Publications by authors named "Yu-Hsiang Kuan"

77 Publications

Glycerol Improves Intracerebral Hemorrhagic Brain Injury and Associated Kidney Dysfunction in Rats.

Antioxidants (Basel) 2021 Apr 19;10(4). Epub 2021 Apr 19.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan.

In stroke patients, the development of acute kidney injury (AKI) is closely linked with worse outcomes and increased mortality. In this study, the interplay between post-stroke and AKI and treatment options was investigated in a rodent model of hemorrhagic stroke. Intrastriatal collagenase injection for 24 h caused neurological deficits, hematoma formation, brain edema, apoptosis, blood-brain barrier disruption, oxidative stress, and neuroinflammation in Sprague Dawley rats. Elevation of serum blood urea nitrogen, serum creatinine, urine cytokine-induced neutrophil chemoattractant-1, and urine Malondialdehyde, as well as moderate histological abnormality in the kidney near the glomerulus, indicated evidence of kidney dysfunction. The accumulation of podocalyxin DNA in urine further suggested a detachment of podocytes and structural deterioration of the glomerulus. Circulating levels of stress hormones, such as epinephrine, norepinephrine, corticosterone, and angiotensin II were elevated in rats with intracerebral hemorrhage. Osmotic agent glycerol held promising effects in alleviating post-stroke brain injury and kidney dysfunction. Although the detailed protective mechanisms of glycerol have yet to be determined, the intrastriatal collagenase injection hemorrhagic stroke model in rats allowed us to demonstrate the functional and structural integrity of glomerulus are targets that are vulnerable to post-stroke injury and stress hormones could be surrogates of remote communications.
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http://dx.doi.org/10.3390/antiox10040623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073011PMC
April 2021

Endoplasmic Reticulum Stress Contributes to Gefitinib-Induced Apoptosis in Glioma.

Int J Mol Sci 2021 Apr 11;22(8). Epub 2021 Apr 11.

Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.

Adequate stress on the Endoplasmic Reticulum (ER) with the Unfolded Protein Response (UPR) could maintain glioma malignancy. Uncontrolled ER stress, on the other hand, predisposes an apoptosis-dominant UPR program. We studied here the proapoptotic actions of the Epidermal Growth Factor Receptor (EGFR) inhibitor gefitinib, with the focus on ER stress. The study models were human H4 and U87 glioma cell lines. We found that the glioma cell-killing effects of gefitinib involved caspase 3 apoptotic cascades. Three branches of ER stress, namely Activating Transcription Factor-6 (ATF6), Protein Kinase R (PKR)-Like ER Kinase (PERK), and Inositol-Requiring Enzyme 1 (IRE1), were activated by gefitinib, along with the elevation of intracellular free Ca, Reactive Oxygen Species (ROS), and NADPH Oxidase2/4 (NOX2/4). Specifically, elevated IRE1 phosphorylation, Tumor Necrosis Factor (TNF) Receptor-Associated Factor-2 (TRAF2) expression, Apoptosis Signal-Regulating Kinase-1 (Ask1) phosphorylation, c-Jun N-Terminal Kinase (JNK) phosphorylation, and Noxa expression appeared in gefitinib-treated glioma cells. Genetic, pharmacological, and biochemical studies further indicated an active ROS/ER stress/Ask1/JNK/Noxa axis causing the glioma apoptosis induced by gefitinib. The findings suggest that ER-stress-based therapeutic targeting could be a promising option in EGFR inhibitor glioma therapy, and may ultimately achieve a better patient response.
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http://dx.doi.org/10.3390/ijms22083934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069544PMC
April 2021

Observation of the Expression of Vascular Endothelial Growth Factor and the Potential Effect of Promoting Hair Growth Treated with Chinese Herbal BeauTop.

Evid Based Complement Alternat Med 2021 17;2021:6667011. Epub 2021 Feb 17.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

Despite minoxidil and finasteride already being approved by the Food and Drug Administration (FDA) for the treatment of hair loss, it is important to identify new and innovative treatments for hair loss, such as looking for a solution in Chinese herbal medicine. One such treatment to consider is BeauTop (BT), whose primary ingredients include (T.Nees), C.A. Mey. (Araliaceae), (Fisch) Bunge (Fabaceae), (Oliv.) Diels (Apiaceae), W.T. Aiton (Oleaceae), (Gaertn.) DC. (Plantaginaceae), and (L.) . (Compositae). The aim of this study was to evaluate whether BT can promote hair growth in C57BL/6 mice and to investigate hair coverage, the expression of vascular endothelial growth factor (VEFG), and the numbers of hair follicles in growth phase after oral administration. A total of 12 C57BL/6 mice were divided into two groups: control group and treatment group BT. BT was administered orally as an extract at a volume of 0.6 g/kg. The control group was treated with distilled water. Each group was treated once a day for 12 consecutive days. To observe the expression of VEGF distribution, the number of hair follicles and the hair coverage were examined on days 4, 8, and 12. By comparing the treatment group and control group, we found that VEGF in the BT group on day 8 presented with a higher area percentage than the control group ( value = 0.003). Hair follicle counting results showed that the BT group was significantly higher than the control group on day 8 ( value = 0.031). Furthermore, hair coverage was shown to be significantly increased in the treatment group BT on day 8 ( value = 0.013). Taken together, these results suggest that Chinese medicine (BT) possesses the potential effect of promoting hair growth through VEGF expression. VEGF is considered the most important mediator for the process of angiogenesis involved in hair growth development.
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http://dx.doi.org/10.1155/2021/6667011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904352PMC
February 2021

Genotoxic effects of 1-nitropyrene in macrophages are mediated through a p53-dependent pathway involving cytochrome c release, caspase activation, and PARP-1 cleavage.

