Publications by authors named "Zhenxiao Jin"

57 Publications

An Overview of the Posttranslational Modifications and Related Molecular Mechanisms in Diabetic Nephropathy.

Front Cell Dev Biol 2021 28;9:630401. Epub 2021 May 28.

Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, The Air Force Medical University, Xi'an, China.

Diabetic nephropathy (DN), a common diabetic microvascular complication, is characterized by its complex pathogenesis, higher risk of mortality, and the lack of effective diagnosis and treatment methods. Many studies focus on the diagnosis and treatment of diabetes mellitus (DM) and have reported that the pathophysiology of DN is very complex, involving many molecules and abnormal cellular activities. Given the respective pivotal roles of NF-κB, Nrf2, and TGF-β in inflammation, oxidative stress, and fibrosis during DN, we first review the effect of posttranslational modifications on these vital molecules in DN. Then, we describe the relationship between these molecules and related abnormal cellular activities in DN. Finally, we discuss some potential directions for DN treatment and diagnosis. The information reviewed here may be significant in the design of further studies to identify valuable therapeutic targets for DN.
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http://dx.doi.org/10.3389/fcell.2021.630401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193943PMC
May 2021

SIRT1/PGC-1α signaling activation by mangiferin attenuates cerebral hypoxia/reoxygenation injury in neuroblastoma cells.

Eur J Pharmacol 2021 Jun 9;907:174236. Epub 2021 Jun 9.

Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China. Electronic address:

Ischemia reperfusion injury (IRI) is associated with poor prognoses in the setting of ischemic brain diseases. Silence information regulator 1 (SIRT1) is a member of the third class of nicotinamide adenine dinucleotide (NAD)-dependent sirtuins. Recently, the role of SIRT1/peroxisome proliferators-activated receptor-γ coactivator 1α (PGC-1α) pathway in organ (especially the brain) protection under various pathological conditions has been widely investigated. Mangiferin (MGF), a natural C-glucosyl xanthone polyhydroxy polyphenol, has been shown to be beneficial to several nervous system diseases and the protective effects of MGF can be achieved through the regulation of SIRT1 signaling. This study is designed to investigate the protective effects of MGF treatment in the setting of cerebral IRI and to elucidate the potential mechanisms. We first evaluated the toxicity of MGF and chose the safe concentrations for the following experiments. MGF exerted obvious neuroprotection against hypoxia/reoxygenation (HR)-induced injury, indicated by restored cell viability and cell morphology, decreased lactate dehydrogenase (LDH) release and reactive oxygen species generation. MGF also restored the protein expressions of SIRT1, PGC-1α, Nrf2, NQO1, HO-1, NRF1, UCP2, and Bcl2 down-regulated by HR treatment. However, SIRT1 siRNA could reverse MGF-induced neuroprotection and decrease the expressions of molecules mentioned above. Taken together, our findings suggest that MGF treatment exerts neuroprotection against HR injury via activating SIRT1/PGC-1α signaling. These findings may provide a theoretical basis for the exploitation of MGF as a potential neuroprotective drug candidate, which may be beneficial for the ischemic stroke patients in clinic.
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http://dx.doi.org/10.1016/j.ejphar.2021.174236DOI Listing
June 2021

The roles of liver X receptor α in inflammation and inflammation-associated diseases.

J Cell Physiol 2021 Jul 10;236(7):4807-4828. Epub 2020 Dec 10.

Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education Life of Sciences, Northwest University, Xi'an, China.

Liver X receptor α (LXRα; also known as NR1H3), an isoform of LXRs, is a member of the nuclear receptor family of transcription factors and plays essential roles in the transcriptional control of cholesterol homeostasis. Previous in-depth phenotypic analyses of mouse models with deficient LXRα have also demonstrated various physiological functions of this receptor within inflammatory responses. LXRα activation exerts a combination of metabolic and anti-inflammatory actions resulting in the modulation and the amelioration of inflammatory disorders. The tight "repercussions" between LXRα and inflammation, as well as cholesterol homeostasis, have suggested that LXRα could be pharmacologically targeted in pathologies such as atherosclerosis, acute lung injury, and Alzheimer's disease. This review gives an overview of the recent advances in understanding the roles of LXRα in inflammation and inflammation-associated diseases, which will help in the design of future experimental researches on the potential of LXRα and advance the investigation of LXRα as pharmacological inflammatory targets.
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http://dx.doi.org/10.1002/jcp.30204DOI Listing
July 2021

Effectiveness of a novel, completely biomaterial valved pulmonary arterial conduit: An study.

