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BACKGROUND Depression increases the risk of cardiovascular disease (CVD). The association between antidepressant medications (ADMs) and CVD remains controversial. Hyperlipidemia is a risk factor for CVD. We conducted a nationwide population-based retrospective cohort study to examine depression and ADM use on the risk of developing hyperlipidemia. The effects of ADMs on the expression of lipogenesis-related hepatic genes were also evaluated. METHODS We obtained data from the Longitudinal Health Insurance Database of Taiwan on patients with new-onset depression and a comparison cohort without depression. A Cox proportional hazards regression model was used to analyze the differences in the risk of developing hyperlipidemia between these two cohorts. We also examined the influence of ADMs on the expression of lipogenesis-related hepatic genes. RESULTS After adjustment for comorbidities and confounding factors, the case group (N = 38,322) had a higher risk for hyperlipidemia than that of the control cohort (N = 38,322) [adjusted hazards ratio (aHR) =1.16]. Patients with depression who did not receive ADM therapy exhibited a significantly higher risk of hyperlipidemia (aHR = 1.61). However, in patients with depression treated with ADMs, the risk of developing hyperlipidemia was significantly lowered compared to the patients without ADMs (all aHR < 0.81). Gene expression analysis indicated that ADMs downregulated the expression of lipogenesis-related hepatic genes. LIMITATIONS Unmeasured confounding risk factors for hyperlipidemia might not have been included in the study. CONCLUSIONS ADMs reduced hyperlipidemia risk in patients with depression, partly by downregulating the expression of lipogenesis-related genes and improving the patients' lipid profiles. Early diagnosis and management of hyperlipidemia would further facilitate the prevention of CVD.

The relationship between depression, antidepressant medications (ADMs), and the risk of subsequent type 2 diabetes mellitus (T2DM) development remains controversial. Thus, we investigated this aspect by a population-based retrospective cohort study using the Longitudinal Health Insurance Database 2000 available in Taiwan. This large, observational study included 46,201 patients with depression and a 1 : 1 age- and sex-matched nondepression cohort enrolled between January 1, 2000, and December 31, 2013, and the newly diagnosed T2DM incidence rates were determined. We estimated the effects of depression on T2DM and the cumulative incidence curves by Cox proportional regression hazard models and Kaplan-Meier methods, respectively. We found that 47.97% of the patients with depression did not receive ADM. Among patients with depression who received ADM, 29.71%, 6.29%, 0.05%, 9.65%, and 6.32% received selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), heterocyclic antidepressants, and other medications, respectively. Patients without ADM treatment had a 39% higher risk of developing T2DM. However, those who received ADM treatment had a significantly lower risk of T2DM development in every treatment category. Depressive disorder treated with ADMs, especially with long-term use, was associated with an 11–48% decrease in the risk of T2DM in all ADM groups; however, heterocyclic antidepressant treatment for shorter periods (

Gout is the most prevalent inflammatory arthritis in adults. Although the link between gout and type 2 diabetes mellitus (T2DM) has been documented, our understanding of the association between urate-lowering therapy (ULT) among gout patients and T2DM development remains poor. We included 69,326 patients with new-onset gout in 2000-2011. Each case was matched randomly with 1 patient without gout during the study period, and 69,326 patients were recognized as the comparison cohort. A Cox proportional hazard regression model was used to analyze differences in the risk of T2DM development between patients with and without gout after considering related comorbidities. After adjusting for potential confounders, the case group had a higher risk of T2DM than the control cohort (adjusted hazard ratio aHR=1.30, 95%confidence interval CI=1.24-1.38; P<0.001). Gout patients without appropriate ULT had significantly higher risk of T2DM development than the control cohort (aHR=1.39; 95%CI=1.30-1.48; P<0.001). Among gout patients, those receiving ULT excluding probenecid (aHR=0.80; 95%CI=0.64-1.00), all had significantly lower risk of T2DM than gout patients without ULT (all aHR<0.90; all P<0.001). In this study, we found that gout increased the risk of T2DM; however, patients with any ULT exhibited a lower risk of T2DM than gout patients without any ULT (all aHR<0.90, P<0.001; excluding probenecid).

