Publications by authors named "I-Hsuan Lin"

49 Publications

Aged Skeletal Muscle Retains the Ability to Remodel Extracellular Matrix for Degradation of Collagen Deposition after Muscle Injury.

Int J Mol Sci 2021 Feb 20;22(4). Epub 2021 Feb 20.

The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11529, Taiwan.

Aging causes a decline in skeletal muscle function, resulting in a progressive loss of muscle mass, quality, and strength. A weak regenerative capacity is one of the critical causes of dysfunctional skeletal muscle in elderly individuals. The extracellular matrix (ECM) maintains the tissue framework structure in skeletal muscle. As shown by previous reports and our data, the gene expression of ECM components decreases with age, but the accumulation of collagen substantially increases in skeletal muscle. We examined the structural changes in ECM in aged skeletal muscle and found restricted ECM degradation. In aged skeletal muscles, several genes that maintain ECM structure, such as transforming growth factor β (TGF-β), tissue inhibitors of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs), and cathepsins, were downregulated. Muscle injury can induce muscle repair and regeneration in young and adult skeletal muscles. Surprisingly, muscle injury could not only efficiently induce regeneration in aged skeletal muscle, but it could also activate ECM remodeling and the clearance of ECM deposition. These results will help elucidate the mechanisms of muscle fibrosis with age and develop innovative antifibrotic therapies to decrease excessive collagen deposition in aged muscle.
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http://dx.doi.org/10.3390/ijms22042123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924602PMC
February 2021

Genome-wide CRISPR/Cas9 knockout screening uncovers a novel inflammatory pathway critical for resistance to arginine-deprivation therapy.

Theranostics 2021 25;11(8):3624-3641. Epub 2021 Jan 25.

TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan.

Arginine synthesis deficiency due to the suppressed expression of ASS1 (argininosuccinate synthetase 1) represents one of the most frequently occurring metabolic defects of tumor cells. Arginine-deprivation therapy has gained increasing attention in recent years. One challenge of ADI-PEG20 (pegylated ADI) therapy is the development of drug resistance caused by restoration of ASS1 expression and other factors. The goal of this work is to identify novel factors conferring therapy resistance. Multiple, independently derived ADI-resistant clones including derivatives of breast (MDA-MB-231 and BT-549) and prostate (PC3, CWR22Rv1, and DU145) cancer cells were developed. RNA-seq and RT-PCR were used to identify genes upregulated in the resistant clones. Unbiased genome-wide CRISPR/Cas9 knockout screening was used to identify genes whose absence confers sensitivity to these cells. shRNA and CRISPR/Cas9 knockout as well as overexpression approaches were used to validate the functions of the resistant genes both and in xenograft models. The signal pathways were verified by western blotting and cytokine release. Based on unbiased CRISPR/Cas9 knockout screening and RNA-seq analyses of independently derived ADI-resistant (ADIR) clones, aberrant activation of the TREM1/CCL2 axis in addition to ASS1 expression was consistently identified as the resistant factors. Unlike ADIR, MDA-MB-231 overexpressing ASS1 cells achieved only moderate ADI resistance both and , and overexpression of ASS1 alone does not activate the TREM1/CCL2 axis. These data suggested that upregulation of TREM1 is an independent factor in the development of strong resistance, which is accompanied by activation of the AKT/mTOR/STAT3/CCL2 pathway and contributes to cell survival and overcoming the tumor suppressive effects of ASS1 overexpression. Importantly, knockdown of TREM1 or CCL2 significantly sensitized ADIR toward ADI. Similar results were obtained in BT-549 breast cancer cell line as well as castration-resistant prostate cancer cells. The present study sheds light on the detailed mechanisms of resistance to arginine-deprivation therapy and uncovers novel targets to overcome resistance. We uncovered TREM1/CCL2 activation, in addition to restored ASS1 expression, as a key pathway involved in full ADI-resistance in breast and prostate cancer models.
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http://dx.doi.org/10.7150/thno.51795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914361PMC
January 2021

Mediator subunit MED1 is required for E2A-PBX1-mediated oncogenic transcription and leukemic cell growth.

Proc Natl Acad Sci U S A 2021 Feb;118(6)

Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065;

The chimeric transcription factor E2A-PBX1, containing the N-terminal activation domains of E2A fused to the C-terminal DNA-binding domain of PBX1, results in 5% of pediatric acute lymphoblastic leukemias (ALL). We recently have reported a mechanism for RUNX1-dependent recruitment of E2A-PBX1 to chromatin in pre-B leukemic cells; but the subsequent E2A-PBX1 functions through various coactivators and the general transcriptional machinery remain unclear. The Mediator complex plays a critical role in cell-specific gene activation by serving as a key coactivator for gene-specific transcription factors that facilitates their function through the RNA polymerase II transcriptional machinery, but whether Mediator contributes to aberrant expression of E2A-PBX1 target genes remains largely unexplored. Here we show that Mediator interacts directly with E2A-PBX1 through an interaction of the MED1 subunit with an E2A activation domain. Results of MED1 depletion by CRISPR/Cas9 further indicate that MED1 is specifically required for E2A-PBX1-dependent gene activation and leukemic cell growth. Integrated transcriptome and cistrome analyses identify pre-B cell receptor and cell cycle regulatory genes as direct cotargets of MED1 and E2A-PBX1. Notably, complementary biochemical analyses also demonstrate that recruitment of E2A-PBX1 to a target DNA template involves a direct interaction with DNA-bound RUNX1 that can be further stabilized by EBF1. These findings suggest that E2A-PBX1 interactions with RUNX1 and MED1/Mediator are of functional importance for both gene-specific transcriptional activation and maintenance of E2A-PBX1-driven leukemia. The MED1 dependency for E2A-PBX1-mediated gene activation and leukemogenesis may provide a potential therapeutic opportunity by targeting MED1 in E2A-PBX1 pre-B leukemia.
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http://dx.doi.org/10.1073/pnas.1922864118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017927PMC
February 2021

Neonatal hyperoxia induces gut dysbiosis and behavioral changes in adolescent mice.

