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AIM Acute diverticulitis (AD) is commonly diagnosed in outpatient and emergency departments and is associated with severe complications such as perforation and fistula. Symptoms of irritable bowel syndrome (IBS), such as abdominal pain, constipation and diarrhoea, are also common with AD. This study aimed to evaluate the strength of a possible association between IBS and AD. METHOD This retrospective study analysed records from Taiwan's National Health Insurance Research Database and involved a total of 25 810 patients, including 12 905 IBS patients diagnosed between 2000 and 2012. The IBS and non-IBS cohorts were matched by propensity score for age, gender, comorbidities and medication, then compared for confounding variables by the chi-square test or Student's t-test. The association between AD and IBS was determined using Cox proportional hazards models. Kaplan-Meier curves assessed the cumulative incidence of AD in IBS patients. RESULTS The overall incidence of AD was 3.95-fold higher in the IBS cohort than in the non-IBS cohort (63.34 vs 16.02 per 100 000 person-years, respectively) and IBS was an independent risk factor for subsequent diagnosis of AD in multivariate Cox proportional hazards regression model adjusted hazards ratio (aHR = 3.84, 95% CI = 2.29-6.44, P

OBJECTIVES: To investigate the association between erectile dysfunction and fibromyalgia, and to clarify related comorbidities and treatment modalities. METHODS: This retrospective cohort study was carried out using 1 million records in the National Health Insurance Research Database. From 2001 to 2012, a total of 53 678 male patients newly diagnosed with fibromyalgia were recruited as the fibromyalgia cohort, and the same number of the non-fibromyalgia cohort was enrolled and matched with propensity score with age, income, comorbidities, and prescribed medications. All records were followed up until the end of 2013. The Cox proportional hazards model was carried out to assess the risk of erectile dysfunction among fibromyalgia patients. RESULTS: The incidence rates of erectile dysfunction were 36.86 and 21.15 (per 10 000 person-years) in the fibromyalgia and non-fibromyalgia cohorts, respectively, and a significantly increased risk of erectile dysfunction in fibromyalgia patients was noted (adjusted hazard ratio 1.69, 95% confidence interval 1.55-1.85, P

Both inflammation and infection are associated with the development of irritable bowel syndrome (IBS) and chronic obstructive pulmonary disease (COPD). The purpose of this study is to further elucidate the association between IBS and COPD through a retrospective cohort study. We enrolled IBS patients diagnosed between 2000 and 2011 with follow-up for at least one year. The non-IBS patients as comparison group were selected with 1:3 matching by propensity score. Statistical analysis was utilized to assess the differences in characteristic distribution, and to compare the cumulative incidence of COPD between the IBS and non-IBS cohorts. We selected 14,021 IBS patients and 42,068 non-IBS patients for comparison. The IBS patients exhibited a significant risk to develop COPD compared with non-IBS patients. Additionally, the cumulative incidence rate of COPD in the IBS cohort increased significantly during the follow-up period of more than ten years, compared to the non-IBS cohort, based on the Kaplan-Meier analysis. The risk of COPD was also significantly decreased in those patients with more than eighteen IBS-related clinical visits. This retrospective cohort study demonstrates the significantly increased risk of COPD in patients with IBS. Therefore, early inspection and prevention of COPD is essential for patients with IBS.

In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emerged to severely impact the global population, creating an unprecedented need for effective treatments. This study aims to investigate the potential of Scutellaria barbata D. Don (SB) as a treatment for SARS-CoV-2 infection through the inhibition of the proteases playing important functions in the infection by SARS-CoV-2. FRET assay was applied to investigate the inhibitory effects of SB on the two proteases involved in SARS-CoV-2 infection, Mpro and TMPRSS2. Additionally, to measure the potential effectiveness of SB treatment on infection inhibition, cellular models based on the Calu3 and VeroE6 cells and their TMPRSS2- expressing derivatives were assessed by viral pseudoparticles (Vpp) infection assays. The experimental approaches were conjugated with LC/MS analyses of the aqueous extracts of SB to identify the major constituent compounds, followed by a literature review to determine the potential active components of the inhibitory effects on protease activities. Our results showed that SB extracts inhibited the enzyme activities of Mpro and TMPRSS2. Furthermore, SB extracts effectively inhibited SARS-CoV-2 Vpp infection through a TMPRSS2-dependent mechanism. The aqueous extract analysis identified six major constituent compounds present in SB. Some of them have been known associated with inhibitory activities of TMPRSS2 or Mpro. Thus, SB may effectively prevent SARS-CoV-2 infection and replication through inhibiting Mpro and TMPRSS2 protease activities.

Objective Cholangiocarcinoma (CCA) is a devastating disease. Interferon α-inducible protein 27 (IFI27), originally known to involve in innate immunity, is later found to intervene in cell proliferation, leading to inventive studies regarding the role of IFI27 in cancer treatment. We aimed to investigate the role of IFI27 in CCA. Materials and methods Cell proliferation, migration, and invasion assays, Western blot, gene transfection and knockdown, immunofluorescent and immunohistochemical stains, and xenograft animal model were applied. Results IFI27 knockdown in CCA cells induced cell cycle arrest in S phase, resulting in lower cell proliferative rate in vitro and in vivo. IFI27 knockdown attenuated CCA cell migration and invasion through inhibition of epithelial-mesenchymal transition, which was supported by increased E-cadherin and decreased N-cadherin and fibronectin. Filamentous actin level was also reduced. IFI27 knockdown further repressed expression and secretion of vascular endothelial growth factor (VEGF-A), a strong stimulator of angiogenesis, through downregulation of c-jun and c-fos, which was supported in vitro by the finding that human vascular endothelial cells grew more slowly in conditioned medium of IFI27 knockdown on CCA cells and in vivo by the lower erythropoietin concentration found in the xenografted tumors derived from IFI27 knockdown on CCA cells. In addition, anti-VEGF-A antibody treatment was able to repress CCA cell growth. To the contrary, IFI27 overexpression could increase CCA cell proliferation, migration, and invasion. Clinically, higher IFI27 expression was linked to inferior overall survival of CCA patients. Conclusion Our data strongly suggest that IFI27 could be deemed as a potential target for CCA treatment.

