Publications by authors named "Yu-Juei Hsu"

92 Publications

Effects of Intradialytic Exercise on Dialytic Parameters, Health-Related Quality of Life, and Depression Status in Hemodialysis Patients: A Randomized Controlled Trial.

Int J Environ Res Public Health 2021 Aug 31;18(17). Epub 2021 Aug 31.

School of Medicine, National Defense Medical Center, Taipei 11490, Taiwan.

Exercise is fundamentally important in managing chronic diseases and improving health-related quality of life (HRQL). However, whether intradialytic exercise is safe through assessment of changes in dialytic parameters and has a positive impact on HRQL and depression status of hemodialysis patients requires further research with diverse racial and cultural populations to identify. This study aimed to evaluate the effects of intradialytic exercise on dialytic parameters, HRQL, and depression status in hemodialysis patients. A randomized controlled trial was conducted at a medical center in Northern Taiwan. Sixty-four hemodialysis patients were recruited using stratified random sampling. Participants were randomized into an experimental group (EG, = 32) or a control group (CG, = 32). The EG received a 12-week intradialytic exercise program while the CG maintained their usual lifestyles. Dialytic parameters, HRQL, and depression status were collected at baseline and at 12 weeks. The results indicated no differences in the dialytic parameters from the baseline between both groups. However, the EG had increased HRQL (ß = 22.6, < 0.001) and reduced depression status (ß = -7.5, = 0.02) at 12 weeks compared to the CG. Therefore, a 12-week intradialytic exercise regime is safe and effective in improving HRQL and reducing depression status for hemodialysis patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph18179205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430543PMC
August 2021

Does Coenzyme Q10 Supplementation Improve Testicular Function and Spermatogenesis in Male Mice with Chronic Kidney Disease?

Biology (Basel) 2021 Aug 17;10(8). Epub 2021 Aug 17.

Department of Nutritional Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan.

The aim of the study was to examine the potential effects of coenzyme Q10 (CoQ10) on reproductive function in a chronic kidney disease (CKD) mouse model. Nine-week-old mice were randomly assigned to two groups: sham surgery ( = 18) and CKD surgery ( = 18). After surgery, the study groups received CoQ10 (10 mg/kg body weight dissolved in corn oil by oral gavage) or corn oil as a vehicle daily for 8 weeks. The groups that underwent 5/6 nephrectomy developed significant elevations of serum BUN and creatinine levels. The CoQ10 treatment significantly increased the serum and testicular CoQ10 levels and alleviated the poor semen quality from incomplete spermatogenesis. The testosterone concentration, in addition to the protein expression of enzymes related to testosterone biosynthesis, was also elevated, and the CKD-induced decrease in antioxidant activity in the testes was significantly ameliorated. The results suggest that CoQ10 could act against CKD-induced testicular dysfunction through improvements in the sperm function, testicular morphology, testosterone levels and related biosynthesis pathways, in addition to antioxidant activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biology10080786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389647PMC
August 2021

Allele-specific RT-PCR for the rapid detection of recurrent SLC12A3 mutations for Gitelman syndrome.

NPJ Genom Med 2021 Aug 13;6(1):68. Epub 2021 Aug 13.

Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.

Recurrent mutations in the SLC12A3 gene responsible for autosomal recessive Gitelman syndrome (GS) are frequently reported, but the exact prevalence is unknown. The rapid detection of recurrent SLC12A3 mutations may help in the early diagnosis of GS. This study was aimed to investigate the prevalence of recurrent SLC12A3 mutations in a Taiwan cohort of GS families and develop a simple and rapid method to detect recurrent SLC12A3 mutations. One hundred and thirty independent Taiwan families with genetically confirmed GS were consecutively enrolled to define recurrent SLC12A3 mutations and determine their prevalence. Using TaqMan probe-based real-time polymerase chain reaction, we designed a mutation detection plate with all recurrent mutations. We validated this mutation detection plate and tested its feasibility in newly diagnosed GS patients. A total of 57 mutations in the SLC12A3 gene were identified and 22 including 2 deep intronic mutations were recurrent mutations consisting of 87.1% (242/278, 18 triple) of all allelic mutations. The recurrent mutation-based TaqMan assays were fully validated with excellent sensitivity and specificity in genetically diagnosed GS patients and healthy subjects. In clinical validation, recurrent mutations were recognized in 92.0% of allelic mutations from 12 GS patients within 4 h and all were confirmed by direct sequencing. Recurrent SLC12A3 mutations are very common in Taiwan GS patients and can be rapidly identified by this recurrent mutation-based SLC12A3 mutation plate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41525-021-00230-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363728PMC
August 2021

Cf-02, a novel benzamide-linked small molecule, blunts NF-κB activation and NLRP3 inflammasome assembly and improves acute onset of accelerated and severe lupus nephritis in mice.

FASEB J 2021 08;35(8):e21785

Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

In the present study, acute onset of severe lupus nephritis was successfully treated in mice using a new, benzamide-linked, small molecule that targets immune modulation and the NLRP3 inflammasome. Specifically, 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02) (a) reduced serum levels of IgG anti-dsDNA, IL-1β, IL-6, and TNF-α, (b) inhibited activation of dendritic cells and differentially regulated T cell functions, and (c) suppressed the NF-κB/NLRP3 inflammasome axis, targeting priming and activating signals of the inflammasome. Moreover, treatment with Cf-02 significantly inhibited secretion of IL-1β in lipopolysaccharide-stimulated macrophages, but this effect was abolished by autophagy induction. These results recommend Cf-02 as a promising drug candidate for the serious renal conditions associated with systemic lupus erythematosus. Future investigations should examine whether Cf-02 may also be therapeutic in other types of chronic kidney disease involving NLRP3 inflammasome-driven signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.202100047RDOI Listing
August 2021

Comparative Effectiveness and Safety of Different Types of Inhaled Long-Acting β-Agonist Plus Inhaled Long-Acting Muscarinic Antagonist vs Inhaled Long-Acting β-Agonist Plus Inhaled Corticosteroid Fixed-Dose Combinations in COPD A Propensity Score-Inverse Probability of Treatment Weighting Cohort Study.

Chest 2021 May 21. Epub 2021 May 21.

