardiac function, due to overwhelming clearance of cellular constituents and proteins. Hence modulation of autophagy to increase cardiomyocyte survival and improve cardiac function is meaningful for the treatment of IHD. Chinese herbal medicine, including extractive compounds and patented drugs, has shown its potential role in treating IHD by addressing autophagy-related mechanisms. This review summarizes the updated knowledge on the molecular basis and modulatory role of autophagy in IHD and the recent progress of Chinese herbal medicine in its treatment.

Magnolol, a constituent of the bark of Magnolia officinalis, has been reported to decrease myocardial stunning and infarct size. In this study, we investigated whether magnolol can reduce renal ischemia and reperfusion (I/R) injury. Renal I/R, induced by a 60-min occlusion of bilateral renal arteries and a 24-h reperfusion, significantly increased blood urea nitrogen (BUN) and creatinine levels, and caused histological damage to the kidneys of rats. Apoptosis, as evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and caspase-3 activation, was significantly increased in the kidneys. Furthermore, serum levels of tumor necrosis factor-$\alpha$ (TNF-$\alpha$), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were significantly elevated, while the interleukin-10 (IL-10) level was suppressed. However, intravenous pretreatment with magnolol at doses of 0.003mg/kg and 0.006mg/kg 10min before renal I/R significantly limited the increases of BUN, creatinine, the histological damage, and apoptosis in the kidneys. The increases in TNF-$\alpha$, IL-1β, and IL-6, and the decrease in IL-10 were also significantly inhibited. Additionally, magnolol increased Bcl-2 and decreased Bax in the kidneys. Phosphorylation of the prosurvival kinases, including Akt and extracellular signal-regulated kinases 1 and 2 (ERK1/2), was elevated, while phosphorylation of the pro-apoptotic mitogen-activated protein kinases, including p38 and c-Jun N-terminal kinase (JNK), was suppressed. In conclusion, magnolol reduces renal I/R injury. The underlying mechanisms for this effect might be related to the prevention of apoptosis, possibly via the inhibition of both extrinsic and intrinsic apoptotic pathways, including the reduction of TNF-$\alpha$ production and the modulation of pro- and anti-apoptotic signaling elements.

Diabetic nephropathy (DN) is a common cause of chronic kidney disease and end-stage renal disease, which can be triggered by oxidative stress. In this study, we investigated the renoprotective effect of the ethyl acetate extract of Salvia miltiorrhiza (EASM) on DN and examined the underlying molecular mechanism. We observed that EASM treatment attenuated metabolic abnormalities associated with hyperglycemic conditions in the experimental DN model. In streptozotocin (STZ)-induced mice, EASM treatment reduced albuminuria, improved renal function and alleviated the pathological alterations within the glomerulus. To mimic the hyperglycemic conditions in DN patients, we used high glucose (25mmol/L) media to stimulate mouse mesangial cells (MMCs), and EASM inhibited high glucose-induced reactive oxygen species. We also observed that EASM enhanced the expression of nuclear factor erythroid-2-related factor 2 (Nrf2), which mediated the anti-oxidant response, and its downstream gene heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) with concomitant decrease of expression of kelch-like ECH-associated protein 1 (keap1) both in vitro and in vivo. Taken together, these results suggest that EASM alleviates the progression of DN and this might be associated with activation of Nrf2.

Microglial activation leads to increased production of proinflammatory enzymes and cytokines, which is considered to play crucial role in neurodegenerative diseases, however there are only a few drugs that target microglia activation. Recent studies have indicated that the Traditional Chinese Medicine, salidroside (Sal), exerted anti-inflammatory effects. According to this evidence, our present study aims to explore the effect of the Sal (a phenylpropanoid glycoside compound which is isolated from rhodiola), on microglia activation in lipopolysaccharide (LPS)-stimulated BV-2 cells. Our results showed that Sal could significantly inhibit the excessive production of Nitric Oxide (NO) and Prostaglandin E2 (PGE₂) in LPS-stimulated BV2 cells. Moreover, Sal treatment could suppress the mRNA and protein expressions of inflammatory enzymes, including Inducible Nitric Oxide Synthase (iNOS) and Cyclooxygenase-2 (COX-2). The mechanisms may be related to the inhibition of the activation of Nuclear Factor-kappaB (NF-$\kappa$B) and endoplasmic reticulum stress. Our study demonstrated that salidroside could inhibit lipopolysaccharide-induced microglia activation via the inhibition of the NF-$\kappa$B pathway and endoplasmic reticulum stress, which makes it a promising therapeutic agent for human neurodegenerative diseases.

Maydis Stigma (MS) is an herb traditionally used in many parts of the world. Previous studies have reported that MS plays a role in several biological activities, including antidiabetic and anticancer activities. However, the effects of a MS ethanolic extract (MSE) on the anti-inflammatory cellular mechanism remain unclear. Here, we investigated the anti-inflammatory properties of MSE and its molecular mechanism both in vitro and in vivo. The effects of MSE on the production of inflammatory mediators, cytokines, and related proteins and the identification of target genes were determined using LPS-stimulated macrophages. We also determined the analgesic and anti-inflammatory effects of MSE by examining acetic acid-induced writhing responses and xylene-induced ear edema in mice. Our results indicated that MSE markedly decreased iNOS and COX-2 levels without causing cytotoxicity and suppressed the secretion of NO in LPS-stimulated macrophages. MSE also inhibited the production of proinflammatory cytokines, such as TNF-$\alpha$, IL-6, and IL-1$\beta$, and induced the expression of HO-1. Moreover, MSE treatment significantly reduced the LPS-stimulated activation of MAPK, NF-$\kappa$B, and AP-1. Furthermore, MSE exerted an analgesic effect on the acetic acid-induced abdominal writhing response test and an anti-inflammatory effect on xylene-induced ear edema in ICR mice. Finally, we investigated the components of MSE using UPLC-ESI-MS and found that it contains the maysin as a marker component. Overall, these observations demonstrate that MSE has anti-inflammatory and antinociceptive effects both in vitro and in vivo, which may provide new scientific evidence for its use as a potential therapeutic agent for the treatment of inflammation.