Exp Ther Med 2020 Sep 19;20(3):1935-1942. Epub 2020 Jun 19.

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.

As a pre-clinical assessment, the present study aimed to investigate the safety and effectiveness of a novel valved pulmonary arterial conduit constructed entirely from biomaterials by transplanting it in the outflow tract of the right ventricle in sheep. Under extracorporeal circulation, the valved pulmonary arterial conduit was used to replace the pulmonary artery of sheep with a beating heart. The performance was assessed at 30, 90 and 180 days post-surgery. Hemodynamic and structural changes were evaluated, and safety was assessed after 180 postoperative days. The hemodynamic effect and biosafety of the implant were further evaluated by observing the changes in various pressure indicators of the heart, echocardiographic results, anatomical and pathological examination results, liver and kidney functions, routine blood tests, a blood coagulation test, and other test results following implantation of the purely biotic valved conduit. The conduit was successfully implanted in 12 sheep and no mortality occurred postoperatively. During the 180-day follow-up, there was no obvious stenosis or regurgitation of the right ventricular outflow tract and pulmonary valve after valved conduit implantation. The findings of autopsy, pathology and laboratory examinations were unremarkable. The implantation of this biosynthetic vascular graft into animals meets the safety and effectiveness requirements for clinical application. This pulmonary arterial conduit has potential clinical application for children with complex congenital heart disease who require pulmonary artery reconstruction to achieve a radical cure.
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http://dx.doi.org/10.3892/etm.2020.8908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401300PMC
September 2020

NLRP3 sparks the Greek fire in the war against lipid-related diseases.

Obes Rev 2020 09 10;21(9):e13045. Epub 2020 May 10.

Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Life of Sciences, Northwest University, Xi'an, China.

In recent years, the obesity rate worldwide has reached epidemic proportions and contributed to the growing prevalence of lipid-related diseases. A strong link between inflammation and metabolism is becoming increasingly evident. Compelling evidence has indicated the activation of the nucleotide-binding and oligomerization domain-like receptor, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome, a cytoplasmic complex containing multiple proteins, in a variety of lipid-related diseases including obesity, atherosclerosis, liver diseases, and type 2 diabetes. Recent studies have further clarified the regulatory mechanisms and the optional therapeutic agents that target NLRP3 inflammasomes. In this study, we review the recent progress in the research on NLRP3 inflammasomes and discuss their implications for a better understanding of inflammation in lipid-related disease and the prospects of targeting the NLRP3 inflammasome for therapeutic intervention.
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http://dx.doi.org/10.1111/obr.13045DOI Listing
September 2020

Melatonin protects against thoracic aortic aneurysm and dissection through SIRT1-dependent regulation of oxidative stress and vascular smooth muscle cell loss.

J Pineal Res 2020 Aug 27;69(1):e12661. Epub 2020 May 27.

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

Melatonin functions as an endogenous protective molecule in multiple vascular diseases, whereas its effects on thoracic aortic aneurysm and dissection (TAAD) and underlying mechanisms have not been reported. In this study, TAAD mouse model was successfully induced by β-aminopropionitrile fumarate (BAPN). We found that melatonin treatment remarkably prevented the deterioration of TAAD, evidenced by decreased incidence, ameliorated aneurysmal dilation and vascular stiffness, improved aortic morphology, and inhibited elastin degradation, macrophage infiltration, and matrix metalloproteinase expression. Moreover, melatonin blunted oxidative stress damage and vascular smooth muscle cell (VSMC) loss. Notably, BAPN induced a decrease in SIRT1 expression and activity of mouse aorta, whereas melatonin treatment reversed it. Further mechanistic study demonstrated that blocking SIRT1 signaling partially inhibited these beneficial effects of melatonin on TAAD. Additionally, the melatonin receptor was involved in this phenomenon. Our study is the first to report that melatonin exerts therapeutic effects against TAAD by reducing oxidative stress and VSMC loss via activation of SIRT1 signaling in a receptor-dependent manner, thus suggesting a novel therapeutic strategy for TAAD.
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http://dx.doi.org/10.1111/jpi.12661DOI Listing
August 2020

Does perturbation in the mitochondrial protein folding pave the way for neurodegeneration diseases?