Thyroid cancer (TC) is the most common endocrine malignancy, and its global incidence has steadily increased over the past 15 years. TC is broadly divided into well-differentiated, poorly differentiated, and undifferentiated types, depending on the histological and clinical parameters. Thus far, there are no effective treatments for undifferentiated thyroid cancers or advanced and recurrent cancer. Therefore, the development of an effective therapeutic is urgently needed for such patients. Piperlongumine (PL) is a naturally occurring small molecule derived from long pepper, it is selectively toxic to cancer cells by generating reactive oxygen species (ROS). In this study, we demonstrate the potential anticancer activity of PL in four TC cell lines. For this purpose, we cultured TC cell lines and analyzed the following parameters: Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction. PL modulated the cell cycle, induced apoptosis, and suppressed tumorigenesis in TC cell lines in a dose- and time-dependent manner through ROS induction. Meanwhile, an intrinsic caspase-dependent apoptosis pathway was observed in the TC cells under PL treatment. The activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL. PL-mediated apoptosis in TC cells was through the ROS-Akt pathway. Finally, the anticancer effect and safety of PL were also demonstrated in vivo. Our findings indicate that PL exhibits antitumor activity and has the potential for use as a chemotherapeutic agent against TC. This is the first study to show the sensitivity of TC cell lines to PL.

High-density lipoprotein (HDL) carbamylation has been known in uremia patients. Paraoxonase-1 (PON-1) is an important HDL protein responsible for HDL anti-oxidant, arylesterase and lactonase activities. PON-1 carbamylation in uremic HDL has never been explored. We isolated HDL from uremia patients and control healthy subjects for study. Sandwich ELISA was used to estimate carbamylated PON-1 protein expression in HDL, and nanoflow liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) was applied to identify the amino acid in PON-1 carbamylated. PON-1 enzyme activities were estimated by substrates conversion method. HDL anti-oxidant activity was gauged by fluorescence changes of indicator dye in the presence of H2O2. Our study results proved that the degree of PON-1 carbamylation was higher in uremic HDL than in control HDL. Sandwich ELISA study showed that carbamylated PON-1 concentration in uremic HDL was 1.49 ± 0.08 fold higher than that in HDL from controls (p

To investigate the particle size distribution of particulate matter and the concentration of specific perfluorinated compounds in indoor dust samples from several locations. Then, we used cell-based assays to investigate the effect of perfluorinated compounds on human corneal epithelial (HCEpiC), endothelial cells (HCEC) and retinal pigment epithelial cells (RPE). Indoor dust samples were collected at five different locations and PM50–10, PM10–2.5, and PM2.5–1 were fractionized. The presence and levels of 8:2 fluorotelomer alcohol, 10:2 fluorotelomer alcohol, and perfluorooctanoic acid were detected by gas chromatography–mass spectrometry. The effect of perfluorooctanoic acid on the activation of reactive oxygen species, transepithelial resistance as well as the expression of interleukin (IL)-6 and IL-8 were determined. The basolateral media of human corneal epithelial or human corneal endothelial cells were used to treat human corneal endothelial or retinal pigment epithelial cells, respectively to indicate the potential of ocular surface inflammation may result in retinal inflammation. Among perfluorinated compounds, only perfluorooctanoic acid was detected in all indoor dust samples. Perfluorooctanoic acid had the highest concentration among all perfluorinated compounds in the samples. Exposure to perfluorooctanoic acid impaired tight junction sealing and increased the levels of reactive oxygen species in human corneal epithelial cells. In human corneal epithelial cells, secretion of IL-6 and IL-8 in both apical and basolateral media was promoted significantly by perfluorooctanoic acid treatment. Stimulation with the basolateral media from perfluorooctanoic acid-treated human corneal epithelial cells induced inflammation in human corneal endothelial cells. The treatment of retinal pigment epithelial cells with the basolateral media from stimulated human corneal endothelial cells also elicited the secretion of proinflammatory cytokines. The results indicate that perfluorooctanoic acid exposure impaired the tight junction of corneal cells and caused inflammatory reactions in the retina. Exposure of the cornea to perfluorooctanoic acid contained in particulate matter might induce oxidative stress and inflammation in the retina and represent a risk factor for age-related macular degeneration.

Patients with gout are at a higher risk of cardiovascular disease, which is associated with hyperlipidemia. Management of gout in Taiwan is poor, and the association between urate-lowering therapy (ULT) among gout patients and hyperlipidemia is unclear. We conducted a retrospective cohort study using data from the Longitudinal Health Insurance Database (LHID) of Taiwan on new-onset gout patients and a comparison cohort without gout. A Cox proportional hazards model was used to analyze differences in the risk of hyperlipidemia between patients with and without gout after considering related comorbidities. We also examined the ULT medications on the hepatic expression of lipogenesis-related genes. After adjusting for potential confounders, the case group (44,413 patients) was found to have a higher risk of hyperlipidemia than the control cohort (177,652 patients) [adjusted hazards ratio aHR = 2.55 ]. Gout patients without antigout treatment had significantly higher risk of hyperlipidemia than the control cohort ( aHR = 3.10 ). Among gout patients receiving ULT, except those receiving probenecid ( aHR = 0.80 ), all had significantly lower risk of hyperlipidemia than gout patients without ULT (all aHR < 0.90 ). Using real-time polymerase chain reaction, we found that most of the antigout drugs decreased the expression of hepatic genes related to lipogenesis in differentiated HepaRG cells. These data indicate that these antigout drugs reduce hyperlipidemia in gout patients, partly via the reduction in expression of lipogenesis-related genes, leading to improved blood lipid profiles. We provide evidence of the strong association between gout and hyperlipidemia and highlight the need for appropriate treatment guidelines.