Background There is an increased bleeding risk following hepatectomy either due to surgical complications or the nature of liver dysfunction among these patients. For better prevention of delayed bleeding in patients undergoing hepatectomy with different kinds of comorbidities and medications, we examined the risk of major bleeding up to 10 years following hepatectomy. Materials and methods This retrospective study used data from Taiwan's National Health Insurance Research Database. Patients who underwent hepatectomy between 2000 and 2012 were identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes. The non-hepatectomy cohort was defined as patients without any record of hepatectomy. Variables including gender, age, comorbidities, and prescribed medications were matched between the hepatectomy and non-hepatectomy cohorts. Results A total of 1155 patients with hepatectomy and 1155 matched non-hepatectomy subjects were included in this study. The risk of major bleeding was significantly higher in the hepatectomy cohort than that of the non-hepatectomy cohort (adjusted hazard ratio: 1.60). The gastrointestinal tract was the most common site of bleeding among patients with bleeding tendencies (adjusted hazard ratio: 1.93). Compared with the non-hepatectomy cohort, patients who underwent hepatectomy were at greater risk of delayed major bleeding in the first decade following surgery (adjusted hazard ratios ranged from 1.56 to 1.70). Conclusion Hepatectomy poses a significant risk of delayed major bleeding, especially in the first decade following surgery. Proper prevention methods and close monitoring for bleeding complications are indicated for patients undergoing hepatic surgeries.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer involving epithelial squamous-cell carcinoma of the nasopharynx that mainly occurs in individuals from East and Southeast Asia. We investigated whether Chinese herbal medicine (CHM) as a complementary therapy offers benefits to these patients. We retrospectively evaluated the Taiwan Cancer Registry (Long Form) database for patients with advanced NPC, using or not using CHM, between 2007–2013. Cox proportional-hazard model and Kaplan‒Meier survival analyses were applied for patient survival. CHM-users showed a lower overall and cancer-related mortality risk than non-users. For advanced NPC patients, the overall mortality risk was 0.799-fold for CHM-users, after controlling for age, gender, and Charlson comorbidity index (CCI) score (Cancer stages 3 + 4: adjusted hazard ratio [aHR]: 0.799, 95% confidence interval [CI]: 0.676–0.943, p = 0.008). CHM-users also showed a lower cancer-related mortality risk than non-users (aHR: 0.71, 95% CI: 0.53–0.96, p = 0.0273). Association rule analysis showed that CHM pairs were Ban-Zhi-Lian (BZL; Scutellaria barbata D.Don) and For single herbs, Bai-Hua-She-She-Cao (Herba Hedyotis Diffusae; Scleromitrion diffusum (Willd.) R.J.Wang (syn. Hedyotis diffusa Willd.) and Mai-Men-Dong (MMD; Ophiopogon japonicus (Thunb.) Ker Gawl.), and Gan-Lu-Yin (GLY) and BHSSC. Network analysis revealed that BHSSC was the core CHM, and BZL, GLY, and Xin-Yi-Qing-Fei-Tang (XYQFT) were important CHMs in cluster 1. In cluster 2, ShengDH, MMD, Xuan-Shen (XS; Scrophularia ningpoensis Hensl.), and Gua-Lou-Gen (GLG; Trichosanthes kirilowii Maxim.) were important CHMs. Thus, as a complementary therapy, CHM, and particularly the 8 CHMs identified, are important for the treatment of advanced NPC patients.

Simple Summary Melanoma is the most dangerous type of skin cancer that develops from the pigment-producing cells known as melanocytes. One of the primary causes of melanoma is ultraviolet light (UV) exposure in those with low levels of the skin pigment melanin. Flavokawain B (FKB) is a naturally occurring chalcone, which is known to possess anti-proliferative pharmacological activity on various cancer cells. However, the effect of FKB on the anti-melanoma pharmacological role has not been investigated. Therefore, in this study, we explored the anti-melanoma properties of FKB on human melanoma cells and the cell death mechanisms that were mediated through the induction of reactive oxygen species (ROS) were investigated via in vitro and in vivo approaches. Our study results support promising application prospects of FKB in the treatment of human melanoma cancer. Abstract Melanoma is the most prevalent type of skin cancer with high mortality rates. This study demonstrates the in vitro and in vivo anticancer properties of chalcone flavokawain B (FKB) induced ROS-mediated apoptosis and autophagy in human melanoma (human epithelial melanoma cell line A375 and/or human skin lymph node derived melanoma cell line A2058) cells. Cell viability was calculated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the expression patterns of various apoptosis, autophagy-associated proteins were determined by Western blot methods. Annexin V was detected by flow cytometry, whereas acidic vesicular organelles (AVOs) and intracellular ROS levels were measured by fluorescence microscopy. The in vivo anticancer properties of FKB were evaluated by xenografting the A375 cells into nude mice. The results convey that FKB inhibited cell viability, B-Raf proto-oncogene, serine/threonine kinase (BRAF)/extracellular signal-regulated kinase (ERK) expression in human melanoma cells. Caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage pathway, and Bcl2 associated X (Bax)/B-cell lymphoma 2 (Bcl-2) dysregulation were involved in the execution of apoptosis. Moreover, FKB-induced autophagy was observed through increased microtubule-associated protein 1A/1B-light chain 3B (LC3-II) accumulation and AVOs formation, which was also associated with an increase in sequestosome 1 (SQSTM1/p62), decreased protein kinase B (AKT)/mammalian target of rapamycin (mTOR) expressions, and dysregulated Beclin-1/Bcl-2 levels. Autophagy inhibitors [3-methyladenine (3-MA)/chloroquine (CQ)] and LC3 silencing suppressed FKB-induced apoptosis by decreasing caspase-3 in melanoma cells. The antioxidant N-acetylcysteine (NAC) diminished FKB-induced apoptotic and autophagic cell death. However, the inhibition of apoptosis decreased FKB-induced autophagy (LC3-I/II). The in vivo study confirmed that FKB inhibited melanoma growth in A375-xenografted nude mice. This study concluded that FKB is critically associated with the execution and generation of ROS-modulated apoptotic and autophagic cell death of melanoma cells. FKB also repressed tumor growth in xenografted nude mice. Therefore, flavokawain B might be a potential anti-tumor agent in human melanoma treatment.