Ecotoxicol Environ Saf 2021 Apr 20;213:112062. Epub 2021 Feb 20.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address:

Genotoxic stress from environmental pollutants plays a critical role in cytotoxicity. The most abundant nitro-polycyclic aromatic hydrocarbon in environmental pollutants, 1-nitropyrene (1-NP), is generated during fossil fuel, diesel, and biomass combustion under sunlight. Macrophages, the key regulators of the innate immune system, provide the first line of defense against pathogens. The toxic effects of 1-NP on macrophages remain unclear. Through a lactate dehydrogenase assay, we measured the cytotoxicity induced by 1-NP. Our results revealed that 1-NP induced genotoxicity also named DNA damage, including micronucleus formation and DNA strand breaks, in a concentration-dependent manner. Furthermore, 1-NP induced p53 phosphorylation and nuclear accumulation; mitochondrial cytochrome c release; caspase-3 and -9 activation and cleavage; and poly (ADP-ribose) polymerase-1 (PARP-1) cleavage in a concentration-dependent manner. Pretreatment with the PARP inhibitor, 3-aminobenzamide, significantly reduced cytotoxicity, genotoxicity, and PARP-1 cleavage induced by 1-NP. Pretreatment with the caspase-3 inhibitor, z-DEVD-fmk, significantly reduced cytotoxicity, genotoxicity, PARP-1 cleavage, and caspase 3 activation induced by 1-NP. Pretreatment with the p53 inhibitor, pifithrin-α, significantly reduced cytotoxicity, genotoxicity, PARP-1 cleavage, caspase 3 activation, and p53 phosphorylation induced by 1-NP. We propose that cytotoxicity and genotoxicity induced by 1-NP by PARP-1 cleavage via caspase-3 and -9 activation through cytochrome c release from mitochondria and its upstream p53-dependent pathway in macrophages.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112062DOI Listing
April 2021

Association Between PM Exposure Level and Primary Open-Angle Glaucoma in Taiwanese Adults: A Nested Case-Control Study.

Int J Environ Res Public Health 2021 02 10;18(4). Epub 2021 Feb 10.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.

Primary open-angle glaucoma (POAG) is the most common type of glaucoma. However, little is known about POAG in adults and exposure to air pollution. The current study aims to investigate whether exposure to particulate matter with a mass median aerodynamic diameter of ≤2.5 μm (PM) is associated with POAG diagnosis. Patient data were obtained from the Longitudinal Health Insurance Database 2010 (LHID2010) of Taiwan for the 2008-2013 period. PM concentration data, collected from the Ambient Air Quality Monitoring Network established by the Environmental Protection Administration of Taiwan, were categorized into four groups according to World Health Organization (WHO) exposure standards for PM. We estimated the odds ratios (ORs) and 95% CIs for risk factors for POAG with logistic regression. The OR of per WHO standard level increase was 1.193 (95% CI 1.050-1.356). Compared with the normal level, the OR of WHO 2.0 level was 1.668 (95% CI 1.045-2.663, < 0.05). After excluding confounding risk factors for POAG in this study, we determined that increased PM exposure is related to POAG risk (ORs > 1, < 0.05). In this study, PM was an independent factor associated with open-angle glaucoma. Further research is required to better understand the mechanisms connecting PM and open-angle glaucoma.
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http://dx.doi.org/10.3390/ijerph18041714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916685PMC
February 2021

Protective Effects of Kirenol against Lipopolysaccharide-Induced Acute Lung Injury through the Modulation of the Proinflammatory NFκB Pathway and the AMPK2-/Nrf2-Mediated HO-1/AOE Pathway.

Antioxidants (Basel) 2021 Jan 31;10(2). Epub 2021 Jan 31.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.

Acute lung injury (ALI) is an acute and life-threatening inflammatory disease of the lung parenchyma that is associated with high mortality worldwide. No therapeutic strategies have been developed for the mitigation of the proinflammatory response that characterizes ALI. Kirenol has anti-inflammatory, antiarthritic, and immunoregulatory effects. In the present study, we investigated the protective effects of kirenol against lipopolysaccharides (LPS)-induced ALI in mice. Kirenol reduced the LPS-induced histopathology changes involving edema and thickening of the interstitial or alveolar walls, infiltration of leukocytes, formation of hyaline membrane. Pretreatment with kirenol reduced leukocytes infiltration in bronchoalveolar lavage fluid (BALF), the alveolar-capillary barrier disruption and lipid peroxidation in lung tissues induced by LPS. Kirenol significantly inhibited the secretion of cytokines, IL-1β, IL6, and TNFα, into the BALF of the mice with LPS-induced ALI through NFκB activation. Moreover, kirenol attenuated the downregulation of the antioxidant enzymes, superoxide dismutase, glutathione peroxidase, and catalase that was induced by LPS. HO-1 expression and the phosphorylation of Nrf2 and AMPK2 were also induced by kirenol. The results indicate that kirenol can be developed as a treatment strategy for ALI, and its effects are induced through the inhibition of the NF-κB proinflammatory pathway and promotion of AMPK2/Nrf2-mediated HO-1 and antioxidant enzymes (AOE) activation.
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http://dx.doi.org/10.3390/antiox10020204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911485PMC
January 2021

Oral treatment for diabetes using α-glucosidase inhibitors was a risk factor for chronic obstructive pulmonary disease: a cohort study.

Int J Med Sci 2021 1;18(3):778-784. Epub 2021 Jan 1.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

Currently, diabetes mellitus (DM) and chronic obstructive pulmonary disease (COPD) have proven to be risk factors for each other. This study aimed to determine the risk relationship between COPD and five common oral medications for DM among patients with DM. This population-based cohort study was conducted from 2008 to 2013. Patient data were retrieved from the Longitudinal Health Insurance Database (LHID) of the National Health Insurance Research Database (NHIRD). After pairing by gender, age, and index date, time-to-event analysis and multiple regression analysis were performed to determine the factors associated with COPD in patients taking oral medication for DM, including age, gender, income, and comorbidities. We identified 1,028 patients who took oral medication for DM and 1,028 controls who did not take oral medication for DM. We observed that the use of α-glucosidase inhibitors was associated with a higher risk of COPD (hazard ratio [HR]: 1.964, 95% confidence interval [CI]: 1.207-2.380). Furthermore, compared with the control group, α-glucosidase inhibitor users had a higher risk of COPD (HR: 2.295, 95% CI: 1.304-4.038), and no significant difference was observed in other oral medications for DM. Based on present results, we could suggest that patients with DM who used α-glucosidase inhibitors are probably a higher risk of COPD. We recommend that in the future, treatment with α-glucosidase inhibitors upregulate the occurrence of COPD might through gastrointestinal side effects and malnutrition.
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http://dx.doi.org/10.7150/ijms.55361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797545PMC
January 2021

Effects of Rutin on Wound Healing in Hyperglycemic Rats.

Antioxidants (Basel) 2020 Nov 13;9(11). Epub 2020 Nov 13.

Department of Nutrition, Chung Shan Medical University, Taichung City 40201, Taiwan.

