ALPK1 Expression Is Associated with Lymph Node Metastasis and Tumor Growth in Oral Squamous Cell Carcinoma Patients.

Oral squamous cell carcinoma (OSCC) is the most common malignant cancer, with high mortality rates in advanced stages. Recent studies have shown that the expression of ALPK1 mRNA and its inhibitory differentiation function are associated with cancer progression. However, the expression and clinicopathologic features of ALPK1 in OSCC remain unexplored. Herein, the authors investigated the expression patterns of ALPK1 in 39 matched OSCC patients and examined the relationship between ALPK1 protein expression and clinicopathologic factors using immunohistochemical scores. Using Western blot analysis, ALPK1 expression was found to be significantly higher in tumor tissues than that in nontumor tissues. Through an immunoreactive scoring system, a significantly higher number of advanced-stage tumor size T4 and lymph node metastasis N2 exhibited higher ALPK1 expression levels than that exhibited by T1/T2/T3 tumors and N0/N1. In addition, ALPK1 protein expression was aberrant in malignant oral cancer cell lines compared with that in pre-malignant oral epithelial cells, whereas minimal expression was observed in normal oral epithelial cells. Knockdown of ALPK1 resulted in a significant reduction in cell growth, migration, and invasion capacity in vitro. Consequently, expression of N-cadherin and vimentin decreased in ALPK1-deficient cells. Thus, these results suggest that ALPK1 serves as a potential biomarker and target for OSCC development in late stages.

ALPK1 regulates streptozotocin-induced nephropathy through CCL2 and CCL5 expressions.

ALPK1 is associated with chronic kidney disease, gout and type 2 diabetes mellitus. Raised renal ALPK1 level in patients with diabetes was reported. Accelerated fibrotic nephropathies were observed in hyperglycaemic mice with up-regulated ALPK1. The aim of this study was to identify the mediators contributing to ALPK1 effect involving in nephropathies induction. The haematoxylin and eosin staining, Masson's trichrome and immunohistochemical analysis of ALPK1, NFkB, CCL2 and CCL5 were performed in the mice kidney. Cytokine antibody array analysis was performed in streptozotocin-treated wild-type mice (WT-STZ) and streptozotocin-treated ALPK1 transgenic mice (TG-STZ). The ALPK1 levels were measured in mice kidney and in cultured cells. We found that the higher levels of renal CCL2/MCP-1, CCL5/Rantes and G-CSF expression in TG-STZ compared with the WT-STZ. Glucose increased ALPK1 expressions in monocytic THP1 and human kidney-2 cells. The protein expression of ALPK1, NFkB and lectin was up-regulated in glucose-treated HK-2 cells. Knockdown of ALPK1 reduced CCL2 and CCL5 mRNA levels, whereas overexpressed ALPK1 increased CCL2 and CCL5 in cultured kidney cells. Taken together, these results show that high glucose increases ALPK1 and chemokine levels in the kidney. Elevated ALPK1 expression enhances renal CCL2 and CCL5 expressions in vivo and in vitro. ALPK1 is a mediator for CCL2 and CCL5 chemokine up-regulation involving in diabetic nephropathies induction.

Arecoline N-oxide regulates oral squamous cell carcinoma development through NOTCH1 and FAT1 expressions.

Areca nut has been evaluated as a group I carcinogen to humans. However, the exact compounds of areca nut causing oral cancer remain unproven. Previous findings from our lab revealed that arecoline N-oxide (ANO), a metabolite of arecoline, exhibits an oral fibrotic effect in immune-deficient NOD/SCID mice. The aim of this study is to investigate the oral potentially malignant disorders (OPMD) inductive activity between areca-alkaloid arecoline and its metabolite ANO in C57BL/6 mice. Our findings show that ANO showed higher activity in inducing hyperplasia with leukoplakia and collagen deposition in C57BL/6 mice compared with the arecoline treated groups. Importantly, immunohistochemical studies showed significant upregulation of NOTCH1, HES1, FAT1, PCNA, and Ki67 expressions in the pathological hyperplastic part. In addition, in vitro studies showed that upregulation of NOTCH1 and FAT1 expressions in ANO treated HGF-1 and DOK cell models. We found that NOTCH1 regulates TP53 expression from NOTCH1 knockdown oral cancer cells. The DNA damage was significantly increased after arecoline and ANO treatment. Further, we found that arecoline-induced H2AX expression was regulated by FMO3. Altogether, our findings show that ANO exhibited higher toxicity in OPMD activity and play a significant role in the induction of areca nut mediated oral tumorigenesis.