Background Hyperthyroidism, the excessive production of thyroid hormones, is most commonly attributed to autoimmune dysfunction such as Graves’ disease. Western medical treatment of hyperthyroidism includes antithyroid medications, radioiodine, and thyroidectomy, all of which are associated with side effects. We describe the successful treatment of two patients with Graves’ disease who used Chinese herbal medicine (CHM) with or without Western medicine. Case presentation Both cases (a 50-year-old female [case 1] and a 56-year-old male [case 2]) received the Chinese herbal formula Jia Wei Xiao Yao San (JWXYS) as well as Prunella vulgaris, Fritillaria thunbergii, and Crassostrea gigas. Elevated thyroid hormone levels were restored to normal after 10 months of treatment in case 1 and 8 months in case 2. Neither patient experienced any complications or side effects during CHM treatment. Notably, symptoms and thyroid hormone levels have remained well controlled in both patients over 1 year of follow-up until the time of this report. To explore the possible mechanisms involved in CHM treatment of hyperthyroidism, we searched biomedical literature databases and reviewed the literature up to June 2020. Conclusions As for the hyperthyroidism almost was controlled by Western medicine instead of CHM, we report that JWXYS as well as Prunella vulgaris, Fritillaria thunbergii, and Crassostrea gigas was a safe and effective formula and we propose that CHM may be considered as either a first choice or combination therapy to control hyperthyroidism.

Background and purpose Pattern differentiation is a critical element of the prescription process for Traditional Chinese Medicine (TCM) practitioners. Application of advanced machine learning techniques will enhance the effectiveness of TCM in clinical practice. The aim of this study is to explore the relationships between clinical features and TCM patterns in breast cancer patients. Methods The dataset of breast cancer patients receiving TCM treatment was recruited from a single medical center. We utilized a neural network model to standardize terminologies and address TCM pattern differentiation in breast cancer cases. Cluster analysis was applied to classify the clinical features in the breast cancer patient dataset. To evaluate the performance of the proposed method, we further compared the TCM patterns to therapeutic principles of Chinese herbal medication in Taiwan. Results A total of 2,738 breast cancer cases were recruited and standardized. They were divided into 5 groups according to clinical features via cluster analysis. The pattern differentiation model revealed that liver-gallbladder dampness-heat was the primary TCM pattern identified in patients. The main therapeutic goals of the top 10 Chinese herbal medicines prescribed for breast cancer patients were to clear heat, drain dampness, and detoxify. These results demonstrated that the neural network successfully identified patterns from a dataset similar to the prescriptions of TCM clinical practitioners. Conclusion This is the first study using machine-learning methodology to standardize and analyze TCM electronic medical records. The patterns revealed by the analyses were highly correlated with the therapeutic principles of TCM practitioners. Machine learning technology could assist TCM practitioners to comprehensively differentiate patterns and identify effective Chinese herbal medicine treatments in clinical practice.

Background The influenza virus is a highly infectious disease, with a notably rapid transmission rate. Autophagy is triggered by viral infection and is a survival mechanism exerted to maintain cellular homeostasis. Catechin is a representative phenolic acid which exerts anti-inflammatory responses against influenza A virus infection. The aim of this study is to explore the anti-H1N1 influenza virus effects by catechin associated with the restoration of autophagy. Methods XTT assay was used to detect cellular viability. The inhibitory effects on the H1N1 influenza virus were assessed by hemagglutination assay, neuraminidase activity, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The protein levels of H1N1 influenza virulence and autophagic markers were detected by Western blot. Results We herein demonstrated that catechin had no cytotoxic effect on both infected and noninfected A549 cells and exerted protective effects on infected A549 cells. The results of the hemagglutination assay, neuraminidase activity, and qRT-PCR to examine viral load demonstrated that catechin effectively inhibited the replication of the H1N1 influenza virus. The virulent M2 protein and viral nucleoprotein were also inhibited after treatment with catechin. As for the autophagic markers, the LC3B protein was notably decreased by catechin in a dose-dependent manner, while the amount of autophagic vacuoles in H1N1 influenza virus-infected cells also decreased after catechin treatment in a dose-dependent manner. Conclusion Collectively, the autophagy activated by the H1N1 influenza virus could be reversed after catechin treatment. This study indicates that catechin effectively inhibits H1N1 viral proliferation and thus may be applied as an adjuvant in future clinical application.

Objective: Chinese herbal medicine (CHM) is frequently applied to patients to improve the symptoms and signs associated with anemia. The aim of this study is to use the claims data from the National Health Insurance Research Database (NHIRD) in Taiwan to analyze CHM prescription patterns and to identify the frequency and combinations of CHM commonly used to treat anemia. Materials and methods: A total of 41,028 patients were diagnosed with anemia in Taiwan within the defined study period. After randomly equal matching for age and sex, data from 7682 patients characterized as CHM users and non-users were analyzed. Network analyses of the 30 most frequently applied herbs and formulas were used to indicate CHM combinations in patients with anemia. Results: Those patients with anemia who were older, office workers, and lived in central areas of Taiwan had higher tendencies toward CHM usage. Based on considerations of comorbidities, anemia patients associated with chronic kidney diseases, diabetes mellitus, and hypertensive diseases preferred Western medical management and demonstrated a lesser likelihood of combining treatment with CHM; by contrast, those with coronary artery disease demonstrated a higher tendency for CHM use. Notably, Astragalus membranaceus (AM) and Gui-Pi-Tang (GPT) were the most commonly prescribed CHM single herb and formula, respectively. The core prescription pattern consisted of AM, Salvia miltiorrhiza (SM), Angelica sinensis (AS), GPT, and Si-Wu-Tang (SWT), as indicated by the associations and frequency of CHM utilization by traditional Chinese medicine (TCM) physicians. Conclusion: This study demonstrates that CHM may be applied as an integral element of treatment for patients with anemia. It also provides insight regarding individual therapy and common clinical practices of TCM physicians in the treatment of anemia. Further research is required to explore potential interactions and possible mechanisms at play with CHM management of anemia. Keywords: Chinese herb medicine, Anemia, Cohort study, Prescription pattern