Nonalcoholic fatty liver disease (NAFLD) is a very common liver disease, and its incidence has significantly increased worldwide. The liver X receptor α (LXRα) is a multifunctional nuclear receptor that controls lipid homeostasis. Inhibition of LXRα transactivation may be beneficial for NAFLD and hyperlipidemia treatment. Ursolic acid (UA) is a plant triterpenoid with many beneficial effects; however, the mechanism of its action on LXRα remains elusive. We evaluated the effects of UA on T0901317 (T090)-induced LXRα activation and steatosis. UA significantly decreased the LXR response element and sterol regulatory element-binding protein-1c ( SREBP-1c) gene promoter activities, mRNA, protein expression of LXRα target genes, and hepatic cellular lipid content in a T090-induced mouse model. A molecular docking study indicated that UA bound competitively with T090 at the LXRα ligand binding domain. UA stimulated AMP-activated protein kinase (AMPK) phosphorylation in hepatic cells and increased corepressor, small heterodimer partner-interacting leucine zipper protein (SMILE) but decreased coactivator, steroid receptor coactivator-1 (SRC-1) recruitment to the SREBP-1c promoter region. In contrast, UA induced SRC-1 binding but decreased SMILE binding to reverse cholesterol transport-related gene promoters in intestinal cells, increasing lipid excretion from intestinal cells. Additionally, UA reduced valproate-induced LXRα mediated and rifampin-induced pregnane X receptor mediated lipogenesis, offering potential treatments for drug-induced hepatic steatosis. Thus, UA displays liver specificity and can be selectively repressed while RCT stimulation by LXRα is preserved and enhanced. This is a novel therapeutic option to treat NAFLD and may be helpful in developing LXR agonists to prevent atherosclerosis.

Liver X receptor α (LXRα) controls important biological and pathophysiological processes such as lipid homeostasis. Inhibiting LXRα transactivation may beneficial in the treatment of nonalcoholic fatty liver disease (NAFLD), which is one of the main causes of liver diseases and hyperlipidemia. Oleanolic acid (OA) is a naturally occurring triterpenoid found in many plants. It has several beneficial effects on biological pathways; however, the mechanisms underlying its effects on LXRα are unclear. Therefore, we evaluated the effects of OA on T0901317-induced LXRα activation and explored whether OA can attenuate hepatic lipogenesis. The results showed that OA significantly decreased the promoter activities of LXR response element and sterol regulatory element binding protein-1c (SREBP-1c). It also decreased the mRNA and protein expression of LXRα target genes. These resulted in reduced hepatocellular lipid content. Our results also revealed that the overall binding pose of OA is similar to the X-ray pose of T0901317. Furthermore, OA stimulated AMP-activated protein kinase phosphorylation in hepatic cells. Additionally, it increased small heterodimer partner-interacting leucine zipper protein (SMILE) but decreased steroid receptor coactivator-1 (SRC-1) recruitment to the SREBP-1c promoter region. OA also enhanced LXRα-mediated induction of reverse cholesterol transport (RCT)-related gene, ATP-binding cassette transporter (ABC) A1, and ABCG1 expression in intestinal cells. It was found that OA increased the binding of SRC-1 but decreased SMILE recruitment to the ABCG1 gene promoter region. Furthermore, it reduced valproate- and rifampin-induced LXRα- and pregnane X receptor-mediated lipogenesis, respectively, which indicates its potential benefit in treating drug-induced hepatic steatosis. The results also show that OA is liver-specific and can be selectively repressed of lipogenesis. Moreover, it preserves and enhances LXRα-induced RCT stimulation. The results show that OA may be a promising treatment for NAFLD. Additionally, it can be used in the development of LXRα agonists to prevent atherosclerosis.

