Association between glucose variation and lower extremity amputation incidence in individuals with type 2 diabetes: a nationwide retrospective cohort study.

AIMS/HYPOTHESIS: Elevated glucose level is one of the risk factors for lower extremity amputation (LEA), but whether glycaemic variability confers independent risks of LEA remains to be elucidated. This study aimed to investigate the association between visit-to-visit glycaemic variability and minor and major LEA risks during 8 years of follow-up in type 2 diabetic individuals aged 50 years and older. METHODS: This retrospective cohort study included 27,574 ethnic Chinese type 2 diabetic individuals aged ≥50 years from the National Diabetes Care Management Program in Taiwan. Glycaemic variability measures were presented as the CVs of fasting plasma glucose (FPG-CV) and of HbA1c (A1c-CV). The effect of glycaemic variability on the incidence of LEA events was analysed using Cox proportional hazards models. RESULTS: After a median follow-up of 8.9 years, 541 incident cases of LEA with a crude incidence density rate of 2.4 per 1000 person-years were observed. After multivariate adjustment, FPG-CV and A1c-CV were found to be significantly associated with minor LEA, with corresponding HRs of 1.53 (95% CI 1.15, 2.04) and 1.34 (95% CI 1.02, 1.77) for the third tertiles of FPG-CV and A1c-CV, respectively. In addition, these associations were stronger amongst older adults with longer diabetes duration (≥3 years) than amongst those with shorter duration (<3 years) (pinteraction < 0.01). CONCLUSIONS/INTERPRETATION: Our study suggests that visit-to-visit variations in HbA1c and FPG are important predictors of minor LEA amongst older adults with type 2 diabetes, particularly for those with more than 3 years of diabetes duration.

Clinical efficacy and IL-17 targeting mechanism of Indigo naturalis as a topical agent in moderate psoriasis.

BACKGROUND: Indigo naturalis is a Traditional Chinese Medicine (TCM) ingredient long-recognized as a therapy for several inflammatory conditions, including psoriasis. However, its mechanism is unknown due to lack of knowledge about the responsible chemical entity. We took a different approach to this challenge by investigating the molecular profile of Indigo naturalis treatment and impacted pathways. METHODS: A randomized, double-blind, placebo-controlled clinical study was conducted using Indigo naturalis as topical monotherapy to treat moderate plaque psoriasis in a Chinese cohort (n = 24). Patients were treated with Indigo naturalis ointment (n = 16) or matched placebo (n = 8) twice daily for 8 weeks, with 1 week of follow-up. RESULTS: At week 8, significant improvements in Psoriasis Area and Severity Index (PASI) scores from baseline were observed in Indigo naturalis-treated patients (56.3% had 75% improvement [PASI 75] response) compared with placebo (0.0%). A gene expression signature of moderate psoriasis was established from baseline skin biopsies, which included the up-regulation of the interleukin (IL)-17 pathway as a key component; Indigo naturalis treatment resulted in most of these signature genes returning toward normal, including down-regulation of the IL-17 pathway. Using an in vitro keratinocyte assay, an IL-17-inhibitory effect was observed for tryptanthrin, a component of Indigo naturalis. CONCLUSIONS: This study demonstrated the clinical efficacy of Indigo naturalis in moderate psoriasis, and exemplified a novel experimental medicine approach to understand TCM targeting mechanisms. TRIAL REGISTRATION: NCT01901705 .

Association between chronic idiopathic urticaria and hypertension: A population-based retrospective cohort study.

BACKGROUND: Chronic idiopathic urticaria (CIU) is defined as urticaria that is not caused by external triggers. The pathogenesis of CIU remains unknown. A previous study investigated whether hypertension is associated with extended duration of CIU. OBJECTIVE: To investigate the possible association between CIU and hypertension. METHODS: We performed a population-based retrospective cohort study of 2,460 patients with CIU and 9,840 age-, sex-, and index year-matched comparison patients, using the National Health Insurance of Taiwan database. The median follow-up periods were 7.13 years for the CIU cohort and 7.20 years for the non-CIU cohort. The distributions by sex and age were similar for both cohorts. RESULTS: The CIU cohort had a 1.37-fold (95% CI, 1.22-1.53) greater risk of developing subsequent hypertension than the non-CIU cohort after adjusting for sex, age, comorbidities, and nonsedating antihistamine use. CONCLUSION: This nationwide retrospective cohort study found that CIU is associated with a higher future risk of hypertension after adjusting for sex, age, comorbidities, and nonsedating antihistamine use. The detailed pathophysiologic mechanisms require further clarification in prospective studies.

