The American Journal of Chinese Medicine

Migraine is a recurrent disease with complex pathogenesis and is difficult to cure. At present, commercially available western migraine drugs are prone to generate side effects while treating the disease. Traditional Chinese medicine (TCM) avoids side effects via treatment with the principles of “treating both symptoms and root causes”, “overall adjustment”, and “treatment based on syndrome differentiation”. Three strategies of drug treatment were developed based on the syndromes, i.e., removing stasis, calming liver Yang, and reinforcing deficiency. Prescriptions of removing stasis mostly contain Chuanxiong rhizome (Chuan Xiong) to remove blood stasis by promoting blood circulation and improve properties of hemorheology, and Da Chuan Xiong Formula (DCXF) is a traditional prescription widely used in clinical practice. Prescriptions of calming liver Yang usually take Ramulus Uncariae cum Uncis (Gou Teng) as the main herb, which can calm the liver Yang via improving vasomotor function, and Tian Ma Gou Teng Decoction (TMGTD) is the representative drug. For reinforcing deficiency, Chinese doctors frequently utilize Angelica Sinensis (Dang Gui) and Astragali Radix (Huang Qi) to nourish blood and Qi in order to improve the weak state of human body; Dang Gui Bu Xue Decoction (DGBXD) is the commonly used prescription. These strategies not only treat the symptoms of diseases but also their root causes, and with the features of multiple targets, in multiple ways. Therefore, TCM prescriptions have obvious advantages in the treatment of chronic diseases such as migraine. In this review, we provided an overview of the pathogenesis of migraine and the function of representative TCM preparations in therapy of migraine as well as the mechanism of action according to effective researches, in order to provide reference and clue for further researches.

Bone mineral density (BMD) has been validated not only for the diagnosis of osteoporosis but also for prediction of the risk of osteoporosis-related fractures. The purpose of this paper was to investigate the overall benefits of herbal medicines on BMD using a meta-analytic method. Systematic searches in PubMed, Medline, Cochrane Central, and China National Knowledge Infrastructure were performed for eligible studies. A meta-analysis was conducted to evaluate the benefits of herbal medicine treatment and conventional treatment for BMD. Herbal medicines frequently used for interventions were pooled in the analysis and further investigated. Seventeen studies were pooled in the meta-analysis and showed that BMD was higher in the herbal medicine group than in the control group (standardized mean difference [SMD]: 0.857; 95% confidence interval [CI]: 0.412 to 1.301). Significant benefits of herbal medicine for BMD were found in the lumbar spine, femoral neck, and femoral trochanter and in postmenopausal women (SMD: 0.600, 95% CI: 0.068 to 1.131) by subgroup analysis. Moreover, through the meta-regression analysis, the age at menopause and the menopause duration were found to influence the herbal intervention effects on BMD. In addition, the most prescribed medicine among the effective herbs in the pooled studies was found to be Epimedium brevicornum Maxim. This paper provides evidence that herbal medicine interventions increase BMD more than conventional treatments in individuals with osteoporosis, especially postmenopausal women. The results of this study suggest that herbal medicines are effective for increasing BMD in individuals with osteoporosis.

As current pain management methods cannot effectively control pain among cancer patients, acupuncture has developed as an adjuvant therapy for cancer pain relief. However, the efficacy of acupuncture in treating cancer pain remains controversial. Here, we briefly introduced the development of pain management, analgesic mechanisms, and acupuncture methods. Meanwhile, a comprehensive overview of acupuncture programs was provided in terms of different cancer types, sources, and degrees. Interestingly, acupuncture can treat both tumor-induced pain and therapy-induced pain well among cancer patients. We preliminarily summarized frequently-used acupoints for different types of cancer pain and found that needle retention time was mostly 30 min, and treatment cycle was two weeks. Additionally, clinicians consistently selected Ashi acupoint or bilateral Zusanli acupoint and combined multiple acupuncture methods for different degrees of cancer pain.