J Chin Med Assoc 2021 Mar;84(3):290-298

Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan, ROC.

Background: Supplemental oxygen is often required to treat preterm infants with respiratory disorders. Experimental studies have demonstrated that hyperoxia results in the disruption of intestinal and neuronal plasticity and myelination of the brain. The association between the neonatal hyperoxia and changes of phenotypes in gut microbiota and in behaviors is not clear to date.

Methods: We designed an animal experiment that C57BL/6 mice pups were reared in either room air (RA) or hyperoxia (85% O2) from postnatal days 1 to 7. From postnatal days 8 to 42, the mice were reared in RA. Intestinal microbiota was sampled from the lower gastrointestinal tract on postnatal days 7 and 42, and behavioral tests were performed and brain tissues were collected on postnatal day 42.

Results: Neonatal hyperoxia decreased intestinal tight junction protein expression and altered intestinal bacterial composition and diversity on postnatal day 7. Among the concrete discriminative features, Proteobacteria and Epsilonbacteraeota were significantly elevated in hyperoxia-reared mice on postnatal days 7 and 42, respectively. Hyperoxia-reared mice exhibited significantly reduced sociability and interest in social novelty and impaired motor coordination compared with RA-reared mice on postnatal day 42. Hyperoxia-reared mice also exhibited significantly reduced myelination and a significantly higher number of apoptotic cells in the brain compared with RA-reared mice on postnatal day 42.

Conclusion: Neonatal hyperoxia during the first week of life altered gut microbiota and reduced brain myelination that might associate with the deficits of social interaction and motor coordination in adolescent mice.
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http://dx.doi.org/10.1097/JCMA.0000000000000488DOI Listing
March 2021

Combined Lycium babarum polysaccharides and C-phycocyanin increase gastric Bifidobacterium relative abundance and protect against gastric ulcer caused by aspirin in rats.

Nutr Metab (Lond) 2021 Jan 6;18(1). Epub 2021 Jan 6.

School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, 11031, Taiwan.

Background: Non-steroidal anti-inflammatory drugs such as aspirin are used for the treatment of cardiovascular disease. Chronic use of low-dose aspirin is associated with the occurrence of gastric ulcer. The aim of this study was to investigate the healing potential of Lycium barbarum polysaccharides (LBP) from Chinese Goji berry and C-phycocyanin (CPC) from Spirulina platensis on gastric ulcer in rats.

Methods: Male Sprague-Dawley rats were divided into five groups: normal, aspirin (700 mg/kg bw), LBP (aspirin + 100 mg/kg bw/d LBP), CPC (aspirin + 50 mg/kg bw/d CPC), and MIX (aspirin + 50 mg/kg bw/d LBP + 25 mg/kg bw/d CPC) groups. Gastric ulcer was developed by daily oral feeding of aspirin for 8 weeks. Treatments were given orally a week before ulcer induction for 9 weeks.

Results: The MIX group elevated gastric cyclooxygenase-1, prostaglandin E, and total nitrite and nitrate levels by 139%, 86%, and 66%, respectively, compared with the aspirin group (p < 0.05). Moreover, the MIX group reduced lipid peroxides malondialdehyde levels by 78% (p < 0.05). The treatment of LBP and/or CPC increased gastric Bifidobacterium relative abundance by 2.5-4.0 times compared with the aspirin group (p < 0.05).

Conclusions: We conclude that combined LBP and CPC enhance gastroprotective factors, inhibit lipid peroxidation, and increase gastric Bifidobacterium relative abundance. Combined LBP and CPC have protective potential against gastric ulcer caused by aspirin in rats.
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http://dx.doi.org/10.1186/s12986-020-00538-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789774PMC
January 2021

Serum Protein Biomarker Findings Reflective of Oxidative Stress and Vascular Abnormalities in Male, but Not Female, Collision Sport Athletes.

Front Neurol 2020 30;11:549624. Epub 2020 Sep 30.

Department of Neuroscience, Monash University, Melbourne, VIC, Australia.

Studies have indicated that concussive and sub-concussive brain injuries that are frequent during collision sports may lead to long-term neurological abnormalities, however there is a knowledge gap on how biological sex modifies outcomes. Blood-based biomarkers can help to identify the molecular pathology induced by brain injuries and to better understand how biological sex affects the molecular changes. We therefore analyzed serum protein biomarkers in male ( = 50) and female ( = 33) amateur Australian rules footballers (i.e., Australia's most participated collision sport), both with a history of concussion (HoC) and without a history of concussion (NoHoC). These profiles were compared to those of age-matched control male ( = 24) and female ( = 20) athletes with no history of neurotrauma or participation in collision sports. Serum levels of protein markers indicative of neuronal, axonal and glial injury (UCH-L1, NfL, tau, p-tau, GFAP, BLBP, PEA15), metabolic (4-HNE) and vascular changes (VEGF-A, vWF, CLDN5), and inflammation (HMGB1) were assessed using reverse phase protein microarrays. Male, but not female, footballers had increased serum levels of VEGF-A compared to controls regardless of concussion history. In addition, only male footballers who had HoC had increased serum levels of 4-HNE. These findings being restricted to males may be related to shorter collision sport career lengths for females compared to males. In summary, these findings show that male Australian rules footballers have elevated levels of serum biomarkers indicative of vascular abnormalities (VEGF-A) and oxidative stress (4-HNE) in comparison to non-collision control athletes. While future studies are required to determine how these findings relate to neurological function, serum levels of VEGF-A and 4-HNE may be useful to monitor subclinical neurological injury in males participating in collision sports.
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http://dx.doi.org/10.3389/fneur.2020.549624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561422PMC
September 2020

WYSIWYG Design of Hypnotic Line Art.