Ageing Res Rev 2020 01 6;57:100997. Epub 2019 Dec 6.

Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, China. Electronic address:

Mitochondria, which are cell compartments that are widely present in eukaryotic cells, have been shown to be involved in a variety of synthetic, metabolic, and signaling processes, thereby playing a vital role in cells. The mitochondrial unfolded protein response (mtUPR) is a response in which mitochondria reverse the signal to the nucleus and maintain mitochondrial protein homeostasis when unfolded and misfolded proteins continue to accumulate. Multiple neurodegeneration diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and familial amyotrophic lateral sclerosis (fALS), are public health challenges. Every year, countless efforts are expended trying to clarify the pathogenesis and treatment of neurological disorders, which are associated with mitochondrial dysfunction to some extent. Numerous studies have shown that mtUPR is involved in and plays an important role in the pathogenesis of neurological disorders, but the exact mechanism of the disorders is still unclear. Further study of the process of mtUPR in neurological disorders can help us more accurately understand their pathogenesis in order to provide new therapeutic targets. In this paper, we briefly review mtUPR signaling in Caenorhabditis elegans (C. elegans) and mammals and summarize the role of mtUPR in neurodegeneration diseases, including AD, PD and fALS.
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http://dx.doi.org/10.1016/j.arr.2019.100997DOI Listing
January 2020

Novel role of sex-determining region Y-box 7 (SOX7) in tumor biology and cardiovascular developmental biology.

Semin Cancer Biol 2020 12 29;67(Pt 1):49-56. Epub 2019 Aug 29.

Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, China. Electronic address:

The sex-determining region Y-box 7 (Sox7) is an important member of the SOX F family, which is characterized by a high-mobility-group DNA-binding domain. Previous studies have demonstrated the role of SOX7 in cardiovascular development. SOX7 expression could be detected in normal adult tissues. Furthermore, the expression levels of SOX7 were different in different tumors. Most studies showed the downregulation of SOX7 in tumors, while some studies reported its upregulation in tumors. In this review, we first summarized the upstream regulators (including transcription factors, microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and some exogenous regulators) and downstream molecules (including factors in the Wnt/β-catenin signaling pathway and some other signaling pathways) of SOX7. Then, the roles of SOX7 in multiple tumors were presented. Finally, the significance of divergent SOX7 expression during cardiovascular development was briefly discussed. The information compiled in this study characterized SOX7 during tumorigenesis and cardiovascular development, which should facilitate the design of future research and promote SOX7 as a therapeutic target.
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http://dx.doi.org/10.1016/j.semcancer.2019.08.032DOI Listing
December 2020

C1q-TNF-related protein-3 attenuates pressure overload-induced cardiac hypertrophy by suppressing the p38/CREB pathway and p38-induced ER stress.

Cell Death Dis 2019 07 8;10(7):520. Epub 2019 Jul 8.

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, 710032, Xi'an, China.

C1q-tumor necrosis factor-related protein-3 (CTRP3) is an adipokine, which exerts protective function in ischemic or diabetic heart injury. However, the role of CTRP3 in cardiac hypertrophy remains unclear. The aim of this study was to investigate the pharmacological effects of CTRP3 on pathological cardiac hypertrophy induced by hypertension. Male C57BL/6 J wild-type (WT) mice, Ctrp3 knockout mice, and mice infected with lentivirus overexpressing mouse Ctrp3 underwent sham surgery or transverse aortic constriction (TAC) surgery. After 4 weeks, cardiac hypertrophy, fibrosis, and cardiac function were examined. Compared with WT mice, Ctrp3 deficiency substantially impaired contractile dysfunction, exacerbated the enlargement of cardiomyocytes and myocardial fibrosis, and reprogramed the expression of pathological genes after TAC. Conversely, CTRP3 overexpression played a role in restoring the left ventricular cardiac contractile function, alleviating cardiac hypertrophy and fibrosis, and inhibiting the expression of hypertrophic and fibrotic signaling in mice after TAC. Furthermore, CTRP3 regulated the expression of the p38/CREB pathway and of the primary modulating factors of the endoplasmic reticulum stress, i.e., GRP78 and the downstream molecules eukaryotic translation inhibition factor 2 submit α, C/EBP homologous protein, and inositol-requiring enzyme-1. Further, inhibition of p38 MAPK by SB203580 blunted the ER stress intensified by Ctrp3 deficiency. In vitro, CTRP3 protected neonatal rat cardiac myocytes against phenylephrine-induced cardiomyocyte hypertrophy. We conclude that CTRP3 protects the host against pathological cardiac remodeling and left ventricular dysfunction induced by pressure overload largely by inhibiting the p38/CREB pathway and alleviating p38-induced ER stress.
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http://dx.doi.org/10.1038/s41419-019-1749-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614451PMC
July 2019