Objective. Human colorectal cancer (CRC) is the third most common cancer; patients with metastatic colorectal cancer (mCRC) show poor prognosis than those with CRC cases. There are no reliable molecular biomarkers for the diagnosis of CRC prognosis except with pathological features. Therefore, it is urgent to develop a biomarker for diagnosis and/or prediction of human CRC. In addition, capping actin protein (CapG) belongs to the gelsolin family and has been reported to contribute on tumor invasion/metastasis in multiple human cancers. Here, we are the first to evaluate the expression of CapG in human CRCs. Study Design. To investigate the expression levels of CapG in human tissue array by immunohistochemistry (IHC) staining. Moreover, the mRNA and protein levels were also confirmed in four CRC cell lines and determined using real-time RT-PCR and Western blotting. Finally, a Matrigel transwell invasion assay was used to evaluate the invasion ability in CapG high or low expression cells. Results. We demonstrated that CapG could be determined in the normal colon tissue and human CRC specimens. However, CapG was significantly overexpressed in the mCRC specimens compared with that in CRC specimens and normal cases. It was also detectable in the four CRC cell lines including mRNA and protein levels. We also found that knockdown of the expression of CapG reduced tumor migration. Conclusions. In this study, we suggested that CapG could be used as a biomarker for metastatic CRC in the clinical specimens. Moreover, our in vitro study demonstrated that CapG might contribute on tumor metastasis in human CRCs.

To characterize the association between epilepsy, use of antiepileptic drugs (AEDs), and the risk of hyperlipidemia, we conducted a nationwide population-based cohort study with data obtained from the National Health Insurance Research Database of Taiwan. The effects of AEDs on lipogenic gene expression were also examined in vitro. We identified 3617 cases involving patients, whose epilepsy was newly diagnosed between 2000 and 2011, and selected a comparison cohort comprising 14,468 patients without epilepsy. The Cox proportional hazards model was used to evaluate the association between epilepsy, AED use, and hyperlipidemia. The incidence rate of hyperlipidemia was higher in the epilepsy cohort than in the comparison cohort, with an adjusted hazard ratio (aHR) of 1.21 [95% confidence interval (CI): 1.06-1.38] after adjusting for comorbidities and medications. Epilepsy patients not taking AEDs had a higher risk of hyperlipidemia (aHR 1.65; 95% CI 1.35-2.03). Among AEDs, only valproate treatment showed a higher risk of hyperlipidemia (aHR 1.53; 95% CI 1.01-2.33), although the dose-dependent effect did not reach statistical significance. In vitro studies with two hepatic cell lines showed that valproate may exert its effects by activating the liver X receptor alpha (LXRα) signaling pathway, inducing the expression of lipogenesis-related genes and increasing cellular lipid contents. In silico calculations concluded that valproate can bind stably with the ligand-binding domain of LXRα. Thus, valproate-induced hepatic lipogenic gene expression may occur through LXRα activation. Predicting the 'off-target' effects of valproate may prove valuable in developing antiepileptic agents with fewer adverse reactions. Monitoring blood lipid levels throughout the course of treatment is recommended.

Background Interactions between transcriptional inducers of cytochrome P450 (CYP450) enzymes and therapeutic drugs may be prevented by antagonizing the activation of a nuclear receptor (NR), pregnane X receptor (PXR, NR1I2), thus improving therapeutic efficacy. Purpose In the present study, we aim to identify that ursolic acid (UA), a widely distributed pentacyclic triterpene, may act as an effective antagonist of PXR and its sister NR receptor, constitutive androstane receptor (CAR, NR1I3). Methods The hepatocellular carcinoma cell line, HepG2, was used to evaluate the promoter activity of PXR and CAR target genes, CYP3A4 and CYP2B6, respectively. Catalytic activities, mRNA, and protein expression of CYP3A4 and CYP2B6 were evaluated in a differentiated HepaRG cell line. Coregulation of PXR with coregulators on CYP3A4 promoter response elements was also been characterized. Results Transient transfection assays showed that UA effectively attenuated CYP3A4 and CYP2B6 promoter activities mediated by rifampin (RIF, human PXR agonist) and CITCO (human CAR agonist). These inhibitory effects were well correlated with the expression and catalytic activities of CYP3A4 and CYP2B6. Furthermore, the interaction of co-regulators with PXR and the transcriptional complexes in the CYP3A4 promoter activity and CYP3A4 promoter xenobiotic response element (everted repeat 6, ER6), respectively, were disrupted in the presence of UA. UA showed an antagonistic effect against PXR, and reversed the cytotoxic effects of isoniazid (INH) induced by RIF. Taken together, these results show that UA inhibits the transactivation effects of PXR and CAR, and reduces the expression and function of CYP3A4 and CYP2B6. Conclusion The present study suggests that UA could be a powerful agent for reducing potentially dangerous interactions between transcriptional inducers of CYP enzymes and therapeutic drugs.

A new amide, pipertaiwanamide (1), has been isolated from the aerial part of Piper taiwanense, together with four known compounds, taiwanamide A (2), taiwanamide B (3), 1-cinnamoylpyrrolidine (4), and N-cinnamoyltyramine (5). The structure of the new compound 1 was determined through spectroscopic and MS analyses. Pipertaiwanamide (1) and N-cinnamoyltyramine (5) exhibited free radical scavenging activity, with IC0.200 values of 12.6 ± 1.4 and 8.5 ± 0.8 𝜇M, respectively, in the diphenylpicrylhydrazyl radical (DPPH) decoloration assay.