Stroke is the leading fatal disease in China. This retrospective study aimed to explore the optimal acupuncture intervention time for long-term efficacy on motor dysfunction in patients suffering from acute ischemic stroke through 1-year of follow-up. Three hundred and nine patients collected at Longhua Hospital from January 2016 to December 2017 were classified into 3 groups based on the acupuncture intervention time, including groups A (within 2 days), B (within 3–7 days) and C (within 8–14 days). All patients had received standard treatment combined with acupuncture therapy. Specifically, acupuncture was performed at the acupoints including LI4 (Hegu), ST40 (Fenglong), DU20 (Baihui), and motor area of the scalp, followed by 2 electroacupuncture protocols based on different muscle tensions once a day for 5 days consecutively. The time-effect relationship was assessed using both the Fugl-Meyer Assessment (FMA) and the modified Barthel index (MBI) on the 90th day and 1st year, respectively. Meanwhile, the modified Rankin scale (mRS), high-sensitivity C-reactive protein (hs-CRP), and fibrinogen (FIB) were also measured during the 1-year follow-up. The favorable outcome rate was 74.4%. One-way univariate analysis of variance (ANOVA) revealed significant differences in FMA and MBI on the 90th day among the 3 groups ($p$ < 0.05), while no significant differences were observed in FMA, MBI or mRS at the 1st year between groups A and B. The levels of hs-CRP and FIB ($p$ < 0.05) were markedly reduced. Binary logistic regression analysis suggested that patients with atrial fibrillation (AF) (odds ratio (OR): 3.156), chronic kidney disease (CKD) (OR: 2.563), diabetes mellitus (DM) (OR: 2.174) or stroke history (OR: 1.883) were more inclined to recover poorly from nerve function deficit ($p$ < 0.05). Earlier acupuncture intervention may have a better long-term effect on motor dysfunction and inflammation during the 1-year follow-up. Moreover, acupuncture within 2 days is probably the optimal treatment time for early recovery on the 90th day.

Alzheimer’s disease (AD) is a neurodegenerative disease and is characterized by the deposition of the $\beta$-Amyloid peptide ($\beta$A), which causes the inflammation of neurons. Bee venom (BV) elicits a strong anti-inflammatory response, and therefore we conducted an in vitro experiment to study the efficacy of BV in an AD cellular model. To mimic AD, the U87MG cell line was incubated for 168 hours with 2.5 $\mu$M $\beta$A. Changes were confirmed by microscopy, and peptides were measured under stain-free conditions using homo-tomography. Sulforhodamine B analysis was performed to analyze the cell viability. Real-Time quantitative polymerase chain reaction (qPCR) analysis was conducted to analyze mRNA expression levels of pro-inflammatory cytokines (NF-$\kappa$B, COX-2, TNF-$\alpha$, IL-1), and Western blot was performed to measure the Caspase-3 protein levels. BV showed no cytotoxicity at concentrations below 10 $\mu$g/mL. The NF-$\kappa$B mRNA levels were not significantly different between the BV group and the control group. The amount of $\beta$A accumulation in the BV group decreased significantly. The mRNA expression levels of COX-2, TNF-$\alpha$, and IL-1 were significantly reduced using 10 $\mu$g/mL of BV compared to those in the control group. Additionally, Caspase-3 levels were also reduced compared to those of the control group when BV was used at a concentration of 10 $\mu$g/mL. BV could inhibit apoptosis and inflammatory responses in an AD cellular model. In addition, it prevented cell accumulation of $\beta$A, an important pathogenic mechanism in AD.

Macrophage autophagy defect is closely related to the progression of atherosclerosis (AS) and is regulated by the triggering receptor expressed on myeloid cell 2 (TREM2). TREM2 is a key factor in the development of Alzheimer’s disease (AD), the deficiency of which leads to anomalous autophagy in microglia. However, the role of TREM2 in the autophagy of plaque macrophages is still unclear. Geniposide (GP) can inhibit AS progression and enhance macrophage autophagy, although the underlying mechanisms remain unknown. We found that high-fat diet (HFD) feeding significantly increased TREM2 levels and inhibited autophagy in the macrophages of ApoE${}^{-/-}$ mice. TREM2 overexpression in RAW264.7 macrophages decreased autophagy via activation of mTOR signaling. GP inhibited the progression of AS in ApoE${}^{-/-}$ mice, reinforced macrophage autophagy, and downregulated TREM2 by inhibiting mTOR signaling. Taken together, augmenting the autophagy levels in plaque macrophages by inhibiting the TREM2/mTOR axis can potentially impede atherosclerotic progression. The promising therapeutic effects of GP seen in this study should be validated in future trials, and the underlying mechanisms have to be elucidated in greater detail.