Division of Pulmonary and Critical Care, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, China. Electronic address:

Background: Despite multiple available fixed-dose combinations (FDCs) of inhaled long-acting β-agonists (LABAs) plus long-acting muscarinic antagonists (LAMAs) and LABAs plus inhaled corticosteroids (ICS) for COPD, uncertainty remains regarding their comparative effects.

Research Question: Can comparative effectiveness and safety of LABA plus LAMA (LABA/LAMA) and LABA plus ICS (LABA/ICS) FDCs vary by different individual components of the dual combinations in COPD?

Study Design And Methods: We conducted a new user, propensity score-inverse probability of treatment weighting cohort study to compare the effectiveness and safety of two frequently used LABA/LAMA FDCs (indacaterol plus glycopyrronium [IND/GLY] and vilanterol plus umeclidinium [VI/UMEC]) vs three commonly prescribed LABA/ICS FDCs (salmeterol plus fluticasone propionate [SAL/FP], formoterol fumarate plus budesonide [FF/BUD], and formoterol fumarate plus beclomethasone dipropionate [FF/BDP]) using the Taiwanese nationwide health-care claims from 2014 through 2017. The primary effectiveness outcome was the annual moderate to severe exacerbation rate, and safety outcomes included risks of severe pneumonia and cardiovascular disease requiring hospitalization. Weighted generalized linear mixed models and Cox proportional hazard models were used to assess the effectiveness and safety outcomes, respectively.

Results: Patients with COPD initiating IND/GLY and VI/UMEC showed an 11% (incidence rate ratio [IRR], 0.89; 95% CI, 0.80-0.98) and 20% (IRR, 0.80; 95% CI, 0.71-0.90) reduced annual rate of moderate to severe exacerbations, respectively, than those initiating SAL/FP, but showed a similar rate as those initiating FF/BUD or FF/BDP. Both LABA/LAMA FDCs, compared with SAL/FP and VI/UMEC vs FF/BDP, were associated with a 27% (hazard ratio [HR], 0.73; 95% CI, 0.59-0.90) to 42% (HR, 0.58; 95% CI, 0.48-0.70) reduced pneumonia risk. Cardiovascular risk was comparable in five groups. An intraclass difference existed in rates of moderate to severe COPD exacerbation and risks of pneumonia among LABA/ICS FDCs, but not between LABA/LAMA FDCs.

Interpretation: Both LABA/LAMAs vs SAL/FP are associated with a lower exacerbation rate and pneumonia risk, but exhibit similar effectiveness and safety outcomes compared with FF/BDP or FF/BUD, suggesting that comparative effects may differ by individual components of the dual therapies in COPD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2021.05.025DOI Listing
May 2021

Lithium Hemodialysis Removal-Related Recurrent Manic Episode in a Bipolar Patient.

Am J Ther 2021 Apr 29. Epub 2021 Apr 29.

Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC Division of Nephrology, Department of Internal Medicine, School of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC Student Counseling Center, National Defense Medical Center, Taipei, Taiwan, ROC.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MJT.0000000000001382DOI Listing
April 2021

Hypoperfusion of the infrapatellar fat pad and its relationship to MRI T2* relaxation time changes in a 5/6 nephrectomy model.

Sci Rep 2021 May 11;11(1):9924. Epub 2021 May 11.

Department and Graduate Institute of Biology and Anatomy, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei, 11490, Taiwan.

The purpose of present study was to longitudinally investigate the alterations in infrapatellar fat pad (IPFP) vascularity in 5/6 nephrectomized rats by using dynamic contrast enhanced (DCE) MRI and IPFP degeneration by using MRI T2* relaxation time. Twelve male Sprague-Dawley rats were assigned to a control group and a 5/6 nephrectomy CKD group. The right knees of all rats were longitudinally scanned by 4.7 T MRI, and serial changes in the IPFP were assessed at 0, 8, 16, 30, and 44 weeks by DCE-MRI (parameters A, k and k) and MRI T2* mapping. After MRI measurements, knee specimens were obtained and evaluated histologically. The CKD group had IPFPs with lower blood volume A and lower permeability k values from 16 weeks (p < 0.05), lower venous washout k value from 30 weeks (p < 0.001), and significantly higher T2* values reflecting adipocyte degeneration beginning at 16 weeks (p < 0.05). The histopathological results confirmed the MRI findings. Hypoperfusion and adipocytes degeneration related to CKD were demonstrated in a rodent 5/6 nephrectomy model. DCE parameters and MRI T2* can serve as imaging biomarkers of fat pad degeneration during CKD progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-89336-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113578PMC
May 2021

A rat toxicological study of intra-arterial injection of Tirapazamine, a hypoxia-activating Cancer therapeutic agent, followed by hepatic artery ligation.

Invest New Drugs 2021 Jun 11;39(3):747-755. Epub 2021 Jan 11.

Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan, Republic of China.

Background Tirapazamine's (TPZ) tolerability after an intra-arterial (IA) injection remains unclear. We investigated TPZ's safety and tolerability in rats by first injecting into the left hepatic artery and then performing a hepatic artery ligation, which recapitulates the transarterial embolization used clinically. Research design and methods: Forty-six rats in five groups were respectively injected with 0, 0.25, 0.50, 1.0, or more than 1.5 mL IA of TPZ (0.7 mg/mL) into the left hepatic artery and then subjected to hepatic artery ligation under laparotomy. Blood samples were collected four times daily up to day 15 after which the rats were euthanized and necropsied. The toxicity profile of IA injection of TPZ followed by hepatic artery ligation was then assessed. Results No significant changes to the rats' body weight and serum total bilirubin were observed. Serum alanine aminotransferase (ALT) levels increased slightly but remained below 100 U/L one day after treatment for most rats. Three rats in Groups 3 and 4 exhibited an over two-fold transient elevation of ALT. All ALT recovered to the baseline at day 14. Liver tissues were collected on day 15 using H&E staining. One rat in Group 3 showed ischemic coagulative necrosis in its liver tissue. Other sporadic pathological changes not related to TPZ doses were observed in Groups 2, 3, 4, and 5. Conclusion TPZ by IA injection followed by embolization is tolerated up to 7 mg/kg. This finding supports the strategy of administering an IA injection of TPZ followed by trans-arterial embolization to the liver.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10637-020-01057-3DOI Listing
June 2021

Continuity of care: evaluating a multidisciplinary care model for people with early CKD via a nationwide population-based longitudinal study.