A new xanthone, garcisubellone (1), has been isolated from the roots of Garcinia subelliptica, together with three known compounds, subelliptenone E (2), 1,5-dihydroxy-3-methoxyxanthone (3), and 1,4,5-trihydroxyxanthone (4). The structure of the new compound 1 was determined through spectroscopic and MS analyses. Garcisubellone (1) and 1,4,5-trihydroxyxanthone (4) exhibited potent inhibition, with IC50 values of 18.3 ± 2.2 and 15.6 ± 2.8 μM, respectively, against formyl-L-methionyl-L-leucyl-Lphenylalanine (fMLP)-induced superoxide anion (O2·–) generation.

A new 2H-pyran-2-one derivative, 4-hydroxy-6-(4-methoxyphenethyl)-2H-pyran-2-one (1), together with four known compounds, 5,6-dehydrokawain (2), dihydro-5,6-dehydrokawain (3), (E)-labda-8(17),12-diene-15,16-dial (4), and quercetin (5) were isolated from the rhizomes of Alpinia zerumbet. (E)-Labda-8(17),12-diene-15,16-dial (4) and quercetin (5) exhibited potent inhibition, with IC50 values of 3.18 ± 1.13 and 1.17 ± 0.13 μg/mL, respectively, against formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced superoxide anion (O 2 − ) generation.

Aloperine, an alkaloid isolated from Sophora alopecuroides, exhibits multiple pharmacological activities including anti-inflammatory, antioxidant, antiallergic, antinociceptive, antipathogenic, and antitumor effects. Furthermore, it exerts protective effects against renal and neuronal injuries. Several studies have reported antitumor effects of aloperine against various human cancers, including multiple myeloma, colon, breast, and prostate cancers, and osteosarcoma. Cell cycle arrest, apoptosis induction, and tumorigenesis suppression have been demonstrated following aloperine treatment. In a previous study, we demonstrated antitumor effects of aloperine on human thyroid cancer cells through anti-tumorigenesis and caspase-dependent apoptosis induction via the Akt signaling pathway. In the present study, we demonstrated the modulation of the autophagy mechanism following the incubation of multidrug-resistant papillary and anaplastic human thyroid cancer cells with aloperine, we also illustrate the underlying mechanisms, including AMPK, Erk, JNK, p38, and Akt signaling pathways. Further investigation revealed the involvement of the Akt signaling pathway in aloperine-modulated autophagy in human thyroid cancer cells. These results indicate a previously unappreciated function of aloperine in autophagy modulation in human thyroid cancer cells.

Liver X receptor (LXR) is a nuclear receptor that regulates various biological processes, including de novo lipogenesis, cholesterol metabolism, and inflammation. Selective inhibition of LXR may aid the treatment of nonalcoholic fatty liver disease (NAFLD). Sesamin is a naturally occurring lignan in many dietary plants and has a wide range of beneficial effects on metabolism. The mechanism underlying sesamin action especially on the regulation of LXR remains elusive. Reporter assays, mRNA and protein expression, and in silico modeling were used to identify sesamin as an antagonist of LXRα. Sesamin was applied to the hepatic HepaRG and intestinal LS174T cells and showed that it markedly ameliorated lipid accumulation in the HepaRG cells, by reducing LXRα transactivation, inhibiting the expression of downstream target genes. This effect was associated with the stimulation of AMP-activated protein kinase (AMPK) signaling pathway, followed by decreased T0901317-LXRα-induced expression of SREBP-1c and its downstream target genes. Mechanistically, sesamin reduced the recruitment of SRC-1 but enhanced that of SMILE to the SREBP-1c promoter region under T0901317 treatment. It regulated the transcriptional control exerted by LXRα by influencing its interaction with coregulators and thus decreased mRNA and protein levels of genes downstream of LXRα and reduced lipid accumulation in hepatic cells. Additionally, sesamin reduced valproate- and rifampin-induced LXRα and pregnane X receptor (PXR) transactivation. This was associated with reduced expression of target genes and decreased lipid accumulation. Thus, sesamin is an antagonist of LXRα and PXR and suggests that it may alleviate drug-induced lipogenesis via the suppression of LXRα and PXR signaling.

