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Objective, To investigate the genetic characteristics of idiopathic central precocious puberty (ICPP) and validate its polygenic risk for early puberty. Design and methods A bootstrap subsampling and genome-wide association study were performed on Taiwanese Han Chinese girls comprising 321 ICPP patients and 148 controls. Using previous GWAS data on pubertal timing, a replication study was performed. A validation group was also investigated for the weighted polygenic risk score (wPRS) of the risk of early puberty. Results A total of 105 SNPs for the risk of ICPP were identified, of which 22 yielded an area under the receiver operating characteristic curve of 0.713 for the risk of early puberty in the validation group. A replication study showed that 33 SNPs from previous GWAS data of pubertal timing were associated with the risk of ICPP (training group: P-value < 0.05). In the validation group, a cumulative effect was observed between the wPRS and the risk of early puberty in a dose-dependent manner (validation group: Cochran–Armitage trend test: P-value < 1.00E−04; wPRS quartile 2 (Q2) (odds ratio (OR) = 5.00, 95% CI: 1.55–16.16), and wPRS Q3 (OR = 11.67, 95% CI: 2.44–55.83)). Conclusions This study reveals the ICPP genetic characteristics with 22 independent and 33 reported SNPs in the Han Chinese population from Taiwan. This study may contribute to understand the genetic features and underlying biological pathways that control pubertal timing and pathogenesis of ICPP and also to the identification of individuals with a potential genetic risk of early puberty.

Background High blood pressure is common and comorbid with type 2 diabetes (T2D). Almost 50% of patients with T2D have high blood pressure. Patients with both conditions of hypertension (HTN) and T2D are at risk for cardiovascular diseases and mortality. The study aim was to investigate genetic risk factors for HTN in T2D patients. Methods This study included 999 T2D (cohort 1) patients for the first genome scan stage and 922 T2D (cohort 2) patients for the replication stage. Here, we investigated the genetic susceptibility and cumulative weighted genetic risk score for HTN in T2D patients of Han Chinese descent in Taiwan. Results Thirty novel genetic single nucleotide polymorphisms (SNPs) were associated with HTN in T2D after adjusting for age and body mass index (P value Conclusions A cumulative weighted genetic risk score composed of 14 SNPs is important for HTN, increased tendency of systolic blood pressure, and may contribute to HTN risk in T2D in Taiwan.

Context Human height is an inheritable, polygenic trait under complex and multilocus genetic regulation. Familial short stature (FSS; also called genetic short stature) is the most common type of short stature and is insufficiently known. Objective To investigate the FSS genetic profile and develop a polygenic risk predisposition score for FSS risk prediction. Design and Setting The FSS participant group of Han Chinese ancestry was diagnosed by pediatric endocrinologists in Taiwan. Patients and Interventions The genetic profiles of 1163 participants with FSS were identified by using a bootstrapping subsampling and genome-wide association studies (GWAS) method. Main Outcome Measures Genetic profile, polygenic risk predisposition score for risk prediction. Results Ten novel genetic single nucleotide polymorphisms (SNPs) and 9 reported GWAS human height-related SNPs were identified for FSS risk. These 10 novel SNPs served as a polygenic risk predisposition score for FSS risk prediction (area under the curve: 0.940 in the testing group). This FSS polygenic risk predisposition score was also associated with the height reduction regression tendency in the general population. Conclusion A polygenic risk predisposition score composed of 10 genetic SNPs is useful for FSS risk prediction and the height reduction tendency. Thus, it might contribute to FSS risk in the Han Chinese population from Taiwan.

Chinese herbal medicines (CHMs) are widely used in Asian countries. They show multiple pharmacological activities, including antiviral activities. The 5′-long terminal repeat (LTR) region of HIV-1, required for viral transcription, is a potential drug target for HIV-1 reactivation and intrinsic cell death induction of infected or latently infected cells. Modulation of HIV-1 reactivation requires interactions between host cell proteins and viral 5′-LTR elements. By evaluation of two CHMs- Xanthium strumarium and Pueraria montana, we found that 1) X. strumarium reactivated HIV-1 latently infected cells in J-Lat 8.4, J-Lat 9.2, U1, and ACH-2 cells in vitro; 2) 27 nuclear regulatory proteins were associated with HIV-1 5′-LTR using deoxyribonucleic acid affinity pull-down and LC-MS/MS analyses; and 3) among them, silencing of XRCC6 reactivated HIV-1 5′-LTR transcriptional activity. We found that X. strumarium inhibits the 5′-LTR associated XRCC6 nuclear regulatory proteins, increases its viral 5′-LTR promoter transcriptional activity, and reactivates HIV-1 latently infected cells in vitro. These findings may contribute to understanding the 5′-LTR activity and the host cell nuclear regulatory protein machinery for reactivating HIV-1 and for future investigations to eradicate and cure HIV-1 infection.

Chinese herbal medicine (CHM) is a complementary natural medicine that is used widely for the treatment of hepatic diseases. The aim of this study was to investigate the effects of the long-term use of CHM for the treatment of liver diseases, as prescribed by TCM doctors, on overall mortality and hepatic outcomes in patients with HCV.We identified 98788 patients with HCV. Of these, 829 and 829 patients who were users and non-users of CHM, respectively, were matched for age, gender, CCI, and comorbidities prior to CHM treatment. The chi-squared test, Cox proportional hazard model, Kaplan--Meier method, and log-rank test were used for comparisons.CHM users had a lower risk of overall mortality than non-users after adjustment for comorbidities by using a multivariate Cox proportional hazard model (p-value0.001; HR: 0.12, 95% CI: 0.06-0.26). In addition,the CHM users had a lower risk of liver cirrhosis than non-users after adjustment for comorbidities (p-value = 0.028; HR: 0.29, 95% CI: 0.09-0.88). The 12-year cumulative incidences of overall mortality and liver cirrhosis were lower in the CHM group (p-value0.05 for both, log rank test). The CHM co-prescription for Dan-Shen, Bie-Jia, Jia-Wei-Xiao-Yao-San =E-Shu was found to occur most often associated for the specific treatment of HCV infection.CHM as adjunctive therapy may reduce the overall mortality and the risk of liver cirrhosis in patients with HCV. The comprehensive list of the herbal medicines that may be used for the treatment of patients with HCV may be useful in future scientific investigations or for future therapeutic interventions to prevent negative hepatic outcomes in patients with HCV.

