Publications by authors named "Chin-San Liu"

119 Publications

Comparison of mitochondrial transplantation by using a stamp-type multineedle injector and platelet-rich plasma therapy for hair aging in naturally aging mice.

Biomed Pharmacother 2020 Oct 21;130:110520. Epub 2020 Jul 21.

Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Anhui, Hefei 230032, China; Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, Anhui, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei 230032, China. Electronic address:

The mechanism of hair loss caused by aging is related to mitochondrial dysfunction. Pep-1-mediated mitochondrial transplantation is a potential therapeutic application for mitochondrial disorders, but its efficacy against hair aging remains unknown. This study compared platelet-rich plasma (PRP) therapy with mitochondrial transplantation for hair restoration and examined the related regulation in naturally aging mice. After dorsal hair removal, 100-week-old mice received weekly unilateral injections of 200 μg of allogeneic mitochondria-labeled 5-bromo-2'-deoxyuridine with (P-Mito) or without Pep-1 conjugation (Mito) or human PRP with a stamp-type electric injector for 1 month. The contralateral sides were used as corresponding sham controls. Compared with the control and corresponding sham groups, all treatments stimulated hair regrowth, and the effectiveness of P-Mito was equal to that of PRP. However, histology revealed that only P-Mito maintained hair length until day 28 and yielded more anagen follicles with abundant dermal collagen equivalent to that of the PRP group. Mitochondrial transplantation increased the thickness of subcutaneous fat compared with the control and PRP groups, and only P-Mito consistently increased mitochondria in the subcutaneous muscle and mitochondrial DNA copies in the skin layer. Therefore, P-Mito had a higher penetrating capacity than Mito did. Moreover, P-Mito treatment was as effective as PRP treatment in comprehensively reducing the expression of aging-associated gene markers, such as IGF1R and MRPS5, and increasing antiaging Klotho gene expression. This study validated the efficacy of mitochondrial therapy in the restoration of aging-related hair loss and demonstrated the distinct effects of PRP treatment.
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http://dx.doi.org/10.1016/j.biopha.2020.110520DOI Listing
October 2020

Antitumor Actions of Intratumoral Delivery of Membrane-Fused Mitochondria in a Mouse Model of Triple-Negative Breast Cancers.

Onco Targets Ther 2020 9;13:5241-5255. Epub 2020 Jun 9.

Vascular and Genomic Center, Changhua Christian Hospital, Changhua 50094, Taiwan.

Background: The transfer of whole mitochondria has been demonstrated to be beneficial for treating breast cancer because it induces apoptosis and drug sensitivity; however, in vivo evidence of this benefit remains scant. The present study compared the transplantation of mitochondria with instinctive (Mito) and membrane-fused morphologies induced by Pep-1 conjugation (P-Mito) using a mouse model of triple-negative breast cancers.

Materials And Methods: Mice with advanced severe immunodeficiency received orthotopic implantation of MDA-MB-231 human breast cancer cells followed by transplants of 5-bromo-2'-deoxyuridine (BrdU)-labeled Mito or P-Mito (200 μg [10 μg/μL]) through intratumoral injection at multiple points once a week for 4 weeks.

Results: After 1 month of consecutive treatment, 8.2% and 14.2% of the BrdU-labeled mitochondria were preserved in tumors of the Mito and P-Mito groups, respectively. Both Pep-1 and P-Mito treatments reduced tumor weight (21.7% ± 2.43% vs 40.6% ± 2.28%) and led to marked inhibition of Ki67 staining and angiogenesis. However, only the P-Mito group exhibited obvious necrosis and DNA fragmentation accompanied by an altered tumor microenvironment, which included reduced oxidative stress and size of cancer-associated fibroblast populations and enhanced immune cell infiltration. Transmission electron microscopy images further revealed an elongated network of perinuclear mitochondria fused with a few peripheral mitochondria in the nonnecrotic area in the P-Mito group as well as increases in mitochondrial fusion proteins and parkin compared with mitochondrial fission proteins.

Conclusion: In this study, the results of mitochondrial transplantation emphasized that the facilitation of mitochondrial fusion is a critical regulator in breast cancer therapy.
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http://dx.doi.org/10.2147/OTT.S238143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294573PMC
June 2020

Radical Scavenging and Antiproliferative Effects of Cordycepin-Rich Ethanol Extract from Brown Rice-Cultivated Cordyceps militaris (Ascomycetes) Mycelium on Breast Cancer Cell Lines.

Int J Med Mushrooms 2019 ;21(7):657-669

Department of Bioresources, Da-Yeh University, Changhua County 515, Taiwan.

The yield and efficacy of bioactive compounds from Cordyceps militaris fruiting bodies and its fermented grains usually vary with the strain used. In this study, we compared the antiproliferative, apoptotic, and antioxidative properties of ethanolic extracts of fruiting bodies and solid-stated fermented rice (FRE) from two wild-type strains of C. militaris applied to human breast cancer cell lines. We observed that FRE of the Zhangzhou strain (FRE-Z) produced a high level of cordycepin and exhibited comprehensive in vitro antioxidant activity against the oxidation of 2,2-diphenyl-1-picrylhydrazyl, superoxide, and hydroxyl radicals and low-density lipoprotein. Only FRE-Z exhibited dose-dependent inhibition of cell proliferation in MCF-7 (0.7 mg/mL) and MDA-MB-231 cells (1 mg/mL) after culturing for 24 h. The antiproliferative effects of FRE-Z were associated with an early stage of apoptosis induction at 4 h of treatment with 0.5 mg/mL FRE-Z in MCF-7 cells. The antiproliferative effect was determined to occur through p53 activation but not through the release of mitochondrial apoptosis-inducing factor or caspase-9 activation for an initial culture period of 16 h. In addition to a transient increase in cellular antioxidant enzyme, Cu/Zn superoxide dismutase was identified in MCF-7 cells after 2 h of treatment with FRE-Z. Therefore, FRE-Z, which exhibits various dose- and exposure time-dependent activities, has potential application in breast cancer chemoprevention.
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http://dx.doi.org/10.1615/IntJMedMushrooms.2019031138DOI Listing
February 2020

Association of cyclophilin A level and pulse pressure in predicting recurrence of cerebral infarction.

Kaohsiung J Med Sci 2020 Feb 31;36(2):122-128. Epub 2019 Oct 31.

Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan.