Myopia is caused by complex genetic and environmental factors. However, information regarding the effect of long-term exposure to air pollutants on the risk of development of myopia is lacking. We collected data from two linked databases: the Taiwan National Health Insurance Research Database (NHIRD) and the Taiwan Air Quality-Monitoring Database (TAQMD). A total of 15,822 children (16.3%) were diagnosed with myopia within the cohort. The incidence rate of myopia increased with exposure to increasing concentrations of particulate matter (PM2.5) and nitrogen oxides (NOx), increasing from 15.8 to 24.5 and from 13.7 to 34.4, per 1000 person-years, respectively. The adjusted hazard ratio for myopia increased with elevated PM2.5 and NOx exposure concentrations in Q4 to 1.57 and 2.60, respectively, compared to those exposed to the corresponding concentrations in Q1. In the animal experiments, PM2.5 induced myopia in hamsters by enhancing inflammation and was inhibited by resveratrol treatment compared to the control group. The change in axial length in the PM2.5 group was 0.386 ± 0.069 mm versus 0.287 ± 0.086 mm in the control group and 0.257 ± 0.059 mm in the PM2.5 + resveratrol group. We provide both clinical and experimental correlations that exposure to ambient air pollutants is associated with the pathogenesis of myopia.

The correlation between hip replacement (Hip-Repl) and chronic osteomyelitis (COM) has not been studied in Asian populations. Thus, we assessed Hip-Repl-related risk of developing COM via a population-based, nationwide, retrospective cohort study. The Hip-Repl cohort was obtained from Taiwan's Longitudinal Health Insurance Database 2000, and included patients who underwent Hip-Repl between 2000 and 2010; the control cohort was also selected from this database. Patients with a history of COM were excluded in both cohorts. We used univariate and multivariate Cox proportional hazards regression models to calculate the adjusted hazard ratios (aHRs) by age, sex, and comorbidities for developing COM. A total of 5349 patients who received a Hip-Repl and 10,372 matched controls were enrolled. In the Hip-Repl group, the risk for COM was 4.18-fold [95 % confidence interval (CI) = 2.24-7.80] higher than that in the control group after adjustment. For patients aged ≤65 years, the risk was 10.0-fold higher (95 % CI = 2.89-34.6). Furthermore, the risk was higher in the Hip-Repl cohort than in the non-Hip-Repl cohort, for both patients without comorbidity (aHR = 16.5, 95 % CI = 2.07-132.3) and those with comorbidity (aHR = 3.49, 95 % CI = 1.78-6.83). The impact of Hip-Repl on the risk for COM was greater among patients not using immunosuppressive drugs, and occurred during the first postoperative year. Patients who received Hip-Repl have an increased risk of developing COM. This risk was higher among males and patients aged 65 years or younger, and during the first postoperative year.

The objective of this study was to evaluate the potential therapeutic effects of betahistine dihydrochloride (betahistine) in a collagen-induced arthritis (CIA) mouse model. CIA was induced in DBA/1 male mice by primary immunization with 100μl of emulsion containing 2mg/ml chicken type II collagen (CII) mixed with complete Freund's adjuvant (CFA) in an 1:1 ratio, and booster immunization with 100μl of emulsion containing 2mg/ml CII mixed with incomplete Freund's adjuvant (IFA) in an 1:1 ratio. Immunization was performed subcutaneously at the base of the tail. After being boosted on day 21, betahistine (1 and 5mg/kg) was orally administered daily for 2weeks. The severity of CIA was determined by arthritic scores and assessment of histopathological joint destruction. Expression of cytokines in the paw and anti-CII antibodies in the serum was evaluated by ELISA. The proliferative response against CII in the lymph node cells was measured by (3)H-thymidine incorporation assay. The frequencies of different CII specific CD4(+) T cell subsets in the lymph node were determined by flow-cytometric analysis. Betahistine treatment attenuated the severity of arthritis and reduced the levels of pro-inflammatory cytokines, including TNF-α, IL-6, IL-23 and IL-17A, in the paw tissues of CIA mice. Lymph node cells from betahistine-treated mice showed a decrease in proliferation, as well as a lower frequency of Th17 cells. In vitro, betahistine suppressed CD4(+) T cell differentiation into Th17 cells. These results indicate that betahistine is effective in suppressing both inflammatory and Th17 responses in mouse CIA and that it may have therapeutic value as an adjunct treatment for rheumatoid arthritis.

A new chalcone, glycyglabrone (1), has been isolated from the roots of Glycyrrhiza glabra, together with three known compounds, licoagrochalcone B (2), licochalcone C (3), and kanzonol Y (4). The structure of the new compound 1 was determined through spectroscopic and MS analyses. Glycyglabrone (1) and licochalcone C (3) exhibited potent free radical scavenging activity, with IC0.200 values of 4.6 ± 0.6 and 8.2 ± 0.9 μM, respectively, in the diphenylpicrylhydrazyl radical (DPPH) decoloration assay.