BACKGROUND Patients with type 2 diabetes mellitus (T2DM) experience a two-fold increased risk of cardiovascular diseases. Genome-wide association studies (GWAS) have identified T2DM susceptibility genetic variants. Interestingly, the genetic variants associated with cardiovascular disease risk in T2DM Han Chinese remain to be elucidated. The present study aimed to investigate the genetic variants associated with cardiovascular disease risk in T2DM. METHODS We performed bootstrapping, GWAS and an investigation of genetic variants associated with cardiovascular disease risk in a discovery T2DM cohort and in a replication cohort. The discovery cohort included 326 cardiovascular disease patients and 1209 noncardiovascular disease patients. The replication cohort included 68 cardiovascular disease patients and 317 noncardiovascular disease patients. The main outcome measures were genetic variants for genetic risk score (GRS) in cardiovascular disease risk in T2DM. RESULTS In total, 35 genetic variants were associated with cardiovascular disease risk. A GRS was generated by combining risk alleles from these variants weighted by their estimated effect sizes (log odds ratio [OR]). T2DM patients with weighted GRS ≥ 12.63 had an approximately 15-fold increase in cardiovascular disease risk (odds ratio = 15.67, 95% confidence interval [CI] = 10.33-24.00) compared to patients with weighted GRS < 10.39. With the addition of weighted GRS, receiver-operating characteristic curves showed that area under the curve with conventional risk factors was improved from 0.719 (95% CI = 0.689-0.750) to 0.888 (95% CI = 0.866-0.910). CONCLUSIONS These 35 genetic variants are associated with cardiovascular disease risk in T2DM, alone and cumulatively. T2DM patients with higher levels of weighted genetic risk score have higher cardiovascular disease risks.

Objective To investigate the association between hormone replacement therapy (HRT) and the risk of bone fracture in menopausal women in Taiwan. Study design The longitudinal, population-based, nested case-control study in Taiwan involved 5269 women aged > 45 years with fractures and 21,076 matched randomly selected controls without fractures. A conditional logistic regression model of analysis was employed. Main outcome measures The association between the risk of bone fracture and various HRT-related parameters, including the timing, dosage, and adherence, was investigated. Results Women with menopausal syndrome were protected from fractures when they received hormone drugs at high cumulative defined daily doses (DDDs) (Cumulative DDDs≥360) (odds ratio [OR]: 0.90, 95 % confidence interval [CI]: 0.82−0.99) and when their adherence was high (over 0.5) (OR: 0.70, 95 % CI: 0.60−0.82). The risk of fracture also decreased with high cumulative DDDs and high adherence combined (OR: 0.71, 95 % CI: 058−0.86). Subgroup analyses suggested that estrogen-containing regimens showed a protective effect against fractures at high cumulative DDDs or when adherence was high. Similar results were also observed with progestogen-containing regimens. Past exposure to an estrogen-containing regimen showed a protective effect against fractures when adherence was high. Past exposure to a progestogen-containing regimen showed a protective effect against fractures at high cumulative DDDs and when adherence was high. Conclusions The results indicate that past exposure to estrogen-containing or progestogen-containing regimens exerts protective effects against bone fracture. These effects increased with higher cumulative DDDs and with adherence in a dose-dependent manner.

The survival of patients with HIV has greatly improved, due to Anti-Retroviral Therapy (ART). However, long-term HIV survivors often develop serious bone abnormalities, possibly due to the interplay of osteoblasts, osteoclasts, HIV ad ART. We evaluated in a nation-wide study in Taiwan the effect of Chinese herbal medicine (CHM) on overall mortality in HIV patients with osteoporosis or fractures. Enrollment period was between 1998 and 2011. Patients with osteoporosis or fractures before the HIV infection, and those with less than 14 days CHM use, were excluded. This left 498 patients, 160 CHM users, 338 without CHM. Univariate Kaplan-Meier and multivariate Cox regression analysis were used to compare the overall mortality in these 2 groups. Due to the nature of Chinese medicine, CHMs inevitably varied. We therefore also used rule mining and network analysis to determine which major CHM clusters were prescribed to the patients. CHM users had a much Lower mortality (hazard ratio (HR) = 0.43, 95% confidence interval (CI): 0.24–0.77, p < 0.005) and higher survival (p = 0.004, log-rank test). Although the CHMs greatly varied, network analysis identified one main cluster of strongly related CHM combinations (Chuan-Xiong-Cha-Tiao-San (CXCTS), Gan-Cao (GC; Glycyrrhiza uralensis Fisch.), Liu-He-Tang (LHT), Huang-Qin-Tang (HQT), Jia-Wei-Ping-Wei-San (JWPWS), and Dang-Gui-Long-Hui-Wan (DGLHuiW)). CHM as an additional treatment strongly improves overall survival in HIV-infected patients with osteoporosis and fractures.