Bisphenol A (BPA), which is known to be an endocrine-disrupting chemical (EDC), is associated not only with estrogen activity and reproductive toxicity but also with a variety of metabolic disorders. BPA affects glucose tolerance, cholesterol biosynthesis, and fatty acid synthesis. Ginseng is a traditional medicinal plant that has been widely used in East Asia for more than 2000 years, and a number of health effects have been reported. Korean Red Ginseng (KRG) has also been shown to have effects on lipid metabolism and body weight reduction in vivo in obese mice. In this study, we administered BPA and KRG to ovariectomized (OVX) ICR mice. BPA (800 mg/kg/day) and KRG (1.2 g/kg/day) were orally administered to OVX mice for 3 days. KRG inhibited the increase in total fatty acid level by BPA as determined by lipid profiling in the liver of OVX mice. In addition, transcriptome analysis showed that KRG inhibited BPA-induced changes in lipid metabolic process-related genes. Our findings suggest that KRG can regulate BPA-induced changes in lipid metabolism.

Blockade of the NOD-like receptor protein 3 (NLRP3) inflammasome has been shown to be effective in halting the progression of non-alcoholic steatohepatitis (NASH). Antrodia cinnamomea is a well-known indigenous medicine used by Taiwanese aboriginal tribes. However, its effect on NASH remains unclear. This study aimed to examine the mechanistic insight of Antrodia cinnamomea extract (ACE) in both in vitro and in vivo models of NASH. Murine RAW264.7 macrophages and human hepatocellular carcinoma HepG2 cells were treated with the indicated concentration of ACE 30 minutes prior to stimulation with lipopolysaccharide (LPS) for 24 h. Levels of inflammatory markers, NLRP3 inflammasome, components, and endoplasmic reticulum (ER) stress markers were analyzed by Western blotting. For the in vivo experiments, male C57BL/6 mice weighing 21–25 g were fed a methionine/choline deficient (MCD) diet along with vehicle or ACE (100 mg/kg) for 10 consecutive days. The serum glutamate pyruvate transaminase (SGPT) levels of the mice were measured. The liver tissues from the mice underwent histological analysis (hematoxylin and eosin staining), and the levels of inflammatory markers, NLRP3 inflammasome components, and autophagy-related proteins were evaluated. ACE significantly inhibited NLRP3 inflammasome activation in vitro and in vivo. In addition, ACE attenuated the severity of MCD-induced steatohepatitis, reduced the levels of oxidative stress markers, and ameliorated inflammatory responses, but restored autophagic flux. Based on these findings, Antrodia cinnamomea could be developed into an anti-non-alcoholic fatty liver disease/NASH agent.

Inflammation regulation is essential for maintaining healthy functions and normal homeostasis of the body. Porphyromonas gingivalis (P. gingivalis) is a gram-negative anaerobic bacterium and a major pathogen that causes oral inflammation and other systemic inflammations. This study aims to examine the anti-inflammatory effects of Agrimonia pilosa Ledeb root extracts (APL-ME) in Porphyromonas gingivalis LPS-induced RAW 264.7 cells and find anti-inflammatory effect compounds of APL-ME. The anti-inflammatory effects of APL-ME were evaluated anti-oxidant activity, cell viability, nitrite concentration, pro-inflammatory cytokines (interleukin-1$\beta$, interleukin-6, tumor necrosis factor (TNF)-$\alpha )$, and anti-inflammatory cytokine (interleukin-10 (IL-10)). Also, Inflammation related genes and proteins, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), expression were decreased by APL-ME and mitogen-activated protein kinase (MAPK) signaling proteins expression was regulated by APL-ME. Liquid chromatography-mass spectrometer (LC/MS)-MS analysis results indicated that several components were detected in APL-ME. Our study indicated that APL-ME suppressed nitrite concentrations, pro-inflammatory cytokines such as IL-1$\beta$, IL-6 and TNF-$\alpha$ in P. gingivalis LPS induced RAW 264.7 cells. However, IL-10 expression was increased by ALP-ME. In addition, protein expressions of COX-2 and iNOS were inhibited APL-ME extracts dose-dependently. According to these results, APL-ME has anti-inflammatory effects in P. gingivalis LPS induced RAW 264.7 cells.