A new benzenoid, propyl 7-methoxybenzo[d][1,3]dioxole-5-carboxylate (1), has been isolated from the stems of Capparis acutifolia, together with five known compounds, rutin (2), 3β-hydroxystigmast-5-en-7-one (3), 6β-hydroxystigmast-4-en-3-one (4), sitosterol trans-ferulate (5), and sitosterol cis-ferulate (6). The structure of the new compound 1 was determined through spectroscopic and MS analyses. Rutin (2) exhibited potent inhibition, with IC50 value of 1.26 ± 0.15 μg/mL, against formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced superoxide anion (O2 ·–) generation.

Physalin A (PA), a withanolide, was isolated from Physalis angulata L. In this study, it is shown that PA can inhibit the production of inflammatory cytokines such as PGE2, NO, IL-1β, IL-6, and TNF-α in LPS-induced RAW 264.7 cells. Furthermore, the results indicated that PA suppressed the IκB/NF-κB and JNK/ AP-1 inflammatory signaling pathways and inhibited the levels of pro-inflammatory factors iNOS and COX-2 in LPS-stimulated RAW 264.7 cells. In the carrageenan-induced mouse hind paw edema study, PA was shown to inhibit the production of inflammatory mediators such as NO, MDA, and TNF-α production. Conversely, the antioxidant factor levels of SOD, CAT, and GPx were all increased by the treated PA. According to the data, we are suggesting that the anti-inflammatory effects of PA may be through the suppressions of the JNK/AP-1 and IκB/NF-κB signaling pathways and up-regulation of the anti-oxidative activity.

Purpose The association between tamoxifen (TMX) treatment and the risk of developing hyperlipidemia remains unclear. Methods The records of 41,726 patients with breast cancer (28,266 received TMX and 13,460 did not) were obtained from the Taiwan National Health Insurance Research Database for the period from January 2000 to December 2008. Three-fold women without breast cancer were the control group (N = 125, 178). The main end point was developing hyperlipidemia during the follow-up. Results During a mean follow-up of 9 years, the patients with breast cancer demonstrated a rate of developing hyperlipidemia that was 6% less (adjusted hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.90-0.97) than that of the control participants without breast cancer. Stratification by age group indicated that only women aged ≥ 55 years who were diagnosed with breast cancer exhibited a significantly reduced risk of hyperlipidemia compared with the control group. With the use of 2 types of adjusted models, we observed that the TMX users (aged ≥ 55 years) consistently exhibited a significantly lower risk of hyperlipidemia than the non-TMX users and control participants (adjusted HRs, 0.79 and 0.82 from models 1 and 2, respectively). Within the 8-year follow-up period, patients with breast cancer and 366 to 1500 days of TMX therapy and > 1500 days of TMX therapy had significantly lower risks of hyperlipidemia compared with patients with ≤ 365 days of TMX therapy (adjusted HR, 0.54; 95% CI, 0.50-0.59; adjusted HR, 0.21; 95% CI, 0.18-0.24, respectively). Conclusions In Asian patients with breast cancer, TMX use was associated with reduced risks of hyperlipidemia.

A new aporphine alkaloid, (+)-(6aR,7R)-7-hydroxy-N-butyrylcaaverine ( 1 ), has been isolated from the roots of Illigera luzonensis. The structure of the new compound 1 was determined through spectroscopic and MS analyses.

A new amide, beilschamide (1), has been isolated from the stem of Beilschmiedia erythrophloia, together with seven known compounds, N-trans-feruloyltyramine (2), N-trans-feruloyloctopamine (3), vanillin (4), α-tocopheryl quinone (5), β-sitostenone (6), β-sitosterol (7), and 6α-hydroxystigmast-4-en-3-one (8). The structure of the new compound 1 was determined through spectroscopic and MS analyses. N-trans-Feruloyloctopamine (3) and beilschamide (1) exhibited cytotoxic effects with IC50 values of 10.3 and 21.2 μg/mL, respectively, against CCRF-CEM cell line.

Interactions between transcriptional inducers of cytochrome P450 (CYP450) and pharmacological agents might decrease drug efficacy and induce side effects. Such interactions could be prevented using an antagonist of the pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Here, we aimed to determine the antagonistic effect of oleanolic acid (OA) on PXR and CAR. OA attenuated the promoter activities, expressions, and enzyme catalytic activities of CYP3A4 and CYP2B6 mediated by rifampin (RIF) and CITCO. Moreover, OA displayed species specificity for rodent PXR. Interaction of coregulators with PXR and transcriptional complexes on the CYP3A4 promoter was disrupted by OA. Additionally, OA reversed the cytotoxic effects of isoniazid induced by RIF. These data demonstrate that OA inhibited the transactivation of PXR and CAR, reduced the expression and function of CYP3A4 and CYP2B6, and may therefore serve as an effective agent for reducing probability adverse interactions between transcriptional inducers of CYP450 and therapeutic drugs.