Sleep disorders affect an estimated 150 million people worldwide and result in adverse health, safety, and work performance-related outcomes that have important economic consequences. In Taiwan, Chinese herbal medicine (CHM) is a complementary natural medicine and has been widely used as an adjunctive therapy.This study aimed to investigate the effect of CHM on dementia risk in patients with sleep disorders in Taiwan.We identified 124,605 patients with sleep disorders between the ages of 20 and 60 years. Of these, 5876 CHM users and 5876 non-CHM users were matched according to age and gender. The chi-squared test, Cox proportional hazard model, Kaplan-Meier method, and log-rank test were used for the comparisons. Association rule mining and network analysis were applied to determine a CHM pattern specialized for sleep disorders.More CHM users did not use sleeping pills than non-CHM users. CHM users had a lower risk of dementia than non-CHM users after adjusting for age, gender, and sleeping pill use (hazard ratio (HR): 0.469, 95% CI = 0.289-0.760; p-value = 0.002). The cumulative incidence of dementia was lower among CHM users (long-rank test, p-value 0.001). Association rule mining and network analysis showed that Ye-Jiao-Teng (YJT; Caulis Polygoni Multiflori; Polygonum multiflorum Thunb), Suan-Zao-Ren-Tang (SZRT), Jia-Wei-Xiao-Yao-San (JWXYS), He-Huan-Pi (HHP; Cortex Albizziae; Albizia julibrissin Durazz.), and Suan-Zao-Ren (SZR; Semen Zizyphi Spinosae; Ziziphus jujuba Mill.) were important CHMs for patients with sleep disorders in Taiwan.A comprehensive list of herbal medicines may be useful for the clinical treatment of patients with sleep disorders, and for future scientific investigations into the prevention of dementia in these patients.

Additional file 1 Figure S1. The cumulative incidence of overall mortality in patients with decompensated liver cirrhosis based on Chinese herbal medicine (CHM) usage (before matching). Figure S2. A flow diagram presenting the study participants enrollment (from the database of outpatient and inpatient). Figure S3. The cumulative incidence of overall mortality in patients with decompensated liver cirrhosis based on Chinese herbal medicine (CHM) usage (from the database of outpatient and inpatient). Table S1 Composition of the most commonly used herbal formulas and single herbs in patients with decompensated liver cirrhosis in Taiwan. Table S2 Hazard ratios (95% CI) for overall mortality of patients with decompensated liver cirrhosis (before matching). Table S3 Demographic characteristics of patients with decompensated liver cirrhosis according to CHM usage in Taiwan (from the database of outpatient and inpatient). Table S4 Hazard ratios (95% CI) for overall mortality of patients with decompensated liver cirrhosis (from the database of outpatient and inpatient). Table S5. Distribution of the cumulative period of CHM treatment of CHM users of patients with decompensated liver cirrhosis in this study in Taiwan (during study period after the index date). Table S6. Average survival time of patients with decompensated liver cirrhosis between CHM and CHM non-users. Table S7. Parameters for counting the cumulative incidence of overall mortality at Fig. 2 for CHM non-users. Table S8. Parameters for counting the cumulative incidence of overall mortality at Fig. 2 for CHM users.

Background: Ovarian cancer is the seventh most commonly diagnosed malignancy worldwide and has the highest mortality rate among all gynecological cancers. Chinese herbal medicine (CHM) is widely applied in Taiwan and has been used in integrated therapies to treat patients with cancer. Methods: Patients with ovarian cancer who were registered in the Taiwan Registry for Catastrophic Illness Patients Database between 1997 and 2012 were considered for this study. A 1:1 individual matching by age was implemented. A total of 101 CHM users and 101 non-CHM users were involved. A Cox proportional hazard regression model was applied to evaluate the hazard ratio of overall mortality. The Kaplan-Meier method and log-rank test were used to calculate the cumulative incidence of the overall survival rate. Association rule mining and network analysis were used to analyze CHM prescription patterns. Results: CHM users showed a significantly lower risk of overall mortality than nonusers (hazard ratio = 0.45, 95% confidence interval = 0.23-0.91; P = .0256; multivariate Cox proportional hazard model). The cumulative incidence of the overall survival probability was higher for CHM users than for non-CHM users (log-rank test, P = .0009). Association rule mining and network analysis suggested that the main CHM cluster was associated with the usage of Bu-Zhong-Yi-Qi-Tang, Chuan-Xiong, and Xi-Xin, followed by the use of Bai-Shao, Da-Huang, and Di-Huang. Conclusions: CHM, as an adjunctive therapy, may reduce the overall mortality in patients with ovarian cancer. A list of herbal medicines that could potentially be used in future studies and clinical trials has also been provided.

Ethnopharmacological relevance Muscular dystrophies are a rare, severe, and genetically inherited group of disorders characterized by progressive loss of muscle fibers, leading to muscle weakness. The current treatment plan for muscular dystrophies includes the use of steroids to slow muscle deterioration by dampening the inflammatory response. Aim of the study Chinese herbal medicine (CHM) has been offered as an adjunctive therapy in Taiwan's medical healthcare plan, making it possible to track CHM usage in patients with muscular dystrophic disease. Therefore, we explored the long-term effects of CHM use on the overall mortality of patients with muscular dystrophies. Materials and methods A total of 581 patients with muscular dystrophies were identified from the database of Registry for Catastrophic Illness Patients in Taiwan. Among them, 80 and 201 patients were CHM users and non-CHM users, respectively. Student's t-test, chi-squared test, Cox proportional hazard model, and Kaplan–Meier curve (log-rank test) were used for evaluation. Association rules and network analyses were performed to explore the combination of CHMs used in muscular dystrophies. Results Compared to non-CHM users, there were more female patients, more comorbidities, including chronic pulmonary disease and peptic ulcer disease in the CHM user group. Patients with prednisolone usage exhibited a lower risk of overall mortality than those who did not, after adjusting for age, sex, use of CHM, and comorbidities. CHM users showed a lower risk of overall mortality after adjusting for age, sex, prednisolone use, and comorbidities. The cumulative incidence of the overall survival was significantly higher in CHM users. Association rule and network analysis showed that one main CHM cluster was commonly used to treat patients with muscular dystrophies in Taiwan. The cluster includes Yin-Qiao-San, Ban-Xia-Bai-Zhu-Tian-Ma-Tang, Zhi-Ke (Citrus aurantium L.), Yu-Xing-Cao (Houttuynia cordata Thunb.), Che-Qian-Zi (Plantago asiatica L.), and Da-Huang (Rheum palmatum L.). Conclusions Our data suggest that adjunctive therapy with CHM may help to reduce the overall mortality among patients with muscular dystrophies. The identification of the CHM cluster allows us to narrow down the key active compounds and may enable future therapeutic developments and clinical trial designs to improve overall survival in these patients.