Cyclophilin A (CypA), secreted from vascular smooth muscle cells and inflammatory cells in response to oxidative stress, promotes vascular atherosclerosis and development of carotid stenosis. Increased concentration of plasma CypA in acute cerebral infarction was demonstrated clinically. The primary aim of this study was to investigate the prognostic impact between CypA level and outcome in patients with acute ischemic stroke. Admission serum CypA concentrations were detected in 66 acute cerebral infarction patients and in 52 healthy individuals. Inflammatory biomarkers, including high-sensitivity C-reactive protein, adhesion molecules, interleukins, and matrix-metalloproteases, were also assessed. We also examined the relationship between plasma biomarkers, blood pressure (BP), pulse pressure, the carotid artery velocity, the prognostic assessment with modified Rankin scale, and stroke recurrence. Plasma CypA concentration was higher on the first day of hospitalization in the high BP stroke group than in normal BP stroke group, which was statistically significant, which was observed even in the third month and sixth month follow-up outpatient periods. For stroke recurrence prediction, there was an important association between the higher (>60) pulse pressure on the seventh day of hospitalization and CypA level on the third month and sixth month follow-up outpatient periods. Our study revealed higher circulating serum levels of CypA in the hypertensive stroke group than in the non-hypertensive stroke group. We expect that elevated plasma CypA level and raised pulse pressure during hospitalization to become valuable biomarkers in predicting stroke recurrence in the sixth month assessment of acute cerebral infarction.
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http://dx.doi.org/10.1002/kjm2.12143DOI Listing
February 2020

Urinary cell-free mitochondrial and nuclear deoxyribonucleic acid correlates with the prognosis of chronic kidney diseases.

BMC Nephrol 2019 10 28;20(1):391. Epub 2019 Oct 28.

Vascular & Genomic Research Center, Changhua Christian Hospital, Changhua, Taiwan.

Introduction: Cell-free deoxyribonucleic acid DNA (cf-DNA) in urine is promising due to the advantage of urine as an easily obtained and non-invasive sample source over tissue and blood. In clinical practice, it is important to identify non-invasive biomarkers of chronic kidney disease (CKD) in monitoring and surveillance of disease progression. Information is limited, however, regarding the relationship between urine and plasma cf-DNA and the renal outcome in CKD patients.

Methods: One hundred and thirty-one CKD patients were enrolled between January 2016 and September 2018. Baseline urine and plasma cell-free mitochondrial DNA (cf-mtDNA) and cell-free nuclear DNA (cf-nDNA) were isolated using quantitative real-time PCR. Estimated glomerular filtration rate (eGFR) measurement was performed at baseline and 6-month follow-up. Favorable renal outcome was defined as eGFR at 6 months minus baseline eGFR> = 0. Receiver operator characteristics (ROC) curve analysis was performed to assess different samples of cf-DNA to predict favorable renal outcomes at 6 months. A multivariate linear regression model was used to evaluate independent associations between possible predictors and different samples of cf-DNA.

Results: Patients with an advanced stage of CKD has significantly low plasma cf-nDNA and high plasma neutrophil gelatinase-associated lipocalin (NGAL) levels. Low urine cf-mtDNA, cf-nDNA levels and low plasma NGAL were significantly correlated with favorable renal outcomes at 6 months. The urine albumin-creatinine ratio (ACR) or urine protein-creatinine ratio (PCR) level is a robust predictor of cf-mtDNA and cf-nDNA in CKD patients. Baseline urine levels of cf-mtDNA and cf-nDNA could predict renal outcomes at 6 months.

Conclusions: Urinary cf-mtDNA and cf-nDNA may provide novel prognostic biomarkers for renal outcome in CKD patients. The levels of plasma cf-nDNA and plasma NGAL are significantly correlated with the severity of CKD.
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http://dx.doi.org/10.1186/s12882-019-1549-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816217PMC
October 2019

Green extraction of healthy and additive free mitochondria with a conventional centrifuge.

Lab Chip 2019 11 18;19(22):3862-3869. Epub 2019 Oct 18.

Graduate Institute of Biomedical Engineering, National Chung-Hsing University, Taichung, Taiwan. and Program in Tissue Engineering and Regenerative Medicine, National Chung-Hsing University, Taichung, Taiwan and Department of Mechanical Engineering, National Chung-Hsing University, Taichung, Taiwan.

In this research, we propose a novel centrifugal device for the massive extraction of healthy mitochondria with a centrifuge used in general laboratories within 30 minutes. The device mainly consists of two key components. One component is a microfluidic device, which is fabricated by photolithography, nickel electroforming, and polydimethylsiloxane casting, for the efficient disruption of the cell membrane. The other component is a stainless steel container, which is manufactured by computer numerical control machining, for the storage of the cell suspension. After assembly, the appropriate number of cells is pushed through the microfluidic device for cell membrane disruption by centrifugal force generated by a general laboratory centrifuge. The solution which contains cell debris and mitochondria are collected to purify the crude mitochondria via differential centrifugation. Compared with the quantity and efficiency of mitochondria isolated from the same number of cells using a conventional kit, device-extracted mitochondria show a more complete mitochondrial electron transport chain complex and a similar number of mitochondria verified by Western blot analysis of mitochondrial complexes I-V and mitochondrial outer membrane protein Tom20, respectively, as well as a normal mitochondrial structure revealed by transmission electron microscopy. Moreover, the mitochondrial membrane potential of device-extracted mitochondria stained with tetramethylrhodamine ethyl ester is higher than that of kit-extracted mitochondria. Furthermore, the coculture of device-extracted mitochondria with fibroblasts revealed that fibroblasts could uptake foreign mitochondria through endocytosis without drug treatment. These results show that the proposed microfluidic device preserves mitochondrial protein structure, membrane integrity, and membrane potential within 30 minutes of extraction and is a useful tool for therapeutic mitochondrial transplantation and regenerative medicine.
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http://dx.doi.org/10.1039/c9lc00633hDOI Listing
November 2019

Organic small molecule for detection and photodegradation of mitochondrial DNA mutations.

J Mater Chem B 2019 10;7(39):5947-5955

Department of Mechanical Engineering, National Chung-Hsing University, Taichung, Taiwan.

A detection and degradation platform was developed to optically quantify the 6-enolate, 8-keto-dG, an important tautomer of mitochondrial mutated DNA 8-oxo-dG. We first found that 6-enolate, 8-keto-dG offers particular fluorescence emission under the conditions between pH ∼ 7 and ∼11. Thus, a mitochondria-targeting photosensitizer NV-12P was prepared to offer simultaneously photoinduced electron transfer and fluorescence resonance energy transfer (FRET) with 6-enolate, 8-keto-dG. Furthermore, NV-12P can also generate a reactive oxygen species to degrade 6-enolate, 8-keto-dG under irradiation conditions. This is the first publication about optical characterization, concentration detection and photodegradation of 6-enolate, 8-keto-dG, either in biological or in vitro applications.
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http://dx.doi.org/10.1039/c9tb01358jDOI Listing
October 2019

Changes in the PGC-1α and mtDNA copy number may play a role in the development of pelvic organ prolapse in pre-menopausal patients.

Taiwan J Obstet Gynecol 2019 Jul;58(4):526-530

Department of Urology, Winnipeg Regional Health Authority, Canada.

Objective: The alternations of mtDNA may play an important role in the molecular pathogenesis and process of Pelvic Organ Prolapse (POP) formation in both pre-menopausal and post-menopausal women. The aim of the present study is to analyze the association between the mitochondrial biogenesis gene and development of POP in the uterosacral ligaments (UL) of pre-menopausal women.