The prevalence of myopia has rapidly increased in recent decades and has led to a considerable global public health concern. In this study, we elucidate the relationship between Kawasaki disease (KD) and the incidence of myopia. We used Taiwan’s National Health Insurance Research Database to conduct a population-based cohort study. We identified patients diagnosed with KD and individuals without KD who were selected by frequency matched based on sex, age, and the index year. The Cox proportional hazards regression model was used to estimate the hazard ratio and 95% confidence intervals for the comparison of the 2 cohorts. The log-rank test was used to test the incidence of myopia in the 2 cohorts. A total of 532 patients were included in the KD cohort and 2128 in the non-KD cohort. The risk of myopia (hazard ratio, 1.31; 95% confidence interval, 1.08–1.58; P<0.01) was higher among patients with KD than among those in the non-KD cohort. The Cox proportional hazards regression model showed that irrespective of age, gender, and urbanization, Kawasaki disease was an independent risk factor for myopia. Patients with Kawasaki disease exhibited a substantially higher risk for developing myopia.

The objective of this study was to evaluate the association between the use of anti-tuberculosis (anti-TB) agents, isoniazid (INH), rifampicin (RIF), and their combination (INH + RIF), and the risk of hepatocellular carcinoma (HCC) in cirrhotic patients. This population-based case-control study was conducted using a research database of Taiwan's National Health Insurance program. Cirrhotic patients first diagnosed with HCC between 1996 and 2011 (n = 50,351), among whom 4,738 were anti-TB medication users, were evaluated. Cirrhotic patients who did not develop HCC within the same period, frequency-matched according to age, sex, and index year, were evaluated as the control group (n = 47,488). The adjusted odds ratio (OR) of HCC was 1.34 [95 % confidence interval (CI), 1.20-1.50] in INH + RIF users compared with non-INH + RIF users. Long-term (>12 months) use of INH, RIF, and INH + RIF was significantly associated with increased risk of HCC, with an adjusted OR of 3.51 (95 % CI, 2.11-5.84), 4.17 (95 % CI, 2.76-4.31), and 7.17 (95 % CI, 4.08-12.6), respectively, after adjusting for age, sex, and comorbidities. An average dose of INH + RIF >16,050 mg/year was associated with increased risk of HCC in cirrhotic patients, with an adjusted OR of 1.48 (95 % CI, 1.27-1.73). Our results indicate that cirrhotic patients with long-term or high-dose INH and RIF treatment, particularly their combination, are associated with increased risk of HCC development.

A new dihydroagarofuran-based sesquiterpene, microjaponin (1), was isolated from the stem of Microtropis japonica. Its structure was determined by in-depth spectroscopic and mass-spectrometric analyses. Microjaponin (1) exhibited potent in vitro antituberculosis activity, with an MIC value of 12.5 μg/ml against Mycobacterium tuberculosis H37 Rv.

Graves’ disease (GD) is a complex, organ-specific autoimmune disease wherein the thyroid gland becomes enlarged and overactive. During GD progression, T cells secrete interleukin-16 (IL-16) to promote inflammation, act as chemoattractants that recruit more inflammatory cells, and activate target cells to enhance the development of GD. To investigate the role of IL-16 in GD, we genotyped 474 patients with GD at 8 single-nucleotide polymorphisms (SNPs) in the IL-16 gene. The IL-16 SNP rs8028364 was found to be associated with GD when compared with the control subjects (P = 2.93 × 10 -17 ; CG genotype: odds ratio [OR] = 0.2 [0.07, 0.59]; CC genotype: OR = 0.03 [0.01, 0.09]). The rs1131445 polymorphism was found to be associated with GD under the allelic model (P = 0.01; G allele: OR = 1.97 [1.17, 3.32]). Sliding-window haplotype analysis by the PLINK program showed that the most significant haplotype was provided by the 6-SNP haplotype window, consisting of rs7182786, rs8028364, rs12907134, rs4128767, rs4072111 and rs8031107 (P = 2.31 × 10 -51 ). We found 2 protective haplotypes: GCAAGG (P = 8.69 × 10 -7 ; OR = 0.22 [0.12, 0.41]) and AGAAGG (P = 0.0012; OR = 0.26 [0.12, 0.6]). In addition, GGGGAA (P = 0.39; OR = 2.32 [1.08, 4.99]) and GGGAGA (P = 1.18 × 10 -5 ; OR = 5.54 [2.50, 12.31]) were found to be the two high-risk haplotypes. These results suggest that polymorphisms in IL-16 may be used as genetic markers for the diagnosis and prognosis of GD.