HIV-infected patients exposed to antiretroviral therapy (ART) have an increased risk for hyperlipidemia and cardiovascular disease. We performed a longitudinal, comprehensive, and population-based study to investigate the cumulative effect of different types of ART regimens on hyperlipidemia risk in the Taiwanese HIV/ART cohort. A total of 13,370 HIV-infected patients (2,674 hyperlipidemia and 10,696 non-hyperlipidemia patients) were recruited after matching for age, gender, and the first diagnosis date of HIV infection by using the National Health Insurance Research Database in Taiwan. Hyperlipidemia risk associated with cumulative ART use, ART adherence, and their combination was assessed. The matched hyperlipidemia group had a larger number of patients using ART and a higher incidence of comorbidities, specifically, respiratory disease and diabetes. Patients with high ART dosage and dose-dependent manner adherence, respectively, demonstrated an increased risk of hyperlipidemia. For single ART regimens, patients receiving nucleoside reverse-transcriptase inhibitors (NRTI/NRTI)- containing regimen had the highest hyperlipidemia risk, followed by protease inhibitor (PI)- containing and non-NRTI- containing regimens. For combination ART regimens, patients receiving a NRTI/NRTI + PI regimen had the highest hyperlipidemia risk. An increased cumulative drug dose was observed in patients who received the PI, NRTI/NRTI, NRTI, and NNRTI regimens in the hyperlipidemia group, when compared to the non-hyperlipidemia group. In conclusion, ART cumulative use, adherence, and regimen may affect hyperlipidemia risk among HIV-infected patients in a dose-dependent manner.

Diabetic retinopathy is a microvascular complication of type 2 diabetes and the leading cause of acquired blindness. In Taiwan, Chinese herbal medicine (CHM) is a popular adjunctive therapy. In this study, we investigated the CHM prescription patterns and their effects. We identified 23,701 subjects with type 2 diabetes in a database, and after matching for age and gender, 6,948 patients each were assigned to CHM and non-CHM groups. In the female subgroups, the cumulative retinopathy probability was lower for the CHM users than that for the CHM non-users (P < 0.001, log-rank test). Among the top 10 CHMs, Jia-Wei-Xiao-Yao-San (JWXYS; 52.9%), Shu-Jing-Huo-Xue-Tang (SJHXT; 45.1%), and Ge-Gen-Tang (GGT; 43.7%) were the most common herbal formulas. Yan-Hu-Suo (48.1%), Ge-Gen (42.1%), and Huang-Qin (HQin; 40.1%) were the most common single herbs. CHM network analysis showed that JWXYS was the core CHM of cluster 1. JWXYS, DS, XF, and SZRT exhibited both of the reductions of H2O2-induced phosphorylation of p38 MAPK and p44/42 MAPK (Erk1/2) in human ARPE-19 retina cells. In cluster 2, SJHXT was the core CHM. SJHXT and NX showed both of the phosphorylation reductions. In cluster 3, GGT was the core CHM, and it reduced the phosphorylation of both MAPKs. In cluster 4, HQin was the core CHM, and it also reduced the phosphorylation of both MAPKs. Our study suggests that adjunctive CHM therapy may reduce diabetic retinopathy via antioxidant activity of the herbs and provides information on core CHM treatments for further scientific investigations or therapeutic interventions.

Evidence for long-term use of Chinese herbal medicine (CHM) as an adjuvant treatment in patients with type 2 diabetes (T2D) remains limited. This study aimed to assess the frequency of use, utilization patterns, and therapeutic effects of adjuvant CHM for ischemic heart disease (IHD) in patients with T2D in Taiwan. We identified 4620 IHD patients with T2D. After matching for age, gender, and insulin use, 988 subjects each were allocated to a CHM group and a non-CHM group. There were no differences in baseline characteristics except for comorbidities. The CHM group contained more cases with chronic obstructive pulmonary disease, hepatitis, ulcer disease, and hyperlipidemia. The cumulative survival probability was higher in CHM users than in matched non-CHM users aged 60 years or older (P < .0001, log rank test) regardless of gender (P = .0046 for men, P = .0010 for women, log rank test). Among the top 12 CHM combinations, Shu-Jing-Huo-Xue-Tang and Shao-Yao-Gan-Cao-Tang (13.6%) were the most common. This dual combination improved antiapoptotic activity in H2O2-exposed H9C2 cells by enhancing phosphorylation of glycogen synthase kinase-3β and p38 mitogen-activated protein kinase and could increase the survival of myocardial cells. Our study suggests that adjuvant CHM therapy may increase the survival probability and provides a comprehensive list for future investigations of the safety and efficacy of CHM for IHD patients with T2D.