BMJ Open 2020 12 29;10(12):e041149. Epub 2020 Dec 29.

School of Health Care Administration, Taipei Medical University, Taipei, Taiwan

Objectives: To control and prevent the burdens associated with chronic kidney disease (CKD), Taiwan's National Health Insurance Administration (NHIA) launched the 'early-CKD programme' in 2011 to extend care and education to patients with CKD. This study aims to evaluate the effectiveness of the early-CKD programme in terms of continuity of care (COC).

Design And Participants: This study used secondary data from 2010 to 2014 provided by the NHIA to identify 86 581 participants each for the intervention and control groups. Patients with CKD who participated in the early-CKD programme between 2011 and 2013 were defined as the intervention group. For the control group, propensity score matching was used to select patients with CKD who did not participate in the programme, but were seen by the same group of physicians.

Intervention: A multidisciplinary care model for patients with early CKD launched in 2011.

Primary Outcome Measures: Outcome variables included the continuity of care index (COCI), which measures a physician's COC; number of essential examinations; and resource utilisation. To better identify the difference between groups, we separated COCI into two groups based on mean: high (above mean) and low (below mean). A generalised estimating equation model was used to examine the effects of the early-CKD programme.

Results: The programme significantly increased the number of essential examinations/tests administered to patients (β=0.61, p<0.001) and improved COCI between physicians and patients (OR=4.18, p<0.001). Medical expenses (β=1.03, p<0.001) and medication expenses (β=0.23, p<0.001) significantly increased after the programme was implemented, but patients' kidney-related hospitalisations and emergency department visits decreased (β=-0.13, p<0.001).

Conclusion: From the COC viewpoint, the programme in Taiwan showed a positive effect on COCI, number of essential examinations and resource utilisation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-041149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778764PMC
December 2020

Effects of Individualized Dietary Phosphate Control Program With a Smartphone Application in Hemodialysis Patients in Taiwan.

Biol Res Nurs 2021 Jul 28;23(3):375-381. Epub 2020 Nov 28.

Division of Nephrology, Department of Internal Medicine, 63452Tri-Service General Hospital, National Defense Medical Center, Taipei.

Background: Hyperphosphatemia in end-stage renal disease patients is prevalent and associated with increasing cardiac mortality. Restricting dietary phosphate intake is a key element in controlling hyperphosphatemia, but most patients fail due to lack of knowledge and sustainability. In this study, we aimed to examine whether incorporating a smartphone application (APP) into a multidisciplinary caring system can decrease the prevalence of hyperphosphatemia in hemodialysis patients.

Methods: We designed a quasi-experimental study to enroll patients undergoing regular hemodialysis and assigned them to receive APP-assisted caring program (ACP group, = 30) or standard education caring program (SCP group, = 30). Both caring programs targeting dietary phosphate control were administered. Patients' general characteristics, self-care efficacy scales, knowledge test of phosphate control, and results of monthly blood biochemistry were analyzed.

Findings: Knowledge of diet phosphate control and self-care efficacy were significantly higher in the ACP group. Notably, the knowledge improvement was higher in patients aged over 60 years. Compared to the SCP group, the percentage of patients with successful hyperphosphatemia control was significantly higher in the ACP group ( = 0.0398).

Conclusion: The APP-assisted caring program benefits patients with regular hemodialysis to achieve better dietary phosphate control without compromising proper protein intake.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1099800420975504DOI Listing
July 2021

CREB/ATF3 signaling mediates indoxyl sulfate-induced vascular smooth muscle cell proliferation and neointimal formation in uremia.

Atherosclerosis 2020 12 8;315:43-54. Epub 2020 Nov 8.

Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan. Electronic address:

Background And Aims: Uremic patients are characterized by an increased risk of atherosclerotic cardiovascular diseases. Vascular smooth muscle cell (VSMC) proliferation contributes to neointimal formation, a main pathological feature in atherosclerosis. Activation of CREB/ATF3 signaling is pivotal in VSMC proliferation, yet its role in uremic atherosclerosis is unknown. This study aimed to explore whether CREB/ATF3 signaling is involved in the molecular mechanism underlying neointimal formation in uremia.

Methods And Results: Treatment of VSMCs with uremic toxin (indoxyl sulfate [IS]) activated cAMP/CREB/ATF3/cyclin D signaling, which was reflected by increased VSMC proliferation. Blocking cAMP/PKA/CREB/ATF3 signaling attenuated the promoting effect of IS on cyclin D1 expression and VSMC proliferation. Loss-of-function and time-dependent experiments showed that ATF3 lies downstream of the CREB signaling. Mutational analysis of cyclin D1 promoter along with chromatin immunoprecipitation assays showed that CREB/ATF3 signaling participated in IS-induced cyclin D transcription. In vivo, phosphorylated CREB (an active form of CREB) and ATF3 were prominently upregulated in the neointima of experimental uremic rats, the atherosclerotic plaques of uremic ApoE mice, and the iliac arteries of uremic patients. Notably, the use of lentivirus to knock down ATF3 in the neointima of balloon-injured arteries could suppress the effect of uremia in vivo, including neointimal formation and cyclin D expression.

Conclusions: In this study, we demonstrated that CREB/ATF3-related signaling may be involved in IS-induced VSMC proliferation and the pathogenesis of neointimal formation during uremia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2020.11.009DOI Listing
December 2020

High phosphate induces skeletal muscle atrophy and suppresses myogenic differentiation by increasing oxidative stress and activating Nrf2 signaling.

Aging (Albany NY) 2020 11 2;12(21):21446-21468. Epub 2020 Nov 2.

Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.

