Apoptotic Cell Death and Inhibition of Wnt/β-Catenin Signaling Pathway in Human Colon Cancer Cells by an Active Fraction (HS7) from Taiwanofungus camphoratus

Aberrant activation of Wnt/β-catenin signaling plays an important role in the development of colon cancer. HS7 is an active fraction extracted from Taiwanofungus camphoratus, which had been widely used as complementary medicine for Taiwan cancer patients in the past decades. In this study, we demonstrated the effects of HS7 on the growth inhibition, apoptosis induction, and Wnt/β-catenin signaling suppression in human colon cancer cells. HS7 significantly inhibited proliferation of HT29, HCT116, and SW480 colon cancer cells in a dose- and time-dependent manner. The apoptosis induction was evidenced by DNA fragmentation and subG1 accumulation, which was associated with increased Bax/Bcl-2 ratio, activation of caspase-3 and cleavage of PARP. By using Tcf-dependent luciferase activity assay, HS7 was found to inhibit the β-catenin/Tcf transcriptional activities. In addition, HS7 strongly suppressed the binding of Tcf complexes to its DNA-binding site shown in electrophoretic mobility shift assay. This inhibition was further confirmed by the decreased protein levels of Tcf-4 and β-catenin. The β-catenin/Tcf downstream target genes, such as survivin, c-myc, cyclin D1, MMP7, and MT1-MMP involved in apoptosis, invasion, and angiogenesis were also diminished as well. These results indicate that Taiwanofungus camphoratus may provide a benefit as integrative medicine for the treatment of colon cancer

HPV infection and p53 inactivation in pterygium

PurposeOur recent report indicated that tumor suppressor gene (p53) mutations and protein aberrant expression were detected in pterygium. Inactivation of p53 by Human papillomavirus (HPV) 16/18 E6 plays a crucial role in cervical tumorigenesis. In this study, we further speculate that p53 inactivation may be linked with HPV infection in pterygium pathogenesis. To investigate the involvement of HPV 16/18 E6 in p53 inactivation in pterygium, the association between HPV 16 or HPV 18 infection, the HPV E6 oncoprotein, and p53 protein expression was analyzed in this study.MethodsHPV 16/18 infection was detected by nested-polymerase chain reaction (nested-PCR), the p53 mutation was detected by direct sequencing, and the p53 and the HPV 16/18 E6 proteins were studied using immunohistochemistry on 129 pterygial specimens and 20 normal conjunctivas.ResultsThe HPV 16/18 was detected in 24% of the pterygium tissues (31 of 129) but not in the normal conjunctiva, and the HPV16/18 E6 oncoprotein was detected in 48.3% of HPV 16/18 DNA-positive pterygium tissues (15 of 31). In addition, p53 protein negative expression in pterygium was correlated with HPV16/18 E6 oncoprotein expression but not with a p53 mutation.ConclusionsHPV 16/18 E6 contributes to HPV-mediated pterygium pathogenesis as it is partly involved in p53 inactivation and is expressed in HPV DNA-positive pterygium

Chinese Herbal Medicine Therapy and the Risk of Mortality for Chronic Hepatitis B Patients with Concurrent Liver Cirrhosis: a Nationwide Population-Based Cohort Study

Chronic hepatitis B (CHB) is increasingly recognized as a public health problem in Taiwan. After affected patients are diagnosed with contaminant liver cirrhosis (LC), adverse clinical outcomes, especially death, are common. This study aimed to investigate the effect of Chinese herbal medicine (CHM), an essential branch of Traditional Chinese medicine (TCM), on the mortality risk among CHB patients with contaminant LC. This longitudinal cohort study used the Taiwanese National Health Insurance Research Database to identify 1522 patients 20–70 years of age with newly diagnosed CHB with LC during 1998–2007. Among them, 508 (33.37%) had received CHM products after the onset of CHB (CHM users), and the remaining 1014 patients (66.63%) were designated as a control group (non-CHM users). All enrollees were followed until the end of 2012 to determine deaths during the study period. We applied the Cox proportional hazards regression model to compute the hazard ratio for the association of CHM use and the subsequent risk of death. During the follow-up period, 156 CHM users and 493 non-CHM users died. After controlling for potential confounders, CHM users were found to have a significantly reduced risk of death compared with non-CHM users by 56%, and the effect was predominantly observed among those treated with CHM for \u3e 180 days. CHM therapy lowered the risk of death among CHB patients with contaminant LC, which supported CHM might provide further treatment options for those with chronic liver diseases

The nucleolar protein NIFK promotes cancer progression via CK1α/β-catenin in metastasis and Ki-67-dependent cell proliferation.