LncRNA-Jak3:Jak3 coexpressed pattern regulates monosodium urate crystal-induced osteoclast differentiation through Nfatc1/Ctsk expression.

LncRNA transcripts have been emerged as gene regulators through transcriptional and posttranscriptional regulation. Monosodium urate monohydrate (MSU) elicits inflammatory response and a critical regulator of bone erosion in gout. The aim of this study is to clarify the pro-osteogenic role of LncRNA in MSU-induced osteoclast differentiation. We performed microarray analysis to identify stage specific expressions of LncRNA and mRNA during osteoclast differentiation in RAW264.7 cells. Among the 314 pairs of LncRNA-mRNA coexpressed patterns in the osteoclast lineage, 22 pairs revealed to have inflammatory function. Importantly, LncRNA-Jak3 and Jak3 co-expression patterns were significantly upregulated in the osteoclasts. In specific, Jak3 contributes to MSU-induced osteoclasts differentiation by positively regulating expression of the osteoclast factor, nuclear factor of activated T-cells 1 (Nfatc1). Mechanistically, LncRNA-Jak3-mediated Nfatc1 activation upregulated cathepsin K (Ctsk) expressions. LncRNA-Jak3 knockdown abolished formation of MSU-induced mature osteoclasts. In addition, we found that gout patients showed increased levels of LncRNA-Jak3 in the mononuclear cells. Our data demonstrate that the critical functional role of LncRNA-Jak3 in osteoclast differentiation via Jak3/Nfatc1/Ctsk axis. Finally, characterization of these regulatory networks is likely to reveal novel drug targets and opportunities for therapeutic intervention in bone erosion.

Variants of ALPK1 with ABCG2, SLC2A9, and SLC22A12 increased the positive predictive value for gout.

We investigated the interactions of ALPK1 variants and the loci of ABCG2, SLC2A9, and SLC22A12 on gout risk. We conducted two case-control studies. Participants were recruited from hospitals (n = 410; 104 gout cases and 306 controls) and communities (n = 678; 373 gout cases and 305 controls) in Taiwan. The genotypes of ALPK1 (rs11726117 M861T, rs231247 R1084R, and rs231253 3' UTR), ABCG2 (rs2231142 Q141K and rs2231137 V12M), SLC2A9 (rs3733591 R265H and rs1014290), and SLC22A12 (rs3825016 H86H, rs11231825 H142H, and rs475688) were genotyped. Under a recessive model, the joint effects of ALPK1 variants and the SNPs rs2231142 of ABCG2, rs1014290 of SLC2A9, or rs475688 and rs3825016 of SLC22A12 were associated with gout. The rs11726117 [CC] of ALPK1 and rs2231142 [TT] of ABCG2 with the sequential addition of the rs1014290 [AA] of SLC2A9 and rs3825016 [CC] of SLC22A12 were associated with gout risk (odds ratio (OR): 13.01, 15.11, and 55.00 and positive predictive value (PPV): 56%, 69%, and 99% in the Han group, respectively; OR: 3.76, 5.78, and 12.30 and PPV: 74%, 80%, and 81% in the aboriginal group, respectively). Combined exposure to the four high-risk genotypes of ALPK1 and the uric-acid-related loci of ABCG2, SLC2A9, and SLC22A12 was associated with an increased gout risk and a high PPV for gout.

Enhanced alpha-kinase 1 accelerates multiple early nephropathies in streptozotocin-induced hyperglycemic mice.