Long-term poor glycemic control negatively affects macrovascular and microvascular diseases, as well as wound restoration. Buckwheat is a good source of rutin (quercetin-3-O-rutoside) and has benefits in regulating blood sugar. This study was to evaluate the antioxidant and anti-inflammatory effects of rutin on wound healing in streptozotocin-induced hyperglycemic rats. Eighteen male Wistar rats were randomly divided into three groups: normal (NDM), hyperglycemic (DM), and hyperglycemic with rutin (DMR). After induction of hyperglycemia for 2 days, a 15 × 15 mm wound was induced on the back of each rat. Intraperitoneal injection of rutin significantly ameliorated diabetes-induced body weight loss and improved metabolic dysfunctions of hyperglycemic rats. Based on appearance and histopathological staining, rutin promotes wound healing and inhibits production of inflammatory cells. The immunoblotting data indicated that rutin promotes production of antioxidant enzymes induced by nuclear factor erythroid 2-related factor 2 (NRF2), inhibits the expression of matrix metalloproteinases (MMPs) regulated by NF-κB, and decreases the expression of vascular endothelial growth factor (VEGF). It also promotes the expression of neurogenic-related protein (UCH-L1). The aforementioned results indicated that rutin reduces oxidative stress and inflammatory response in hyperglycemic rats, promoting wound healing and subsequently reducing the risk of wound ulcers.
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http://dx.doi.org/10.3390/antiox9111122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696622PMC
November 2020

Safrole-induced expression of proinflammatory responses is associated with phosphorylation of mitogen-activated protein kinase family and the nuclear factor-κB/inhibitor of κB pathway in macrophages.

Tzu Chi Med J 2020 Oct-Dec;32(4):344-350. Epub 2020 Aug 6.

Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan.

Objective: Safrole, also called shikimol and Sassafras, is the carcinogenic and phenylpropanoid compound extracted from Sassafras tree and anise, betel, and camphor. Moreover, a high concentration of safrole can be occur in the saliva because of betel nut or areca quid chewing which a common habit observed in Southern and Southeastern Asia. Notably, macrophages are crucial phagocytic cells of the immune system. Nonetheless, to date, no evidence has been reported regarding safrole-induced proinflammatory response and the corresponding mechanism in macrophages.

Materials And Methods: In the present study, the cytokines expression, NO generation, protein phosphorylation, and expression were assessed by enzyme-linked immunosorbent assay, Griess reagent, and Western blot assay, respectively.

Results: In this study, we determined that safrole induces the generation of nitric oxide and proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and IL-6 in RAW264.7 macrophages in a concentration-dependent manner. Furthermore, inhibitor of κB (IκB) degradation was caused by safrole in a concentration-dependent manner. In addition, the phosphorylation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) family, including p38 MAPK, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase, was induced by safrole began to increase at 10 μM and attained a plateau at 100 μM.

Conclusion: These results indicated that safrole induces the expression of proinflammatory responses in macrophages through the NF-κB/IκB pathway and its upstream factor, MAPK family phosphorylation.
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http://dx.doi.org/10.4103/tcmj.tcmj_78_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605287PMC
August 2020

Rutin-protected BisGMA-induced cytotoxicity, genotoxicity, and apoptosis in macrophages through the reduction of the mitochondrial apoptotic pathway and induction of antioxidant enzymes.

Environ Toxicol 2020 Aug 24. Epub 2020 Aug 24.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

Bisphenol-A-glycidyldimethacrylate (BisGMA) is a resin monomer frequently used in dentin restorative treatments. The leakage of BisGMA monomer from BisGMA-based polymeric resins can lead to cytotoxicity in macrophages. Rutin has various beneficial bioeffects, including antioxidation and antiinflammation. In this study, we found that pretreatment of RAW264.7 macrophages with rutin-inhibited cytotoxicity induced by BisGMA in a concentration-dependent manner. BisGMA-induced apoptosis, which was detected by levels of phosphatidylserine from the internal to the external membrane and formation of sub-G1, and genotoxicity, which was detected by cytokinesis-blocked micronucleus and single-cell gel electrophoresis assays, were inhibited by rutin in a concentration-dependent manner. Rutin suppressed the BisGMA-induced activation of caspase-3 and -9 rather than caspase-8. Rutin inhibited the activation of the mitochondrial apoptotic pathway, including cytochrome C release and mitochondria disruption, after macrophages were treated with BisGMA. Finally, BisGMA-induced reactive oxygen species (ROS) generation and antioxidant enzyme (AOE) deactivation could be reversed by rutin. Parallel trends were observed in the elevation of AOE activation and inhibition of ROS generation, caspase-3 activity, mitochondrial apoptotic pathway activation, and genotoxicity. These results suggested that rutin suppressed BisGMA-induced cytotoxicity through genotoxicity, the mitochondrial apoptotic pathway, and relatively upstream factors, including reduction of ROS generation and induction of AOE.
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http://dx.doi.org/10.1002/tox.23009DOI Listing
August 2020

Propofol Improved Glucose Tolerance Associated with Increased FGF-21 and GLP-1 Production in Male Sprague-Dawley Rats.

Molecules 2020 Jul 15;25(14). Epub 2020 Jul 15.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan.

Anesthetics, particularly volatile anesthetics, have been shown to impair glucose metabolism and cause hyperglycemia, closely linking them with mortality and morbidity as related to surgery. Beyond being an anesthetic used for general anesthesia and sedation, intravenous hypnotic propofol displays an effect on glucose metabolism. To extend the scope of propofol studies, its effects on glucose metabolism were evaluated in male Sprague-Dawley rats of various ages. Unlike chloral hydrate and isoflurane, propofol had little effect on basal glucose levels in rats at 2 months of age, although it did reduce chloral hydrate- and isoflurane-induced hyperglycemia. Propofol reduced postload glucose levels after either intraperitoneal or oral administration of glucose in both 7- and 12-month-old rats, but not those at 2 months of age. These improved effects regarding propofol on glucose metabolism were accompanied by an increase in insulin, fibroblast growth factor-21 (FGF-21), and glucagon-like peptide-1 (GLP-1) secretion. Additionally, an increase in hepatic FGF-21 expression, GLP-1 signaling, and FGF-21 signaling, along with a decrease in endoplasmic reticulum (ER) stress, were noted in propofol-treated rats at 7 months of age. Current findings imply that propofol may turn into insulin-sensitizing molecules during situations of existing insulin resistance, which involve FGF-21, GLP-1, and ER stress.
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http://dx.doi.org/10.3390/molecules25143229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397023PMC
July 2020

Quercetin protects against cerebral ischemia/reperfusion and oxygen glucose deprivation/reoxygenation neurotoxicity.