IEEE Trans Vis Comput Graph 2020 Oct 21;PP. Epub 2020 Oct 21.

Hypnotic line art is a modern form in which white narrow curved ribbons, with the width and direction varying along each path over a black background, provide a keen sense of 3D objects regarding surface shapes and topological contours. However, the procedure of manually creating such line art work can be quite tedious and time-consuming. In this paper, we present an interactive system that offers a What-You-See-Is-What-You-Get (WYSIWYG) scheme for producing hypnotic line art images by integrating and placing evenly-spaced streamlines in tensor fields. With an input picture segmented, the user just needs to sketch a few illustrative strokes to guide the construction of a tensor field for each part of the objects therein. Specifically, we propose a new method which controls, with great precision, the aesthetic layout and artistic drawing of an array of streamlines in each tensor field to emulate the style of hypnotic line art. Given several parameters for streamlines such as density, thickness, and sharpness, our system is capable of generating professional-level hypnotic line art work. With great ease of use, it allows art designers to explore a wide variety of possibilities to obtain hypnotic line art results of their own preferences.
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http://dx.doi.org/10.1109/TVCG.2020.3032734DOI Listing
October 2020

Cytoskeletal disorganization underlies PABPN1-mediated myogenic disability.

Sci Rep 2020 10 19;10(1):17621. Epub 2020 Oct 19.

Human Genetics Department, Leiden University Medical Center, Leiden, The Netherlands.

Muscle wasting and atrophy are regulated by multiple molecular processes, including mRNA processing. Reduced levels of the polyadenylation binding protein nucleus 1 (PABPN1), a multifactorial regulator of mRNA processing, cause muscle atrophy. A proteomic study in muscles with reduced PABPN1 levels suggested dysregulation of sarcomeric and cytoskeletal proteins. Here we investigated the hypothesis that reduced PABPN1 levels lead to an aberrant organization of the cytoskeleton. MURC, a plasma membrane-associated protein, was found to be more abundant in muscles with reduced PABPN1 levels, and it was found to be expressed at regions showing regeneration. A polarized cytoskeletal organization is typical for muscle cells, but muscle cells with reduced PABPN1 levels (named as shPAB) were characterized by a disorganized cytoskeleton that lacked polarization. Moreover, cell mechanical features and myogenic differentiation were significantly reduced in shPAB cells. Importantly, restoring cytoskeletal stability, by actin overexpression, was beneficial for myogenesis, expression of sarcomeric proteins and proper localization of MURC in shPAB cell cultures and in shPAB muscle bundle. We suggest that poor cytoskeletal mechanical features are caused by altered expression levels of cytoskeletal proteins and contribute to muscle wasting and atrophy.
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http://dx.doi.org/10.1038/s41598-020-74676-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572364PMC
October 2020

Gastroprotective effect of Lycium barbarum polysaccharides and C-phycocyanin in rats with ethanol-induced gastric ulcer.

Int J Biol Macromol 2020 Dec 12;165(Pt A):1519-1528. Epub 2020 Oct 12.

School of Nutrition and Health Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan; Master Program in Global Health and Development, Taipei Medical University, Taipei 110, Taiwan; Nutrition Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan. Electronic address:

This study investigated the gastroprotective effect of Lycium barbarum polysaccharides (LBP) and C-phycocyanin (C-PC) in rats with ethanol-induced gastric ulcer. Rats were divided into 5 groups: normal, ulcer, ulcer treated with 100 mg/kg bw LBP, ulcer treated with 50 mg/kg bw C-PC, and ulcer treated with 50 mg/kg bw LBP and 25 mg/kg bw C-PC. Pretreatment with LBP and/or C-PC was given a week before ulcer induction. Ulcer induction was produced by 50% ethanol administration orally every other day for 4 weeks. After 5-week treatment, the histopathological observation showed that LBP or C-PC attenuated the severity of gastric mucosal damage. LBP decreased serum malondialdehyde (MDA) levels and gastric interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) levels, and myeloperoxidase (MPO) activity. C-PC decreased serum MDA levels and gastric tumor necrosis factor-α (TNF-α), IL-1β, IL-6, ICAM-1 levels, and MPO activity. Combined LBP and C-PC decreased serum MDA levels and gastric TNF-α, IL-1β, IL-6, and ICAM-1 levels. LBP and/or C-PC increased gastric heat shock protein 70 and non-protein sulfhydryl compounds. Rats with ulcer and treatment had enriched with the family Bacillaceae. Therefore, pretreatment with LBP and/or C-PC attenuated ethanol-induced gastric ulcer in rats via suppressing oxidation and inflammation and increasing gastroprotection.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.10.037DOI Listing
December 2020

Preference about Laws for the Legal Recognition of Same-Sex Relationships in Taiwanese People Before and After Same-Sex Marriage Referenda: A Facebook Survey Study.

Int J Environ Res Public Health 2020 03 18;17(6). Epub 2020 Mar 18.

Department of Psychiatry, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi City 60002, Taiwan.