Alpha-kinase 1 (ALPK1) is associated with chronic kidney disease (CKD), type 2 diabetes mellitus and gout. Elevated ALPK1 levels have been observed in the kidneys of patients with diabetes and the white blood cells of patients with gout. As renal injury is a common outcome of CKD, diabetes and gout, the aim of this study was to investigate the effect of ALPK1 in the development of renal injury in a hyperglycemic condition. Hyperglycemia was induced in wild-type and ALPK1 transgenic mice by an intraperitoneal injection of streptozotocin (STZ). Functional and histological examinations were performed after 3weeks. STZ-treated ALPK1 transgenic mice exclusively showed arteriolar sclerosis and fibrous thickening of the Bowman's capsule in the kidney. This was accompanied by body weight loss, severe hyperglycemia, and low serum insulin levels. Renal renin and serum renin protein levels were higher in STZ-treated ALPK1 transgenic mice, whereas cGKII protein level was decreased by ALPK1 in human embryonic kidney 293 (HEK293) cells. ALPK1 up-regulated TGF-beta1 levels and transcription of fibrosis-related genes, including MMP-9, FIBRONECTIN, and TIMP1. MSU crystals increased ALPK1 transcription in cultured kidney cells. Finally, ALPK1 enhanced production of MSU crystals-induced IL-1beta in mice. Stimulation of soluble sodium urate induced IL-1beta and Alpk1 mRNA production in mice kidney. Taken together, these data show that an increase in ALPK1 results in accelerated fibrotic nephropathies, primarily through the enhancement of renin, TGF-beta1, and IL-1beta. Renal or blood ALPK1 levels are involved in the induction of fibrotic renal injury in an experimental model of hyperglycemia.

URAT1 inhibition by ALPK1 is associated with uric acid homeostasis.

Objective: The aim of this study was to identify a protein for urate transporter 1 (URAT1) regulation. Methods: The clinical dataset consisted of 492 case-control samples of Han Chinese (104 gout and 388 controls). Three alpha kinase 1 ( ALPK1 ) and SLC22A12 loci associated with high gout risk and uric acid levels were genotyped. The overexpression of ALPK1 on URAT1 protein expression was evaluated in vivo in h ALPK1 transgenic mice. The in vitro protein levels of ALPK1 and URAT1 in ALPK1 small interfering RNA-transfected human kidney-2 cells with MSU crystal stimulation were examined. Results: ALPK1 , which is a single nucleotide polymorphism (SNP) of rs11726117 (M861T; T), reduced the risk of gout via the SLC22A12 gene SNPs rs3825016 and rs475688, as compared with the subject of ALPK1 rs11726117 (C) allele {rs11726117 [CT + TT] vs rs3825016, odds ratio [OR] 0.39 [95% confidence interval (CI) 0.23, 0.67]; rs11726117 [CT + TT] vs rs475688, OR 0.39 [95% CI 0.23, 0.67]}. ALPK1-overexpressed mice demonstrated lower levels of URAT1 protein ( P = 0.0045). Mouse endogenous ALPK1 proteins were detected in renal proximal tubule cells. MSU crystals inhibited URAT1 expressions through an upregulation of ALPK1 in human kidney-2 cells. Conclusion: Elevated ALPK1 expression decreased URAT1 expression. ALPK1 might prevent the impact of urate reuptake via SLC22A12 and appeared to be negatively associated with gout. ALPK1 is a potential repressor of URAT1 protein expression.

Self-determined motivation and exercise behaviour in COPD patients.

The purpose of this study was to evaluate the self-determined motivation predictors of exercise behaviour following pulmonary rehabilitation in COPD recipients. This cross-sectional study was conducted with 135 COPD patients. A demographic questionnaire, clinical factors, behavioural regulations in exercise questionnaire, and leisure time exercise questionnaire were used to collect data. A logistic regression model was used to identify the predictors associated with demographics and self-determined motivation types regarding physical activity. Education level, episodes of acute exacerbation within 2 years, and identified regulation were significant predictors of executing physical activities with high metabolic equivalents. The results of this study imply that healthcare providers need to be aware of the importance of exercise motivation among COPD patients.

AURKA Phe31Ile polymorphism interacted with use of alcohol, betel quid, and cigarettes at multiplicative risk of oral cancer occurrence.