Skeletal muscle wasting represents both a common phenotype of aging and a feature of pathological conditions such as chronic kidney disease (CKD). Although both clinical data and genetic experiments in mice suggest that hyperphosphatemia accelerates muscle wasting, the underlying mechanism remains unclear. Here, we showed that inorganic phosphate (Pi) dose-dependently decreases myotube size, fusion index, and myogenin expression in mouse C2C12 skeletal muscle cells. These changes were accompanied by increases in reactive oxygen species (ROS) production and Nrf2 and p62 expression, and reductions in mitochondrial membrane potential (MMP) and Keap1 expression. Inhibition of Pi entry, cytosolic ROS production, or Nrf2 activation reversed the effects of high Pi on Nrf2, p62, and myogenin expression. Overexpression of Nrf2 respectively increased and decreased the promoter activity of -Luc and -Luc reporters. Analysis of nuclear extracts from gastrocnemius muscles from mice fed a high-Pi (2% Pi) diet showed increased Nrf2 phosphorylation in sham-operated and 5/6 nephrectomized (CKD) mice, and both increased p62 phosphorylation and decreased myogenin expression in CKD mice. These data suggest that high Pi suppresses myogenic differentiation and promotes muscle atrophy through oxidative stress-mediated protein degradation and both canonical (ROS-mediated) and non-canonical (p62-mediated) activation of Nrf2 signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.103896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695395PMC
November 2020

A High Phosphorus Diet Impairs Testicular Function and Spermatogenesis in Male Mice with Chronic Kidney Disease.

Nutrients 2020 Aug 28;12(9). Epub 2020 Aug 28.

Department of Nutritional Science, Fu Jen Catholic University, Taipei 242, Taiwan.

Hyperphosphatemia is a serious complication in chronic kidney disease (CKD) that occurs due to insufficient excretion of phosphorus during failure of renal function. Both CKD and an excessive phosphorus intake have been reported to increase oxidative stress and result in poor male fertility, but little is known about the reproductive function of the CKD under a poorly controlled phosphate intake. Eight-week-old C57BL/6 mice ( = 66) were randomly divided into four groups: a sham operation group received a chow diet as control (SC group, = 14), CKD-induced mice received a chow diet (CKDC group, = 16), control mice received a high phosphorus (HP) diet (SP group, = 16), and CKD-induced mice received a HP diet (CKDP group, = 20). CKD was induced by performing a 5/6 nephrectomy. The chow diet contained 0.6% phosphorus, while the HP diet contained 2% phosphorus. Impaired testicular function and semen quality found in the CKD model may result from increased oxidative stress, causing apoptosis and inflammation. The HP diet aggravated the negative effects of testicular damage in the CKD-induced mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12092624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551469PMC
August 2020

Aldehyde dehydrogenase 2 protects against abdominal aortic aneurysm formation by reducing reactive oxygen species, vascular inflammation, and apoptosis of vascular smooth muscle cells.

FASEB J 2020 07 28;34(7):9498-9511. Epub 2020 May 28.

Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies aldehydes by converting them to carboxylic acids. ALDH2 deficiency is known to increase oxidative stress. Increased oxidative stress plays a pivotal role in abdominal aortic aneurysm (AAA) pathogenesis. Reactive oxygen species (ROS) promote degradation of the extracellular matrix (ECM) and vascular smooth muscle cell (VSMC) apoptosis. Reducing oxidative stress by an ALDH2 activator could have therapeutic potential for limiting AAA development. We hypothesized that ALDH2 deficiency could increase the risk for AAA by decreasing ROS elimination and that an ALDH2 activator could provide an alternative option for AAA treatment. The National Center for Biotechnology (NCBI) Gene Expression Omnibus (GEO) database was used. Human aortic smooth muscle cells (HASMCs) were used for the in vitro experiments. Gene-targeted ALDH2*2 KI knock-in mice on a C57BL/6J background and apolipoprotein E knockout (ApoE KO) mice were obtained. An animal model of AAA was constructed using osmotic minipumps to deliver 1000 ng/kg/min angiotensin II (AngII) for 28 days. Patients with AAA had significantly lower ALDH2 expression levels than normal subjects. ALDH2*2 KI mice were susceptible to AngII administration, exhibiting significantly increased AAA incidence rates and increased aortic diameters. Alda-1, an ALDH2 activator, reduced AngII-induced ROS production, NF-kB activation, and apoptosis in HASMCs. Alda-1 attenuated AngII-induced aneurysm formation and decreased aortic expansion in ApoE KO mice. We concluded that ALDH2 deficiency is associated with the development of AAAs in humans and a murine disease model. ALDH2 deficiency increases susceptibility to AngII-induced AAA formation by attenuating anti-ROS effects and increasing VSMC apoptosis and vascular inflammation. Alda-1 was shown to attenuate the progression of experimental AAA in a murine model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201902550RRRDOI Listing
July 2020

Use of antipsychotics and the risk of acute respiratory failure among adults: A disease risk score-matched nested case-control study.

Br J Clin Pharmacol 2020 11 30;86(11):2204-2216. Epub 2020 May 30.

Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.

Aims: Evidence on acute respiratory failure (ARF) from antipsychotics is scant, and only 1 population-based study examined this drug safety issue in chronic obstructive pulmonary disease patients. Antipsychotics have been frequently prescribed off-label in adults, but whether antipsychotic use carries an increased ARF risk among adult patients is uncertain.

Methods: We adopted a nested case-control study analysing 716 493 adults aged ≥20 years, identified from the Taiwan nationwide healthcare claims records between January 2000 and December 2013. Among the study cohort, 7084 adults with ARF and 12,785 disease risk scored-matched randomly selected controls were analysed. Multivariable logistic regression models were employed to estimate odds ratios of ARF with antipsychotic usages.

Results: Current, recent, and recent past use of antipsychotics was associated with a 2.33-fold (95% confidence interval [CI] = 2.06-2.64), 1.79-fold (95% CI = 1.43-2.25) and 1.41-fold (95% CI = 1.20-1.66) increased risk of ARF, respectively, compared with nonuse, while antipsychotics discontinued >90 days carried no risk. A dose-dependent association was observed with current therapy of antipsychotics (test for trend, P < .001), in which antipsychotic use at >1 defined daily dose yielded the highest risk of 6.53-fold (95% CI = 3.33-12.79). The findings were robust to using carbamazepine as an active comparator.

Conclusion: Antipsychotic use was associated with an increased risk of ARF in adult patients. The risk was dose-dependent and markedly higher with current use of antipsychotic agents at doses of 1 defined daily dose and above, <10% of this cohort. Physicians should be vigilant about any respiratory symptoms in patients currently receiving antipsychotics at such dose.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.14321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576632PMC
November 2020

Reply to An et al.

Am J Physiol Renal Physiol 2020 02;318(2):F507-F508

Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, China.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajprenal.00016.2020DOI Listing
February 2020

Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor.