The efficacy and safety of a Chinese herbal product (Xiao-Feng-San) for the treatment of refractory atopic dermatitis: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Severe and widespread atopic dermatitis often fails to respond adequately to topical steroids and oral antihistamines and requires immunomodulatory drugs which, although effective, have undesirable toxic effects. METHODS: In this prospective, randomized, double-blind, placebo-controlled trial, 71 patients with severe intractable atopic dermatitis were given an 8-week treatment with oral Xiao-Feng-San (XFS; 47 patients) or placebo (24 patients). Total lesion score, erythema score, surface damage score, pruritus score and sleep score were measured at 4-week intervals. RESULTS: Fifty-six patients completed both the treatment and follow-up periods. The decrease in the total lesion score in the treatment group at 8 weeks was significantly greater than that of the placebo group (79.7 ± 5.8% vs. 13.5 ± 7.64%; p < 0.001). There was also a statistically significant difference between the treatment and placebo groups with regard to erythema, surface damage, pruritus and sleep scores. The difference between the 2 groups was still significant for all outcome measures except the erythema score at the 12-week follow-up, 4 weeks after the 8-week treatment had ended. Patients reported no side effects from treatment, although some commented on the unpalatability of the medication. CONCLUSION: Our study results suggest that the traditional Chinese herbal medicine XFS may be an alternative choice of therapy for severe, refractory, extensive and nonexudative atopic dermatitis.

The anti-TH17 polarization effect of Indigo naturalis and tryptanthrin by differentially inhibiting cytokine expression.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal medicine Qing-Dai (also known as Indigo naturalis) extracted from indigo-bearing plants including Baphicacanthus cusia (Ness) Bremek was previously reported to exhibit anti-psoriatic effects in topical treatment. TH17 was later established as a key player in the pathogenesis of psoriasis. We investigated the anti-TH17 effect of Indigo naturalis and its active compounds. The aim of this study is to evaluate the toxicity of Indigo naturalis (IN) and its derivatives on five cell types involved in psoriasis, and to study the anti-inflammatory mechanism for the toxicity. MATERIALS AND METHODS: Following the fingerprint and quantity analysis of indirubin, indigo, and tryptanthrin in IN extract, we used MTS kits to measure the anti-proliferative effect of IN and three active compounds on five different cell types identified in psoriatic lesions. Quantitative RT-PCR analysis was used to measure the expression of various genes identified in the activated keratinocytes and TH17 polarized gene expression in RORγt-expressing T cells. RESULTS: We showed that IN differentially inhibited the proliferation of keratinocytes and endothelial cells but not monocytes, fibroblasts nor Jurkat T cells. Among three active compounds identified in IN, tryptanthrin was the most potent compound to reduce their proliferation. In addition to differentially reducing IL6 and IL8 expression, both IN and tryptanthrin also potently decreased the expression of anti-microbial S100A9 peptide, CCL20 chemokine, IL1B and TNFA cytokines, independent of NF-κB-p65-activation. Their attenuating effect was also detected on the expression of signature cytokines or chemokines induced during RORγT-induced TH17 polarization. CONCLUSIONS: We were the first to confirm a direct anti-TH17 effect of both IN herbal extract and tryptanthrin.

Derivation and validation of a clinical prediction model for assessing the risk of lower extremity amputation in patients with type 2 diabetes.

AIM: This study aims to develop and validate a lower extremity amputation (LEA) risk score system in persons with type 2 diabetes. METHODS: A retrospective population-based cohort study was conducted among eligible 21,484 participants in the derivation set and 10,742 participants in the validation set who were enrolled in the Taiwan National Diabetes Care Management Program. The risk score system was developed following the steps proposed by the Framingham Heart Study with a Cox proportional hazards model algorithm. Discrimination ability was assessed by the receiver operating characteristic curve, and calibration was performed by Hosmer-Lemeshow test. RESULTS: A total of 504 patients developed LEA at an average follow-up of 7.4 years. The point scores were derived from 15 predictors as follows: age, gender, duration of type 2 diabetes, body mass index, HbA1c, triglyceride, eGFR, variation of fasting blood glucose, comorbidities of stroke, diabetes retinopathy, hypoglycemia and foot ulcer, anti-diabetes medication, and use of diuretics and nitrates. The c-statistics for predicting 3-, 5-, and 8-year LEA risks were 0.80 [95% confidence interval (CI) 0.76-0.83], 0.78 (0.75-0.81), and 0.76 (0.74-0.79) in the derivation set, respectively, and 0.81 (0.76-0.85), 0.77 (0.73-0.81), and 0.74 (0.71-0.77) in the validation set, respectively. CONCLUSIONS: A new risk score for LEA was developed and validated in the clinical setting with good discriminatory ability. Poor glycemic control, glucose variation, comorbidities, and medication use were identified as predictive factors for LEA in patients with type 2 diabetes.