OBJECTIVES: The expression levels of two DNA repair genes (CHAF1A and CHAF1B) and a chromosome segregation gene (AURKA) were susceptible to arecoline exposure, a major alkaloid of areca nut. We hypothesize that genetic variants of these genes might also be implicated in the risk of oral cancer and could be modified by substance use of betel quid or alcohol and cigarettes. MATERIAL AND METHODS: A case-control study, which included 507 patients with oral cancer and 717 matched controls, was performed in order to evaluate the cancer susceptibility by the tagging single-nucleotide polymorphisms (tagSNPs) in AURKA, CHAF1A, and CHAF1B using a genotyping assay and gene-environment interaction analysis. RESULTS: The Phe31Ile polymorphism (rs2273535, T91A) of AURKA was significantly associated with an increased risk of oral cancer (odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.2-3.5). The gene dosage of the 91A allele also showed a significant trend in risk of oral cancer (P = 0.008). Furthermore, we found the AURKA 91AA homozygote was modifiable by substance use of alcohol, betel quid, and cigarettes (ABC), leading to increased risk of oral cancer in an additive or a multiplicative model (combined effect indexes = 1.2-4.0 and 1.5-2.2, respectively). However, no association was observed between the genetic variants of CHAF1A or CHAF1B and oral cancer risk in the study. CONCLUSION: These findings reveal the functional Phe31Ile polymorphism tagSNP of AURKA may be a strong susceptibility gene in ABC-related oral cancer occurrence. CLINICAL RELEVANCE: The results of this betel-related oral cancer study provide the evidence of environment-gene interaction for early prediction and molecular diagnosis.

Arecoline induces TNF-alpha production and Zonula Occludens-1 redistribution in mouse Sertoli TM4 cells.

BACKGROUND: Arecoline, a major alkaloid in Areca nut has the ability to induce oxidative stress. The effect of Areca nut, arecoline on reducing sperm quality and quantity were documented previously using several animal models. Junction disruption by down-regulation of the junction-adhesive protein via oxidative stress is an important route mediating abnormal spermatogenesis. Therefore, in this present study, we investigated the functional role of arecoline on junctional proteins. RESULTS: To analyze direct effects of arecoline on testis cells, confluent mouse testicular Sertoli cell line TM4 was exposed to arecoline. Arecoline decreased insoluble zonula occludens-1 (ZO-1) protein expression in TM4 cells, however, arecoline treatment increased TNF-alpha production in both TM4 and monocytic THP1 cells. In addition, ERK1/2 inhibitor PD98059 reversed arecoline effects on TNF-alpha and ZO-1. CONCLUSIONS: Arecoline increases the production of TNF-alpha and induces protein redistribution of ZO-1. All these results explain the role of arecoline in male reproductive dysfunction, besides its cytotoxic induction.

Combining brief recall and ketamine treatment prevents stress-primed methamphetamine memory reinstatement via heightening mPFC GABA activity.

This study aimed to assess whether brief recall of methamphetamine (MA) memory, when combined with ketamine (KE) treatment, may prevent stress-primed MA memory reinstatement. Combining 3-min recall and KE facilitated MA memory extinction and resistance to subsequent stress-primed reinstatement. Such combination also produced glutamate metabotropic receptor 5 (mGluR5) upregulation in animals' medial prefrontal cortex (mPFC) γ-amino-butyric acid (GABA) neuron. Accordingly, chemogenetic methods were employed to bi-directionally modulate mPFC GABA activity. Following brief recall and KE-produced MA memory extinction, intra-mPFC mDlx-Gi-coupled-human-muscarinic-receptor 4 (hM4Di)-infused mice receiving compound 21 (C21) treatment showed eminent stress-primed reinstatement, while their GABA mGluR5 expression seemed to be unaltered. Intra-mPFC mDlx-Gq-coupled-human-muscarinic-receptor 3 (hM3Dq)-infused mice undergoing C21 treatment displayed MA memory extinction and resistance to stress-provoked reinstatement. These results suggest that combining a brief recall and KE treatment and exciting mPFC GABA neuron may facilitate MA memory extinction and resistance to stress-primed recall. mPFC GABA neuronal activity plays a role in mediating brief recall/KE-produced effects on curbing the stress-provoked MA seeking.