Nucleolar protein interacting with the FHA domain of pKi-67 (NIFK) is a Ki-67-interacting protein. However, its precise function in cancer remains largely uninvestigated. Here we show the clinical significance and metastatic mechanism of NIFK in lung cancer. NIFK expression is clinically associated with poor prognosis and metastasis. Furthermore, NIFK enhances Ki-67-dependent proliferation, and promotes migration, invasion in vitro and metastasis in vivo via downregulation of casein kinase 1α (CK1α), a suppressor of pro-metastatic TCF4/β-catenin signaling. Inversely, CK1α is upregulated upon NIFK knockdown. The silencing of CK1α expression in NIFK-silenced cells restores TCF4/β-catenin transcriptional activity, cell migration, and metastasis. Furthermore, RUNX1 is identified as a transcription factor of CSNK1A1 (CK1α) that is negatively regulated by NIFK. Our results demonstrate the prognostic value of NIFK, and suggest that NIFK is required for lung cancer progression via the RUNX1-dependent CK1α repression, which activates TCF4/β-catenin signaling in metastasis and the Ki-67-dependent regulation in cell proliferation

Integration of Chinese Herbal Medicine into Routine Care Was Related to Lower Risk of Chronic Kidney Disease in Patients with Rheumatoid Arthritis: A Population-Based Nested Case–Control Study in Taiwan

Objective Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used as the first-line agents for the symptomatic relief of rheumatoid arthritis (RA), but it may insidiously provoke the onset of renal diseases, especially chronic kidney disease (CKD). While Chinese herbal medicine (CHM) has become an increasingly popular adjunctive therapy among RA groups, there are currently no available data on the effect of CHM use towards risk of CKD. This study aimed to explore on a population-level whether CHM use decreases sequent CKD risk among them. Methods In this nested case–control study retrieved from the nationwide insurance database of Taiwan from 2000 to 2012, we looked at the association between CHM use and the likelihood of developing CKD, with a focus on usage intensity. Cases with CKD claims were defined and matched to one randomly selected control case. Conditional logistic regression was then applied to estimate odds ratio (OR) of CKD from CHM treatment measured before the index date. For each OR, we calculated a 95% confidence interval for CHM use relative to the matched control. Results This nested case–control study included 5464 patients with RA, where after matching comprised 2712 cases and 2712 controls. Among them, there were 706 and 1199 cases that ever received CHM treatment, respectively. After the adjustment, CHM use in RA individuals was related to a lower likelihood of CKD, with an adjusted OR of 0.49 (95% CI: 0.44–0.56). Additionally, a dose-dependent, reverse association was found between the cumulative duration of CHM use and risk of CKD. Conclusion Integrating CHM into conventional therapy may reduce the likelihood of developing CKD, which could be a reference in instituting novel preventive strategies to improve treatment outcomes and reduce related fatalities for RA subjects

Association between use of non–vitamin k oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation

Importance:  Non–vitamin K oral anticoagulants (NOACs) are commonly prescribed with other medications that share metabolic pathways that may increase major bleeding risk. Objective:  To assess the association between use of NOACs with and without concurrent medications and risk of major bleeding in patients with nonvalvular atrial fibrillation. Design, Setting, and Participants:  Retrospective cohort study using data from the Taiwan National Health Insurance database and including 91 330 patients with nonvalvular atrial fibrillation who received at least 1 NOAC prescription of dabigatran, rivaroxaban, or apixaban from January 1, 2012, through December 31, 2016, with final follow-up on December 31, 2016. Exposures:  NOAC with or without concurrent use of atorvastatin; digoxin; verapamil; diltiazem; amiodarone; fluconazole; ketoconazole, itraconazole, voriconazole, or posaconazole; cyclosporine; erythromycin or clarithromycin; dronedarone; rifampin; or phenytoin. Main Outcomes and Measures:  Major bleeding, defined as hospitalization or emergency department visit with a primary diagnosis of intracranial hemorrhage or gastrointestinal, urogenital, or other bleeding. Adjusted incidence rate differences between person-quarters (exposure time for each person during each quarter of the calendar year) of NOAC with or without concurrent medications were estimated using Poisson regression and inverse probability of treatment weighting using the propensity score. Results:  Among 91 330 patients with nonvalvular atrial fibrillation (mean age, 74.7 years [SD, 10.8]; men, 55.8%; NOAC exposure: dabigatran, 45 347 patients; rivaroxaban, 54 006 patients; and apixaban, 12 886 patients), 4770 major bleeding events occurred during 447 037 person-quarters with NOAC prescriptions. The most common medications co-prescribed with NOACs over all person-quarters were atorvastatin (27.6%), diltiazem (22.7%), digoxin (22.5%), and amiodarone (21.1%). Concurrent use of amiodarone, fluconazole, rifampin, and phenytoin with NOACs had a significant increase in adjusted incidence rates per 1000 person-years of major bleeding than NOACs alone: 38.09 for NOAC use alone vs 52.04 for amiodarone (difference, 13.94 [99% CI, 9.76-18.13]); 102.77 for NOAC use alone vs 241.92 for fluconazole (difference, 138.46 [99% CI, 80.96-195.97]); 65.66 for NOAC use alone vs 103.14 for rifampin (difference, 36.90 [99% CI, 1.59-72.22); and 56.07 for NOAC use alone vs 108.52 for phenytoin (difference, 52.31 [99% CI, 32.18-72.44]; P < .01 for all comparisons). Compared with NOAC use alone, the adjusted incidence rate for major bleeding was significantly lower for concurrent use of atorvastatin, digoxin, and erythromycin or clarithromycin and was not significantly different for concurrent use of verapamil; diltiazem; cyclosporine; ketoconazole, itraconazole, voriconazole, or posaconazole; and dronedarone. Conclusions and Relevance:  Among patients taking NOACs for nonvalvular atrial fibrillation, concurrent use of amiodarone, fluconazole, rifampin, and phenytoin compared with the use of NOACs alone, was associated with increased risk of major bleeding. Physicians prescribing NOAC medications should consider the potential risks associated with concomitant use of other drugs