Mol Cell 2020 01 14;77(2):213-227.e5. Epub 2019 Nov 14.

Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan; Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan; Graduate Institutes of Life Sciences and Biochemistry, National Defense Medical Center, Taipei, Taiwan. Electronic address:

Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molcel.2019.10.023DOI Listing
January 2020

Antiproteinuria Effect of Calcitriol in Patients With Chronic Kidney Disease and Vitamin D Deficiency: A Randomized Controlled Study.

J Ren Nutr 2020 May 6;30(3):200-207. Epub 2019 Nov 6.

Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Electronic address:

Objective: Vitamin D has been demonstrated to lessen proteinuria severity in chronic kidney disease (CKD). Compared with healthy populations, patients with CKD may have lower serum levels of 1,25-dihydroxy vitamin D (1,25-(OH)2 D) and 25-hydroxy vitamin D (25-(OH) D). We investigated the effect of  oral low-dose active vitamin D (calcitriol at 0.25 μg, 3 times weekly) on urinary protein excretion.

Design And Methods: We conducted a nonblinded and non-placebo-controlled study. In total, 60 patients with CKD (average estimated glomerular filtration rate of >15 mL/min) who received a stable dose of angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI) were enrolled in this 24-week study. We randomly assigned these patients to the vitamin D group (oral calcitriol at 0.25 μg 3 times weekly with an ACEI or ARB) or the control group (ACEI or ARB). Change in the urine protein/creatinine ratio (uPCR) was the primary endpoint in this study.

Results: The mean baseline uPCRs of the 2 groups were comparable (1.84 ± 0.83 g/g vs. 2.02 ± 0.97 g/g, control vs. vitamin D group; P = .46). After the 24-week treatment, the uPCRs were significantly lower than the baseline values in the vitamin D group (1.35 ± 0.64 g/g; P < .05) but not in the control group. The values of uPCR decreased significantly at 8, 16, and 24 weeks (P < .05 vs. baseline) in the vitamin D group. The values of uPCRs were significantly lower in the vitamin D group than in the control group at 8, 16, and 24 weeks (P < .05). A positive correlation was discovered between reduction in uPCRs at 24-week and baseline 25-(OH) D serum level in the vitamin D group (r = 0.738, P < .001).

Conclusion: Supplementary low-dose active vitamin D could reduce proteinuria in CKD patients with low serum 25-(OH) D levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.jrn.2019.09.001DOI Listing
May 2020

Tryptophan metabolite 5-methoxytryptophan ameliorates arterial denudation-induced intimal hyperplasia via opposing effects on vascular endothelial and smooth muscle cells.

Aging (Albany NY) 2019 10 9;11(19):8604-8622. Epub 2019 Oct 9.

Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan.

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, particularly among older adults. Despite the advent of medical technology, restenosis is still an issue after interventional procedures. Tryptophan metabolite 5-methoxytryptophan (5-MTP) has recently been shown to protect against systemic inflammatory responses. This study aimed to investigate the function and mechanisms of 5-MTP in interventional procedure-induced restenosis. We found that after mouse femoral artery denudation with a guide wire, 5-MTP accelerated recovery of endothelium in the denuded area and reduced vascular leakage and intimal thickening. 5-MTP increased endothelial cell proliferation in the denuded arteries and rescued TNF-α-reduced endothelial cell proliferation and migration, likely via maintaining vascular endothelial growth factor receptor 2 activation. In contrast, 5-MTP preserved differentiated phenotype of medial vascular smooth muscle cells (VSMCs) and decreased VSMC proliferation and migration. Furthermore, 5-MTP maintained expression levels of critical transcription factors for VSMC marker gene expressions via attenuated activation of p38 MAPK and NFκB-p65. Our findings uncover a novel protective mechanism of 5-MTP in restenosis. In response to denudation injury, 5-MTP attenuates intimal hyperplasia via concerted but opposing actions on endothelial cells and VSMCs. Taken together, our results suggest that 5-MTP is a valuable therapeutic target for arterial injury-induced restenosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.102350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814618PMC
October 2019

Activities of Ca-related ion channels during the formation of kidney stones in an infection-induced urolithiasis rat model.

Am J Physiol Renal Physiol 2019 11 11;317(5):F1342-F1349. Epub 2019 Sep 11.

Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.

Bacterial infection has long been recognized to contribute to struvite urinary stone deposition; however, its contribution to the development of chronic kidney stones has not been extensively investigated. In the present study, we hypothesized another possible method of bacteria contributing to the formation of calcium oxalate (CaOx) that accounts for the biggest part of the kidney stone. Bacteria may play important roles by influencing renal Ca-related ion channel activities, resulting in chronic inflammation of the kidney along with rapid aggregation of stones. We examined the correlation among infection-promoted CaOx kidney stones and alterations in Ca-related ion channels in an animal model with experimentally induced and foreign body infection. After the bladder was infected for 7 days, the data demonstrated that stones were presented and induced severe renal tubular breakage as well as altered levels of monocyte chemoattractant protein-1, cyclooxygenase-2, osteopontin, and transient receptor potential vanilloid member 5 expression, reflecting responses of kidney ion channels. Monocyte chemoattractant protein-1, osteopontin, and transient receptor potential vanilloid member 5 expression was significantly downregulated over time, indicating the chronic inflammation phase of the kidney and accelerated aggregation of CaOx crystals, respectively, whereas cyclooxygenase-2 exhibited no differences. These results indicated that bacterial infection is considerably correlated with an alteration in renal Ca-related ion channels and might support specific and targeted Ca-related ion channel-based therapeutics for urolithiasis and related inflammatory renal damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajprenal.00199.2019DOI Listing
November 2019

Factors associated with length of hospital stay among dialysis patients with nontraumatic acute abdomen: a retrospective observational study.

Singapore Med J 2020 Nov 6;61(11):605-612. Epub 2019 Sep 6.

Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

Introduction: Nontraumatic acute abdomen (NTAA) in dialysis patients is a challenging issue. The aetiologies of NTAA vary considerably depending on the renal replacement therapy (RRT) modality. Although haematological parameters and contributing factors have been reported to be associated with outcomes for dialysis patients, their clinical effect on the length of hospital stay (LOS) remains unknown.