Monoamine oxidase A variants are associated with heavy betel quid use.

Few studies have investigated whether genetic abnormalities predispose individuals to heavy betel quid (BQ) use. One of the major ingredients of BQ, arecoline, is known to affect the expression of monoamine oxidase A (MAO-A). We investigated the extent to which arecoline inhibits MAO-A expression and the role of MAO-A polymorphisms in BQ use in Taiwanese aborigines. Cytotoxicity assays, microarrays and quantitative reverse transcriptase-polymerase chain reaction were used to examine the effects of arecoline and areca nut extract (ANE) on cell viability and MAO-A expression in neuroblastoma SH-SY5Y cells. After identifying the effective concentrations of arecoline and ANE in vitro, we examined the in vivo effects of these compounds using a rat model system. Our results indicate that arecoline and ANE inhibit MAO-A expression both in vitro and in vivo. In addition, we examined the correlation between plasma MAO-A activity and cumulative exposure to BQ in humans. We recruited 1307 aborigines from a large-scale community-based survey to determine whether MAO-A variants were associated with high BQ use and a preference for use with smoking or alcohol and whether gender bias existed. MAO-A expression was significantly downregulated by arecoline and ANE at 100-200 µg/ml and in rat whole brains on days 30 and 45. MAO-A activity levels in human plasma were positively correlated with the extent of BQ exposure, and individuals with at-risk alleles exhibited lower activity, although this result did not reach statistical significance. We found two single nucleotide polymorphism (SNPs) in aboriginal males [rs2283725, odds ratio (OR) = 2.04; rs5953210, OR = 2.03] and females (rs2283725, OR = 1.54; rs5953210, OR = 1.59) that were associated with heavy BQ use. Those individuals carrying at-risk alleles who drank alcohol were twice as likely to be heavy BQ users. However, the effects of these SNPs on BQ use were significant even after controlling for alcohol use. Our results suggest that two specific loci may confer a susceptibility to BQ abuse and affect MAO-A enzymatic activity.

Recurrent vasodilator-refractory acute coronary syndrome as the exclusive manifestation of Graves disease.

Whether recurrent acute coronary syndrome could be the exclusive manifestation of Graves disease remains unreported. We describe a premenopausal woman who had angiographically normal coronary arteries yet had 3 episodes of acute coronary events in forms of unstable angina, ST elevation, and non-ST elevation myocardial infarction despite the active therapy of calcium-channel blockade. She was finally diagnosed as with Graves disease, treated with antithyroid medication, and free from any angina relapse for up to 18 months. Thus, recurrent coronary events might be the only manifestation of subclinical hyperthyroidism in patients with angiographically normal coronary arteries and could only be prevented by antithyroid agents instead of conventional vasodilators.

Long noncoding RNA HAR1A regulates oral cancer progression through the alpha-kinase 1, bromodomain 7, and myosin IIA axis.

Studies suggested that long noncoding HAR1A RNA may be a tumor suppressor, but its association with oral cancer remains unclear. Here, we show the functional role and mechanisms of HAR1A in oral cancer progression. Microarray analysis was performed to screen the related candidates of long noncoding RNA (lncRNA) in human monocytes. Following lncRNA HAR1A, the regulation of HAR1A, ALPK1, myosin IIA, and BRD7 was tested using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in oral cancer cells. The inflammatory and epithelial-to-mesenchymal transition marker expressions were analyzed using enzyme-linked immunosorbent assay and western blot. Phenotypic experiments were verified by colony formation assay, transwell migration assay, and Annexin V-apoptotic assay. In the nuclei of cancer cells, HAR1A functions upstream of signaling pathways and knockdown of HAR1A promoted ALPK1 expression and downregulated BRD7 resulting in inflammation and oral cancer progression. In monocytes, the expressions of TNF-α and CCL2 were increased following HAR1A knockdown and reduced following ALPK1 knockdown. HAR1A knockdown upregulated the expression of ALPK1, slug, vimentin, fibronectin, and N-cadherin but reduced the expression of E-cadherin in oral cancer cells. Myosin IIA was primarily located in the cytoplasm and that its decrease in the nuclei of oral cancer cells was likely to demonstrate suppressive ability in late-stage cancer. Our findings suggest that the HAR1A, BRD7, and myosin IIA are tumor suppressors while ALPK1 has oncogene-like property in the nucleus and is involved in inflammation and oral cancer progression. More research for HAR1A activators or ALPK1 inhibitors is required to develop potential therapeutic agents for advanced oral cancer. KEY MESSAGES: lncRNA HAR1A, BRD7, and myosin IIA are tumor suppressors whereas ALPK1 has an oncogenic-like property in the nucleus. lncRNA HAR1A/ALPK1/BRD7/myosin IIA axis plays a critical role in the progression of oral cancer. lncRNA HAR1A localizes upstream of signaling pathways to inhibit ALPK1 expression and then upregulated BRD7. lncRNA HAR1A and ALPK1 are involved in cancer progression via epithelial-to-mesenchymal transition regulations. ALPK1 inhibitors are potential kinase-targeted therapeutic agents for patients with advanced oral cancer.