Materials And Methods: Seventy one pre-menopausal women, all below 52 years of age, were enrolled in this study. UL biopsies were obtained from uterine specimens taken from 33 women with POP (n = 33, study group) and 38 myoma patients without POP (n = 38, control group). Quantitative Real-Time PCR was performed to measure mitochondrial DNA (mtDNA) copy number and mtDNA. Western blotting and immunohistochemistry were used to assess the protein expression of PGC-1α, TFAM, NRF-1 and NRF-2. Statistical analysis was performed using SPSS statistical software and the Mann-Whitney U test, and the continuous variables were analyzed using the Student's t-test in demographic data.

Results: There were no significant differences in the patient demographics between the two groups (p > 0.05). The mtDNA copy number in the UL of pre-menopausal patients with prolapse was significantly higher than that in the no prolapse group (p = 0.008). There were no significant differences between the mtDNA of the POP and non-POP groups, but a significantly higher expression of PGC-1α in the POP group compared to the non-POP group (1.59 ± 1.30 v.s. 0.66 ± 0.53; p = 0.036). The expression of TFAM in the POP group was higher than in the non-POP group). There was no significant difference in the TFAM(p = 0.377), NRF-1 and NRF-2 expression between the POP and non-POP groups (p = 0.647; p = 0.682).

Conclusions: Changes in the PGC-1α and mtDNA copy number may play a role in the development of Pelvic Organ Prolapse in pre-menopausal patients.
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http://dx.doi.org/10.1016/j.tjog.2019.05.017DOI Listing
July 2019

Treadmill training increases the motor activity and neuron survival of the cerebellum in a mouse model of spinocerebellar ataxia type 1.

Kaohsiung J Med Sci 2019 Nov 4;35(11):679-685. Epub 2019 Jul 4.

Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan.

Spinocerebellar ataxia (SCA) type 1 (SCA1) is a rare autosomal dominant disorder that is characterized by worsening of disordered coordination, ataxia of the trunk, and other neurological symptoms. Physical activity improves both mobility and the daily living activities of patients with SCA. Intervention with daily regular treadmill exercise may slow the deterioration of cerebellar neurons in SCA1. Therefore, the signal changes and performance of cerebellar neurons after exercise in SCA1 was investigated in this study. We employed a transgenic mouse model of SCA1, generated by amplifying the cytosine-adenine-guanine trinucleotide repeat expansions, and the mice underwent 1 month of moderate daily treadmill exercise for 1 hour. The rotarod test revealed that the motor function of the SCA1 mice that underwent training was superior to that of the control SCA1 mice, which did not undergo training. Moreover, the cerebellar pathology revealed preserved Purkinje neurons stained by carbindin with an increase of the neuronal Per Arnt Sim domain protein 4, a key regulation in the structural and functional plasticity of neurons, in the excised SCA1 mice relative to the controls. The mechanism was related to an increase of phosphorylation of ribosomal protein S6, a downstream target of the mammalian target of rapamycin pathway, but not to autophagy activation. This study determined that regular treadmill exercise may play a crucial role in the viable support of cerebellar neurons in SCA1.
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http://dx.doi.org/10.1002/kjm2.12106DOI Listing
November 2019

Protective roles of carbonic anhydrase 8 in Machado-Joseph Disease.

J Neurosci Res 2019 10 3;97(10):1278-1297. Epub 2019 Jun 3.

Department of Life Science, Tunghai University, Taichung, Taiwan, Republic of China.

Machado-Joseph disease (MJD)/Spinocerebellar ataxia type 3 (SCA3) is an inherited neurodegenerative disease that can lead to a regression of motor coordination and muscle control in the extremities. It is known that expansion of CAG repeats encodes abnormally long polyQ in mutant ataxin-3, the disease protein. It is also noted that mutant ataxin-3 interacts with 1,4,5-trisphosphate receptor type 1 (IP3R1) and induces abnormal Ca release. Previously, we have shown a significant increase in the expression of carbonic anhydrase VIII (CA8) in SK-N-SH-MJD78 cells, which are human neuroblastoma cells overexpressing mutant ataxin-3 with 78 glutamine repeats. In the current study, we showed the presence of significantly increased CA8 expression in MJD mouse cerebellum in either early or late disease stage, with a gradual decrease in CA8 expression as the MJD mice naturally aged. By immunofluorescence and immunoprecipitation analysis, we also found that CA8 co-localized and interacted with mutant ataxin-3 in SK-N-SH-MJD78 cells harboring overexpressed CA8 (SK-MJD78-CA8). In addition, we found that SK-MJD78-CA8 cells, as well as cerebellar granule neurons (CGNs) of MJD transgenic (Tg) mouse with overexpressed CA8, were more resistant to reactive oxygen species (ROS) stress than the control cells. Importantly, overexpression of CA8 in SK-MJD78-CA8 cells and in MJD CGNs rescued abnormal Ca release and caused an increase in cell survival. In summary, we demonstrate the protective function of CA8 in MJD disease models and speculate that the declining expression of CA8 following an initial increased expression may be related to the late onset phenomenon of MJD.
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http://dx.doi.org/10.1002/jnr.24474DOI Listing
October 2019

Mitochondrial transplantation regulates antitumour activity, chemoresistance and mitochondrial dynamics in breast cancer.

J Exp Clin Cancer Res 2019 Jan 23;38(1):30. Epub 2019 Jan 23.

Vascular and Genomic Center, Changhua Christian Hospital, Changhua, 50094, Taiwan.

Background: The transfer of whole mitochondria that occurs during cell contact has been found to support cancer progression. However, the regulatory role of mitochondria alone is difficult to elucidate due to the complex microenvironment. Currently, mitochondrial transplantation is an available approach for restoring mitochondrial function in mitochondrial diseases but remains unclear in breast cancer. Herein, effects of mitochondrial transplantation via different approaches in breast cancer were investigated.

Methods: Whole mitochondria (approximately 10.5 μg/ml) were transported into MCF-7 breast cancer cells via passive uptake or Pep-1-mediated delivery. Fresh mitochondria isolated from homeoplasmic 143B osteosarcoma cybrids containing mitochondrial DNA (mtDNA) derived from health individuals (Mito) or mtDNA with the A8344G mutation (Mito) were conjugated with cell-penetrating peptide Pep-1 (P-Mito) or not conjugated prior to cell co-culture. Before isolation, mitochondria were stained with MitoTracker dye as the tracking label. After 3 days of treatment, cell viability, proliferation, oxidative stress, drug sensitivity to Doxorubicin/Paclitaxel and mitochondrial function were assessed.