J Nutr Biochem 2020 09 30;83:108436. Epub 2020 May 30.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung City, Taiwan. Electronic address:

Beyond nutrition effect, quercetin is applied as a complement or an alternative for promoting human health and treating diseases. However, its complicated neuroprotective mechanisms have not yet been fully elucidated. This study provides evidence of an alternative target for quercetin, and sheds light on the mechanisms of its neuroprotection against cerebral ischemia/reperfusion (I/R) injury in Sprague-Dawley rats. Oral pretreatment using quercetin has alleviated cerebral I/R-induced neurological deficits, brain infarction, blood-brain barrier disruption, oxidative stress, TNF-α and IL-1β mRNA expression, along with apoptotic caspase 3 activity. The neuroprotective, anti-oxidative, anti-inflammatory, and anti-apoptotic effects of quercetin were replicated in rat hippocampal slice cultures and neuron/glia cultures which suffered from oxygen-glucose deprivation and reoxygenation (OGDR). Biochemical studies revealed a reduction of extracellular signal-regulated kinase (ERK) and Akt phosphorylation, along with an increase in protein tyrosine and serine/threonine phosphatase activity in cerebral I/R rat cortical tissues and OGDR hippocampal slice and neuron/glia cultures. Quercetin alleviated the changes in ERK/Akt phosphorylation and protein phosphatase activities. Inhibition of ERK or Akt alone was enough to cause apoptotic cell death and cytotoxicity in hippocampal slice cultures and neuron/glia cultures, while activators of ERK or Akt alleviated OGDR-induced cytotoxicity. Taken together, our results demonstrate that quercetin alleviated the increment of protein tyrosine and serine/threonine phosphatase activity, along with the reduction of ERK and Akt phosphorylation, which may play pivotal roles in the expansion of brain injury after cerebral I/R.
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http://dx.doi.org/10.1016/j.jnutbio.2020.108436DOI Listing
September 2020

Toxic Effects of Urethane Dimethacrylate on Macrophages Through Caspase Activation, Mitochondrial Dysfunction, and Reactive Oxygen Species Generation.

Polymers (Basel) 2020 Jun 22;12(6). Epub 2020 Jun 22.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, 402 Taichung, Taiwan.

Urethane dimethacrylate (UDMA) is a dimethacrylate-based resin monomer that can react with other related monomers and inorganic particles, causing hydrophobic polymerization through cross-linking upon light activation. UDMA polymers are commonly used for the reconstruction and reinforcement of teeth and bones. UDMA can become unbound and be released from light-cured polymer resins. Thus far, no evidence exists on the toxic effects of UDMA and its related working mechanisms for macrophages. Therefore, in the present study, we investigated the cytotoxicity, mode of cell death, DNA damage, caspase activities, mitochondrial dysfunction, and reactive oxygen species (ROS) generation in RAW264.7 macrophages treated with UDMA using the lactate dehydrogenase (LDH) assay kit, Annexin V-FITC and PI assays, micronucleus formation and comet assay, caspase fluorometric assay, JC-1 assay, and 2',7'-dichlorofluorescin diacetate (DCFH-DA) assay, respectively. Our results show that UDMA induced cytotoxicity; apoptosis and necrosis; genotoxicity, which is also called DNA damage; increased caspase-3, -8, and -9 activities; mitochondrial dysfunction; and intracellular ROS generation in a concentration-dependent manner in RAW264.7 macrophages. Thus, based on the observed inhibited concentration parallel trends, we concluded that UDMA induces toxic effects in macrophages. Furthermore, UDMA-induced intracellular ROS generation, cytotoxicity, and DNA damage were reduced by N-acetyl-L-cysteine.
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http://dx.doi.org/10.3390/polym12061398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361960PMC
June 2020

-Glucosidase Inhibitor Can Effectively Inhibit the Risk of Tuberculosis in Patients with Diabetes: A Nested Case-Control Study.

Biomed Res Int 2020 19;2020:8085106. Epub 2020 May 19.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

Diabetes mellitus (DM) and tuberculosis (TB) are major public health and economic burdens. DM increases Mycobacterium tuberculosis (M.tb) infection rates and treatment durations. This study evaluated the relationship between five classes of oral DM medications and TB infection risk in DM patients. We used longitudinal records from the Taiwan Longitudinal Health Insurance Research Database. DM patients were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 250 and A code A181. TB patients were identified using ICD-9-CM code 010.x-017.x. Oral DM medications were divided into five classes: sulfonylureas, biguanides, meglitinides, -glucosidase inhibitors (AGIs), and thiazolidinediones. Users were classified as nonusers, low-concentration users, and high-concentration users. The incidence rate ratio (IRR) was derived using multivariate Poisson regression to calculate the relative risk of TB infection. DM patients using low- and high-concentration AGIs had significantly lower TB infection risks compared with nonusers. The IRRs of the sulfonylureas and AGI users were [CI] 0.693-0.948) and (95% CI 0.651-0.995), respectively. The other four classes of medications exhibited no significant effect on TB infection risk in DM patients. Furthermore, DM patients using high-concentration AGIs had a significantly lower TB infection risk compared with those using low-concentration AGIs (IRR 0.918, 95% CI: 0.854-0.987). We noted a dose-response relationship in the effects of DM medications on TB risk. Accordingly, we suggest that DM patients use AGIs to benefit from their protective effect on TB infection risk.
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http://dx.doi.org/10.1155/2020/8085106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254087PMC
March 2021

Effects of β-Adrenergic Blockade on Metabolic and Inflammatory Responses in a Rat Model of Ischemic Stroke.

Cells 2020 06 1;9(6). Epub 2020 Jun 1.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan.

Ischemic stroke provokes an inflammatory response concurrent with both sympathetic nervous system activation and hyperglycemia. Currently, their crosstalk and consequences in stroke outcomes are of clinical attraction. We have provided experimental evidence showing the suppressive effects of the nonselective β-adrenoreceptor antagonist propranolol on hyperglycemia, inflammation, and brain injury in a rat model experiencing cerebral ischemia. Pretreatment with propranolol protected against postischemic brain infarction, edema, and apoptosis. The neuroprotection caused by propranolol was accompanied by a reduction in fasting glucose, fasting insulin, glucose tolerance impairment, plasma C-reactive protein, plasma free fatty acids, plasma corticosterone, brain oxidative stress, and brain inflammation. Pretreatment with insulin alleviated-while glucose augmented-postischemic brain injury and inflammation. Additionally, the impairment of insulin signaling in the gastrocnemius muscles was noted in rats with cerebral ischemia, with propranolol improving the impairment by reducing oxidative stress and tumor necrosis factor-α signaling. The anti-inflammatory effects of propranolol were further demonstrated in isoproterenol-stimulated BV2 and RAW264.7 cells through its ability to decrease cytokine production. Despite their potential benefits, stroke-associated hyperglycemia and inflammation are commonly linked with harmful consequences. Our findings provide new insight into the anti-inflammatory, neuroprotective, and hypoglycemic mechanisms of propranolol in combating neurodegenerative diseases, such as stroke.
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http://dx.doi.org/10.3390/cells9061373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349353PMC
June 2020

β-Funaltrexamine Displayed Anti-inflammatory and Neuroprotective Effects in Cells and Rat Model of Stroke.

