Ju Pi Li

Genetic variants in PLCB4/PLCB1 as susceptibility loci for coronary artery aneurysm formation in Kawasaki disease in Han Chinese in Taiwan.

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.

Chinese Herbal Medicine Treatment Improves the Overall Survival Rate of Individuals with Hypertension among Type 2 Diabetes Patients and Modulates In Vitro Smooth Muscle Cell Contractility

Type 2 diabetes (T2D) is a chronic, multifactorial, and metabolic disorder accounting for 90% diabetes cases worldwide. Among them, almost half of T2D have hypertension, which is responsible for cardiovascular disease, morbidity, and mortality in these patients. The Chinese herbal medicine (CHM) prescription patterns of hypertension individuals among T2D patients have yet to be characterized. This study, therefore, aimed to determine their prescription patterns and evaluate the CHM effect. A cohort of one million randomly sampled cases from the National Health Insurance Research Database (NHIRD) was used to investigate the overall survival rate of CHM users, and prescription patterns. After matching CHM and non-CHM users for age, gender and date of diagnosis of hypertension, 980 subjects for each group were selected. The CHM users were characterized with slightly longer duration time from diabetes to hypertension, and more cases for hyperlipidaemia. The cumulative survival probabilities were higher in CHM users than in non-CHM users. Among these top 12 herbs, Liu-Wei-Di-Huang-Wan, Jia-Wei-Xiao-Yao-San, Dan-Shen, and Ge-Gen were the most common herbs and inhibited in vitro smooth muscle cell contractility. Our study also provides a CHM comprehensive list that may be useful in future investigation of the safety and efficacy for individuals with hypertension among type 2 diabetes patients.

Effect of Chinese herbal medicine on stroke patients with type 2 diabetes

ETHNOPHARMACOLOGICAL RELEVANCE Complications of type 2 diabetes (T2D) include stroke, which is a cerebrovascular disturbance characterized by reduced blood flow in the brain, leading to death or physical disability. Chinese herbal medicine (CHM) has been widely used in ancient China for the treatment of diabetes and stroke by supplementing Qi and activating blood circulation. AIM OF THE STUDY This study aimed to investigate the frequencies and patterns of CHM treatment for stroke patients with T2D and the outcomes of long-term use in Taiwan. MATERIALS AND METHODS We identified 3079 stroke patients (ICD-9-CM: 430-438) with T2D. We allocated 618 stroke patients, matched for age, gender, and T2D-to-stroke duration, to both CHM and non-CHM groups. Chi-square test, conditional multivariable logistic regression, Kaplan-Meier method, and the log-rank test were used in this study. RESULTS The CHM group was characterized by more cases of chronic obstructive pulmonary disease, ulcer disease, hyperlipidemia, tobacco use, and higher income. The cumulative survival probability was higher in the CHM group (P<0.001, log rank test); after adjusting for comorbidities, income, and urbanization level, this group also exhibited a lower mortality hazard ratio (0.37, 95% confidence interval [0.25-0.55]). Shu-Jing-Huo-Xue-Tang, Xue-Fu-Zhu-Yu-Tang, and Du-Huo-Ji-Sheng-Tang; and Dan-Shen, Niu-Xi, and Yan-Hu-Suo represented the top three formulas and herbs, respectively. CONCLUSION The use of CHM as adjunctive therapy may improve the overall survival (OS) of stroke patients with T2D. The list of the comprehensive herbal medicines that they used might be useful in future large-scale, randomized clinical investigations of agent effectiveness, safety, and potential interactions with conventional treatments in stroke patients with T2D.

Characteristics of Chinese herbal medicine usage in ischemic heart disease patients among type 2 diabetes and their protection against hydrogen peroxide-mediated apoptosis in H9C2 cardiomyoblasts

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.

Effect of antiretroviral therapy use and adherence on the risk of hyperlipidemia among HIV-infected patients, in the highly active antiretroviral therapy era

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.

Effects of Chinese herbal medicines on the occurrence of diabetic retinopathy in type 2 diabetes patients and protection of ARPE-19 retina cells by inhibiting oxidative stress

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.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.

Effects of Chinese herbal medicine on hyperlipidemia and the risk of cardiovascular disease in HIV-infected patients in Taiwan

ETHNOPHARMACOLOGICAL RELEVANCE 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. AIM OF THE STUDY 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. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Association of β-Lactam-Sensitive Haemophilus influenzae Type B with Adenoid Biofilm Formation in Patients with Adenoidectomy Surgery

BACKGROUND Chronic adenoid infection by β-lactam-resistant Haemophilus influenzae type b (Hib) and biofilm formation contribute to adenoid hyperplasia. Middle ear disease consequently remains a critical issue in the pediatric population. The aim of this study was to investigate the correlation of Hib biofilm formation with middle ear effusion with adenoid hyperplasia (MEE-AH) and with pediatric obstructive sleep apnea (OSA). METHODS A total of 384 patients with adenoidectomy from January 2008 to December 2012 were recruited in this investigation. Thirty-two patients (14 female and 18 male; age 4-13 years) who obtained routine adenoidectomy surgery had Hib-positive cultures were enrolled in a retrospective manner. By using polysomnography, 18 patients were diagnosed as having MEE-AH with chronic adenotonsillitis, and 14 patients were diagnosed as having pediatric OSA. The results of the Hib biofilm, antibiotic resistance profiles, and scanning electron microscopy observation, which correlated with the clinical diagnosis, were analyzed by the chi-square test and Fisher exact test. RESULTS Biofilm formation by Hib was significantly present in the patients with MEE-AH rather than patients with OSA. β-lactam-sensitive Hib were resistant to augmentin because of the adenoid biofilm formation. However, this finding was uncommon in the pediatric OSA group. CONCLUSIONS Properly treating β-lactam-sensitive Hib infection may be an important issue in reducing MEE-AH and adenoid vegetation in the pediatric population. Further research is warranted to elucidate the association of Hib-related biofilm formation with treatment failure and the need to consider earlier surgical intervention.

Characteristics of Chinese herbal medicine usage and its effect on survival of lung cancer patients in Taiwan

ETHNOPHARMACOLOGICAL RELEVANCE 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. AIM OF THE STUDY 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. MATERIALS AND METHODS 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. RESULTS 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], p < 0.001), after adjusting for comorbidities. The trend was also observed that the cumulative survival probability was higher in CHM than in non-CHM users (p < 0.0001, 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. CONCLUSION 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.

KCNQ1 variants associate with hypertension in type 2 diabetes and affect smooth muscle contractility in vitro

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.