Arecoline N-oxide initiates oral carcinogenesis and arecoline N-oxide mercapturic acid attenuates the cancer risk.

Arecoline N-oxide (ANO), an oxidative metabolite of the areca nut, is a predictable initiator in carcinogenesis. The mechanisms of arecoline metabolites in human cancer specimens is still limited. This present study aims to estimate the oral squamous cell carcinoma (OSCC) inductive activity between arecoline metabolites in human cancer specimens/OSCC cells. We have collected 22 pairs (tumor and non-tumor part) of patient's specimens and checked for clinical characteristics. The identification of arecoline and its metabolites levels by using LC-MS/MS. The NOD/SCID mice model was used to check the OSCC inductive activity. The tumor part of OSCC samples exhibited higher levels of arecoline and ANO. Besides, ANO treated mice accelerates the NOTCH1, IL-17a and IL-1ß expressions compared to the control mice. ANO exhibited higher cytotoxicity, intracellular ROS levels and decline in antioxidant enzyme levels in OC-3 cells. The protein expression of NOTCH1 and proliferation marker levels are significantly lower in NOM treated cells. Overall, ANO induced initial stage carcinogenesis in the oral cavity via inflammation, ROS and depletion of antioxidant enzymes. Arecoline N-oxide mercapturic acid (NOM) attenuates the initiation of oral carcinogenesis.

Cell cycle arrest and apoptosis induction by Juniperus communis extract in esophageal squamous cell carcinoma through activation of p53-induced apoptosis pathway.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers. It has a high mortality rate and requires novel effective drugs and therapeutic approaches. Juniperus communis (JCo), used to flavor gin and food, has been documented to have anti-tumor activity. The aim of this study was to investigate the antitumor activity of JCo extract against ESCC and its possible mechanisms. JCo extract suppressed cell growth in ESCC and showed higher selection for ESCC cells than normal cells compared to the clinical drug 5-fluorouracil (5-FU). JCo extract induced cell cycle arrest at the G0/G1 phase by regulating the expression of p53/p21 and CDKs/cyclins, triggering cell apoptosis by activating both the extrinsic (Fas/FasL/Caspase 8) and intrinsic (Bcl-2/Bax/Caspase 9) apoptosis pathways. Moreover, a combination treatment of JCo and 5-FU synergistically inhibited proliferation of ESCC cells. These results suggest that JCo extract is a potential natural therapeutic agent for esophageal cancer, as it could induce cell cycle arrest and apoptosis in ESCC cells.

Effect of antidepressants for cessation therapy in betel-quid use disorder: a randomised, double-blind, placebo-controlled trial.