Methods: We retrospectively analysed 52 dialysis patients (peritoneal dialysis [PD], n = 33; haemodialysis [HD], n = 19) and 30 non-dialysis patients (as controls) between January 2011 and December 2014. To attenuate the selection bias, non-dialysis patients with NTAA were matched to cases at a ratio of 1:1 by age, gender and comorbidities (diabetes mellitus and hypertension). Their demographic characteristics, laboratory data, clinical assessment scores and LOS were analysed.

Results: The PD group exhibited a significantly higher neutrophil percentage, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR); longer LOS; and lower lymphocyte percentage and absolute lymphocyte count than the control group. After multivariate analysis adjustment, female gender, longer RRT duration and higher intact parathyroid hormone (iPTH) levels were associated with a lower probability of being discharged home. In the dialysis group, a higher iPTH level (> 313 μg/mL) was positively correlated with longer LOS. iPTH level combined with NLR can be used as a surrogate marker for predicting longer LOS (p < 0.001).

Conclusion: NTAA dialysis patients with female gender, longer RRT duration and higher iPTH levels are prone to experiencing longer LOS. In addition, the combination of iPTH and NLR is a significant determinant for LOS in NTAA dialysis patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11622/smedj.2019106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040919PMC
November 2020

Roles of the hypoximir microRNA-424/322 in acute hypoxia and hypoxia-induced pulmonary vascular leakage.

FASEB J 2019 11 28;33(11):12565-12575. Epub 2019 Aug 28.

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

Acute mountain sickness (AMS) occurs in up to 25% of unacclimatized persons who ascend to 3000 m and can result in high-altitude pulmonary edema (HAPE). MicroRNAs (miRs) can regulate gene expression at the post-transcriptional level. Hypoxia selectively disrupts endothelial tight junction complexes through a hypoxia-inducible factor-1α (HIF-1α)-dependent mechanism. Though increased HIF-1α expression is associated with adaptation and protection from AMS development in the early stage of hypoxia, a downstream effector of HIF-1α, VEGF, can induce overzealous endothelial barrier dysfunction, increase vascular permeability, and ultimately result in HAPE and high-altitude cerebral edema. We hypothesized that the fine-tuning of downstream effectors by miRs is paramount for the preservation of endothelial barrier integrity and the prevention of vascular leakage. We found that several miRs were up-regulated in healthy volunteers who were subjected to a 3100-m height. By reviewing the literature and using online bioinformatics prediction software, we specifically selected miR-424 for further investigation because it can modulate both HIF-1α and VEGF. Hypoxia-induced miR-424 overexpression is HIF-1α dependent, and miR-424 stabilized HIF-1α, decreased VEGF expression, and promoted vascular endothelial cadherin phosphorylation. In addition, hypoxia resulted in endothelial barrier dysfunction with increased permeability; miR-424 thus attenuated hypoxia-induced endothelial cell senescence and apoptosis. miR-322 knockout mice were susceptible to hypoxia-induced pulmonary vascular leakage. miR-322 mimics improved hypoxia-induced pulmonary vascular leakage . We conclude that several miRs were up-regulated in healthy adult volunteers subjected to hypobaric hypoxemia. miR-424/322 could modulate the HIF-1α-VEGF axis and prevent hypoxia-induced pulmonary vascular leakage under hypoxic conditions.-Tsai, S.-H., Huang, P.-H., Tsai, H.-Y., Hsu, Y.-J., Chen, Y.-W., Wang, J.-C., Chen, Y.-H., Lin, S.-J. Roles of the hypoximir microRNA-424/322 in acute hypoxia and hypoxia-induced pulmonary vascular leakage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201900564RRDOI Listing
November 2019

Investigation of the variants at the binding site of inflammatory transcription factor NF-κB in patients with end-stage renal disease.

BMC Nephrol 2019 08 5;20(1):300. Epub 2019 Aug 5.

School of Public Health and Graduate institute of Life Sciences, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei City, 114, Taiwan, Republic of China.

Background: A chronic inflammatory state is a prominent feature in patients with end-stage renal disease (ESRD). Nuclear factor-kappa B (NF-κB) is a transcription factor that regulates the expression of genes involved in inflammation. Some genetic studies have demonstrated that the NF-κB genetic mutation could cause kidney injury and kidney disease progression. However, the association of a gene polymorphism in the transcription factor binding site of NF-κB with kidney disease is not clear.

Methods: We used the Taiwan Biobank database, the University of California, Santa Cruz, reference genome, and a chromatin immunoprecipitation sequencing database to find single nucleotide polymorphisms (SNPs) at potential binding sites of NF-κB. In addition, we performed a case-control study and genotyped 847 patients with ESRD and 846 healthy controls at Tri-Service General Hospital from 2015 to 2016. Furthermore, we used the ChIP assay to identify the binding activity of different genotypes and used Luciferase reporter assay to examine the function of the rs9395890 polymorphism.

Result: The results of biometric screening in the databases revealed 15 SNPs with the potential binding site of NF-κB. Genotype distributions of rs9395890 were significantly different in ESRD cases and healthy controls (P = 0.049). The ChIP assay revealed an approximately 1.49-fold enrichment of NF-κB of the variant type TT when compared to that of the wild-type GG in rs9395890 (P = 0.027; TT = 3.20 ± 0.16, GT = 2.81 ± 0.20, GG = 1.71 ± 0.18). The luciferase reporter assay showed that the NF-κB binding site activity in T allele was slightly higher than that in G allele, though it is not significant.

Conclusions: Our findings indicate that rs9395890 is associated with susceptibility to ESRD in Taiwan population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-019-1471-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683452PMC
August 2019

Compound K inhibits priming and mitochondria-associated activating signals of NLRP3 inflammasome in renal tubulointerstitial lesions.

Nephrol Dial Transplant 2020 01;35(1):74-85

Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

Background: Renal tubulointerstitial lesions (TILs), a key pathological hallmark for chronic kidney disease to progress to end-stage renal disease, feature renal tubular atrophy, interstitial mononuclear leukocyte infiltration and fibrosis in the kidney. Our study tested the renoprotective and therapeutic effects of compound K (CK), as described in our US patent (US7932057B2), on renal TILs using a mouse unilateral ureteral obstruction (UUO) model.