Int J Mol Sci 2020 May 29;21(11). Epub 2020 May 29.

Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan.

Chronic treatment involving opioids exacerbates both the risk and severity of ischemic stroke. We have provided experimental evidence showing the anti-inflammatory and neuroprotective effects of the μ opioid receptor antagonist β-funaltrexamine for neurodegenerative diseases in rat neuron/glia cultures and a rat model of cerebral Ischemia/Reperfusion (I/R) injury. Independent of in vitro Lipopolysaccharide (LPS)/interferon (IFN-γ)-stimulated neuron/glia cultures and in vivo cerebral I/R injury in Sprague-Dawley rats, β-funaltrexamine downregulated neuroinflammation and ameliorated neuronal degeneration. Alterations in microglia polarization favoring the classical activation state occurred in LPS/IFN-γ-stimulated neuron/glia cultures and cerebral I/R-injured cortical brains. β-funaltrexamine shifted the polarization of microglia towards the anti-inflammatory phenotype, as evidenced by decreased nitric oxide, tumor necrosis factor-α, interleukin-1β, and prostaglandin E2, along with increased CD163 and arginase 1. Mechanistic studies showed that the suppression of microglia pro-inflammatory polarization by β-funaltrexamine was accompanied by the reduction of NF-κB, AP-1, cyclic AMP response element-binding protein, along with signal transducers and activators of transcription transcriptional activities and associated upstream activators. The effects of β-funaltrexamine are closely linked with its action on neuroinflammation by switching microglia polarization from pro-inflammatory towards anti-inflammatory phenotypes. These findings provide new insights into the anti-inflammatory and neuroprotective mechanisms of β-funaltrexamine in combating neurodegenerative diseases, such as stroke.
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http://dx.doi.org/10.3390/ijms21113866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313048PMC
May 2020

Evaluation of cytotoxicity, apoptosis, and genotoxicity induced by indium chloride in macrophages through mitochondrial dysfunction and reactive oxygen species generation.

Ecotoxicol Environ Saf 2020 Apr 27;193:110348. Epub 2020 Feb 27.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address:

Due to rapid advances in the era of electronic technologies, indium has played the important material for the production of liquid crystal display screens in the semiconductor and optoelectronic industries. The present study focuses on evaluating the toxic effects and related mechanisms of indium chloride (InCl) on RAW264.7 macrophages. Cytotoxicity was induced by InCl in a concentration- and time-dependent manner. InCl had the ability to induce macrophage death through apoptosis rather than through necrosis. According to the cytokinesis-block micronucleus assay and alkaline single-cell gel electrophoresis assay, InCl induced DNA damage, also called genotoxicity, in a concentration-dependent manner. Cysteine-dependent aspartate-directed protease (caspase)-3, -8, and -9 were activated by InCl in a concentration-dependent manner. Mitochondria dysfunction and cytochrome c release from the mitochondria were induced by InCl in a concentration-dependent manner. Downregulation of BCL2 and upregulation of BAD were induced by InCl in a concentration-dependent manner. More, we proposed that InCl treatment generated reactive oxygen species (ROS) in a concentration-dependent manner. In conclusion, the current study revealed that InCl induced macrophage cytotoxicity, apoptosis, and genotoxicity via a mitochondria-dependent apoptotic pathway and ROS generation.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110348DOI Listing
April 2020

Epidemiological Characteristics of Postoperative Sepsis.

Open Med (Wars) 2019 31;14:928-938. Epub 2019 Dec 31.

Department of Pharmacology, School of Medicine, Chung Shan Medical University; Department of Pharmacy, Chung Shan Medical University Hospital, No.110, Sec. 1, Jianguo N. Rd, Taichung, Taiwan, Republic of China.

Background: Postoperative sepsis is a major type of sepsis. Sociodemographic characteristics, incidence trends, surgical procedures, comorbidities, and organ system dysfunctions related to the disease burden of postoperative sepsis episodes are unclear.

Methods: We analyzed epidemiological characteristics of postoperative sepsis based on the ICD-9-CM codes for the years 2002 to 2013 using the Longitudinal Health Insurance Databases of Taiwan's National Health Insurance Research Database.

Results: We identified 5,221 patients with postoperative sepsis and 338,279 patients without postoperative sepsis. The incidence of postoperative sepsis increased annually with a crude mean of 0.06% for patients aged 45-64 and 0.34% over 65 years. Patients with postoperative sepsis indicated a high risk associated with the characteristics, male sex (OR:1.375), aged 45-64 or ≥ 65 years (OR:2.639 and 5.862), low income (OR:1.390), aged township (OR:1.269), agricultural town (OR:1.266), and remote township (OR:1.205). Splenic surgery (OR:7.723), Chronic renal disease (OR:1.733), cardiovascular dysfunction (OR:2.441), and organ system dysfunctions had the highest risk of postoperative sepsis.

Conclusion: Risk of postoperative sepsis was highest among men, older, and low income. Patients with splenic surgery, chronic renal comorbidity, and cardiovascular system dysfunction exhibited the highest risk for postoperative sepsis. The evaluation of high-risk factors assists in reducing the disease burden.
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http://dx.doi.org/10.1515/med-2019-0110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972282PMC
December 2019

Correlation between Gout and Coronary Heart Disease in Taiwan: A Nationwide Population-Based Cohort Study.

Acta Cardiol Sin 2019 Nov;35(6):634-640

Department of Pharmacology, Chung Shan Medical University.

Background: Gout is the most common inflammatory arthritis in adult males. Patients with gout are at a higher risk of coronary heart disease (CHD). This study aimed to investigate the correlation between gout and CHD.

Methods: This was a retrospective cohort study that used data from the Longitudinal Health Insurance Database of Taiwan. The study subjects were 46,140 patients with new-onset gout during 2003-2010. To avoid selection bias, we used propensity score matching. A Cox proportional hazard model was used to analyze differences in the risk of CHD between patients with and without gout after controlling for related variables.

Results: The patients with gout had a higher risk of CHD than the patients without gout [adjusted hazards ratio (HR) = 1.34, 95% confidence interval (CI): 1.23-1.45]. The risk of CHD increased with older age. Other related factors for CHD included gender (female vs. male, adjusted HR = 0.86, 95% CI: 0.79-0.93), hypertension (adjusted HR = 1.53, 95% CI: 1.42-1.65), hyperlipidemia (adjusted HR = 1.18, 95% CI: 1.07-1.29), and diabetes mellitus (adjusted HR = 1.24, 95% CI: 1.13-1.36).