Objective The purpose of this case report was to elucidate how Chinese herbal medicine (CHM) was used safely in this patient undergoing interferon beta (IFNβ-1a) treatment and was associated with reduction in the side effects the patient had experienced when using IFNβ-1a treatment alone. Clinical features and outcome A 30-year-old man was diagnosed with MS in December 2014. For two years, he suffered from severe flu-like symptoms as side effects of IFNβ-1a treatment. He subsequently received treatment with Chinese herbal medicine. During a two-month period of treatment with CHM, the patient responded well, with most of the symptoms induced by IFNβ-1a ameliorated. The fever subsided. Incidence rates of dizziness and headaches were reduced. The health condition compared to the prior year increased by 50%. According to CCMQ and SF-36 assessments, CHM had the beneficial effects of recovering the yin-yang balance, harmonizing the qi, and regulating the blood state; essentially, improving the patient’s comfort level and quality of life. Conclusions IFNβ-1a injections will damage qi and cause blood stasis in MS patients, thereby causing various side effects and weakening the body’s immune system. Bu-Zhong-Yi-Qi-Tang, associated with Salvia miltiorrhiza, Ligusticum chuanxiong, Angelica dahurica and Polygonum multiflorum Thunb., is an effective prescription to ameliorate such symptoms and signs in patients with MS.

Ethnopharmacological relevance There is a decided lack of in-depth studies to evaluate the effectiveness of Chinese Herbal Medicine (CHM) as an adjuvant therapy on the incidence of chronic hepatitis in patients with colon cancer. Aim of the study The aim of this study is to assess whether CHM treatment decreased the incidence of chronic hepatitis in colon cancer patients who received conventional Western medical treatment. Materials and methods A Taiwanese nationwide population-based study of colon cancer patients receiving Western medicine treatment in conjunction with CHM treatment, using data provided by the National Health Insurance (NHI) Research Database, was conducted. A total of 61676 patients were diagnosed with colon cancer in Taiwan within the defined study period, from 1997 to 2010. After randomly equal matching for age, sex, excluding patients younger than 18 years of age, chronic hepatitis before colon cancer diagnosis date, receiving acupuncture and/or moxibustion and taking CHM for less than 30 days, data from 155 patients were analyzed. Hazard ratios of incidence rate of chronic hepatitis were used to determine the influence of CHM and the therapeutic potential of herbal products in treating patients with colon cancer. Results CHM used for patients with colon cancer exhibited significantly decreased incidence rates of chronic hepatitis [hazard ratio (HR)=0.53; 95% confidence interval (CI):0.38–0.74], with multivariate adjustment, compared to those without CHM use. The protective effect of CHM treatment with statistical significance across the stratification of age, gender, co-morbidity and treatment modality was noted. The cumulative incidence of chronic hepatitis was also reduced in patients with colon cancer receiving CHM treatment during a five-year period. In this study, we provide the ten most used single herbs and herbal formulas that were prescribed for patients with colon cancer; moreover, we identify the eight single herbs and five formulas used in CHM treatment which significantly decreased incidence of chronic hepatitis among colon cancer patients. Conclusions This nationwide retrospective cohort study determined that therapy using CHM as an adjuvant modality may have a significant impact on liver protection in patients with colon cancer.

OBJECTIVES To investigate the effectiveness of Chinese herbal medicine for the treatment of urinary incontinence in patients with chronic obstructive pulmonary disease. METHODS We carried out a retrospective cohort study using the National Health Insurance Research Database. From a cohort of 1 million records between 1996 and 2013, a total of 202 279 patients with newly onset chronic obstructive pulmonary disease were initially recruited. We matched with propensity score 3967 patients who received Chinese herbal medicine by age, sex, year of chronic obstructive pulmonary disease diagnosis, urbanization, comorbidities and chronic obstructive pulmonary disease medications. All participants received follow-up visits until the end of 2013 to record the incidence rate of urinary incontinence. The Cox proportional hazards model was applied to assess the association between Chinese herbal medicine use and the risk of urinary incontinence among chronic obstructive pulmonary disease patients. RESULTS The incidence rates of urinary incontinence were 57.33 and 108.15 (per 10 000 person-years) in the Chinese herbal medicine and non-Chinese herbal medicine cohorts, respectively, showing a significantly lower risk of urinary incontinence in Chinese herbal medicine users (aHR = 0.56, 95% CI = 0.45-0.69, P

Several inherited human diseases have been linked to mitochondrial aminoacyl-tRNA synthetases (mtARSs). Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a leukodystrophy caused by mutations in the DARS2 gene which encodes mitochondrial aspartyl-tRNA synthetase. As mitochondrial ARSs are key components of the mitochondrial translation apparatus, we investigated the effects of DARS2 mutations on mitochondrial functions and mitochondrial morphology in an LBSL patient. In fibroblasts from the patient with LBSL, biosynthesis of respiratory chain complex proteins encoded by mitochondrial DNA was decreased, while those encoded by nuclear DNA were not. Cellular oxygen consumption rates and respiratory control ratio were decreased in the LBSL patient; in addition, fragmentation of mitochondria was increased, while their tubular elongation and interconnectivity were decreased. Taken together, these findings suggest that DARS2 mutations impair translations of mitochondrial DNA-encoded respiratory chain complex proteins, consequently causing dysfunction of cellular respiration and impediment of mitochondrial dynamics, which highlights the role of mtARSs in the maintenance of normal mitochondrial bioenergetics and dynamics.

Background and purpose: Lung cancer has high global incidence and mortality rates. Chronic obstructive pulmonary disease (COPD) is strongly associated with lung cancer and is an independent risk factor for lung cancer with or without smoking. Chinese herbal medicines (CHMs) are used to treat COPD. This study sought to determine whether CHM treatment effectively decreases the incidence of lung cancer in COPD patients receiving conventional Western medical treatment.Methods: Records obtained from the National Health Insurance Research Database (NHIRD) were used to identify 81,780 adults aged ≥18 years newly diagnosed with COPD in Taiwan between 2000 and 2010. Among them, 11,180 received CHMs after COPD diagnosis and 23,319 did not (non-CHM). After excluding patients with missing basic demographic information, each group consisted of 2,682 patients. Statistical methods analyzed the baseline characteristics for both groups and we performed a Cox proportional hazard regression analysis to examine the incidence of lung cancer. The cumulative incidence of lung cancer in COPD patients with or without CHM treatment was calculated by the Kaplan-Meier method. The association between herbs and formulas was examined by NodeXL to perform a network analysis of CHM.Results: COPD patients using CHM had a lower risk for lung cancer (adjusted hazards ratio [aHR] = 0.36, 95% confidence interval [CI] = 0.24–0.53, p < 0.001). Older age was associated with a higher risk of lung cancer: patients aged 40–59 years (aHR = 5.32, 95% CI = 2.19–12.94, p < 0.001) and those aged ≥60 years (aHR = 16.75, 95% CI = 7.54–37.23, p < 0.001) were at significantly greater risk compared with patients aged 18–39 years. CHM use was associated with a trend for a lower cumulative incidence of lung cancer compared with non-CHM use (p < 0.001). Among the 10 most commonly used single herbs and formulas used to decrease the risk of lung cancer in COPD patients, Fritillariae thunbergii was the most commonly used single herb and Xiao Qing Long Tang the most commonly used formula.Conclusion: The findings from this nationwide retrospective cohort study indicate that CHM as adjunctive therapy in COPD treatment regimens may reduce the risk of lung cancer in this vulnerable patient population.