Results: Compared with P-Mito, a small portion of Mito adhered to the cell membrane, and this was accompanied by a slightly lower fluorescent signal by foreign mitochondria in MCF-7 cells. Both transplantations induced cell apoptosis by increasing the nuclear translocation of apoptosis-inducing factor; inhibited cell growth and decreased oxidative stress in MCF-7 cells; and increased the cellular susceptibility of both the MCF-7 and MDA-MB-231 cell lines to Doxorubicin and Paclitaxel. Mitochondrial transplantation also consistently decreased Drp-1, which resulted in an enhancement of the tubular mitochondrial network, but a distinct machinery through the increase of parkin and mitochondrial fusion proteins was observed in the Mito and P-Mito groups, respectively. Furthermore, although there were no differences in energy metabolism after transplantation of normal mitochondria, metabolism was switched to the energetic and glycolytic phenotypes when the mitochondria were replaced with dysfunctional mitochondria, namely, Mito and P-Mito, due to dramatically induced glycolysis and reduced mitochondrial respiration, respectively. Consequently, transplant-induced growth inhibition was abolished, and cell growth in the Mito group was even higher than that in the control group.

Conclusion: This study reveals the antitumour potential of mitochondrial transplantation in breast cancer via distinct regulation of mitochondrial function.
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http://dx.doi.org/10.1186/s13046-019-1028-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343292PMC
January 2019

Cyclophilin A and CD147 associate with progression of diabetic nephropathy.

Free Radic Res 2018 Dec 20;52(11-12):1456-1463. Epub 2018 Dec 20.

a School of Medicine , Chung Shan Medical University , Taichung , Taiwan.

To find the associations of circulating cyclophilin A (CyP A) and CD147/EMMPRIN with renal outcomes in type 2 diabetes patients and possible pathogenesis involved. Total 131 patients were recruited since 2004. Glycated hemoglobin, blood glucose and urine albumin-creatinine ratio levels at baseline and every 3 months were measured. Plasma CyP A and CD147 were also measured at baseline. Patients were divided into two groups based upon the median level of the baseline plasma CyP A value: < 93.64 ng/mL (group A, n = 65), ≥ 93.64 ng/mL (group B, n = 66). The estimated glomerular filtration rate was calculated at each follow-up visit. Besides, mitochondrial function assay by cellular mitochondrial energy utility was studied when cells were exposed to glucose or exogenous CyP A or both. Multivariate analysis, using median level (93.64) ng/mL as the cut-off value, revealed that circulating CyP A and CD147 levels at baseline were associated with the baseline estimated glomerular filtration rate (eGFR) (p = .042 and p = .001 separately) in cross-sectional analysis. Longitudinally, higher baseline plasma CyP A level was also correlated to a rapid decline in eGFR (p = .016). The results were also significant when using the continuous plasma CyP A level (p = .003). In cells exposed to glucose, results of oxygen consumption rate (OCR) showed a significant reduction in basal respiration, maximal respiration and ATP production. Depressed OCR further occurred when incubated with both of CyP A and glucose. Plasma CyP A and CD147 can serve as indicators of renal disease progression in type 2 diabetes patients.
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http://dx.doi.org/10.1080/10715762.2018.1523545DOI Listing
December 2018

Dysphagia with fatal choking in oculopharyngeal muscular dystrophy: Case report.

Medicine (Baltimore) 2018 Oct;97(43):e12935

Department of Neurology.

Rationale: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset progressive muscle disorder typically characterized by ptosis, difficulty in swallowing, and proximal limb weakness. Underdiagnosis of OPMD is common in Asian countries and results in delayed diagnoses and fatal events.

Patient Concerns: Here, we report the case of a 53-year-old female who suffered from progressive dysphagia and experienced several choking events involving solid material. An extensive family history of dysphagia was noted, and 2 family members had died as a result of aspiration.

Diagnoses: PABPN1 genotyping and DNA sequence analysis revealed a heterozygous (GCG)10(GCA)3GCG mutation that led to the diagnosis of OPMD.

Interventions: Rehabilitation exercises, namely, the Shaker exercise and the Masako maneuver, were suggested.

Outcomes: Improved swallowing ability with safe food intake was noted after 2 months of training. Surgical intervention will be considered when progression of the disease is noted.

Lessons: Underdiagnosis and a lack of awareness of OPMD may lead to choking, aspiration pneumonia, and death in multiple members of affected families. Currently, there is no definitive treatment for OPMD, but rehabilitation exercises and surgical intervention are helpful in relieving dysphagia.
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http://dx.doi.org/10.1097/MD.0000000000012935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221716PMC
October 2018

Aminoglycoside-associated nonsyndromic deafness and speech disorder in mitochondrial A1555G mutation in a family: A case report.

Medicine (Baltimore) 2018 Oct;97(42):e12878

Department of Neurology.

Rationale: Mitochondrial DNA mutations have been associated with many maternal inherited diseases. A1555G mutation in mtDNA effects the gene code for rRNA, resulting in the structural change of human ribosome rending it susceptible to binding of the common antibiotic, aminoglycosides. Such mutation has linked with non-syndromic hearing loss and is one of the most common mtDNA mutations in Asian populations.

Patient Concerns: A 50-year-old Taiwanese female visited our neurology department with concern for multiple members with hearing loss in her family, including herself.

Diagnoses: Physical examination findings were not significant besides hearing loss and brain MRI did not reveal any lesions. BAEP confirmed bilateral peripheral sensory deficit. Given the multiple cases of hearing loss in the family, a genetic cause was suspected. Using PCR and sequences chromatogram technique we have identified A1555G mutation on her mtDNA affecting region codes for 12S rRNA. Additionally, we observed severe speech disorder in two young family members with the onset of hearing loss began in their early childhood.

Interventions: The patient declined any form of intervention at the time for personal reasons.

Outcomes: The patient was satisfied with the diagnosis, her and her families are continuously followed by our neurology department.

Lessons: We report on a family with mtDNA mutation hearing loss that is related to exposure to aminoglycosides. Children with such mutation are at high risk for impaired linguistic function. Early identification and intervention with cochlear implant should be considered.
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http://dx.doi.org/10.1097/MD.0000000000012878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211905PMC
October 2018

The relationship between optic atrophy 1 polymorphism and normal tension glaucoma in Taiwan.

Taiwan J Ophthalmol 2018 Apr-Jun;8(2):82-86

Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan.

Purpose: The purpose of this research is to evaluate the relationship between of optic atrophy 1 (OPA1) polymorphism and normal tension glaucoma (NTG) by surveying patients from central Taiwan. This study finding could help us to understand the impact of OPA1 polymorphism on glaucoma.

Methods: We try to identify the effect of OPA1 polymorphism by comparing the clinical presentation in three catalogs of gene polymorphism in patients with NTG. Our research team includes patients with NTG from central Taiwan and assesses the OPA1 intervening sequence 8 (IVS8) + 4 C->T and IVS8 + 32 T->C polymorphism. We divide these patients into three OPA1 IVS8 + 4 subgroups, CC, CT, TT, and three IVS8 + 32 subgroups, TT, TC, CC. By collecting their ocular clinical data, systemic background, and other possible factors related to the presentation of glaucoma, we can compare these characters of each polymorphism subgroup.