Background Liver cirrhosis is one of the main causes of the morbidity and mortality in liver diseases. Chinese herbal medicine (CHM) has long been used for the clinical treatment of liver diseases. This study was designed to explore the usage frequency and prescription patterns of CHM for patients with decompensated liver cirrhosis and to evaluate the long-term effects of CHM on overall mortality. Methods Two thousand four hundred sixty-seven patients with decompensated liver cirrhosis (ICD-9-CM code: 571.2, 571.5, and 571.6) diagnosed between 2000 and 2009 in Taiwan were identified from the registry for catastrophic illness patients. Of these, 149 CHM users and 298 CHM non-users were matched for age, gender, and Charlson comorbidity index score. The chi-squared test, paired Student’s t-test, Cox proportional hazard model, and Kaplan–Meier method were applied for various comparisons between these groups of patients. Results CHM-treated patients showed a lower overall mortality risk compared with non-treated patients (Multivariable: p p = 0.0002). The strongest CHM co-prescription pattern- Yin-Chen-Hao-Tang (YCHT) → Long-Dan-Xie-Gan-Tang (LDXGT) had the highest support, followed by Zhi-Zi (ZZ) → Yin-Chen-Wu-Ling-San (YCWLS) and Bai-Hua-She-She-Cao (BHSSC) → Da-Huang (DaH). Conclusion CHM, as adjunct therapy, might decrease the risk of overall mortality in patients with decompensated liver cirrhosis. CHM co-prescription patterns and network analysis showed that comprehensive herbal medicines have a protective role against liver fibrosis. Further studies are required to enhance the knowledge of safety and efficacy of CHM in patients with decompensated liver cirrhosis.

Liver cancer is the sixth most diagnosed cancer globally, and the second leading cause of cancer-related deaths. Surgical resection is a procedure performed to remove cancerous tissue from the liver. Chinese herbal medicine (CHM) is a complementary natural medicine system widely used for treatment of hepatic diseases in Asian countries. We investigated the effects on overall mortality of long-term use of CHM for treatment of patients with liver cancer who underwent surgical resection at the Taiwan Center for Medicine. We identified 1504 patients with liver cancer who underwent surgical resection. Of these patients, 210 CHM users and 210 non-users were selected, and were matched for age, gender, radiotherapy, and chemotherapy prior to CHM treatment. Chi-squared test, Cox proportional hazard modeling, the Kaplan-Meier method, log-rank test, association rule mining, and network analysis were used as statistical methods in this study. CHM users showed a significantly lower risk of overall mortality than non-users (HR: 0.57, 95% CI = 0.40-0.81; p = 0.0025; multivariate Cox proportional hazard model), and a lower 10-year cumulative incidence of overall mortality (p 0.05; log rank test). Association rule mining and network analysis suggested that Bai-Hua-She-She-Cao, Ban-Zhi-Lian, and Suan-Zao-Ren were the most effective CHMs. Therefore, we concluded that use of CHM as adjunctive therapy may reduce overall mortality in patients with liver cancer who underwent surgical resection. A list of herbal medicines with potential as future therapeutic interventions to prolong the life-span of patients with liver cancer who underwent surgical resection is also provided.

Supplemental material, Supplementary_Materials_08122019 for Integrated Chinese Herbal Medicine Therapy Improves the Survival of Patients With Ovarian Cancer by Cherry Yin-Yi Chang, Pei-Yuu Yang, Fuu-Jen Tsai, Te-Mao Li, Jian-Shiun Chiou, Chao-Jung Chen, Ting-Hsu Lin, Chiu-Chu Liao, Shao-Mei Huang, Bo Ban, Wen-Miin Liang and Ying-Ju Lin in Integrative Cancer Therapies

Ethnopharmacological relevance Osteoporosis is one of the most common bone diseases; it is characterized by bone loss and is a risk factor for hip fracture. Chinese herbal medicines (CHMs) and their related natural compounds have been used for treating many diseases, including bone diseases, since ancient times in China and are regarded as a cost-effective complementary therapy. Aim of the study The goal of this study was to investigate the osteoprotective mechanisms of these three Chinese herbs and their related natural compounds. The effects of CHMs and related natural compounds on RANKL-induced osteoclastogenesis in vitro were investigated. Materials and methods A network pharmacology method was applied to study CHM-related natural compounds and their osteoporosis targets. In addition, their effect on RANKL-induced osteoclastogenesis in RAW264.7 cells was also investigated in vitro. Results Radix dipsaci, Eucommiae cortex, and Rhizoma drynariae exhibited protective effects against mortality in hip fracture patients. Furthermore, these three herbs inhibited RANKL-induced TRAP activities and reduced the expression of bone resorption-related genes in RAW264.7 cells. Network analysis of natural compound (ingredient)-target interactions identified 11 natural compounds. Signal pathway analyses suggested that these compounds may target cytokine-cytokine receptor interactions, including RANKL-induced osteoclastogenesis. Five novel natural compounds exhibited reduced RANKL-induced TRAP activities and bone resorption-related gene expression. Conclusion The clinically used CHMs, Radix dipsaci, Eucommiae cortex, and Rhizoma drynariae, and natural compounds obtained from them may suppress RANKL-induced osteoclastogenesis in vitro.