Ferulic acid altered IL-17A/IL-17RA interaction and protected against imiquimod-induced psoriasis-like skin injury in mice.

Ferulic acid (FA), a phenolic phytochemical, is commonly found in grains, vegetables, and fruits. Interleukin-17A (IL-17A) and IL-17 receptor A (IL-17RA) interaction is one of important therapeutic targets for psoriasis. Here we analyzed the FA effects on IL-17A/IL-17RA interaction and psoriasis-like skin injury induced by imiquimod (IMQ). IL-17A-blocking assay and docking analysis showed that FA interacted with Trp-67, Gln-94, and Glu-95 residues of IL-17A via hydrogen bonds and consequently abolished the binding of IL-17RA to IL-17A. Mice were topically given with IMQ and orally given with various amounts of FA for 14 consecutive days. FA attenuated IMQ-induced psoriasis-like skin lesions in a dose-dependent manner, and the epidermal thickness of mice treated with 100 mg/kg FA was reduced by 53.48 ±â€¯4.44% in comparison with sham. Global analysis of differentially expressed genes showed that IMQ and FA significantly affected immune response, metabolism, and mitogen-activated protein kinase signaling pathways. Immunohistochemical staining showed that FA inhibited the infiltration and the cytokine secretion of Th17 cell, dendritic cell, and granulocyte subsets in psoriatic skin tissues. In conclusion, we newly identified that oral administration of FA protected against IMQ-induced psoriatic skin injury in mice. Moreover, its protection was associated with the interference of IL-17A/IL-17RA interaction.

Inhibition of lipopolysaccharide-induced interleukin-1beta and tumor necrosis factor-alpha production by menthone through nuclear factor-kappaB signaling pathway in HaCat cells.

Menthone, the Chinese old remedy extracted from genus Mentha, has been widely used as a cooling agent, a counterirritant for pain relief, and for the treatment of pruritus. However, its detail mechanisms for interfering inflammatory reaction remain unknown. In this study, we found that menthone can suppress the lipopolysaccharide (LPS)-induced proinflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), as well as nuclear factor kappaB (NF-kappaB) activity induced by LPS and other inflammatory agents, including 12-O-tetradecanoylphorbol-13-acetate, hydrogen peroxide, okadaic acid, and ceramide. Furthermore, our data also demonstrated that the translocation of NF-kappaB activated by LPS into the nucleus was suppressed by menthone, and I-kappaB and beta-transducin repeat containing protein (beta-TrCP) were both involved in this suppression. To sum up, this study has provided molecular evidence for menthone effect on the LPS-induced cytokine production, NF-kappaB activation, and the involvement of I-kappaB and beta-TrCP.

Dry eye syndrome and the subsequent risk of chronic fatigue syndrome-a prospective population-based study in Taiwan.

BACKGROUND AND AIM: The clinical association between dry eye syndrome (DES) and chronic fatigue syndrome (CFS) remain unclear with less evidences. We aimed to investigate the relationship between CFS and DES using a national insurance and prospective cohort study. METHODS: Data from the Longitudinal Health Insurance Database 2000 was applied to estimate the incidence of CFS among patients with DES, and their age- and sex-matched controls without DES over a long-term follow-up period. All participants were CFS free at baseline, before the interval (2005-2007), but were later diagnosed with CFS. DES patients and its relative matched controls were excluded prevalent CFS before the same interval. RESULTS: We identified 884 patients with DES and 3,536 matched controls in baseline and estimated the hazard ratios for incident CFS in the follow-up period. Patients with DES had a 2.08-fold considerably increasing risk of developing CFS, compared to non-DES group. An elevated risk of developing CFS remained (1.61-fold risk) even after adjusting for age, sex, and comorbidities. There was a presence of increasing risk in DES-related CFS when CFS-related comorbidities existing (adjusted hazard ratio, 1.98, 95% confidence interval, 1.19-3.29; p < 0.01). The subsequent risk for CFS between DES and non-DES patients was significant increased with three or more annual medical visits, the adjusted risk for CFS was 4.88-fold risk (95% CI, 2.26-10.58, p < 0.001). CONCLUSION: We recommended that physicians should be aware of the increased risk of CFS among DES patients and adequately assess the health impacts among these patients.

Oral Administration of Vanillin Improves Imiquimod-Induced Psoriatic Skin Inflammation in Mice.