Conclusions: We found correlations between gout and CHD and other influencing factors including hypertension, hyperlipidemia, and diabetes mellitus. We also found that gender and age were associated with CHD.
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http://dx.doi.org/10.6515/ACS.201911_35(6).20190403BDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859095PMC
November 2019

Nerolidol Suppresses the Inflammatory Response during Lipopolysaccharide-Induced Acute Lung Injury via the Modulation of Antioxidant Enzymes and the AMPK/Nrf-2/HO-1 Pathway.

Oxid Med Cell Longev 2019 16;2019:9605980. Epub 2019 Nov 16.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

Acute lung injury (ALI) is a life-threatening disease that is characterised by the rapid onset of inflammatory responses. Lipopolysaccharide (LPS) is an endotoxin that plays an important role in triggering ALI via pneumonia and sepsis. However, no effective therapeutic strategies are currently available to treat ALI. Nerolidol is an aliphatic sesquiterpene alcohol that is found in the essential oils of many flowers as well as floral plants. It has been shown to exhibit anti-inflammatory, antioxidant, and anticancer properties. Herein, we show that nerolidol pretreatment counteracted the histopathological hallmarks in LPS-induced ALI mice. Indeed, nerolidol pretreatment inhibited LPS-induced alveolar-capillary barrier disruption, lung edema, and lipid peroxidation. Moreover, nerolidol pretreatment prevented the LPS from decreasing the enzymatic activities of superoxide dismutase, catalase, and glutathione peroxidase. Importantly, nerolidol treatment enhanced phosphorylation of AMP-activated protein kinase (AMPK) and expression of nuclear factor erythroid-derived 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1). Taken together, our study reveals the novel protective effects of nerolidol in LPS-induced ALI via the induction of antioxidant responses and activation of the AMPK/Nrf-2/HO-1 signalling pathway.
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http://dx.doi.org/10.1155/2019/9605980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885193PMC
May 2020

Heart valve operations associated with reduced risk of death from mitral valve disease but other operations associated with increased risk of death: a national population-based case-control study.

J Cardiothorac Surg 2019 Sep 14;14(1):165. Epub 2019 Sep 14.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, No.110, Sec. 1, Jianguo N. Rd, Taichung, Taiwan, Republic of China.

Background: Mitral valve disease is the most common heart valve disease worldwide. Heart valve operation is the predominant treatment strategy for heart valve disease. This study analyzed the death risk from heart valve disease with respect to the frequency of heart valve operation and other operations in patients with mitral valve disease.

Materials And Methods: We conducted a retrospective nationwide population-based case-control study using a claims dataset from Taiwan's National Health Insurance Research Database. The case and control groups enrolled mitral valve disease patients from 2002 to 2013 who had either underwent an heart valve operation procedure or not, respectively. Conditional logistic regression was estimated the odds ratios (ORs) associated with various risk factors for heart valve operation-related death, including other operations and comorbidities.

Results: A total of 25,964 patients with mitral valve disease were recruited for the study and divided into heart valve operation (600 patients) and non-heart valve operation (25,364 patients) groups. After matching, a total of 1800 non-heart valve operation patients were selected for final analysis. Heart valve operation was associated with decreased risk of death (adjusted OR [aOR] 0.439), but operations related to other cardiovascular disease (CVD, aOR 3.691), respiratory conditions (aOR 3.210), and the urinary system (aOR 1.925) were associated with increased risk of death for patients with mitral valve disease. Patients with mitral valve disease and diabetes (aOR 1.505), chronic kidney disease (CKD, aOR 3.760), or emphysema (aOR 2.623) also had a higher risk of death. Patients who underwent more heart valve operations had a lower risk of death from mitral valve disease, but patients who underwent more other operations had a higher risk of death from mitral valve disease.

Conclusions: The death risk for patients with mitral valve disease patients could be lowered by more frequently performing heart valve operations. However, the risk of death is increased for patients with mitral valve disease who more frequently undergo other operations, chiefly those for other CVD system, respiratory conditions, and urinary system, or have comorbidities such as diabetes, chronic kidney disease, and emphysema.
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http://dx.doi.org/10.1186/s13019-019-0984-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744637PMC
September 2019

Influence of PM Exposure Level on the Association between Alzheimer's Disease and Allergic Rhinitis: A National Population-Based Cohort Study.

Int J Environ Res Public Health 2019 09 11;16(18). Epub 2019 Sep 11.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.

Alzheimer's disease (AD) is an irreversible neurodegenerative disease that leads to dementia, health impairment, and high economic cost. Allergic rhinitis (AR) is a chronic inflammatory and allergic disease of the respiratory system that leads to health problems and has major effects on the daily lives of patients and their caregivers. Particulate matter (PM) refers to air pollutants 2.5 μm or less in diameter that are a source of concern because of their role in numerous diseases, including AR and other neurodegenerative diseases. To date, no study has demonstrated how PM exacerbates AR and results in AD. We conducted a national population-based cohort study by obtaining patient data from the National Health Insurance Research Database of Taiwan for the 2008-2013 period. PM concentration data were obtained from the ambient air quality monitoring network established by the Environmental Protection Administration of Taiwan. Monthly PM exposure levels were categorized into quartiles from Q1-Q4. The Cox proportional hazards analysis, after adjusting for age, sex, low income, and urbanization level, revealed that patients with AR had an elevated risk of developing AD (hazard ratio (HR): 2.008). In addition, the cumulative incidence of AD in the AR group was significantly higher than in the comparison group. The PM levels at Q2-Q4 (crude HR: 1.663-8.315; adjusted HR: 1.812-8.981) were stratified on the basis of the PM exposure group and revealed that AR patients exposed to PM are significantly prone to develop AD. In addition, the logistic regression analyses, after adjustment, demonstrated that an increase in the PM exposure level at Q2-Q4 (adjusted odds ratio (OR): 2.656-5.604) increased the risk of AR in AD patients. In conclusion, an increased PM exposure level could be correlated with AR, which could in turn cause AD. AR increased the risk of AD, in which exposure to PM increases the higher probability of AD.
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http://dx.doi.org/10.3390/ijerph16183357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765937PMC
September 2019

Fibronectin Promotes Cell Growth and Migration in Human Renal Cell Carcinoma Cells.

Int J Mol Sci 2019 Jun 7;20(11). Epub 2019 Jun 7.

Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.

The prognostic and therapeutic values of fibronectin have been reported in patients with renal cell carcinoma (RCC). However, the underlying mechanisms of malignancy in RCC are not completely understood. We found that silencing of fibronectin expression attenuated human RCC 786-O and Caki-1 cell growth and migration. Silencing of potential fibronectin receptor integrin α5 and integrin β1 decreased 786-O cell ability in movement and chemotactic migration. Biochemical examination revealed a reduction of cyclin D1 and vimentin expression, transforming growth factor-β1 (TGF-β1) production, as well as Src and Smad phosphorylation in fibronectin-silenced 786-O and Caki-1 cells. Pharmacological inhibition of Src decreased 786-O cell growth and migration accompanied by a reduction of cyclin D1, fibronectin, vimentin, and TGF-β1 expression, as well as Src and Smad phosphorylation. In 786-O cells, higher activities in cell growth and migration than in Caki-1 cells were noted, along with elevated fibronectin and TGF-β1 expression. The additions of exogenous fibronectin and TGF-β1 promoted Caki-1 cell growth and migration, and increased cyclin D1, fibronectin, vimentin, and TGF-β1 expression, as well as Src and Smad phosphorylation. These findings highlight the role of fibronectin in RCC cell growth and migration involving Src and TGF-β1 signaling.
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http://dx.doi.org/10.3390/ijms20112792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600362PMC
June 2019

Prescribing Trend of Antirheumatic Drugs in Taiwan and Risk of Cardiovascular Disease in Patients with Rheumatoid Arthritis: A Nationwide Cohort Study.

Biomed Res Int 2019 20;2019:7987529. Epub 2019 Feb 20.

Department of Health Services Administration, China Medical University, Taichung 40402, Taiwan.

We aimed to investigate the prescribing trend of antirheumatic drugs and assess the risk of cardiovascular disease in patients with rheumatoid arthritis in Taiwan. This study was a retrospective cohort study, conducted based on the Taiwan National Health Insurance Research Database. The study subjects were 15,366 new rheumatoid arthritis patients from 2003 to 2010. To avoid selection bias, we applied propensity score matching to obtain general patients, as the control group. Cox proportional hazard model was used to evaluate the risk of cardiovascular disease in rheumatoid arthritis patients. The most common prescriptions of rheumatoid arthritis were nonsteroidal anti-inflammatory drugs. After controlling for related variables, rheumatoid arthritis patients had a higher risk of cardiovascular disease than general patients (adjusted hazard ratio [aHR] = 1.31; 95% confidence interval [CI]: 1.23-1.39). Age was the most significantly associated risk factor with the cardiovascular disease. Other observed risk factors for cardiovascular disease included hypertension (aHR = 1.57, 95% CI: 1.48-1.65), diabetes mellitus (aHR = 1.47, 95% CI: 1.38-1.57), and chronic kidney disease (aHR = 1.48, 95% CI: 1.31-1.66). Patients with rheumatoid arthritis indeed had a higher risk of incident cardiovascular diseases. Besides, age, hypertension, diabetes mellitus, and chronic kidney disease were also associated with a higher risk of cardiovascular disease.
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http://dx.doi.org/10.1155/2019/7987529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402220PMC
July 2019

Correlation between diabetes mellitus and periodontitis in Taiwan: A nationwide cohort study.

Diabetes Res Clin Pract 2019 Apr 14;150:245-252. Epub 2019 Mar 14.

Department of Health Services Administration, China Medical University, Taichung, Taiwan. Electronic address:

Aims: The mechanism underlying the association of diabetes mellitus (DM) and periodontitis is not clear. This study aimed to investigate the correlation between DM and periodontitis.

Methods: This study was a retrospective cohort study, which conducted based on the Taiwan National Health Insurance Research Database. The study subjects were 39,384 new-onset DM patients who aged above 20 years old from 2005 to 2012. To avoid selection bias, we applied propensity score matching to obtain patients without DM, as the control group. Cox proportional hazard model was used to analyze the risk of periodontitis in patients with DM.

Results: After controlling for related variables, Patients with DM had a higher risk for periodontitis compared with the patients without DM (adjusted hazard ratios [aHR] = 1.04, 95% confidence interval [CI]: 1.01-1.08). Patients with hypertension (HTN) had no higher risk for periodontitis (aHR = 0.96, 95% CI: 0.92-1.00). Patients with dyslipidemia and rheumatoid arthritis (RA) patients both had a higher risk for periodontitis (aHR = 1.26, 95% CI: 1.19-1.34; aHR = 1.41, 95% CI: 1.19-1.67).

Conclusions: There is a correlation between DM and periodontitis. Patients with DM may have a higher risk of incident periodontitis. Besides, age, HTN, dyslipidemia, and RA are also associated with incident periodontitis.
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http://dx.doi.org/10.1016/j.diabres.2019.03.019DOI Listing
April 2019

Expression of pro-inflammatory cytokines and mediators induced by Bisphenol A via ERK-NFκB and JAK1/2-STAT3 pathways in macrophages.

Environ Toxicol 2019 Apr 4;34(4):486-494. Epub 2019 Jan 4.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

Macrophages not only play an important role in the innate immune response but also participate in many inflammatory and infectious diseases including asthma, diabetes, obesity, cardiovascular diseases, and cancers. Bisphenol A (BPA) is the most commonly used component for plastic products. However, BPA is an endocrine disruptor for mammals and participates in several inflammatory and infectious diseases. Up until now, there are no researches demonstrated the potential role of BPA in macrophage activation and its relative mechanism. BPA promoted the generation of proinflammatory cytokines IL-1β, IL-6, and TNFα in a concentration-dependent manner (P < 0.05). BPA was identified to increase the expression of proinflammatory mediators NO and PGE2, and its upstream factors iNOS, COX2, and cPLA2 in a concentration-dependent manner (P < 0.05). Phosphorylation and nuclear translocation of NF-κB p65 were significantly induced by BPA via IκB degradation (P < 0.05). In addition, phosphorylation of ERK significantly induced by BPA at a concentration which was less than that for phosphorylation of p38 MAPK and JNK (P < 0.05). Furthermore, phosphorylation of STAT3 significantly induced by BPA at a concentration lower than that for phosphorylation of STAT1 (P < 0.05). Phosphorylation of JAK1 and JAK2 was also significantly induced by BPA in a concentration-dependent manner (P < 0.05).
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http://dx.doi.org/10.1002/tox.22702DOI Listing
April 2019

Anti-inflammatory and Neuroprotective Effects of Fungal Immunomodulatory Protein Involving Microglial Inhibition.