Genetic loci that contribute to type 2 diabetes (T2D) susceptibility have been identified. However, the genetic determinants of hypertension risk in T2D are limited. We aimed to investigate the genetic architecture of hypertension risk in T2D. We performed a genome-wide association study in a T2D cohort composed of 454 hypertensive and 545 non-hypertensive patients, and replicated the results in a second independent T2D cohort composed of 563 hypertensive patients and 359 nonhypertensive patients. Eighteen genetic loci exhibited associations with hypertension risk in these two cohorts with combined odds ratios (ORs) ranging from 1.16 to 2.75 after adjusting for age, gender, body mass index, and comorbidities (p = 0.0423 to 0.00592). A genetic risk score (GRS) was created by combing these risk alleles weighted by their estimated effect sizes (log OR). T2D patients with weighted GRS > 19 showed 6-fold increase in hypertension risk (OR: 5.77, 95% confidence interval: 3.91-8.51) compared to patients with weighted GRS < 15. Receiver-operating characteristic (ROC) curves of the regression models showed that the area under the curve (AUC) improved when the weighted GRS (AUC = 0.6799) was added to a model that included the covariates with conventional risk factors (AUC = 0.8295). We also observed a regression tendency, which showed that each weighted GRS increased systolic blood pressure by 2.10 mm Hg (slope = 2.10; p = 0.0001). These 18 genetic loci are associated with hypertension risk and systolic blood pressure levels in T2D and are implicated for further functional studies on hypertension occurrence in T2D. Funding Statement: This study was supported by grants from the China Medical University (CMU102-PH-01), the China Medical University Hospital (DMR-105-031, DMR-105-098, DMR-107-042, DMR-108-113, and DMR-108-114), the National Science Council, the Ministry of Science and Technology, Taiwan (MOST 105-2314-B-039 -037 -MY3, MOST 106-2320-B-039-020, MOST 106-2320-B-039-030, and MOST 106-2320-B-039 -017 -MY3), and China Medical University under the Aim for Top University Plan of the Ministry of Education, Taiwan. Declaration of Interests: The authors declare no conflicts of interest relevant to the contents of this paper. Ethics Approval Statement: All study participants provided informed consent, and the study design was approved by the appropriate ethics review boards.

Human height can be described as a classical and inherited trait model. Genome-wide association studies (GWAS) have revealed susceptible loci and provided insights into the polygenic nature of human height. Familial short stature (FSS) represents a suitable trait for investigating short stature genetics because disease associations with short stature have been ruled out in this case. In addition, FSS is caused only by genetically inherited factors. In this study, we explored the correlations of FSS risk with the genetic loci associated with human height in previous GWAS, alone and cumulatively. We systematically evaluated 34 known human height single nucleotide polymorphisms (SNPs) in relation to FSS in the additive model (p p ZBTB38, ZNF638, LCORL, CABLES1, CDK10, and TSEN15—are located in the nucleus and have been implicated in embryonic, organismal, and tissue development. In conclusion, our study suggests that 13 human height GWAS-identified SNPs are associated with FSS risk both alone and cumulatively.

In Taiwan, lung cancer remains one of the deadliest cancers. Survival of lung cancer patients remains low, ranging from 6% to 18%. Studies have shown that Chinese herbal medicine (CHM) can be used to induce cell apoptosis and exhibit anti-inflammatoryanti-inflammatory activities in cancer cells.This study aimed to investigate the frequencies and patterns of CHM treatment for lung cancer patients and the effect of CHM on their survival probability in Taiwan.We identified 6939 lung cancer patients (ICD-9-CM: 162). We allocated 264 CHM users and 528 CHM-non users, matched for age, gender, duration, and regular treatment. Chi-square test, conditional multivariable logistic regression, Kaplan-Meier method, and the log-rank test were used in this study.The CHM group was characterized by a longer follow up time and more cases of hyperlipidemia and liver cirrhosis. This group exhibited a lower mortality hazard ratio (0.48, 95% confidence interval [0.39-0.61], p0.001), after adjusting for comorbidities. The trend was also observed that the cumulative survival probability was higher in CHM than in non-CHM users (p0.0001, log rank test). Analysis of their CHM prescription pattern revealed that Bu-Zhong-Yi-Qi-Tang (BZYQT), Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT), and Bai-He-Gu-Jin-Tang (BHGJT); and Bei-Mu (BM), Xing-Ren (XR) and Ge-Gen (GG) were found to be the top three formulas and herbs, respectively. Among them, BM was the core CHM of the major cluster, and Jie-Geng (JG) and Mai-Men-Dong-Tang (MMDT) were important CHMs by CHM network analysis.The use of CHM as an adjunctive therapy may reduce the mortality hazard ratio of lung cancer patients. The investigation of their comprehensive CHM prescription patterns might be useful in future large-scale, randomized clinical investigations of agent effectiveness, safety, and potential interactions with conventional treatments for lung cancer patients.

Due to the development of antiretroviral therapy (ART), HIV/AIDS is now regarded as a treatable chronic disease. Chinese herbal medicine (CHM) is a type of complementary and alternative medicine (CAM) that has been widely applied in the healthcare system in Taiwan.The aim of this study was to investigate the frequency of use and patterns of prescription for the CHM-based treatment of HIV-infected patients and to assess the long-term effects of CHM on hyperlipidemia and cardiovascular disease events in these patients.We identified 21,846 HIV-infected patients (ICD-9-CM: 042-044, 079, and V08 codes). Of these, 1083 and 2166 patients who used CHM and were non-users, respectively, were matched for age, gender, and ART use before CHM. The chi-squared test, Cox proportional hazard model, Kaplan-Meier method, and the log-rank test were used for comparisons between these two groups.CHM users had a lower risk of hyperlipidemia compared with non-users after adjusting for comorbidities by using a multivariate Cox proportional hazard model (P = 0.0011; HR: 0.66, 95% CI: 0.52-0.85). In addition, the CHM users had a lower risk of cardiovascular disease compared with non-users after adjusting for comorbidities (P = 0.0004; HR: 0.67, 95% CI: 0.53-0.83). The 10-year cumulative incidences of hyperlipidemia and cardiovascular disease were lower in the CHM group (P 0.0001 for both, log rank test). Among the 12 most commonly used CHMs in these patients, Jia-Wei-Xiao-Yao-San (JWXYS) (46.1%), Ge-Gen-Tang (GGT) (40.6%), and Yin-Qiao-San (YQS) (38.0%) were the most common herbal formulas used. Huang-Qin (HQin) (44.6%), Yan-Hu-Suo (YHS) (40.5%), and Jie-Geng (JG) (39.5%) were the most commonly used single herbs. A CHM network analysis showed that JG was the core CHM in one cluster, and BM, MXSGT, and HQin were important CHMs in that cluster. In the other cluster, YHS was the core CHM, and SYGCT and JWXYS were important CHMs.CHM as adjunctive therapy may reduce hyperlipidemia and the risk for cardiovascular disease in HIV-infected patients. The list of the comprehensive herbal medicines that the patients used might be useful in further scientific investigations or therapeutic interventions for preventing atherosclerosis among HIV-infected patients.