Results: We find that all patients do not have OPA1 IVS8 + 4 C->T polymorphism while some of them do have IVS8 + 32 T->C polymorphism. NTG with OPA1 IVS8 + 32 T->C polymorphism inclines to have more nasal-step type visual field defect ( = 0.016) and inferior nerve fiber layer thickness loss ( = 0.098) in comparison to NTG with IVS8 + 32 wild type.

Conclusions: The OPA1 IVS8 + 32 T->C polymorphism partake to the phenotype and prognosis of NTG in central Taiwan. Even though our findings are far from clear enough to serve as guides for the differentiation of NTG etiologies, they still give us a glimpse of the impact of OPA1 in chronic optic neuropathy.
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http://dx.doi.org/10.4103/tjo.tjo_92_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055317PMC
July 2018

Cyclophilin A: A Predictive Biomarker of Carotid Stenosis in Cerebral Ischemic Stroke.

Curr Neurovasc Res 2018 ;15(2):111-119

Department of Neurology, Changhua Christian Hospital, Changhua 500, Taiwan.

Background: Cyclophilin A plays a pathogenic role in the development and progression of atherosclerosis, which can be assessed by measuring carotid intima-media thickness. The primary aim of this study was to examine the interaction between plasma Cyclophilin A level and carotid intima-media thickness in patients with acute ischemic stroke.

Method: Plasma concentration of Cyclophilin A was measured on admission in 66 consecutive patients who had been hospitalized for acute cerebral stroke and in 52 case-control subjects without a history of acute stroke. Subjects in both groups also underwent ultrasound B-mode imaging to measure the mean and maximum intima-media thickness of the carotid artery. Inflammatory biomarkers including high-sensitivity C-reactive protein and fibrinogen were also assessed.

Results: We found that the plasma concentration of Cyclophilin A was significantly higher in patients with acute ischemic stroke (p = 0.042). Increased Cyclophilin A was also correlated with carotid intima-media thickness in the patient group (p < 0.001). Among the risk factors for cerebral stroke examined in this study, only hypertension was significantly associated with plasma Cyclophilin A level.

Conclusion: Increased plasma Cyclophilin A levels might be involved in the pathophysiology of acute ischemic stroke and Cyclophilin A might serve as a biomarker in risk assessment of acute stroke patients.
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http://dx.doi.org/10.2174/1567202615666180516120959DOI Listing
May 2019

Far-infrared Radiation Improves Motor Dysfunction and Neuropathology in Spinocerebellar Ataxia Type 3 Mice.

Cerebellum 2019 Feb;18(1):22-32

Vascular and Genomic Center, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 50094, Taiwan.

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine neurodegenerative disease resulting from the misfolding and accumulation of a pathogenic protein, causing cerebellar dysfunction, and this disease currently has no effective treatments. Far-infrared radiation (FIR) has been found to protect the viability of SCA3 cells by preventing mutant ataxin-3 protein aggregation and promoting autophagy. However, this possible treatment still lacks in vivo evidence. This study assessed the effect of FIR therapy on SCA3 in vivo by using a mouse model over 28 weeks. Control mice carried a healthy wild-type ATXN3 allele that had a polyglutamine tract with 15 CAG repeats (15Q), whereas SCA3 transgenic mice possessed an allele with a pathological polyglutamine tract with expanded 84 CAG (84Q) repeats. The results showed that the 84Q SCA3 mice displayed impaired motor coordination, balance abilities, and gait performance, along with the associated loss of Purkinje cells in the cerebellum, compared with the normal 15Q controls; nevertheless, FIR treatment was sufficient to prevent those defects. FIR significantly improved performance in terms of maximal contact area, stride length, and base support in the forepaws, hindpaws, or both. Moreover, FIR treatment supported the survival of Purkinje cells in the cerebellum and promoted the autophagy, as reflected by the induction of autophagic markers, LC3II and Beclin-1, concomitant with the reduction of p62 and ataxin-3 accumulation in cerebellar Purkinje cells, which might partially contribute to the rescue mechanism. In summary, our results reveal that FIR confers therapeutic effects in an SCA3 transgenic animal model and therefore has considerable potential for future clinical use.
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http://dx.doi.org/10.1007/s12311-018-0936-3DOI Listing
February 2019

Caffeic acid and resveratrol ameliorate cellular damage in cell and Drosophila models of spinocerebellar ataxia type 3 through upregulation of Nrf2 pathway.

Free Radic Biol Med 2018 02 13;115:309-317. Epub 2017 Dec 13.

Department of Nutrition, Chung Shan Medical University, No. 110, Sec. 1, Chien-Kuo N. Rd., Taichung 40203, Taiwan, ROC; Department of Nutrition, Chung Shan Medical University Hospital, Taichung 40203, Taiwan, ROC. Electronic address:

Polyglutamine (polyQ)-expanded mutant ataxin-3 protein, which is prone to misfolding and aggregation, leads to cerebellar neurotoxicity in spinocerebellar ataxia type 3 (SCA3), an inherited PolyQ neurodegenerative disease. Although the exact mechanism is unknown, the pathogenic effects of mutant ataxin-3 are associated with dysregulation of transcription, protein degradation, mitochondrial function, apoptosis, and antioxidant potency. In the present study we explored the protective role and possible mechanism of caffeic acid (CA) and resveratrol (Res) in cells and Drosophila expressing mutant ataxin-3. Treatment with CA and Res increased the levels of antioxidant and autophagy protein expression with consequently corrected levels of reactive oxygen species, mitochondrial membrane potential, mutant ataxin-3, and the aggregation of mutant ataxin-3 in SK-N-SH-MJD78 cells. Moreover, in SK-N-SH-MJD78 cells, CA and Res enhanced the transcriptional activity of nuclear factor erythroid-derived-2-like 2 (Nrf2), a master transcription factor that upregulates the expression of antioxidant defense genes and the autophagy gene p62. CA and Res improved survival and motor performance in SCA3 Drosophila. Additionally, the above-mentioned protective effects of CA were also observed in CA-supplemented SCA3 Drosophila. Notably, blockade of the Nrf2 pathway by use of small interfering RNA annulled the health effects of CA and Res on SCA3, which affirmed the importance of the increase in Nrf2 activation by CA and Res. Additional studies are need to dissect the protective role of CA and Res in modulating neurodegenerative progression in SCA3 and other polyQ diseases.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.12.011DOI Listing
February 2018

Modulation of mitochondrial dynamics by treadmill training to improve gait and mitochondrial deficiency in a rat model of Parkinson's disease.

Life Sci 2017 Dec 3;191:236-244. Epub 2017 Oct 3.

Department of Neurology, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua 50094, Taiwan; Vascular and Genomic Center, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua 50094, Taiwan. Electronic address:

Purpose: Parkinson's disease (PD) is a progressive degenerative central nervous system disorder that particularly impairs motor function. As PD advances, gait disorders become more pronounced and are often difficult to treat with current pharmacological therapies. Physical activity improves both mobility in and the daily living activities of patients with PD. Mitochondrial alterations and oxidative stress contribute to PD progression. Therefore, the association between mitochondria and exercise in PD and the implicated regulation of mitochondrial proteins was explored in this study.