Berberine (BBR), an isoquinoline alkaloid, is a well-known bioactive compound contained in medicinal plants used in traditional and folk medicines. In this study, we investigated the subcellular localization and the apoptotic mechanisms of BBR were elucidated. First, we confirmed the incorporation of BBR into the cell visually. BBR showed antiproliferative activity and promptly localized to the nucleus from 5min to 15min after BBR treatment in HL-60 human promyelocytic leukemia cells. Next, we examined the antiproliferative activity of BBR (1) and its biosynthetically related compounds (2-7) in HL-60 cells. BBR exerted strongest antiproliferative activity among 1-7 and the results of structures and activity relation suggested that a methylenedioxyl group in ring A, an $O$-alkyl group at C-9 position, and the frame of isoquinoline may be necessary for antiproliferative activity. Moreover, BBR showed the most potent antiproliferative activity in HL-60 cells among human cancer and normal cell lines tested. Next, we examined the effect of BBR on molecular events known as apoptosis induction. In HL-60 cells, BBR induced chromatin condensation and DNA fragmentation, and triggered the activation of PARP, caspase-3 and caspase-8 without the activation of caspase-9. BBR-induced DNA fragmentation was abolished by pretreatment with inhibitors against caspase-3 and caspase-8, but not against caspase-9. ERK and p38 were promptly phosphorylated after 15 min of BBR treatment, and this was correlated with time of localization to the nucleus of BBR. These results demonstrated that BBR translocated into nucleus immediately after treatments and induced apoptotic cell death by activation of caspase-3 and caspase-8.

Forsythiae Fructus, Lianqiao in Chinese, is one of the most fundamental herbs in Traditional Chinese Medicine. Both green Forsythia (GF) and ripe Forsythia (RF) are referred to Forsythiae Fructus in medicinal applications. In most cases, they are used without distinction. In this study, a metabolomics approach was performed to compare componential differences of two Forsythiae Fructus aqueous extracts subtypes. Principal component analysis (PCA) score plots from the UPLC-MS data showed clear separation between the two subtypes, indicating there are significant differences in the chemical components between GF and RF. Meanwhile, the anticancer activity of them was also compared. GF exhibited much stronger antitumor activity than RF against B16-F10 murine melanoma both in vitro and in vivo. 15 chemical compounds were identified as specific markers for distinguishing GF and RF. Among these marker compounds, forsythoside I, forsythoside A, forsythoside E and pinoresinol were demonstrated to be key important active compounds that account for the different anticancer efficacies of GF and RF. Our data suggest that GF and RF should be distinctively used in clinical applications, particularly in the anticancer formulas, in which GF should be preferentially prescribed.

Cinobufacini, a traditional Chinese medicine, has been used widely for cancer treatment, such as hepatocellular carcinoma (HCC), sarcoma, and leukemia. Previous studies done by our lab indicated that cinobufacini could suppress HCC cells through mitochondria-mediated and Fas-mediated apoptotic pathways. Here, we use a combination of cinobufacini and doxorubicin to inhibit the growth of HCC cells. The combination group induced more significant apoptosis by affecting proteins and RNA of apoptosis-related elements, such as Bcl-2, Bax, Bid, and cytochrome c. Furthermore, cinobufacini, as a mixture of a number of components, had stronger apoptosis-inducing activity than particular individual components or a simple mixture of a few components. Overall, these results suggested that the combination of cinobufacini and doxorubicin may provide a new strategy for inhibiting the proliferation of HCC cells.

Nasopharyngeal carcinoma (NPC) is characterized by a high incidence of metastasis in the neck lymph nodes, resulting in a poor prognosis and posing challenges for treatment. In this study, we investigated the in vitro antimetastatic properties of Rubus idaeus extract (RIE) on human nasopharyngeal carcinoma cells. HONE-1, NPC-39 and NPC-BM cells were subjected to RIE treatment, and effects on the migration and invasion of tumor cells were analyzed. The results showed that RIE suppressed the migration and invasion of NPC cells. Gelatin zymography assay, Western blotting and real-time PCR showed that matrix metalloproteinases-2 (MMP-2) enzyme activity, protein expression and mRNA levels were down-regulated by RIE treatment. To identify the signaling pathway, mitogen-activated protein kinase proteins were examined, which showed that phosphorylation of ERK1/2 was inhibited after the treatment of RIE. In summary, our data showed that RIE inhibited the migration and invasion of NPC cells by suppressing the expression of MMP-2 by down-regulating the ERK1/2 signaling pathway, suggesting that Rubus idaeus may serve as chemotherapeutic and chemopreventive agent for NPC.