Vanillin is one of the most widely used flavoring products worldwide. Psoriasis is a chronic inflammatory skin disorder. The interleukin-23 (IL-23)/interleukin-17 (IL-17) axis plays a critical role in psoriasis. Here, we analyzed the effect of vanillin on imiquimod (IMQ)-induced psoriatic skin inflammation in mice. Mice were treated topically with IMQ on the back skin and orally with various amounts of vanillin for 7 consecutive days. Vanillin significantly improved IMQ-induced histopathological changes of skin in a dose-dependent manner. The thickness and number of cell layers of epidermis were reduced by 29 ± 14.4 and 27.8 ± 11%, respectively, in mice given 100 mg/kg of vanillin. A microarray showed that a total of 9042 IMQ-upregulated genes were downregulated by vanillin, and the biological pathways involved in the immune system and metabolism were significantly altered by vanillin. The upregulated expressions of IL-23, IL-17A, and IL-17F genes were suppressed by vanillin, with fold changes of -3.07 ± 0.08, -2.06 ± 0.21, and -1.62 ± 0.21, respectively. Moreover, vanillin significantly decreased both the amounts of IL-17A and IL-23 and the infiltration of immune cells in the skin tissues of IMQ-treated mice. In conclusion, our findings suggested that vanillin was an effective bioactive compound against psoriatic skin inflammation. Moreover, the downregulation of IL-23 and IL-17 expression suggested that vanillin was a novel regulator of the IL-23/IL-17 axis.

Ginger and Zingerone Ameliorate Lipopolysaccharide-Induced Acute Systemic Inflammation in Mice, Assessed by Nuclear Factor-κB Bioluminescent Imaging.

Ginger is a commonly used spice in cooking. In this study, we comprehensively evaluated the anti-inflammatory activities of ginger and its component zingerone in lipopolysaccharide (LPS)-induced acute systemic inflammation in mice via nuclear factor-κB (NF-κB) bioluminescent imaging. Ginger and zingerone significantly suppressed LPS-induced NF-κB activities in cells in a dose-dependent manner, and the maximal inhibition (84.5% ± 3.5% and 96.2% ± 0.6%) was observed at 100 µg/mL ginger and zingerone, respectively. Moreover, dietary ginger and zingerone significantly reduced LPS-induced proinflammatory cytokine production in sera by 62.9% ± 18.2% and 81.3% ± 6.2%, respectively, and NF-κB bioluminescent signals in whole body by 26.9% ± 14.3% and 38.5% ± 6.2%, respectively. In addition, ginger and zingerone suppressed LPS-induced NF-κB-driven luminescent intensities in most organs, and the maximal inhibition by ginger and zingerone was observed in small intestine. Immunohistochemical staining further showed that ginger and zingerone decreased interleukin-1ß (IL-1ß)-, CD11b-, and p65-positive areas in jejunum. In conclusion, our findings suggested that ginger and zingerone were likely to be broad-spectrum anti-inflammatory agents in most organs that suppressed the activation of NF-κB, the production of IL-1ß, and the infiltration of inflammatory cells in mice.

Application of bioactivity database of Chinese herbal medicine on the therapeutic prediction, drug development, and safety evaluation.

AIM OF THE STUDY: Chinese herbal medicine has been used for the treatments of various diseases for years. However, it is often difficult to analyze their biological activities and molecule mechanisms because of their complex nature. In this study, we applied DNA microarray to analyze the biological events induced by herbal formulae, predict the therapeutic potentials of formulae, and evaluate the safety of formulae. MATERIALS AND METHODS: Mice were administrated orally with 15 formulae for 7 consecutive days, and the gene expression profiles in liver or kidney were further analyzed by transcriptomic tools. RESULTS: Our data showed that most formulae altered the metabolic pathways, such as glutathione metabolism and oxidative phosphorylation, and regulatory pathways, such as antigen processing and presentation and insulin-like growth factor signaling pathway. By comparing the gene expression signatures of formulae with those of disease states or drugs, we found that mice responsive to formula treatments might be related to disease states, especially metabolic and cardiovascular diseases, and drugs, which exhibit anti-cancer, anti-inflammatory, and anti-oxidative effects. Moreover, most formulae altered the expression levels of cytochrome p450, glutathione S-transferase, and UDP glycosyltransferase genes, suggesting that caution should be paid to possible drug interaction of these formulae. Furthermore, the similarities of gene expression profiles between formulae and toxic chemicals were low in kidney, suggesting that these formulae might not induce nephrotoxicities in mice. CONCLUSIONS: This report applied transcriptomic tools as a novel platform of translational medicine for Chinese herbal medicine. This platform will not only for understanding the therapeutic mechanisms involving herbal formulae and gene interactions, but also for the new theories in drug discovery.