Methods: In this study, we developed a unilateral 6-hydroxydopamine rat model of PD and executed 4weeks of treadmill training. Motor behavior was evaluated through gait change analysis (the CatWalk method) and rotational testing. The viability of dopaminergic neurons, mitochondrial function, and oxidative stress in the substantia nigra and striatum were investigated through Western blot and immunohistochemical staining.

Key Findings: Treadmill training improved the performance of gait parameters in terms of maximal area, swing speed, stride length, and stance phase; treadmill training also reduced methamphetamine-induced rotation. This training not only improved dopaminergic neuron viability but also recovered mitochondrial function and attenuated oxidative stress in PD rats. The mechanism may be associated with the facilitation of mitochondrial turnover, including facilitation of mitochondrial fusion, fission, and clearance accompanying increased quantities of mitochondria.

Significance: Treadmill exercise improved gait speed and balance, reduced oxidative stress, improved mitochondrial fusion and fission, increased mitochondrial amounts, and potentially attenuated dopaminergic neuron degeneration. Consequently, mitochondrial quality was improved in PD rats.
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http://dx.doi.org/10.1016/j.lfs.2017.10.003DOI Listing
December 2017

H2O2 induces caveolin‑1 degradation and impaired mitochondrial function in E11 podocytes.

Mol Med Rep 2017 Nov 18;16(5):7841-7847. Epub 2017 Sep 18.

Vascular and Genomic Center, Changhua Christian Hospital, Changhua 50094, P.R. China.

Increased intercellular reactive oxygen species (ROS) levels are the major cause of podocyte injury with proteinuria. Caveolin‑1 (CAV‑1) is an essential protein component of caveolae. CAV‑1 participates in signal transduction and endocytic trafficking. Recent research has indicated that CAV‑1 regulates oxidative stress‑induced pathways. The present study used hydrogen peroxide (H2O2) at nontoxic concentrations to elevate the level of ROS in E11 podocytes. Treatment with 500 and 1,000 µM H2O2 for 1 h significantly reduced CAV‑1 expression levels. Simultaneously, the treatment significantly reduced the expression of the antioxidant enzymes glutamine‑cysteine ligase catalytic subunit, superoxide dismutase 2 and catalase. To determine the role of CAV‑1 in mediating oxidative stress, E11 podocytes were administered antenapedia‑CAV‑1 (AP‑CAV‑1) peptide for 48 h. The AP‑CAV‑1 treatment enhanced CAV‑1 expression and inhibited cyclophilin A expression, thus reducing ROS‑induced inflammation. Moreover, CAV‑1 protected against H2O2‑induced oxidative stress responses by enhancing the expression of antioxidant enzymes. Furthermore, CAV‑1 attenuated H2O2‑induced changes oxidative phosphorylation, and the expression of optic atrophy 1 and translocase of the inner membrane 23, as well as preserving mitochondrial function. CAV‑1 treatment significantly suppressed apoptosis, as indicated by a higher B‑cell lymphoma 2/BCL2‑associated X protein ratio. Therefore, enhancing the expression of CAV‑1 may be an important therapeutic consideration in treating podocyte injury.
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http://dx.doi.org/10.3892/mmr.2017.7497DOI Listing
November 2017

Treatment with Caffeic Acid and Resveratrol Alleviates Oxidative Stress Induced Neurotoxicity in Cell and Drosophila Models of Spinocerebellar Ataxia Type3.

Sci Rep 2017 09 14;7(1):11641. Epub 2017 Sep 14.

Department of Nutrition, Chung Shan Medical University, No. 110, Sec. 1, Chien-Kuo N. Rd., Taichung, 40203, Taiwan.

Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a polyglutamine (polyQ) repeat in the protein ataxin-3 which is involved in susceptibility to mild oxidative stress induced neuronal death. Here we show that caffeic acid (CA) and resveratrol (Res) decreased reactive oxygen species (ROS), mutant ataxin-3 and apoptosis and increased autophagy in the pro-oxidant tert-butyl hydroperoxide (tBH)-treated SK-N-SH-MJD78 cells containing mutant ataxin-3. Furthermore, CA and Res improved survival and locomotor activity and decreased mutant ataxin-3 and ROS levels in tBH-treated SCA3 Drosophila. CA and Res also altered p53 and nuclear factor-κB (NF-κB) activation and expression in tBH-treated cell and fly models of SCA3, respectively. Blockade of NF-κB activation annulled the protective effects of CA and Res on apoptosis, ROS, and p53 activation in tBH-treated SK-N-SH-MJD78 cells, which suggests the importance of restoring NF-κB activity by CA and Res. Our findings suggest that CA and Res may be useful in the management of oxidative stress induced neuronal apoptosis in SCA3.
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http://dx.doi.org/10.1038/s41598-017-11839-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599504PMC
September 2017

Personal exposure to fine particulate matter and benzo[a]pyrene from indoor air pollution and leukocyte mitochondrial DNA copy number in rural China.

Carcinogenesis 2017 09;38(9):893-899

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, Rockville, MD, 20850, USA.

Households in Xuanwei and Fuyuan, China, possess hazardous levels of fine particulate matter with an aerodynamic diameter <2.5 microns (PM2.5) and polycyclic aromatic hydrocarbons (PAHs) from coal combustion. Previous studies found that increased exposure to PM2.5 and benzo[a]pyrene (BaP; a PAH) were associated with decreased mitochondrial DNA copy number (mtDNAcn), a marker of oxidative stress. We further evaluated these associations in a cross-sectional study of 148 healthy non-smoking women from Xuanwei and Fuyuan. Personal exposure to PM2.5 and BaP was measured using portable devices. MtDNAcn was measured using qPCR amplification of leukocyte DNA that was collected after air measurements. Linear regression models were used to estimate the associations between personal exposure to PM2.5 and BaP, and mtDNAcn adjusted for age, body mass index (BMI) and fuel type. We found inverse associations between exposure to PM2.5 and BaP, and mtDNAcn. Each incremental log-μg/m3 increase in PM2.5 was associated with a significant decrease in mtDNAcn of -10.3 copies per cell [95% confidence interval (95% CI): -18.6, -2.0; P = 0.02]. Additionally, each log-ng/m3 increase in BaP was associated with a significant decrease in mtDNAcn of -5.4 copies per cell (95% CI: -9.9, -0.8, P = 0.02). Age, BMI, fuel type and coal mine type were not significantly associated with mtDNAcn. Exposure to PM2.5 and BaP may alter mitochondrial dynamics in non-smoking Chinese women. MtDNAcn may be a potential mediator of indoor air pollution on chronic disease development.
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http://dx.doi.org/10.1093/carcin/bgx068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862333PMC
September 2017

Sinulariolide suppresses LPS‑induced phenotypic and functional maturation of dendritic cells.