Objectives Much epidemiological evidence links diabetes mellitus (DM) to the development of multiple cancers and, in particular, the development of hepatocellular carcinoma (HCC). The aim of this study was to investigate whether Chinese herbal medicine (CHM) reduces the incidence of HCC in patients receiving Western antidiabetic drugs. Interventions and main outcome measures This retrospective cohort study used data from the National Health Insurance Research Database involving 81,105 diabetic patients, including 5122 CHM users and 25,966 non-CHM users. Analyses of treatment effects were adjusted for covariates including gender, age, comorbidities, antidiabetic drugs and liver medications. NodeXL software performed a network analysis to identify the 50 most commonly used CHM herbs and formulas. Results In Cox proportional hazards models adjusted for demographic and clinical characteristics, DM patients exposed to adjuvant CHM therapy were significantly less likely to develop HCC compared with non-CHM users (adjusted hazard ratio [aHR] 0.59; 95 % confidence interval [CI], 0.41-0.87; p = 0.01). Kaplan-Meier analysis revealed a lower 10-year cumulative risk of HCC among CHM users compared with non-CHM users. Amongst the 10 individual CHM herbs and herbal formulas most commonly prescribed for DM, the most frequent were Salvia miltiorrhiza (Dan Shen) and Liu Wei Di Huang Wan, respectively. Conclusion This nationwide retrospective cohort study from Taiwan provides some valuable insights into the prescribing characteristics of CHM treatment in patients with DM. Compared with use of Western antidiabetic medications alone, use of adjuvant CHM effectively reduces the incidence of HCC in patients with DM.

Mitochondrial dysfunction and oxidative stress are underlying contributors to Parkinson's disease (PD). The reduction of aberrant proteins and dysfunctional mitochondria through constitutive autophagy is essential for neuronal survival. We investigated the neuroprotective effects of the natural red wine extract, resveratrol, on the Complex I inhibitor, rotenone-induced oxidative stress SH-SY5Y cellular model. With rotenone exposure, cellular reactive oxygen species (ROS), apoptosis and cell death increased at both 6 and 18 h; at the same time, mitochondrial membrane potential (ΔΨm) and the balance of mitochondrial dynamic proteins were disrupted, resulting with fragmented mitochondria. Rotenone was also noted to elevate autophagy initiation but downregulate the autophagy flux. Pretreatment with resveratrol to rotenone exposed cells lowered cellular ROS, apoptosis, and increased survival rates. Resveratrol administration also recovered rotenone induced ΔΨm, mitochondria dynamics alteration, and elongated fragmented mitochondria. Both autophagic induction and autophagic flux were enhanced with resveratrol pre-treatment which is compatible with cellular survival. The mitogen-activated protein kinase (MEK) inhibitor, U0126, abolished the rescuing effect of resveratrol on rotenone treated neurons through the inhibition of autophagy flux. Thus, our work implies that the neuroprotective effect of resveratrol works in part through modulation of mitochondria dynamics and upregulating autophagic flux via the MEK/extracellular signal-regulated kinase (ERK) signalling pathway.

Chronic kidney disease (CKD) is a serious complication affecting patients with chronic hepatitis. The effectiveness of CHM for the prevention of CKD in hepatitis patients remains unclear. Therefore, we conducted a retrospective cohort study to investigate the effectiveness of CHM in preventing the development of CKD in hepatitis patients. From a subdataset of the Taiwan National Health Insurance Research Database (NHIRD), we included 19,409 patients newly diagnosed with hepatitis B and hepatitis C between the years 2000 and 2010. After exclusion criteria and 1 : 1 propensity score matching process, we compared demographic factors, comorbidities, and correlated drugs between the CHM and non-CHM cohorts. Statistical analysis was applied to evaluate the differences in characteristic distributions and to compare the cumulative incidence of CKD between the CHM and non-CHM cohorts. This study showed that the patients suffering from hepatitis C with CHM treatment more than 90 days as an adjuvant therapy combined with western medical treatment modalities exhibited a decreased risk of developing CKD (hazard ratio (HR) = 0.40, 95% confidence interval (CI) = 0.21–0.76, p value p value = 0.004) for the CHM cohort. For further reference, we herein offer the ten most frequently prescribed single herbs and herbal formulas; as such, Salviae miltiorrhizae and Jia-Wei-Xiao-Yao-San were the most commonly prescribed single herb and formula, respectively. This nationwide retrospective cohort study provides evidence that CHM is an effective adjuvant treatment to decrease the risk of developing CKD in hepatitis C patients.

Traditional Chinese Medicine (TCM) is an experiential form of medicine with a history dating back thousands of years. The present study aimed to utilize neural network analysis to examine specific prescriptions for colorectal cancer (CRC) in clinical practice to arrive at the most effective prescription strategy. The study analyzed the data of 261 CRC cases recruited from a total of 141,962 cases of renowned veteran TCM doctors collected from datasets of both the DeepMedic software and TCM cancer treatment books. The DeepMedic software was applied to normalize the symptoms/signs and Chinese herbal medicine (CHM) prescriptions using standardized terminologies. Over 20 percent of CRC patients demonstrated symptoms of poor appetite, fatigue, loose stool, and abdominal pain. By analyzing the prescription patterns of CHM, we found that Atractylodes macrocephala (Bai-zhu) and Poria (Fu-ling) were the most commonly prescribed single herbs identified through analysis of medical records, and supported by the neural network analysis; although there was a slight difference in the sequential order. The study revealed an 81.9% degree of similarity of CHM prescriptions between the medical records and the neural network suggestions. The patterns of nourishing Qi and eliminating dampness were the most common goals of clinical prescriptions, which corresponds with treatments of CRC patients in clinical practice. This is the first study to employ machine learning, specifically neural network analytics to support TCM clinical diagnoses and prescriptions. The DeepMedic software may be used to deliver accurate TCM diagnoses and suggest prescriptions to treat CRC.