Bilateral Superficial Cervical Plexus Block Combined with General Anesthesia Administered in Thyroid Operations

We investigated the analgesic efficacy of bilateral superficial cervical plexus block in patients undergoing thyroidectomy and to determine whether it reduces the adverse effects of general anesthesia. We prospectively recruited 162 patients who underwent elective thyroid operations from March 2006 to October 2007. They were randomly assigned to receive a bilateral superficial cervical block (12 ml per side) with isotonic saline (group A; n = 56), bupivacaine 0.5% (group B; n = 52), or levobupivacaine 0.5% (group C; n = 54) after induction of general anesthesia. The analgesic efficacy of the block was assessed with: intraoperative anesthetics (desflurane), numbers of patients needing postoperative analgesics, the time to the first analgesics required, and pain intensity by visual analog scale (VAS). Postoperative nausea and vomiting (PONV) for 24 h were also assessed by the “PONV grade.” We also compared hospital stay, operative time, and discomfort in swallowing. There were no significant differences in patient characteristics. Each average end-tidal desflurane concentration was 5.8, 3.9, and 3.8% in groups A, B, and C, respectively (p < 0.001). Fewer patients in groups B and C required analgesics (A: B: C = 33:8:7; p < 0.001), and it took longer before the first analgesic dose was needed postoperatively (group A: B: C = 82.1:360.8:410.1 min; p < 0.001). Postoperative pain VAS were lower in groups B and C for the first 24 h postoperatively (p < 0.001). Incidences of overall and severe PONV were lower, however, there were not sufficient numbers of patients to detect differences in PONV among the three groups. Hospital stay was shorter in group B and group C (p = 0.011). There was no significant difference in operative time and postoperative swallowing pain among the three groups. Bilateral superficial cervical plexus block reduces general anesthetics required during thyroidectomy. It also significantly lowers the severity of postoperative pain during the first 24 h and shortens the hospital stay

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

Background/Aims: Immunological mechanisms can be triggered as a response to central nervous system insults and can lead to seizures. In this study an investigation was made to determine if glatiramer acetate (GA), an immunomodulator currently used in the treatment of multiple sclerosis, could protect rats from pilocarpine-induced seizures and chronic epilepsy. Methods: Two groups of adult male Sprague-Dawley rats, experimental (GA) and control, were used in the study. The systemic IL-1α and IL-1β levels at baseline were checked as well as status epilepticus (SE), and the spontaneous recurrent seizure (SRS) stage by enzyme-linked immunosorbent assay. The GA group was given GA (150 μg/kg, ip) and the control group was given a saline injection prior to pilocarpine-induced seizures. Seizure susceptibility, severity and mortality were evaluated, using Racine seizure classification and hippocampal damage was evaluated by Nissl staining. The GA group received GA (150 μg/kg/day, ip) daily after SE, and the chronic spontaneous seizures were evaluated by long-term video recording, and mossy fiber sprouting was evaluated by Timm staining. The IL-1α and IL-1β levels were correlated with seizure activities. The TNF-α level in the hippocampus was determined at the SRS stage by immunohistochemistry. The effect of GA on ionic currents and action potentials (APs) in NG108-15 differentiated neurons was investigated using patch-clamp technology. Results: It was found that latency to severe seizures was significantly longer in the GA (p < 0.01) group, which also had SE of shorter duration and less frequent SRS (p < 0.01). GA attenuated acute hippocampal neuron loss and chronic mossy fiber sprouting in the CA3 and the SRS-reduction correlated with the reduction of IL-1α, but not with IL-1β or TNF-α levels. Mechanistically, GA reduced the peak amplitude of voltage-gated Na+ current (INa), with a negative shift in the inactivation curve of INa and reduced the amplitude of APs along with decreased firing of APs. Conclusion: GA might serve as a neuroexcitability modulator which attenuates pilocarpine-induced acute and chronic excitotoxicity. Sodium channel attenuation was partially independent of the immunomodulatory effect