AIMS: More than one-half of betel-quid (BQ) chewers have betel-quid use disorder (BUD). However, no medication has been approved. We performed a randomised clinical trial to test the efficacy of taking escitalopram and moclobemide antidepressants on betel-quid chewing cessation (BQ-CC) treatment. METHODS: We enrolled 111 eligible male BUD patients. They were double-blinded, placebo-controlled and randomised into three treatment groups: escitalopram 10 mg/tab daily, moclobemide 150 mg/tab daily and placebo. Patients were followed-up every 2 weeks and the length of the trial was 8 weeks. The primary outcome was BQ-CC, defined as BUD patients who continuously stopped BQ use for ⩾6 weeks. The secondary outcomes were the frequency and amount of BQ intake, and two psychological rating scales. Several clinical adverse effects were measured during the 8-week treatment. RESULTS: Intention-to-treat analysis shows that after 8 weeks, two (5.4%), 13 (34.2%) and 12 (33.3%) of BUD patients continuously quit BQ chewing for ⩾6 weeks among placebo, escitalopram, moclobemide groups, respectively. The adjusted proportion ratio of BQ-CC was 6.3 (95% CI 1.5-26.1) and 6.8 (95% CI 1.6-28.0) for BUD patients who used escitalopram and moclobemide, respectively, as compared with those who used placebo. BUD patients with escitalopram and moclobemide treatments both exhibited a significantly lower frequency and amount of BQ intake at the 8th week than those with placebo. CONCLUSIONS: Prescribing a fixed dose of moclobemide and escitalopram to BUD patients over 8 weeks demonstrated treatment benefits to BQ-CC. Given a relatively small sample, this study provides preliminary evidence and requires replication in larger trials.

Combination of celecoxib and calyculin-A inhibits epithelial-mesenchymal transition in human oral cancer cells.

Expression of cyclo-oxygenase-2 (COX-2) and protein phosphatase 2A (PP2A) deactivation occurs frequently in oral squamous cell carcinoma (OSCC). We initially assessed COX-2 and PP2A protein expression in OSCC specimens using immunohistochemical (IHC) staining and western blot analysis. We found strong COX-2 and phosphorylated PP2A (p-PP2A) expression in OSCC samples. No significant difference in total PP2A expression was observed between cancer and nontumor tissues. The effect of combining COX-2 inhibitor and celecoxib (CXB) with the PP2A inhibitor, calyculin-A (CLA) on the OSCC cell line, HSC3, was evaluated in vitro. We found that a combination of 1 nM CLA and 50 µM CXB significantly inhibited cell viability, and migration and invasion of HSC3 cells. Western blots for AKT, p-AKT, ERK, p-ERK, E-cadherin, vimentin and ß-catenin were conducted after treatment with CXB and/or CLA. Increased E-cadherin and decreased ß-catenin expression were found in CXB or CLA treated hsc-3 cells, whereas the combined CXB and CLA treatment showed no difference in E-cadherin or ß-catenin expression. Our findings suggest that CLA alone was more effective than CXB alone, but not in the combined drug treatment.

Association between heart rate recovery after exercise and renal function in patients referred for treadmill exercise test.

INTRODUCTION: Heart rate recovery (HRR) is a marker of parasympathetic activity recovery after exercise, and it is associated with cardiovascular mortality and total mortality. Impaired renal function is also associated with cardiac mortality. The aim of this study was to investigate the association between HRR after exercise and renal function in patients referred for a treadmill exercise test. PATIENTS AND METHODS: This cross-sectional study was conducted at a regional hospital in southern Taiwan. Patients who completed a symptom-limited treadmill exercise test from January 2015 to February 2018 were recruited. Before the treadmill exercise test, patients were asked to complete a questionnaire on the past disease history and lifestyle factors. Serum creatinine measurement within two years prior to or after the date of the treadmill exercise test of the patients was also obtained from the medical records for these patients. Estimated glomerular filtration rate (eGFR) was calculated. Simple and multiple linear regression analyses were performed to investigate the association between one-minute HRR and eGFR. RESULTS: A total of 2,825 patients completed the treadmill exercise test, and serum creatinine measurement was identified from medical records for 2,153 patients (76.2%). Multiple linear regression analysis revealed that a lower eGFR was significantly associated with lower one-minute HRR (P< 0.001), adjusting for other significant independent factors, including age, waist circumference, type 2 diabetes mellitus, and smoking. CONCLUSIONS: In this cross-sectional observational study, a lower eGFR was significantly and independently associated with decreased one-minute HRR, suggesting that parasympathetic activity recovery after exercise could be impaired by a decrease in renal function.