Background and purpose Investigation of the relationship between mitochondrial DNA (mtDNA) variants and Parkinson disease (PD) remains an issue awaiting more supportive evidence. Moreover, an affirming cellular model study is also lacking. Methods The index mtDNA variants and their defining mitochondrial haplogroup were determined in 725 PD patients and 744 non-PD controls. Full-length mtDNA sequences were also conducted in 110 cases harboring various haplogroups. Cybrid cellular models, composed by fusion of mitochondria-depleted rho-zero cells and donor mitochondria, were used for a rotenone-induced PD simulation study. Results Multivariate logistic regression analysis revealed that subjects harboring the mitochondrial haplogroup B5 have resistance against PD (odds ratio 0.50, 95% confidence interval 0.32–0.78; P = 0.002). Furthermore, a composite mtDNA variant group consisting of A10398G and G8584A at the coding region was found to have resistance against PD (odds ratio 0.50, 95% confidence interval 0.33–0.78; P = 0.001). In cellular studies, B4 and B5 cybrids were selected according to their higher resistance to rotenone, in comparison with cybrids harboring other haplogroups. The B5 cybrid, containing G8584A/A10398G variants, showed more resistance to rotenone than the B4 cybrid not harboring these variants. This is supported by findings of low reactive oxygen species generation and a low apoptosis rate in the B5 cybrid, whereas a higher expression of autophagy was observed in the B4 cybrid particularly under medium dosage and longer treatment time with rotenone. Conclusions Our studies, offering positive results from clinical investigations and cybrid experiments, provide data supporting the role of variant mtDNA in the risk of PD.

Osteosarcoma is an aggressive bone cancer arising from primitive transformed cells of mesenchymal origin to form malignant osteoid. Phyllanthus urinaria [Formula: see text]P. urinaria[Formula: see text] is a widely used folk medicine in cancer treatment, however the mechanism of P. urinaria inhibited human osteosarcoma is unclear. The present study was aimed at investigating the antitumoral effects of an aqueous P. urinaria on human osteosarcoma in vivo and the related underlying mechanisms, mainly focusing on mitochondrial dynamic dysfunction. Our results showed that oral administration of P. urinaria to mice led to significant inhibition of tumor development without substantial changes to body weight or major organs. Histological examinations with H&E, Giemsa, and Masson trichrome stains confirmed inhibition of tumor growth by the P. urinaria treatment. Immunohistochemical staining of proliferation markers antigen KI-67 (Ki67) and proliferating cell nuclear antigen (PCNA), as well as a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay demonstrated a decrease of tumor proliferation and an increase of apoptosis, which was associated with the modulation of B-cell lymphoma 2 (Bcl-2) family activating the caspase cascade in the P. urinaria-treated mice. The neovascularization marker cluster of differentiation 31 (CD31) was inhibited in P. urinaria-treated xenografts, implicating the potential anti-angiogenic effect of P. urinaria. P. urinaria treatment resulted in a significant decrease in the mitochondrial fusion proteins, including mitofusin 1/2 (Mfn1/2) and optic atrophy type 1 (Opa1), as well as an increase in the fission protein dynamin-related protein 1 (Drp1). The results of this study suggest mitochondrial dysfunction is associated with dynamic change that is involved in the apoptosis and anti-angiogenesis elicited by P. urinaria.

Introduction Species of Tinospora are used as herbal remedies for the treatment of various diseases with very few toxic effects having been reported. Tinospora cordifolia (TCF) has been reported to effectively prevent hepatotoxicity. However, there are an increasing number of cases revealing that Tinospora crispa (TCP) might have the negative effect of inducing hepatotoxicity. Because of the similar leaves, people may mistake TCP for TCF, and consume it with the purpose of protecting liver function. Objective Find out the misusing level of TCP and TCF and which chemical compound in TCP might induce hepatotoxicity. Methods We report two cases of acute fulminant hepatitis associated with chronic use of TCP. Given that the two herbs were misidentified in these two reports, we investigated the frequency of erroneous identification by using three keywords (“Guduchi”, “Tinospora cordifolia”, “Tinospora crispa”) to search images from the Google Images database. To further clarify the influence of liver function between TCP and TCF, we searched PubMed (up to 29 July 2018) for relevant publications on clinical trials or case reports. Results Based on web review, over 35 percent of websites failed to accurately identify these two herbs. The different effects on liver function between TCP and TCF were compared through literature review. It indicated that TCF exerted liver protection, TCP had a contrary effect, suggesting its cis-Clerodane-type furano-diterpenoids might be an important factor of inducing hepatotoxicity. Conclusions We concluded that people might cause hepatic injury or even death without correctly identifying these two Tinospora species.

Background and purpose: Chinese herbal medicine (CHM) is frequently applied in conjunction with western pharmacotherapy to relieve symptoms in patients with CKD. However, evidence-based research into the effectiveness of CHM use as applied to treat CKD is limited and warrants further investigation. The aim of this study is to assess whether adjunctive treatment with CHM affected survival rate of CKD patients undergoing conventional western medical management.Methods: A total of 14,718 CKD patients, including 6,958 CHM users and 7,760 non-CHM users, were recruited from the Longitudinal Health Insurance Database 2000, a sub-dataset of the National Health Insurance Research Database, to conduct this study. Demographic characteristics, including sex, age, job type, residential area, and comorbidity were considered as covariates to adjust the analysis. A network analysis of treatments, including with herbal formulas and single herbs, was performed to investigate the core patterns of CHM use for the treatment of CKD patients. The Kaplan-Meier method was used to determine the survival rate between CHM and non-CHM groups.Results: After matching for sex and age, there were 550 subjects in both the CHM and non-CHM cohorts. Other than presence of diabetes (adjusted OR = 0.57, p < 0.001) and urinary tract infection (adjusted OR = 0.69, p < 0.05), sex, age, job type, area of residence, and other comorbidities indicated no special preference for CHM use among subjects. Salvia miltiorrhiza Bunge (SM) and Ji-Sheng-Shen-Qi-Wan (JSSQW) were the most frequent single herb and formula, respectively, prescribed for patients with CKD. The most frequent CHM combination between herbs and formulas was JSSQW, associated with Rheum officinale Baill. (RO), SM and Astragalus membranaceus (Fisch.) Bunge (AM). The long-term survival rate demonstrated significant benefits for CHM users within a 12-year follow-up period (P < 0.004).Conclusion: This nationwide retrospective cohort study provides valuable insight into the characteristics and prescription patterns of CHM usage in CKD patients. JSSQW associated with RO, SM, and AM is the most common CHM prescription. CHM improves long-term survival in patients with CKD, suggesting that CHM is an effective adjuvant therapy for CKD.