This study examined the factors related to the preference about laws to legalize same-sex relationships in participants of the first wave of a survey (Wave 1, 23 months before the same-sex marriage referendum) and the second wave of a survey (Wave 2, 1 week after the same-sex marriage referendum) in Taiwan. The data of 3286 participants in Wave 1 and 1370 participants in Wave 2 recruited through a Facebook advertisement were analyzed. Each participant completed an online questionnaire assessing their attitude toward the legal recognition of same-sex relationships, preference about laws to legalize same-sex relationships (establishing same-sex couple laws outside the Civil Code vs. changing the Civil Code to include same-sex marriage laws), belief in the importance of legalizing same-sex relationships, and perceived social attitudes toward the legal recognition of same-sex relationships. The results revealed that those who did not support legalizing same-sex relationships were more likely to prefer establishing same-sex couple laws outside the Civil Code than those who supported the legalization. The form of law preferred to legalize same-sex relationships significantly changed between Wave 1 and Wave 2. Multiple factors, including gender, age, sexual orientation, belief in the importance of legalizing same-sex relationships to human rights and the social status of sexual minorities, and perceived peers' and families' attitudes toward the legal recognition of same-sex relationships, were significantly associated with the preference of laws, although these associations varied among heterosexual and non-heterosexual participants and at various stages of the survey.
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http://dx.doi.org/10.3390/ijerph17062000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142610PMC
March 2020

Preference about Laws for the Legal Recognition of Same-Sex Relationships in Taiwanese People Before and After Same-Sex Marriage Referenda: A Facebook Survey Study.

Int J Environ Res Public Health 2020 03 18;17(6). Epub 2020 Mar 18.

Department of Psychiatry, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi City 60002, Taiwan.

This study examined the factors related to the preference about laws to legalize same-sex relationships in participants of the first wave of a survey (Wave 1, 23 months before the same-sex marriage referendum) and the second wave of a survey (Wave 2, 1 week after the same-sex marriage referendum) in Taiwan. The data of 3286 participants in Wave 1 and 1370 participants in Wave 2 recruited through a Facebook advertisement were analyzed. Each participant completed an online questionnaire assessing their attitude toward the legal recognition of same-sex relationships, preference about laws to legalize same-sex relationships (establishing same-sex couple laws outside the Civil Code vs. changing the Civil Code to include same-sex marriage laws), belief in the importance of legalizing same-sex relationships, and perceived social attitudes toward the legal recognition of same-sex relationships. The results revealed that those who did not support legalizing same-sex relationships were more likely to prefer establishing same-sex couple laws outside the Civil Code than those who supported the legalization. The form of law preferred to legalize same-sex relationships significantly changed between Wave 1 and Wave 2. Multiple factors, including gender, age, sexual orientation, belief in the importance of legalizing same-sex relationships to human rights and the social status of sexual minorities, and perceived peers' and families' attitudes toward the legal recognition of same-sex relationships, were significantly associated with the preference of laws, although these associations varied among heterosexual and non-heterosexual participants and at various stages of the survey.
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http://dx.doi.org/10.3390/ijerph17062000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142610PMC
March 2020

Long-term Proton Pump Inhibitor Administration Caused Physiological and Microbiota Changes in Rats.

Sci Rep 2020 01 21;10(1):866. Epub 2020 Jan 21.

TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.

Proton pump inhibitors (PPIs) are used for the long-term treatment of gastroesophageal disorders and the non-prescription medicines for acid reflux. However, there is growing concerns about PPI misuse, overuse and abuse. This study aimed to develop an animal model to examine the effects of long-term use of PPI in vivo. Twenty one Wistar rats were given omeprazole orally or intravenously for 30 days, and caerulein as a positive control. After euthanization, the serum and stool were collected to perform MS-based quantitative analysis of metabolites. We carried out 16S-based profiling of fecal microbiota, assessed the expression of bile acid metabolism regulators and examined the immunopathological characteristics of bile ducts. After long-term PPI exposure, the fecal microbial profile was altered and showed similarity to those observed in high-fat diet studies. The concentrations of several metabolites were also changed in various specimens. Surprisingly, morphological changes were observed in the bile duct, including ductal epithelial proliferation, micropapillary growth of biliary epithelium, focal bile duct stricture formation and bile duct obstruction. These are characteristics of precancerous lesions of bile duct. FXR and RXRα expressions were significantly reduced, which were similar to that observed in cholangiocarcinoma in TCGA and Oncomine databases. We established a novel animal model to examine the effects of long-term use of omeprazole. The gut microbes and metabolic change are consequences of long-term PPI exposure. And the results showed the environment in vivo tends to a high-fat diet. More importantly, we observed biliary epithelial hyperplasia, which is an indicator of a high-fat diet.
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http://dx.doi.org/10.1038/s41598-020-57612-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972906PMC
January 2020

Upregulation of Cisd2 attenuates Alzheimer's-related neuronal loss in mice.

J Pathol 2020 03 13;250(3):299-311. Epub 2020 Jan 13.

Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.

CDGSH iron-sulfur domain-containing protein 2 (Cisd2), a protein that declines in an age-dependent manner, mediates lifespan in mammals. Cisd2 deficiency causes accelerated aging and shortened lifespan, whereas persistent expression of Cisd2 promotes longevity in mice. Alzheimer's disease (AD) is the most prevalent form of senile dementia and is without an effective therapeutic strategy. We investigated whether Cisd2 upregulation is able to ameliorate amyloid β (Aβ) toxicity and prevent neuronal loss using an AD mouse model. Our study makes three major discoveries. First, using the AD mouse model (APP/PS1 double transgenic mice), the dosage of Cisd2 appears to modulate the severity of AD phenotypes. Cisd2 overexpression (∼two-fold) significantly promoted survival and alleviated the pathological defects associated with AD. Conversely, Cisd2 deficiency accelerated AD pathogenesis. Secondly, Cisd2 overexpression protected against Aβ-mediated mitochondrial damage and attenuated loss of neurons and neuronal progenitor cells. Finally, an increase in Cisd2 shifted the expression profiles of a panel of genes that are dysregulated by AD toward the patterns observed in wild-type mice. These findings highlight Cisd2-based therapies as a potential disease-modifying strategy for AD. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065100PMC
March 2020

Degree of lipid saturation affects depressive-like behaviour and gut microbiota in mice.