Mol Med Rep 2017 Nov 13;16(5):6992-7000. Epub 2017 Sep 13.

Department of Medical Research, Changhua Christian Hospital, Changhua 50006, Taiwan, R.O.C.

The dendritic cell (DC) maturation process is essential for the development of T cell responses and immune tolerance. Accordingly, DCs are considered a major target in the development of immunomodulating agents. In the present study, the effect of sinulariolide, an active compound isolated from the cultured soft coral Sinularia flexibilis, on lipopolysaccharide (LPS)‑induced murine bone marrow‑derived DCs was evaluated. The different phenotypes, cytokine secretion and the mix‑lymphocyte reaction of DCs were detected using flow cytometry and ELISA. The experimental results revealed that the phenotypic and functional maturation of DCs stimulated by LPS were markedly reduced by sinulariolide in a concentration‑dependent manner, including the expression of co‑stimulatory molecules (CD40, CD80 and CD86). In addition, sinulariolide reduced the release of tumor necrosis factor‑α, interleukin (IL)‑6, IL‑12 and nitric oxide from the LPS‑activated DCs, decreased their abilities to stimulate allogeneic T cell proliferation, and inhibited LPS‑induced nuclear factor‑κB pathways. These findings offer novel insight into the immunopharmacological function of sinulariolide and its effects on DCs.
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http://dx.doi.org/10.3892/mmr.2017.7480DOI Listing
November 2017

Peptide-mediated delivery of donor mitochondria improves mitochondrial function and cell viability in human cybrid cells with the MELAS A3243G mutation.

Sci Rep 2017 09 6;7(1):10710. Epub 2017 Sep 6.

Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan.

The cell penetrating peptide, Pep-1, has been shown to facilitate cellular uptake of foreign mitochondria but further research is required to evaluate the use of Pep-1-mediated mitochondrial delivery (PMD) in treating mitochondrial defects. Presently, we sought to determine whether mitochondrial transplantation rescue mitochondrial function in a cybrid cell model of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) disease. Following PMD, recipient cells had internalized donor mitochondria after 1 h, and expressed higher levels of normal mitochondrial DNA, particularly at the end of the treatment and 11 days later. After 4 days, mitochondrial respiratory function had recovered and biogenesis was evident in the Pep-1 and PMD groups, compared to the untreated MELAS group. However, only PMD was able to reverse the fusion-to-fission ratio of mitochondrial morphology, and mitochondria shaping proteins resembled the normal pattern seen in the control group. Cell survival following hydrogen peroxide-induced oxidative stress was also improved in the PMD group. Finally, we observed that PMD partially normalized cytokine expression, including that of interleukin (IL)-7, granulocyte macrophage-colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF), in the MELAS cells. Presently, our data further confirm the protective effects of PMD as well in MELAS disease.
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http://dx.doi.org/10.1038/s41598-017-10870-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587702PMC
September 2017

Depleted Leukocyte Mitochondrial DNA Copy Number Correlates With Unfavorable Left Ventricular Volumetric and Spherical Shape Remodeling in Acute Myocardial Infarction After Primary Angioplasty.

Circ J 2017 Nov 16;81(12):1901-1910. Epub 2017 Jun 16.

Department of Nephrology, Changhua Christian Hospital.

Background: Left ventricular (LV) shape influences LV systolic function. It is possible to assess LV shape using 3-D echocardiography sphericity index (SI). Maintaining mitochondrial DNA copy number (MCN) is important for preserving mitochondrial function and LV systolic function after acute myocardial infarction (AMI). Information is limited, however, regarding the relationship between leukocyte MCN and the subsequent change in LV shape after AMI.Methods and Results:Fifty-five AMI patients undergoing primary angioplasty were recruited. Plasma MCN was measured before primary angioplasty using quantitative polymerase chain reaction. 3-D echocardiography measurement of SI was performed at baseline, and at 1-, 3-, and 6-month follow-up. AMI subjects with MCN lower than the median had a higher 6-month SI and LV volume compared with those with higher MCN. Baseline echocardiographic parameters were similar between the 2 groups. MCN was negatively correlated with 3- and 6-month SI, and 3- and 6-month LV volume. On multiple linear regression analysis, baseline plasma MCN could predict LV SI and LV volume at 6 months after primary angioplasty for AMI, even after adjusting for traditional prognostic factors.

Conclusions: In AMI patients, higher plasma leukocyte MCN at baseline was associated with favorable LV shape and remodeling at 6-month follow-up. Plasma leukocyte MCN may provide a novel prognostic biomarker for LV remodeling after AMI.
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http://dx.doi.org/10.1253/circj.CJ-17-0088DOI Listing
November 2017

A prospective study of mitochondrial DNA copy number and the risk of prostate cancer.

Cancer Causes Control 2017 Jun 29;28(6):529-538. Epub 2017 Mar 29.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Purpose: Evidence suggests that mitochondrial DNA (mtDNA) copy number increases in response to DNA damage. Increased mtDNA copy number has been observed in prostate cancer (PCa) cells, suggesting a role in PCa development, but this association has not yet been investigated prospectively.

Methods: We conducted a nested case-control study (793 cases and 790 controls) of men randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) to evaluate the association between pre-diagnosis mtDNA copy number, measured in peripheral blood leukocytes, and the risk of PCa. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) and polytomous logistic regression to analyze differences in associations by non-aggressive (Stage I/II AND Gleason grade < 8) or aggressive (Stage III/IV OR Gleason grade ≥ 8) PCa.

Results: Although mtDNA copy number was not significantly associated with PCa risk overall (OR 1.23, 95% CI 0.97-1.55, p = 0.089), increasing mtDNA copy number was associated with an increased risk of non-aggressive PCa (OR 1.29, 95% CI 1.01-1.65, p = 0.044) compared to controls. No association was observed with aggressive PCa (OR 1.02, 95% CI 0.64-1.63, p = 0.933). Higher mtDNA copy number was also associated with increased PSA levels among controls (p = 0.014).

Conclusions: These results suggest that alterations in mtDNA copy number may reflect disruption of the normal prostate glandular architecture seen in early-stage disease, as opposed to reflecting the large number of tumor cells seen with advanced PCa.
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http://dx.doi.org/10.1007/s10552-017-0879-xDOI Listing
June 2017

Interrelations Between Mitochondrial DNA Copy Number and Inflammation in Older Adults.

J Gerontol A Biol Sci Med Sci 2017 Jul;72(7):937-944

Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan.

Background: Interplays between inflammation and mitochondrial biology are reported. Here, we examined the cross-sectional interrelationships of mitochondrial DNA copy number (mtDNACN) and inflammation and their interaction with physical functioning.

Methods: A total of 1990 community-dwelling adults aged 65 years and older who were participating in the Healthy Aging Longitudinal Study in Taiwan underwent measurements of peripheral-blood leukocytes MtDNACN, multiple inflammatory markers, grip strength, and gait speed.