Background: Kawasaki disease (KD) is an acute, self-limited vasculitis in infants and young children. Interleukin-10 (IL-10) is a potent cytokine that exerts pleiotropic effects on immunoregulation and inflammation. Elevated IL-10 serum levels have been reported in the KD patients. Methods: In this study, we investigated whether IL-10 genetic polymorphisms contribute to coronary artery aneurysm (CAA) development among KD patients in Taiwan. A total of 58 KD patients with CAA and 277 unrelated healthy children matched for sex and age were enrolled for this study. Results: Higher G allele frequencies of IL-10 at -1082 position were observed in KD patients with CAA compared to the controls (P = 0.016, OR: 2.86,95%CI,1.17‐6.98).Inaddition,higher IL-10 GCC haplotype frequencies were also observed in KD patients with CAA (P = 0.016, OR: 2.85, 95% CI, 1.17‐6.98). Conclusion: Our data support the possibility that IL-10 gene polymorphisms may be related with CAA development of KD in Taiwanese population. J. Clin. Lab. Anal. 28:461‐464, 2014. C � 2014 Wiley Periodicals, Inc.

Background Chinese herbal medicines (CHMs) are a resource of natural compounds (ingredients) and their potential chemical derivatives with anticancer properties, some of which are already in clinical use. Bei–Mu (BM), Jie–Geng (JG), and Mai–Men–Dong–Tang (MMDT) are important CHMs prescribed for patients with lung cancer that have improved the survival rate. Hypothesis/Purpose The aim of this study was to systemically investigate the mechanisms of action of these CHM products in lung cancer cells. Methods We used a network pharmacology approach to study CHM product-related natural compounds and their lung cancer targets. In addition, the underlying anti-lung cancer effects of the natural compounds on apoptosis, cell cycle progression, autophagy, and the expression of related proteins was investigated in vitro. Results Ingredient-lung cancer target network analysis identified 20 natural compounds. Three of these compounds, ursolic acid, 2-(3R)-8,8-dimethyl-3,4-dihydro-2H-pyrano(6,5-f)chromen-3-yl)-5-methoxyphenol, and licochalcone A, inhibited the proliferation of A549 lung cancer cells in a dose-dependent manner. Signal pathway analyses suggested that these three ingredients may target cellular apoptosis, anti-apoptosis, and cell cycle-related proteins. These three ingredients induced apoptosis through the regulation of the expression of apoptotic and anti-apoptotic proteins, including B-cell lymphoma-2 and full-length and cleaved poly(ADP-ribose) polymerase proteins. They also induced cell cycle arrest in S and G2/M phases and autophagy in A549 cells. Conclusion The pharmacological mechanisms of ingredients from MMDT on lung cancer may be strongly associated with their modulatory effects on apoptosis, autophagy, cell cycle progression, and cell proliferation.

KCNQ1 encodes a potassium voltage-gated channel and represents a susceptibility locus for type 2 diabetes mellitus (T2DM). Here, we explored the association between KCNQ1 polymorphisms and hypertension risk in individuals with T2DM, as well as the role of KCNQ1 in vascular smooth muscle cell contraction in vitro. To investigate the relationship between KCNQ1 and the risk of developing hypertension in patients with T2DM, we divided the T2DM cohort into hypertension (n = 452) and non-hypertension (n = 541) groups. The Mann-Whitney U test, chi-square test, and multivariate regression analyses were used to assess the clinical characteristics and genotypic frequencies. In vitro studies utilized the rat aortic smooth muscle A10 cell line. Patients in the hypertension group were significantly older at the time of enrollment and had higher levels of body mass index, waist-to-hip ratio, and triglyceride than those in the non-hypertension group. The KCNQ1 rs3864884 and rs12576239 genetic variants were associated with hypertension in T2DM. KCNQ1 expression was lower in the individuals with the CC versus the CT and TT genotypes. Smooth muscle cell contractility was inhibited by treatment with a KCNQ1 inhibitor. These results suggest that KCNQ1 might be associated with hypertension in individuals with T2DM.

Background A significant percentage of Taiwanese neonatal HB immunization recipients have subsequently exhibited low anti-HB titers at non-protective or undetectable levels. Several mechanisms have been proposed to explain this phenomenon, including low vaccination responsiveness, deficient lymphocyte function, inappropriate antigen processing and presentation, and abnormal cytokine secretion. Methods To determine genetic influences resulting in high anti-HB titers, we divided a study cohort of 183 individuals into an anti-HBs ≥ 1000 mIU/mL group and a 10–1000 mIU/mL anti-HBs titer group. Chi-square tests were used to compare genotype and allelic frequencies between the two groups. Results Data from univariate and multivariate regression analyses of cytokine and cytokine receptor gene variants indicate (a) increased potential of high anti-HB titers in the presence of the TT genotype of the IL - 4 rs2243250 SNP (OR = 3.19; p = 0.012) and the AA genotype of the IL - 4R rs1805010 SNP (OR = 2.25; p = 0.048), and (b) individuals carrying the TT genotype of the IL - 4 rs2243250 SNP had anti-HB titers at levels that were almost twice as high as those in individuals carrying the CC genotype (478.8 mIU/mL and 290.3 mIU/mL, respectively; p = 0.033). Conclusion Genetic determinants, especially IL - 4 and IL - 4R , may contribute to high anti-HB titers in immune responses to HB vaccinations.