Int J Food Sci Nutr 2020 Jun 23;71(4):440-452. Epub 2019 Oct 23.

School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan, ROC.

This study explored the effects of the degree of lipid saturation on depressive behaviour and gut microbiota in mice. Thirty-two mice were divided into normal (N), Prozac (NP), lard (L) and fish oil (F) groups. After a 12-week dietary intervention, the open field test (OFT) and the forced swim test (FST) were conducted before sacrifice. The mice in the L group exhibited anxiety-like behaviours in the OFT and depressive-like behaviours in the FST. A significant difference was observed in β-diversity indices between the L group and the F group. The abundance of and was significantly higher in the F group than in the L and N groups. The prefrontal cortex fatty acid composition was altered in various lipid-treated groups and was highly correlated with depressive-like behaviours. In conclusion, the degree of lipid saturation affects depressive-like behaviour, gut microbiota composition, and the prefrontal cortex fatty acid profile in mice.
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http://dx.doi.org/10.1080/09637486.2019.1681380DOI Listing
June 2020

Fish Oil, but Not Olive Oil, Ameliorates Depressive-Like Behavior and Gut Microbiota Dysbiosis in Rats under Chronic Mild Stress.

Biomolecules 2019 09 21;9(10). Epub 2019 Sep 21.

School of Nutrition and Health Sciences, Taipei Medical University, Taipei 11031, Taiwan.

Background: This study investigated the effects of fish oil and olive oil in improving dysbiosis and depressive-like symptoms.

Methods And Results: Male rats were fed normal, fish oil-rich or olive oil-rich diets for 14 weeks. Chronic mild stress (CMS) was administered from week 2. The sucrose preference test (SPT) and forced swimming test (FST) were used to determine depressive-like behavior. The SPT results revealed that the CMS, CMS with imipramine (CMS+P) treatment, and CMS with olive oil diet (CMS+O) groups exhibited significantly reduced sucrose intake from week 8, whereas the fish oil diet (CMS+F) group exhibited significantly reduced sucrose intake from week 10. The FST results showed that the immobile time of the CMS+F group was significantly less than that of the CMS-only group. Next generation sequencing (NGS) results showed CMS significantly reduced the abundance of and increased that of and . However, the CMS+F group showed an increase in the abundance of , , and , whereas the CMS+O group showed an increase in the abundance of .

Conclusions: CMS stimuli altered the gut microbiome in depressed rats. Fish oil and olive oil exerted part of a prebiotic-like effect to ameliorate dysbiosis induced by CMS. However, only fish oil ameliorated depressive-like symptoms.
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http://dx.doi.org/10.3390/biom9100516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843453PMC
September 2019

Fish Oil, but Not Olive Oil, Ameliorates Depressive-Like Behavior and Gut Microbiota Dysbiosis in Rats under Chronic Mild Stress.

Biomolecules 2019 09 21;9(10). Epub 2019 Sep 21.

School of Nutrition and Health Sciences, Taipei Medical University, Taipei 11031, Taiwan.

Background: This study investigated the effects of fish oil and olive oil in improving dysbiosis and depressive-like symptoms.

Methods And Results: Male rats were fed normal, fish oil-rich or olive oil-rich diets for 14 weeks. Chronic mild stress (CMS) was administered from week 2. The sucrose preference test (SPT) and forced swimming test (FST) were used to determine depressive-like behavior. The SPT results revealed that the CMS, CMS with imipramine (CMS+P) treatment, and CMS with olive oil diet (CMS+O) groups exhibited significantly reduced sucrose intake from week 8, whereas the fish oil diet (CMS+F) group exhibited significantly reduced sucrose intake from week 10. The FST results showed that the immobile time of the CMS+F group was significantly less than that of the CMS-only group. Next generation sequencing (NGS) results showed CMS significantly reduced the abundance of and increased that of and . However, the CMS+F group showed an increase in the abundance of , , and , whereas the CMS+O group showed an increase in the abundance of .

Conclusions: CMS stimuli altered the gut microbiome in depressed rats. Fish oil and olive oil exerted part of a prebiotic-like effect to ameliorate dysbiosis induced by CMS. However, only fish oil ameliorated depressive-like symptoms.
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http://dx.doi.org/10.3390/biom9100516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843453PMC
September 2019

Rrm2b deletion causes mitochondrial metabolic defects in renal tubules.

Sci Rep 2019 09 13;9(1):13238. Epub 2019 Sep 13.

TMU Research Center of Cancer Translational Medicine, Taipei Medical University, 11031, Taipei, Taiwan.

Renal diseases impose considerable health and economic burdens on health systems worldwide, and there is a lack of efficient methods for the prevention and treatment due to their complexity and heterogeneity. Kidneys are organs with a high demand for energy produced by mitochondria, in which Rrm2b has critical functions as reported. The Rrm2b kidney-specific knockout mice we generated exhibited age-dependent exacerbated features, including mitochondrial dysfunction and increased oxidative stress; additionally, resulted in severe disruption of mitochondria-related metabolism. Rrm2b is vital not only to supply dNTPs for DNA replication and repair, but also to maintain structural integrity and metabolic homeostasis in mitochondria. Thence, Rrm2b deletion might induce chronic kidney defects in mice. This model can facilitate exploration of novel mechanisms and targeted therapies in the kidney diseases and has important translational and clinical implications.
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http://dx.doi.org/10.1038/s41598-019-49663-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744457PMC
September 2019

Phosphorylation of CEP83 by TTBK2 is necessary for cilia initiation.

J Cell Biol 2019 10 27;218(10):3489-3505. Epub 2019 Aug 27.