Methods: Renal pathology was performed and renal draining lymph nodes were subjected to flow cytometry analysis. Mechanism-based experiments included the analysis of mitochondrial dysfunction, a model of tubular epithelial cells (TECs) under mechanically induced constant pressure (MICP) and tandem mass tags (TMT)-based proteomics analysis.

Results: Administration of CK ameliorated renal TILs by reducing urine levels of proinflammatory cytokines, and preventing mononuclear leukocyte infiltration and fibrosis in the kidney. The beneficial effects clearly correlated with its inhibition of: (i) NF-κB-associated priming and the mitochondria-associated activating signals of the NLRP3 inflammasome; (ii) STAT3 signalling, which in part prevents NLRP3 inflammasome activation; and (iii) the TGF-β-dependent Smad2/Smad3 fibrotic pathway, in renal tissues, renal TECs under MICP and/or activated macrophages, the latter as a major inflammatory player contributing to renal TILs. Meanwhile, TMT-based proteomics analysis revealed downregulated renal NLRP3 inflammasome activation-associated signalling pathways in CK-treated UUO mice.

Conclusions: The present study, for the first time, presents the potent renoprotective and therapeutic effects of CK on renal TILs by targeting the NLRP3 inflammasome and STAT3 signalling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfz073DOI Listing
January 2020

TLR2 Promotes Vascular Smooth Muscle Cell Chondrogenic Differentiation and Consequent Calcification via the Concerted Actions of Osteoprotegerin Suppression and IL-6-Mediated RANKL Induction.

Arterioscler Thromb Vasc Biol 2019 03;39(3):432-445

From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Maioli, Taiwan (G.-L.L., C.-C.Y., J.-Y.W., H.-C.L., Y.-F.W., Y.-Y.K., Y.-T.H., C.-C.K.).

Objective- Vascular smooth muscle cell (VSMC) transformation to an osteochondrogenic phenotype is an initial step toward arterial calcification, which is highly correlated with cardiovascular disease-related morbidity and mortality. TLR2 (Toll-like receptor 2) plays a pathogenic role in the development of vascular diseases, but its regulation in calcification of arteries and VSMCs remains unclear. We postulate that TLR2-mediated inflammation participates in mediating atherosclerotic arterial calcification and VSMC calcification. Approach and Results- We found that ApoE Tlr2 genotype in mice suppressed high-fat diet-induced atherosclerotic plaques formation during initiation but progressively lost its preventative capacity, compared with ApoE mice. However, TLR2 deficiency prohibited high-fat diet-induced advanced atherosclerotic calcification, chondrogenic metaplasia, and OPG (osteoprotegerin) downregulation in the calcified lesions. Incubation of VSMCs in a calcifying medium revealed that TLR2 agonists significantly increased VSMC calcification and chondrogenic differentiation. Furthermore, TLR2 deficiency suppressed TLR2 agonist-mediated VSMC chondrogenic differentiation and consequent calcification, which were triggered via the concerted actions of IL (interleukin)-6-mediated RANKL (receptor activator of nuclear factor κB ligand) induction and OPG suppression. Inhibition experiments with pharmacological inhibitors demonstrated that IL-6-mediated RANKL induction is signaled by p38 and ERK1/2 (extracellular signal-regulated kinase 1/2) pathways, whereas the OPG is suppressed via NF-κB (nuclear factor κB) dependent signaling mediated by ERK1/2. Conclusions- We concluded that on ligand binding, TLR2 activates p38 and ERK1/2 signaling to selectively modulate the upregulation of IL-6-mediated RANKL and downregulation of OPG. These signaling pathways act in concert to induce chondrogenic transdifferentiation of VSMCs, which in turn leads to vascular calcification during the pathogenesis of atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.118.311874DOI Listing
March 2019

Proteinuria: Associated with poor outcome in patients with small cell lung cancer.

J Cancer Res Ther 2018 Sep;14(Supplement):S688-S693

Division of Nephrology, Department of Medicine, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan.

Objective: Although proteinuria has been increasingly reported in lung cancers, especially small cell lung cancer (SCLC), its clinical impact in patients with SCLC remains unknown.

Materials And Methods: We analyzed patients with newly-diagnosed SCLC confirmed by clinical, radiological, and pathological features over a 7-year period. Pretreatment proteinuria was assessed by quantitative analysis of 24-h urine before receiving chemotherapy. The demographic, laboratory characteristics and its impact on survival outcome were evaluated.

Results: There were 140 SCLC patients with the mean age of 70.2 years, extensive stage (89.3%), and male predominance (81.4%). Significant proteinuria (>300 mg/day) occurred in 17.4% (24/140) patients. Patients with proteinuria had significant higher serum blood urea nitrogen, lower total calcium, total protein, albumin levels, and lower creatinine clearance (Ccr) (24-h Ccr). Daily protein excretion was negatively correlated with serum total protein, albumin, and Ccr. Using a multivariable Cox proportional hazard model, proteinuria (hazard ratio, 1.943, 95% confidence interval 1.148-3.259, P = 0.010), along with poor performance status and serum albumin, were independent risk factors of all-cause mortality. Proteinuria was also associated with poor survival status (6.08 vs. 11.88 months, P < 0.001), especially in those who had severe proteinuria (>2 g/day).

Conclusions: Proteinuria is not uncommon and associated with all-cause mortality in patients with SCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/0973-1482.191037DOI Listing
September 2018

Risk of Severe Cardiovascular Events From Add-On Tiotropium in Chronic Obstructive Pulmonary Disease.

Mayo Clin Proc 2018 10 10;93(10):1462-1473. Epub 2018 Aug 10.

School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China. Electronic address:

Objective: To examine the risk of cardiovascular disease (CVD) from tiotropium added to inhaled long-acting β agonists (LABAs) and inhaled corticosteroids (ICSs) in a nationwide population with chronic obstructive pulmonary disease (COPD).

Patients And Methods: This nested case-control study included 65,966 patients with COPD treated with LABAs and ICSs identified from the Taiwan nationwide health care claims database from January 1, 2007, through June 30, 2011. Cases were all patients with a first primary diagnosis of ischemic heart disease, heart failure, stroke, or arrhythmia from inpatient or emergency care settings during follow-up, and each was matched with 4 disease risk score-matched controls from risk sets. The use of tiotropium in the year before the index/event date was measured, stratified by duration since therapy initiation, concomitant COPD medications, and dosage form. Conditional logistic regression models were used to estimate odds ratios of the CVD risk from add-on tiotropium therapy.