Background and Purpose: Drynaria fortunei J. Sm (D. fortunei), known as Gu-Sui-Bu, is used in traditional Chinese medicine to treat common injuries, including bone fractures and bruising. The specific functional mechanisms of the angiogenic and endothelial cell migration properties of D. fortunei are currently unclear. Thus, the purpose of this study is to validate the potential angiogenic and cellular migration properties and related mechanisms by D. fortunei both in vivo and in vitro. Experimental Approach: The present study investigates, both in vivo and in vitro, the wound healing effects of D. fortunei as associated with angiogenesis, specifically by the modulation of matrix metalloproteinases (MMPs) and upregulation of vascular endothelial growth factor (VEGF) ligand/receptors. In order to determine the potential angiogenic effects of D. fortunei, in vivo neovascularization of chick chorioallantoic membranes (CAMs) assay, and directed in vivo angiogenesis assay (DIVVA) were performed, while in vitro scratch wound healing, migration, and matrix-induced tube formation assays were performed by using human umbilical vascular endothelial cells (HUVECs). Furthermore, we used qPCR to analyze the gene expressions and Western blot to observe protein expressions of MMP-2, MMP-14, TIMP-2, RECK, and VEGF/VEGFRs. Results: This study identified five major compounds from the water extract of D. fortunei: protocatechuic acid, caffeic acid 4-O-β-D-glucopyranoside, 5,7-dihydroxychromone-7-O-rutinoside, neoeriocitrin, and naringin. D. fortunei was confirmed to activate in vivo angiogenesis by CAM and DIVVA assays. D. fortunei further exhibited in vitro angiogenic effects associated with cell migration, as demonstrated by the tube formation assay, transwell migration assay, and scratch wound healing assay. The extracellular MMP-2 activity was found to be dose-dependently augmented both in vitro and in vivo by D. fortunei. The mRNA and protein expressions of MMP-2, and MMP-14 were increased; while the tissue inhibitor metalloproteinase-2 (TIMP-2), and reversion-inducing cysteine-rich protein with kazal motifs (RECK) were both decreased. Furthermore, D. fortunei activated the gene and protein expressions of VEGF-A, -B, and VEGFR-2, -3. Conclusion: D. fortunei increased MMP-2 activity, thereby stimulating angiogenesis and cell migration, both in vivo and in vitro, as a result of MMP-2 and TIMP-2 balance modulation and the activation of VEGF/VEGFRs expression.

Objective Urolithiasis is a common medical condition affecting the urinary tract. Typical symptoms reported by patients include colic pain and hematuria. Some patients may undergo surgical intervention or lithotripsy to remove the stones. In this case, we demonstrated that Chinese herbal medicine (CHM) was an effective modality to remove stones in a patient with urolithiasis. Clinical features and outcome A 47-year-old man suffered from right flank pain and hematuria for three months and was diagnosed with an upper third ureteral stone obstruction with right hydronephrosis. He had received extracorporeal shock wave lithotripsy (ESWL) three times before his first CHM visit, but it was unsuccessful. Therefore, he sought CHM for further intervention. His symptoms subsided, and the image study showed complete removal of the ureteral stone after regular therapy with Zhi Bai Di Huang Wan ( ) combined with Lygodii spora ( ), Curcumae radix ( ), Endothelium Corneum Gigeriae Galli ( ), Lysimachiae herba ( ), Orthosiphon stamineus ( ) for approximately four months. Neither complications nor side-effects were noted during the CHM treatment. Conclusions In this case, we concluded that CHM may be an effective alternative therapy for the treatment of ureteral stones, and furthermore, may also be applied as an option to salvage failed ESWL procedures.

Gallic acid is a trihydroxybenzoic acid found in natural herbal plants. Gallic acid has been reported to inhibit the migration and invasive capability of various cancers. Little is known about the underlying mechanisms of invasion responsible for cancer metastasis via gallic acid. The present study was intended to investigate the anti-invasive effect of gallic acid on human nasopharyngeal carcinoma cells (NPC-BM1) and its related mechanism. Gallic acid inhibited the invasion of NPC-BM1 cells dose- and time-dependently without significant cytotoxic effect. Affymetrix oligonucleotide microarray analysis revealed matrix metalloproteinase-1 (MMP-1) as the most down-regulated gene in NPC-BM1 cells by gallic acid. The cytosolic and secreted MMP-1 levels were both found to be inhibited by gallic acid as demonstrated by western blot analysis and ELISA respectively. The mRNA expression and transcription of MMP-1 gene was also down-regulated as determined by RT/real-time PCR and promoter activity assay. The expression of two major transcription binding factors in the MMP-1 promoter, AP-1 and ETS-1, were demonstrated to be reduced by gallic acid in NPC-BM1 cells. The effect of gallic acid was associated with the inhibition of p38 MAPK signaling pathway. In addition, gallic acid enhanced the gene expression of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) which further suppressed the MMP-1 activity. These findings may be useful to develop a novel chemotherapeutic agent to inhibit the metastasis of nasopharyngeal cancer.