Int J Mol Sci 2018 Nov 21;19(11). Epub 2018 Nov 21.

Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.

Microglia polarization of classical activation state is crucial to the induction of neuroinflammation, and has been implicated in the pathogenesis of numerous neurodegenerative diseases. Fungal immunomodulatory proteins are emerging health-promoting natural substances with multiple pharmacological activities, including immunomodulation. Herein, we investigated the anti-inflammatory and neuroprotective potential of fungal immunomodulatory protein extracted from (GMI) in an in vitro rodent model of primary cultures. Using primary neuron/glia cultures consisting of neurons, astrocytes, and microglia, a GMI showed an alleviating effect on lipopolysaccharide (LPS)/interferon-γ (IFN-γ)-induced inflammatory mediator production and neuronal cell death. The events of neuroprotection caused by GMI were accompanied by the suppression of Nitric Oxide (NO), Tumor Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β), and Prostaglandin E2 (PGE2) production, along with the inhibition of microglia activation. Mechanistic studies showed that the suppression of microglia pro-inflammatory polarization by GMI was accompanied by the resolution of oxidative stress, the preservation of protein tyrosine phosphatase and serine/threonine phosphatase activity, and the reduction of NF-κB, AP-1, cyclic AMP response element-binding protein (CREB), along with signal transducers and activators of transcription (Stat1) transcriptional activities and associated upstream activators. These findings suggest that GMI may have considerable potential towards the treatment of neuroinflammation-mediated neurodegenerative diseases.
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http://dx.doi.org/10.3390/ijms19113678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274830PMC
November 2018

Safrole induced cytotoxicity, DNA damage, and apoptosis in macrophages via reactive oxygen species generation and Akt phosphorylation.

Environ Toxicol Pharmacol 2018 Dec 29;64:94-100. Epub 2018 Sep 29.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address:

Safrole is a natural compound categorized as a group 2B carcinogen extracted from betel quid chewing, which is a common practice of psychoactive habits integrated into social and cultural ceremonies among serveral million people, especially in Southern or Southeastern Asia. Safrole is one of the major risk compunds for development of oral squamous cell carcinoma and hepatocellular carcinoma via DNA adduction. In innate immunity, macrophages are the predominant cells for non-specific first line defense against pathogens in oral tissue. Up to now, there is no evidence to implicate the potential toxicological effect of safrole on macrophages. In this study, we found safrole induced the generation of reactive oxygen species (ROS) and myeloperoxidase (MPO) in RAW264.7 macrophages in a concentration-dependent manner. Furthermore, cytotoxicity, DNA damage, and apoptosis were caused by safrole in a concentration-dependent manner. While the activation of antioxidative enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) was reduced, the phosphorylation of Akt was induced by safrole in a concentration-dependent manner. These results indicated that the induction of cytotoxicity, DNA damage, and apoptosis in macrophages by safrole was through generation of ROS and inhibition of antioxidative enzymes possibly via Akt phosphorylation.
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http://dx.doi.org/10.1016/j.etap.2018.09.012DOI Listing
December 2018

Bisphenol A exhibits cytotoxic or genotoxic potential via oxidative stress-associated mitochondrial apoptotic pathway in murine macrophages.

Food Chem Toxicol 2018 Dec 9;122:215-224. Epub 2018 Oct 9.

Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan; Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address:

Bisphenol A (BPA) is primarily used in production of polycarbonate plastics and epoxy resins including plastic containers. BPA is an endocrine disruptor and supposes to induce asthma and cancer. However, so far only a few evidences have shown the BPA-induced toxic effect and its related mechanism in macrophages. BPA demonstrated cytotoxic effect on RAW264.7 macrophages in a concentration and time-dependent manner. BPA induces necrosis, apoptosis, and genotoxicity in a concentration-dependent manner. Phosphorylation of cytochrome C (cyto C) and p53 was due to mitochondrial disruption via BCL2 and BCL-X downregulation and BAX, BID, and BAD upregulation. Both caspase-dependent, including caspase-9, caspase-3, and PARP-1 cleavage, and caspase-independent, such as nuclear translocation of AIF, pathways were activated by BPA. Furthermore, generation of reactive oxygen species (ROS) and reduction of antioxidative enzyme activities were induced by BPA. Parallel trends were observed in the effect of BPA on cytotoxicity, apoptosis, genotoxicity, p53 phosphorylation, BCL2 family expression exchange, caspase-dependent and independent apoptotic pathways, and ROS generation in RAW264.7 macrophages. Finally, BPA-exhibited cytotoxicity, apoptosis, and genotoxicity could be inhibited by N-acetylcysteine. These results indicated that the toxic effect of BPA was functioning via oxidative stress-associated mitochondrial apoptotic pathway in macrophages.
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http://dx.doi.org/10.1016/j.fct.2018.09.078DOI Listing
December 2018

Cadmium nitrate-induced neuronal apoptosis is protected by N-acetyl-l-cysteine via reducing reactive oxygen species generation and mitochondria dysfunction.

Biomed Pharmacother 2018 Dec 18;108:448-456. Epub 2018 Sep 18.

Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address:

Cigarette smoking is a well-established risk factor for various diseases, such as cardiovascular diseases, neurodegeneration, and cancer. Cadmium nitrate (Cd(NO)) is one of the major products from the cigarette smoke. Up to now, no supporting evidence on Cd(NO)-induced apoptosis and its related working mechanism in neurons has been found. In present study, the mode of cell death, caspase activities, reactive oxygen species (ROS) generation, and mitochondrial dysfunction in N2a cells, which are neuron-like cells, were assessed by Annexin V-FITC and PI assays, caspase fluorometric assay, DCFH-DA fluorescence assay, and JC-1 fluorescence assay respectively. The results showed that not only Cd(NO) induced apoptosis and necrosis but also the activities of caspase-3 and -9 expressed in a concentration-dependent manner. In addition, Cd(NO) also induced both mitochondrial dysfunction and ROS generation in a concentration-dependent manner. All these indicated that in N2a cells parallel trends could be observed in apoptosis, caspase-3 and -9 activities, mitochondrial dysfunction, and ROS generation when induced by Cd(NO). Furthermore, Cd(NO)-induced apoptosis, caspases activities, mitochondrial dysfunction, and ROS generation were reduced by N-acetyl-l-cysteine (NAC). These results indicated that Cd(NO)-induced neuronal apoptosis was reduced by NAC via intrinsic apoptotic caspase cascade activities and their up-stream factors, including mitochondrial dysfunction and ROS generation.
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http://dx.doi.org/10.1016/j.biopha.2018.09.054DOI Listing
December 2018