Results: From the study cohort, with a mean age of 70.3 years (interquartile range, 61.8-79.4 years), 3188 CVD cases (incidence rate, 6.2 [95% CI, 6.0-6.4] cases per 100 person-years) and 12,349 matched controls were identified. The new use of tiotropium was associated with a 1.88-fold (95% CI, 1.44-2.46) increased CVD risk within 30 days of therapy initiation, and the association was sustained up to 60 days after treatment initiation (adjusted odds ratio, 1.71; 95% CI, 1.08-2.70). The risk persisted across all tiotropium regimens, with a case-crossover analysis, and in comparison with new add-on theophylline therapy.

Conclusion: Tiotropium newly added to LABA/ICS combination therapy was associated with an increased cardiovascular risk in patients with COPD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mayocp.2018.05.030DOI Listing
October 2018

MicroRNA-132 targeting PTEN contributes to cilostazol-promoted vascular smooth muscle cell differentiation.

Atherosclerosis 2018 07 26;274:1-7. Epub 2018 Apr 26.

Division of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan, Taiwan.

Background And Aims: Cilostazol, beyond its antiplatelet effect, is also capable of promoting vascular smooth muscle cell (VSMC) differentiation. The aim of this study was to explore the potential role of PTEN, known to associate with VSMC differentiation, and its related microRNA (miRNA) in cilostazol-dependent effects.

Methods And Results: Microarray analysis in balloon-injured rat carotid arteries comparing with and without balloon injury revealed that miR-132 was differentially expressed. Bioinformatic analysis predicts PTEN as a novel target of miR-132. Western blot and quantitative real-time reverse transcription-polymerase chain reaction along with in situ hybridization documented that cilostazol treatment enhanced PTEN and reduced miR-132 expression in the neointima of balloon-injured arteries. Treatment of cultured rat VSMCs with cilostazol resulted in the up-regulation of PTEN mRNA and the down-regulation of miR-132, supporting an in vitro relevance. Co-transfection experiments showed that transfection of miR-132 mimic into VSMCs suppressed PTEN 3'UTR activities, further reflecting that PTEN is the direct target of miR-132. Over-expression of miR-132 in VSMCs led to an attenuation of cilostazol-induced PTEN and its downstream VSMC differentiation marker (calponin) expression, confirming the critical role of miR-132 in VSMC differentiation. Transient transfection studies demonstrated that cilostazol reduced the activity of miR-132 promoter, which was mediated via cyclic AMP response element-binding protein. Notably, the use of lentivirus to over-express miR-132 in the neointima of balloon-injured arteries could reverse the effect of cilostazol in vivo.

Conclusions: These results suggest that miR-132 by targeting PTEN may be an important regulator in mediating cilostazol actions on VSMC differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2018.04.030DOI Listing
July 2018

Association between angiotensin II receptor type 1 A1166C polymorphism and chronic kidney disease.

Oncotarget 2018 Mar 12;9(18):14444-14455. Epub 2018 Feb 12.

School of Public Health, National Defense Medical Center, Taiwan, ROC.

Studies of the association between angiotensin II receptor type 1 A1166C (AGTR1 A1166C) polymorphism and chronic kidney disease (CKD) risk have yielded conflicting results. We conducted a combined case-control study and meta-analysis to better define this association. The case-control study included 634 end-stage renal disease (ESRD) patients and 739 healthy controls. AGTR1 A1166C genotype was determined using polymerase chain reaction and iPLEX Gold SNP genotyping methods. The meta-analysis included 24 studies found in the PubMed and Cochrane Library databases. Together, the case-control study and meta-analysis included 36 populations (7,918 cases and 6,905 controls). We found no association between the C allele and ESRD (case-control study: OR: 1.02, 95% CI: 0.77-1.37; meta-analysis: OR: 1.07; 95% CI: 0.97-1.18). Co-dominant, dominant, and recessive model results were also not significant. No known environmental factors moderated the effect of AGTR1 A1166C on CKD in our gene-environment interaction analysis. Sensitivity analysis showed an AGTR1 A1166C-CKD association in Indian populations (OR: 1.46, 95% CI: 1.26-1.69), but not in East Asian or Caucasian populations. Additional South Asian studies will be required to confirm the potential role of this polymorphism in CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.24469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865681PMC
March 2018

The regulation of NLRP3 inflammasome expression during the development of cardiac contractile dysfunction in chronic kidney disease.

Oncotarget 2017 Dec 6;8(69):113303-113317. Epub 2017 Dec 6.

Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Chronic inflammation plays a crucial role in the long-term complications in patients with chronic kidney disease (CKD). This study aimed to assess the role of NLR pyrin domain-containing protein (NLRP3) inflammasome in cardiac contractile dysfunctions in CKD. The cardiac contractile function was evaluated and the expression of NLRP3 inflammasome and related cytokines in the heart was assessed in a murine sham-operated and 5/6 nephrectomy CKD model . , H9c2 cells were treated with uremic toxin indoxyl sulfate (IS), with or without NLRP3 inflammasome inhibition, which was achieved by using small interfering RNA (siRNA)-mediated knockdown of the gene. Moreover, the activation of nuclear factor κB (NF-κB) signaling and apoptosis marker levels were assessed in the IS-treated H9c2 cells. The results demonstrated that CKD can lead to the development of cardiac contractile dysfunction associated with the upregulation of NLRP3 inflammasome, IL-1β, IL-18, and contribute to the myocardial apoptosis. experiments showed the upregulation of inflammasome, IL-1β, and IL-18 levels, and cell apoptosis in the IS-treated H9c2 cells through the activation of NF-κB signaling pathway. The transfection of cells with si-NLRP3 was shown to alleviate IL-1β, IL-18, and cell apoptosis. Moreover, decreased cell viability induced by IS was shown to be attenuated by IL-1β or IL-18-neutralizing antibody. In summary, CKD can result in the development of cardiac contractile dysfunction associated with the upregulation of NLRP3 inflammasome/IL-1β/IL-18 axis induced by the uremic toxins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.22964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768329PMC
December 2017
-->