The study aim was to compare the long-term effect of Western medicine and combined treatment with Traditional Chinese Medicine (TCM) and Western medicine on the prognosis (survival rate, symptom distress, physical function, and quality of life) of patients with lung cancer.Longitudinal study.Two medical centers, one each in Northern and Southern Taiwan.Patients newly diagnosed with lung cancer and treated with Western medicine (n = 54) or TCM plus Western medicine (n = 30).Symptom distress, physical function, and quality of life were measured by using the Symptom Distress Scale, Eastern Cooperative Oncology Group-Performance Status Rating, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC QLQ-LC13), respectively. Data on these measures were collected at baseline (before treatment) and 1, 3, 6, and 12 months after starting treatment. Survival was estimated by Kaplan-Meier curves. Group differences in outcomes were analyzed by generalized estimating equations.Treatment groups did not differ significantly at baseline for demographic information; disease severity; symptom distress; or EORTC QLQ-C30 and QLQ-LC13 scores, except for pain and dyspnea. After adjustment for these baseline effects, the combined-treatment group had better physical function and role function than the Western medicine group at 6 months (p 0.05). The combined treatment group had better cumulative survival, but this difference did not reach significance.To more precisely estimate the long-term effectiveness of combined treatment on the prognosis of patients with lung cancer, future studies should standardize the number of TCM visits; increase the number of participants by continuous recruitment; and ask patients to complete daily logs with single-item measures of outcomes, such as symptom distress, quality of life, and physical function. Similar studies are suggested in patients with different cancers to develop a collaborative model using Western medicine and TCM.

Tanshinone IIA (Tan IIA), a phytochemical derived from the roots of Salvia miltiorrhiza, has been shown to inhibit growth and induce apoptosis in various cancer cells. The association of its inhibitory effect on the primary malignant bone tumor, osteosarcoma, with mitochondrial dysfunction remains unclear. This study aimed to investigate the anti-proliferative effects of Tan IIA on human osteosarcoma 143B cells both in vitro and in vivo. Administration of Tan IIA to NOD-SCID mice implanted with 143B cells led to significant inhibition of tumor development. The inhibition of proliferation, migration, and invasion was observed in 143B cells treated with Tan IIA. The tumor proliferation markers, Ki67 and PCNA, were suppressed and apoptosis by TUNEL assay was activated respectively. Apoptosis in the Tan IIA-treated 143B cells and xerograft mice was associated with the activation of caspase cascade via the modulation of Bcl-2 family. The CD31 was inhibited in Tan IIA-treated xenografts to indicate anti-neovasculization. Tan IIA administration resulted in a significant decrease in the mitochondrial fusion proteins, Mfn1/2 and Opa1, as well as an increase in the fission protein Drp1. We concluded that mitochondrial dysfunction associated with dynamic change was involved in apoptosis and anti-angiogenesis elicited by Tan IIA.

We conducted a National Health Insurance Research Database-based Taiwanese nationwide population-based cohort study to evaluate whether Chinese herbal medicine (CHM) treatment decreased the incidence of chronic hepatitis in breast cancer patients receiving chemotherapy and/or radiotherapy. A total of 81171 patients were diagnosed with breast cancer within the defined study period. After randomly equal matching, data from 13856 patients were analyzed. Hazard ratios of incidence rate of chronic hepatitis were used to determine the influence and therapeutic potential of CHM in patients with breast cancer. The patients with breast cancer receiving CHM treatment exhibited a significantly decreased incidence rate of chronic hepatitis even across the stratification of age, CCI score, and treatments. The cumulative incidence of chronic hepatitis for a period of seven years after initial breast cancer diagnosis was also reduced in the patients receiving CHM treatment. The ten most commonly used single herbs and formulas were effective in protecting liver function in patients with breast cancer, where Hedyotis diffusa and Jia-Wei-Xiao-Yao-San were the most commonly used herbal agents. In conclusion, our study provided information that western medicine therapy combined with CHM as an adjuvant modality may have a significant impact on liver protection in patients with breast cancer.

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. In basic studies, the regulation of autophagy has offered promising results for HCC treatment. This study aimed to address the question of whether amiodarone can improve survival rates in HCC patients associated with autophagy. Using datasets from the National Health Insurance Research Database, we enrolled patients over 18 years of age that had been diagnosed with HCC between January 1997 and December 2010. Amiodarone and non-amiodarone users were matched at a 1:1 frequency, according to all variables. Additionally, HepG2 cells treated with amiodarone were evaluated by cell viability and autophagic change. Autophagic signaling was examined by immunoblotting and tissue array immunohistochemistry. Of the 10,946 patients diagnosed with HCC, each cohort included 221 patients after 1:1 propensity score matching. The median survival was 36.70 months for the amiodarone users, and 24.48 months for the non-amiodarone users. After adjusting for age, gender, comorbidities and treatment, amiodarone users had a significantly lower risk of mortality. Amiodarone users also demonstrated an improved 3-year survival rate. Furthermore, amiodarone treatment-induced autophagy in HepG2 cells was demonstrated by autophagosome formation associated with increasing LC3B-II, P62, and Beclin-1 expression. Autophagic flux also increased following amiodarone treatment with bafilomycin A1. SiRNA of LC3B knocked down endogenous LC3B formation and restored HepG2 cell viability. This study provides epidemiologic evidence that amiodarone via autophagic degradation machinery may offer survival benefits for HCC patients with a history of arrhythmia. Further randomized, blinded, and placebo-controlled trials are warranted for patients with HCC.

Naringin has been reported to have an anti-atherosclerosis effect but the underlying mechanism is not fully understood. The aim of this study is to investigate the impact of naringin on the TNF-α-induced expressions of cell adhesion molecules, chemokines and NF-κB signaling pathway in human umbilical vein endothelial cells (HUVECs). The experiments revealed that naringin, at concentrations without cytotoxicity, dose-dependently inhibited the adhesion of THP-1 monocytes to the TNF-α-stimulated HUVECs. The TNF-α-induced expressions of cell adhesion molecules, including VCAM-1, ICAM-1 and E-selectin, at both the mRNA and protein levels, were significantly suppressed by naringin in a dose dependent manner. In addition, the TNF-α-induced mRNA and protein levels of chemokines, including fractalkine/CX3CL1, MCP-1 and RANTES, were also reduced by naringin. Naringin significantly inhibited TNF-α-induced nuclear translocation of NF-κB, which resulted from the inhibited phosphorylation of IKKα/β, IκB-α and NF-κB. Altogether, we proposed that naringin modulated TNF-α-induced expressions of cell adhesion molecules and chemokines through the inhibition of TNF-α-induced activation of IKK/NF-κB signaling pathway to exert the anti-atherosclerotic effect.