Institute of Biochemistry and Molecular Biology, College of Life Science, National Yang-Ming University, Taipei, Taiwan

Primary cilia are microtubule-based organelles that play important roles in development and tissue homeostasis. Tau-tubulin kinase-2 (TTBK2) is genetically linked to spinocerebellar ataxia type 11, and its kinase activity is crucial for ciliogenesis. Although it has been shown that TTBK2 is recruited to the centriole by distal appendage protein CEP164, little is known about TTBK2 substrates associated with its role in ciliogenesis. Here, we perform superresolution microscopy and discover that serum starvation results in TTBK2 redistribution from the periphery toward the root of distal appendages. Our biochemical analyses uncover CEP83 as a bona fide TTBK2 substrate with four phosphorylation sites characterized. We also demonstrate that CEP164-dependent TTBK2 recruitment to distal appendages is required for subsequent CEP83 phosphorylation. Specifically, TTBK2-dependent CEP83 phosphorylation is important for early ciliogenesis steps, including ciliary vesicle docking and CP110 removal. In summary, our results reveal a molecular mechanism of kinase regulation in ciliogenesis and identify CEP83 as a key substrate of TTBK2 during cilia initiation.
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http://dx.doi.org/10.1083/jcb.201811142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781440PMC
October 2019

Phthalate exposure alters gut microbiota composition and IgM vaccine response in human newborns.

Food Chem Toxicol 2019 Oct 26;132:110700. Epub 2019 Jul 26.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Electronic address:

Postnatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, is associated with allergy development in childhood, suggesting that DEHP exposure may dysregulate immune response in infants. We investigated whether DEHP exposure in newborns through medical treatment affected the gut microbiota pattern and vaccine response, which are both related to immune development. In this prospective cohort study from May 1, 2016 through July 31, 2017, newborns with respiratory distress who were given intravenous infusions (IVs) were enrolled as the DEHP group, and newborns who did not receive IVs were enrolled as the control group. We excluded patients with perinatal maternal probiotics, vaginal delivery, antibiotic treatment, and exclusive human milk or formula feeding. Of 118 infants, urinary phthalate metabolite analysis revealed that the calculated DEHP concentrations of the newborns treated with IVs (n = 15) were higher than those in the control group (n = 10) (p = 0.0001). DEHP exposure altered bacterial communities both in composition and diversity, particularly decreases in Rothia sp. and Bifidobacterium longum in the DEHP group. Furthermore, DEHP exposure significantly enhanced anti-HBsAg-IgM responses in the DEHP group (p = 0.013). Early-life DEHP exposure alter gut microbiota of newborns and may change their immune responses in later life.
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http://dx.doi.org/10.1016/j.fct.2019.110700DOI Listing
October 2019

A high linoleic acid diet exacerbates metabolic responses and gut microbiota dysbiosis in obese rats with diabetes mellitus.

Food Funct 2019 Feb;10(2):786-798

School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan.

Dietary polyunsaturated fatty acid (PUFA) levels may affect inflammatory responses and lipid metabolism. Gut microbiota diversity is strongly associated with chronic inflammatory disease, diabetes mellitus (DM), and obesity through abnormal energy homeostasis. In this study, the association between metabolic responses and gut microbiota diversity at different dietary n-6/n-3 PUFA ratios was evaluated in DM rats. Obesity and DM were induced in rats by using a high-fat diet and streptozotocin (STZ), respectively. The obese DM rats were assigned to three groups and administered regular (R), high (H), and low (L) n-6/n-3 ratio diets (n-6/n-3 = 6.39, 3.02, and 9.29, respectively) for 6 weeks. Some metabolic parameters and gut microbiota of the rats were analysed. The results revealed that a high linoleic acid diet increased the plasma and kidney interleukin 6 levels, whereas a low n-6/n-3 ratio diet ameliorated blood glucose homeostasis, reduced plasma tumour necrosis factor α levels, and inhibited systematic inflammation. DM rats exhibited low gut microbiota diversity; however, compared with the R group, the L and H groups did not exhibit alterations in the α-diversity (Observed, Chao 1, Shannon and Simpson). The percentage of Firmicutes was lower in the DM groups than in the non-DM group; however, the L group showed a nonsignificantly higher Firmicutes/Bacteroidetes ratio than did the other groups. Thus, a low n-6/n-3 ratio diet can improve blood glucose homeostasis, reduce systematic inflammation, ameliorate glomerular basal membrane thickening, reduce the expression of receptors of advanced glycation end products in renal vessel walls, and prevent diabetic nephropathies.
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http://dx.doi.org/10.1039/c8fo02423eDOI Listing
February 2019

Gli2 modulates cell cycle re-entry through autophagy-mediated regulation of the length of primary cilia.

J Cell Sci 2018 12 17;131(24). Epub 2018 Dec 17.

Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan

The primary cilium is a tiny cell protrusion known to transduce key extracellular signals, including those of the sonic hedgehog pathway, which activates Gli transcription factors for various cellular functions. To understand the significance of the Gli2 transcription factor in fibroblasts, we establish a Gli2-knockout NIH3T3 cell line by CRISPR/Cas9 technology. Surprisingly, NIH3T3 fibroblasts lacking Gli2 expression through gene knockout or RNA interference possess longer primary cilia after stimulation of ciliogenesis by serum starvation. This lengthening of primary cilia is associated with enhanced autophagy-mediated Ofd1 degradation, and can be reversed by pharmacological and genetic inhibition of autophagy. Meanwhile, flow cytometry reveals that Gli2 NIH3T3 fibroblasts exhibit a delay in cell cycle re-entry after serum re-stimulation. Ablation of their primary cilia through Kif3a knockdown rescues the delay in cell cycle re-entry. These results suggest that Gli2 plays an unexpected role in cell cycle re-entry through an autophagy-mediated regulation on ciliary length in fibroblasts.
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http://dx.doi.org/10.1242/jcs.221218DOI Listing
December 2018

DNA primase polypeptide 1 (PRIM1) involves in estrogen-induced breast cancer formation through activation of the G2/M cell cycle checkpoint.