Olea europaea is a beneficial edible plant with a number of biological activities like anti-inflammatory, anti-oxidant, antithrombic, antihyperglycemic, and anti-ischemic activities. The mechanisms behind the antiphotoaging and anti-inflammatory effects of Olea europaea are not fully understood. To investigate how an ethanol extract of Olea europaea (Oe-EE) exerts these effects, we explored its activities in human keratinocytes and dermal fibroblasts. We assessed the anti-oxidant effects of Oe-EE via 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2$\prime$-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) assays and measured the expression levels of matrix metalloproteinases (MMPs), cyclooxygenase-2, interleukin (IL)-6, tumor necrosis factor (TNF)-$\alpha$, and moisturizing factors. Antiphotoaging and anti-inflammatory mechanisms of Oe-EE were explored by assessing signaling molecule activation via immunoblotting. Oe-EE treatment decreased the mRNA expression level of MMPs, cyclooxygenase-2, IL-6, and TNF-$\alpha$ and restored type I collagen, filaggrin, and sirtuin 1 expression in UVB-irradiated cells. Furthermore, Oe-EE inhibited the activities of several activator protein 1 regulatory enzymes, including extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), and inhibited nuclear factor (NF)-$\kappa$B pathway signaling proteins. Therefore, our results indicate that Oe-EE has photoaging-protective and anti-inflammatory effects.

Autophagy is an important tightly controlled cellular process that regulates cellular homeostasis and is involved in deciding cell fate such as cell survival and death. The role of autophagy in many intracellular signaling pathways explains its interaction with other different types of cell death, including apoptosis and immunogenic cell death (ICD). The reports showed the complex and intriguing relationship existing between autophagy and immune system signaling pathways. However, the role of autophagy in ICD remains to be clearly elucidated. In this study, we demonstrated that Brucine, a clinically-used small molecule in traditional Chinese medicine, elicited autophagy inhibition. Brucine also triggered cell stress and induced features of ICD, including calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release in MDA-MB-231 and CT26 cancer cells. Brucine impaired autolysosomal degradation and exerted a feedback regulation of ERK1/2-mTOR-p70S6K signaling cascade. Brucine-elicited ICD was confirmed by the rejection of CT26 tumor cells, implanted in the mice after vaccination with Brucine-treated CT26 cells. The impaired autophagy contributed to Brucine-induced ICD, as knock-down of Atg5 significantly reduced Brucine-elicited CRT exposure and HMGB1 release. Our results revealed Brucine as a novel autophagy regulator, ICD inducer and hitherto undocumented role of autophagy in ICD. Thus, these results imply the importance of Brucine in cancer immunotherapy. Therefore, Brucine may be used as an ICD inducer and improve its application in cancer treatment with minimized toxicity.

Antrodia cinnamomea has been shown to possess antitumor activity. This study investigated the effects and mechanisms of Antrodia cinnamomea extract (ACE) on growth and migration of human non-small cell lung cancer A549 cells. The effect of ACE on cell viability was determined by MTT assay and fluorescent live-cell imaging. The apoptotic effect of ACE was determined by cell cycle distribution using flow cytometry. A P53-mediated apoptosis pathway was identified by measuring protein expression of p53 and Bcl-2 with Western blotting. Additionally, mRNA expression of p53 and Bcl-2 and Bax was detected by qRT-PCR. The effect of ACE on cancer cell migration was confirmed by a wound-healing assay. Expression of MMP-2 and MMP-9 at the protein and gene levels was determined by western blot and qRT-PCR analysis. This study demonstrates the inhibitory effect of ACE on A549 cell proliferation in a dose-response manner with an $E{C}_{50}=101\mu g/ml$. It was determined that ACE concentration at $600\mu g/ml$ induced cell cycle arrest at S phase in A549 cells. The apoptosis-regulating protein p53 expression was enhanced and also associated with the downregulation of Bcl-2 in ACE treatment cells. The mRNA expression of p53 and Bcl-2 associated with Bxa was consistent with protein expression. The inhibition of migration of cancer cells treated with ACE was clearly evident. At the same time, suppression of expression of MMP-2 and MMP-9 at protein and mRNA levels was observed. The findings of this study highlight ACE as a potential agent of adjuvant therapy for lung cancer.