Kawasaki disease (KD) is an acute, inflammatory and self-limited vasculitis affecting infants and young children. Coronary artery aneurysm (CAA) formation is the major complication of KD and the leading cause of acquired cardiovascular disease among children. To identify susceptible loci that might predispose patients with KD to CAA formation, a genome-wide association screen was performed in a Taiwanese KD cohort. Patients with both KD and CAA had longer fever duration and delayed intravenous immunoglobulin treatment time. After adjusting for these factors, 100 susceptibility loci were identified. Four genes were identified from a single cluster of 35 using the Ingenuity Pathway Analysis (IPA) Knowledge Base. Silencing KCNQ5, PLCB1, PLCB4 and PLCL1 inhibited the effect of lipopolysaccharide-induced endothelial cell inflammation with varying degrees of proinflammatory cytokine expression. PLCB1 showed the most significant inhibition. Endothelial cell inflammation was also inhibited by using a phospholipase C (PLC) inhibitor. The single nucleotide polymorphism rs6140791 was identified between PLCB4 and PLCB1. Plasma PLC levels were higher in patients with KD and CC+CG rs6140791genotypes and these genotypes were more prevalent in patients with KD who also had CAA. Our results suggest that polymorphism of the PLCB4/B1 genes might be involved in the CAA pathogenesis of KD.

Tumour necrosis factor-α (TNF-α), an important proinflammatory cytokine, exerts a variety of physiological and pathogenic effects that lead to tissue destruction. Studies on the association of TNF-α genetic polymorphisms with systemic lupus erythematosus (SLE) have yielded inconclusive results. We investigated the association of TNF-α genetic polymorphisms (−1031T/C, −863C/A, −857T/C, −308A/G and +489A/G) with SLE in Taiwanese patients and controls. Our results indicate that 1) the frequency of the A-allele at −863 position was significantly higher in SLE patients (odds ratio = 1.46; 95% CI = 1.02–2.08); 2) the frequency of the A-allele at +489 position was significantly higher in SLE patients (odds ratio = 1.79; 95% CI = 1.21–2.65); 3) the AA or GA genotype frequencies at +489 position were significantly increased in SLE patients (AA genotype: odds ratio = 11.20; 95% CI = 1.36–92.55; GA genotype: odds ratio = 1.63; 95% CI = 1.03–2.58); 4) no significant association of TNF-α haplotypic distributions was observed, except for the haplotypes TCCGA, CACGA and CCCGG; and 5) the genotype frequency of the polymorphisms at −1031 was significantly different in patients with antinuclear antibodies ( P = 0.022). The allele and genotype frequencies of the polymorphisms at −863 were not significantly different. The genotype frequency of the polymorphisms at −857 was significantly different in patients with haematological disorder ( P = 0.025). The frequency of A allele of the polymorphisms at −308 was significantly increased in patients with malar rash ( P = 0.033), discoid rash ( P = 0.023), photosensitivity ( P = 0.037), oral ulcers ( P = 0.002) and serositis ( P = 0.029). The genotype frequency of the polymorphisms at +489 was significantly different in patients with discoid rash and photosensitivity (data not shown; discoid rash, P = 0.031; photosensitivity, P = 0.044). These results suggest that TNF-α genetic polymorphisms contribute to SLE susceptibility in the Taiwanese population.

Background: Wilson’s disease (WD) is a genetic disorder involving the metabolism of copper. WD patients exhibit a wide range of disease phenotypes, including Kayser-Fleischer rings in the cornea, predominant progressive hepatic disease, neurological diseases, and/or psychiatric illnesses, among others. Patients with exon12 mutations of the ATP7B gene have progressive hepatic disease. An ATP7B gene that lacks exon12 retains 80% of its copper transport activities, suggesting that alternative splicing of ATP7B gene may provide alternative therapeutic ways for patients with inherited sequence variants and mutations of this gene. Purpose: We aimed to search for possible Chinese herbs and related compounds for modulating ATP7B premRNA splicing. Methods: We used an ATP7B exon11-12-13 mini-gene vector as a model and screened 18 Chinese herbal extracts and four compounds from Schizonepeta to determine their effects on ATP7B pre-mRNA splicing in vitro. Results: We found that Schizonepeta demonstrated the greatest potential for alternative splicing activity. Specifically, we found that p-coumaric acid from this herb enhanced ATP7B exon12 exclusion through the down-regulation of heterogeneous ribonucleoprotein (hnRNP) A1 protein expressions. Conclusion: These results suggest that there are herbs or herb-related compounds that could modify the alternative splicing of the ATP7B gene via a mechanism that regulates pre-mRNA splicing.

Background Patients with Kawasaki disease (KD), a pediatric systemic vasculitis, may develop coronary artery aneurysm (CAA) as a complication. To investigate the role of glutamate receptors in KD and its CAA development, we performed genetic association studies. Methods and results We examined the whole family of glutamate receptors by genetic association studies in a Taiwanese cohort of 262 KD patients. We identified glutamate receptor ionotropic, kainate 1 (GRIK1) as a novel susceptibility locus associated with CAA formation in KD. Statistically significant differences were noted for factors like fever duration, 1st Intravenous immunoglobulin (IVIG) used time (number of days after the first day of fever) and the GRIK1 (rs466013, rs425507, and rs38700) genetic variants. This significant association persisted even after using multivariate regression analysis (Full model: for rs466013: odds ratio =2.12; 95% CI =1.22-3.65; for rs425507: odds ratio =2.16; 95% CI =1.26-3.76; for rs388700: odds ratio =2.16; 95% CI =1.26-3.76). Conclusions We demonstrated that GRIK1 polymorphisms are associated CAA formation in KD, even when adjusted for fever duration and IVIG used time, and may also serve as a genetic marker for the CAA formation in KD. Electronic supplementary material The online version of this article (doi:10.1186/2045-3701-4-67) contains supplementary material, which is available to authorized users.