Int J Cancer 2019 02 21;144(3):615-630. Epub 2018 Nov 21.

Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan.

The DNA primase polypeptide 1 (PRIM1) is responsible for synthesizing small RNA primers for Okazaki fragments generated during discontinuous DNA replication. PRIM1 mRNA expression levels in breast tumor samples were detected by real-time PCR analysis. Xenografted tumor model was established to study the carcinogenic role of PRIM1 and its potential therapeutic applications. The average PRIM1 mRNA (copy number × 10 /μg) expression was 4.7-fold higher in tumors than in normal tissue (*p = 0.005, n = 254). PRIM1 was detected preferentially at a higher level (>40-fold) in poorly differentiated tumor tissues (n = 46) compared with more highly differentiated tumors tissues (n = 10) (*p = 0.005). Poor overall survival rate was correlated to the estrogen receptor positive (ER+, n = 20) patients with higher PRIM1 expression when compare to the ER- (n = 10) patients (Chi Square test, p = 0.03). Stable expression of PRIM1-siRNA in the ER+ BT-474 cells-xenograft tumors significantly reduced tumor volume in SCID mice (*p = 0.005). The anti-tumoral effects of inotilone isolated from Phellinus linteus was tested and had significant effects on the inhibition of PRIM1 protein expression in ER+ breast cancer cells. In vivo study was performed by administering inotilone (10 mg/kg, twice a week for 6 weeks), which resulted in significantly reduced BT-474-xenografted tumor growth volume compared with control (n =5 per group, *p < 0.05). This study provides evidences for the prognostic effects of PRIM1 with poor overall survival rate in the ER+ patients and will be valuable to test for therapeutic purpose.
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http://dx.doi.org/10.1002/ijc.31788DOI Listing
February 2019

Skeletal muscle in aged mice reveals extensive transformation of muscle gene expression.

BMC Genet 2018 08 8;19(1):55. Epub 2018 Aug 8.

The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, No.250, Wu-Hsing Street, Taipei, 11031, Taiwan.

Background: Aging leads to decreased skeletal muscle function in mammals and is associated with a progressive loss of muscle mass, quality and strength. Age-related muscle loss (sarcopenia) is an important health problem associated with the aged population.

Results: We investigated the alteration of genome-wide transcription in mouse skeletal muscle tissue (rectus femoris muscle) during aging using a high-throughput sequencing technique. Analysis revealed significant transcriptional changes between skeletal muscles of mice at 3 (young group) and 24 (old group) months of age. Specifically, genes associated with energy metabolism, cell proliferation, muscle myosin isoforms, as well as immune functions were found to be altered. We observed several interesting gene expression changes in the elderly, many of which have not been reported before.

Conclusions: Those data expand our understanding of the various compensatory mechanisms that can occur with age, and further will assist in the development of methods to prevent and attenuate adverse outcomes of aging.
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http://dx.doi.org/10.1186/s12863-018-0660-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083496PMC
August 2018

Erratum to: Whole Genome DNA Methylation Analysis of Brachypodium distachyon Using Next-Generation Sequencing (BS-seq).

Authors:
I-Hsuan Lin

Methods Mol Biol 2018 ;1667:E1

Research Center of Cancer Translational Medicine, Taipei Medical University, No. 250 Wu-Xing Street, Taipei, 11031, Taiwan.

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http://dx.doi.org/10.1007/978-1-4939-7278-4_19DOI Listing
January 2018

Whole Genome DNA Methylation Analysis Using Next-Generation Sequencing (BS-seq).

Authors:
I-Hsuan Lin

Methods Mol Biol 2018 ;1667:223-287

Research Center of Cancer Translational Medicine, Taipei Medical University, No. 250 Wu-Xing Street, Taipei, 11031, Taiwan.

Plant methylation is widely evident and has played crucial roles ranging in defining the epi-genome variations during abiotic and biotic stress. Variations in epi-genomic level has observed not only in the symmetrical as well as the non-symmetrical sequences. Plethora of these epi-genomic variations have been widely also demonstrated at the flowering, tissue-specific, and also at developmental stages revealing a strong association of the observed epi-alleles to the physiological state. In the present chapter, epi-genomic analysis of the s has been described with functional workflow and illustrated methodology.
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http://dx.doi.org/10.1007/978-1-4939-7278-4_17DOI Listing
June 2018

Correlated 5-Hydroxymethylcytosine (5hmC) and Gene Expression Profiles Underpin Gene and Organ-Specific Epigenetic Regulation in Adult Mouse Brain and Liver.

PLoS One 2017 26;12(1):e0170779. Epub 2017 Jan 26.

Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.

Background: DNA methylation is an epigenetic mechanism essential for gene regulation and vital for mammalian development. 5-hydroxymethylcytosine (5hmC) is the first oxidative product of the TET-mediated 5-methylcytosine (5mC) demethylation pathway. Aside from being a key intermediate in cytosine demethylation, 5hmC may have potential regulatory functions with emerging importance in mammalian biology.

Methods: Here, we investigate the global 5hmC enrichment in five brain structures, including cerebellum, cerebral cortex, hippocampus, hypothalamus and thalamus, as well as liver tissues from female and male adult mice by using chemical capture-based technique coupled with next-generation sequencing. At the same time, we carried out total RNA sequencing (RNA-seq) to analyze the transcriptomes of brain regions and liver tissues.