Results: Principal components analysis revealed two inflammatory factors: factor 1 (high-sensitivity C-reactive protein [hs-CRP], white blood cell count, fibrinogen and interleukin-6 [IL-6]); factor 2 (tumor necrosis factor receptor 1, D-dimer and soluble interleukin-6 receptor). Participants with severe physical functioning impairment (low grip strength and gait speed) had higher (p < .05) levels of factor 1 and 2, but not mtDNACN, than did those with moderately impaired (low grip strength or gait speed) and normal physical functioning. MtDNACN was negatively related to factor 1 (r = -.221, p < .001) but not factor 2 (r = -.002, p = .938). Increased factor 1 was strongly associated with higher odds of physical functioning impairment in those with a low mtDNACN (adjusted odds ratios [OR] of moderate physical function impairment 1.21, 95% CI 1.01-1.44; adjusted OR of severe physical function impairment 1.52, 95% CI 1.25-1.85) but not in those with a high mtDNACN (p for interaction = .016).

Conclusions: A low mtDNACN was associated with an inflammation exhibiting elevated hs-CRP, IL-6, fibrinogen, and white blood cell count, and strengthened the association of this inflammation with physical functioning impairment.
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http://dx.doi.org/10.1093/gerona/glx033DOI Listing
July 2017

The Different Effects of Atorvastatin and Pravastatin on Cell Death and PARP Activity in Pancreatic NIT-1 Cells.

J Diabetes Res 2016 27;2016:1828071. Epub 2016 Nov 27.

Diabetes Research Laboratory, Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan; Graduate Institute of Integrative Medicine, China Medical University, Taichung, Taiwan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.

Statins have been widely used drugs for lowering low-density lipoprotein and for preventing heart attack and stroke. However, the increased risk for developing diabetes during extended stain use and the molecular mechanisms remain unclear. The objective of this study was to elucidate the signaling pathway and biological function between necrosis and autophagy induced by atorvastatin (AS) and pravastatin (PS). Here we observed that atorvastatin (AS) can increase intracellular reactive oxygen species (ROS) and induce necrotic cell death and autophagy in NIT-1 cells, whereas pravastatin (PS) does not cause ROS and cell death but also induces autophagy. PARP1 exhibited a dual role in modulating necrosis and autophagy in AS- and PS-treated NIT-1 cells through RIP1-RIP3-MLKL pathway and PARP1-AMPK-mTOR pathway. Lastly, AS treatment induced mitochondrial morphology injury significantly more than PS treatment did. Thus, the PARP1 activation should be considered in the development of effective statin therapies for diabetes. Future studies may examine specific mechanisms and pathways in mitochondria, autophagy, and oxidative stress .
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http://dx.doi.org/10.1155/2016/1828071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5149701PMC
May 2017

High plasma coenzyme Q10 concentration is correlated with good left ventricular performance after primary angioplasty in patients with acute myocardial infarction.

Medicine (Baltimore) 2016 Aug;95(31):e4501

Division of Cardiology, Department of Internal Medicine, Changhua Christian Hospital Institute of Statistics and Information Science, National Changhua University of Education Vascular and Genomic Research Center Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua School of Medicine, Chung Shan Medical University, Taichung Department of Neurology, Changhua Christian Hospital, Changhua Graduate Institute of Integrative Medicine, China Medical University, Taichung, Taiwan.

Exogenous administration of coenzyme Q10 (CoQ10) has been shown in experimental models to have a protective effect against ischemia-reperfusion injury. However, it is unclear whether follow-up plasma CoQ10 concentration is prognostic of left ventricular (LV) performance after primary balloon angioplasty in patients with acute ST segment elevation myocardial infarction (STEMI).We prospectively recruited 55 patients with STEMI who were treated with primary coronary balloon angioplasty. Plasma CoQ10 concentrations were measured before primary angioplasty (baseline) and 3 days, 7 days, and 1 month after STEMI using high-performance liquid chromatography. Echocardiography was performed at baseline and at 6-month follow-up. The control group comprised 54 healthy age- and sex-matched volunteers.Serial circulating CoQ10 concentrations significantly decreased with time in the STEMI group. The LV ejection fraction at 6-month follow-up positively correlated with the 1-month plasma CoQ10 tertile. Higher plasma CoQ10 concentrations at 1 month were associated with favorable LV remodeling and systolic function 6 months after STEMI. Multiple linear regression analysis showed that changes in CoQ10 concentrations at 1-month follow-up were predictive of LV systolic function 6 months after STEMI. Changes in CoQ10 concentrations correlated negatively with baseline oxidized low-density lipoprotein and fibrinogen concentrations and correlated positively with leukocyte mitochondrial copy number at baseline.Patients with STEMI who had higher plasma CoQ10 concentrations 1 month after primary angioplasty had better LV performance at 6-month follow-up. In addition, higher plasma CoQ10 concentration was associated with lower grade inflammatory and oxidative stress status. Therefore, plasma CoQ10 concentration may serve as a novel prognostic biomarker of LV systolic function after revascularization therapy for acute myocardial infarction.
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http://dx.doi.org/10.1097/MD.0000000000004501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979854PMC
August 2016

Far-infrared radiation protects viability in a cell model of Spinocerebellar Ataxia by preventing polyQ protein accumulation and improving mitochondrial function.

Sci Rep 2016 07 29;6:30436. Epub 2016 Jul 29.

Vascular and Genomic Center, Changhua Christian Hospital, Changhua 50094, Taiwan.

Far infrared radiation (FIR) is currently investigated as a potential therapeutic strategy in various diseases though the mechanism is unknown. Presently, we tested if FIR mediates beneficial effects in a cell model of the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3). SCA3 is caused by a mutation leading to an abnormal polyglutamine expansion (PolyQ) in ataxin-3 protein. The consequent aggregation of mutant ataxin-3 results in disruption of vital cell functions. In this study, neuroblastoma cells (SK-N-SH) was transduced to express either non-pathogenic ataxin-3-26Q or pathogenic ataxin-3-78Q proteins. The cells expressing ataxin-3-78Q demonstrated decreased viability, and increased sensitivity to metabolic stress in the presence rotenone, an inhibitor of mitochondrial respiration. FIR exposure was found to protect against these effects. Moreover, FIR improved mitochondrial respiratory function, which was significantly compromised in ataxin-3-78Q and ataxin-3-26Q expressing cells. This was accompanied by decreased levels of mitochondrial fragmentation in FIR treated cells, as observed by fluorescence microscopy and protein expression analysis. Finally, the expression profile LC3-II, Beclin-1 and p62 suggested that FIR prevent the autophagy inhibiting effects observed in ataxin-3-78Q expressing cells. In summary, our results suggest that FIR have rescuing effects in cells expressing mutated pathogenic ataxin-3, through recovery of mitochondrial function and autophagy.
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http://dx.doi.org/10.1038/srep30436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965738PMC
July 2016