Results: Our results reveal preferential 5hmC enrichment in the gene bodies of expressed genes, and 5hmC levels of many protein-coding genes are positively correlated with RNA expression intensity. However, more than 75% of genes with low or no 5hmC enrichment are genes encode for mitochondrial proteins and ribosomal proteins despite being actively transcribed, implying different transcriptional regulation mechanisms of these housekeeping genes. Brain regions developed from the same embryonic structures have more similar 5hmC profiles. Also, the genic 5hmC enrichment pattern is highly tissue-specific, and 5hmC marks genes involving in tissue-specific biological processes. Sex chromosomes are mostly depleted of 5hmC, and the X inactive specific transcript (Xist) gene located on the X chromosome is the only gene to show sex-specific 5hmC enrichment.

Conclusions: This is the first report of the whole-genome 5hmC methylome of five major brain structures and liver tissues in mice of both sexes. This study offers a comprehensive resource for future work of mammalian cytosine methylation dynamics. Our findings offer additional evidence that suggests 5hmC is an active epigenetic mark stably maintained after the global reprogramming event during early embryonic development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170779PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5268415PMC
August 2017

Regulation of IL-20 Expression by Estradiol through KMT2B-Mediated Epigenetic Modification.

PLoS One 2016 2;11(11):e0166090. Epub 2016 Nov 2.

Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei 11221, Taiwan, Republic of China.

Cytokines are low molecular weight regulatory proteins, or glycoproteins, with both tumor-promoting and inhibitory effects on breast cancer growth. Different cytokines play important roles in breast cancer initiation and progression. Here, we show that of the 39 interleukin (IL) genes, IL-20 is the only gene over-expressed in MCF-7 cells treated with estradiol (E2) and that induction of IL-20 expression by estrogen was epigenetically regulated. Methylation of histone H3K4 in the IL-20 promoter was shown to occur via the specific recruitment of KMT2B by estrogen receptor alpha (ERα), but not by other members of the mixed-lineage leukemia (MLL) family of histone methyltransferases. Depletion of KMT2B, or IL-20, disrupts estrogen signaling, attenuates cell proliferation, reduces colony formation, and results in cell cycle arrest. Furthermore, we demonstrated that KMT2B-mediated epigenetic modification also affected the expression of several ERα target genes. IL-20 and KMT2B expression were also associated with ERα-positive breast cancer tissues. We have revealed an important role for KMT2B in the epigenetic transcriptional regulation of cytokine IL-20, and other ERα-responsive genes, in breast cancer cells. Inhibition of IL-20 and KMT2B may have therapeutic benefits in ERα-positive breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166090PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091760PMC
June 2017

An H2A Histone Isotype, H2ac, Associates with Telomere and Maintains Telomere Integrity.

PLoS One 2016 26;11(5):e0156378. Epub 2016 May 26.

Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, 11221, Taiwan, Republic of China.

Telomeres are capped at the ends of eukaryotic chromosomes and are composed of TTAGGG repeats bound to the shelterin complex. Here we report that a replication-dependent histone H2A isotype, H2ac, was associated with telomeres in human cells and co-immunoprecipitates with telomere repeat factor 2 (TRF2) and protection of telomeres protein 1 (POT1), whereas other histone H2A isotypes and mutations of H2ac did not bind to telomeres or these two proteins. The amino terminal basic domain of TRF2 was necessary for the association with H2ac and for the recruitment of H2ac to telomeres. Depletion of H2ac led to loss of telomeric repeat sequences, the appearance of dysfunctional telomeres, and chromosomal instability, including chromosomal breaks and anaphase bridges, as well as accumulation of telomere-associated DNA damage factors in H2ac depleted cells. Additionally, knockdown of H2ac elicits an ATM-dependent DNA damage response at telomeres and depletion of XPF protects telomeres against H2ac-deficiency-induced G-strand overhangs loss and DNA damage response, and prevents chromosomal instability. These findings suggest that the H2A isotype, H2ac, plays an essential role in maintaining telomere functional integrity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156378PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882029PMC
July 2017

Suppression of antioxidant Nrf-2 and downstream pathway in H9c2 cells by advanced glycation end products (AGEs) via ERK phosphorylation.

Biochimie 2015 Nov 26;118:8-14. Epub 2015 Jul 26.

Graduate Institute of Medical Sciences, Collage of Health Science, Tainan, Taiwan; Innovate Research Center of Medicine, Chang Jung Christian University, Tainan, Taiwan.

Diabetic cardiomyopathy is related to oxidative stress and correlated with the presence of advanced glycation end products (AGEs). In a clinical setting, AGEs can be detected in patients presenting diabetic cardiomyopathy; however, the underlying mechanism has yet to be elucidated. In our previous study, AGEs increase cell hypertrophy via ERK phosphorylation in a process closely related to ROS production. Thus, we propose that AGEs regulate the antioxidant gene nuclear factor-erythroid 2-related factor (Nrf-2). In H9c2 cells treated with AGEs, the expression of Nrf-2 was reduced; however, ERK phosphorylation was shown to increase. Treatment with H2O2 was also shown to increase Nrf-2 and ERK phosphorylation. In cells pretreatment with ROS scavenger NAC, the effects of H2O2 were reduced; however, the effects of the AGEs remained largely unchanged. Conversely, when cells were pretreated with PD98059 (ERK inhibitor), the expression of Nrf-2 was recovered following treatment with AGEs. Our results suggest that AGEs inhibit Nrf-2 via the ERK pathway; however, this influence is partly associated with ROS. Our finding further indicated that AGEs possess both ROS-dependent and ROS-independent pathways, resulting in a reduction in Nrf-2. This report reveals an important mechanism underlying the regulation of diabetic cardiomyopathy progression by AGEs.
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http://dx.doi.org/10.1016/j.biochi.2015.07.019DOI Listing
November 2015