Tetrahydrocurcumin Ameliorates Diabetic Cardiomyopathy by Attenuating High Glucose-Induced Oxidative Stress and Fibrosis via Activating the SIRT1 Pathway.

Oxid Med Cell Longev 2019 9;2019:6746907. Epub 2019 May 9.

Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, The Air Force Medical University, Xi'an, 710032 Shaanxi, China.

Hyperglycemia-induced oxidative stress and fibrosis play a crucial role in the development of diabetic cardiomyopathy (DCM). Tetrahydrocurcumin (THC), a major bioactive metabolite of natural antioxidant curcumin, is reported to exert even more effective antioxidative and superior antifibrotic properties as well as anti-inflammatory and antidiabetic abilities. This study was designed to investigate the potential protective effects of THC on experimental DCM and its underlying mechanisms, pointing to the role of high glucose-induced oxidative stress and interrelated fibrosis. In STZ-induced diabetic mice, oral administration of THC (120 mg/kg/d) for 12 weeks significantly improved the cardiac function and ameliorated myocardial fibrosis and cardiac hypertrophy, accompanied by reduced reactive oxygen species (ROS) generation. Mechanically, THC administration remarkably increased the expression of the SIRT1 signaling pathway both and , further evidenced by decreased downstream molecule Ac-SOD2 and enhanced deacetylated production SOD2, which finally strengthened antioxidative stress capacity proven by repaired activities of SOD and GSH-Px and reduced MDA production. Additionally, THC treatment accomplished its antifibrotic effect by depressing the ROS-induced TGF1/Smad3 signaling pathway followed by reduced expression of cardiac fibrotic markers -SMA, collagen I, and collagen III. Collectively, these finds demonstrated the therapeutic potential of THC treatment to alleviate DCM mainly by attenuating hyperglycemia-induced oxidative stress and fibrosis via activating the SIRT1 pathway.
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http://dx.doi.org/10.1155/2019/6746907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532281PMC
December 2019

SOX11: friend or foe in tumor prevention and carcinogenesis?

Ther Adv Med Oncol 2019 3;11:1758835919853449. Epub 2019 Jun 3.

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.

Sex-determining region Y-related high-mobility-group box transcription factor 11 (SOX11) is an essential member of the SOX transcription factors and has been highlighted as an important regulator in embryogenesis. SOX11 studies have only recently shifted focus from its role in embryogenesis and development to its function in disease. In particular, the role of SOX11 in carcinogenesis has become of major interest in the field. SOX11 expression is elevated in a wide variety of tumors. In many cancers, dysfunctional expression of SOX11 has been correlated with increased cancer cell survival, inhibited cell differentiation, and tumor progression through the induction of metastasis and angiogenesis. Nevertheless, in a limited number of malignancies, SOX11 has also been identified to function as a tumor suppressor. Herein, we review the correlation between the expression of SOX11 and tumor behaviors. We also summarize the mechanisms underlying the regulation of SOX11 expression and activity in pathological conditions. In particular, we focus on the pathological processes of cancer targeted by SOX11 and discuss whether SOX11 is protective or detrimental during tumor progression. Moreover, SOX11 is highlighted as a clinical biomarker for the diagnosis and prognosis of various human cancer. The information reviewed here should assist in future experimental designs and emphasize the potential of SOX11 as a therapeutic target for cancer.
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http://dx.doi.org/10.1177/1758835919853449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547177PMC
June 2019

Endoplasmic reticulum stress and NLRP3 inflammasome: Crosstalk in cardiovascular and metabolic disorders.

J Cell Physiol 2019 Feb 11. Epub 2019 Feb 11.

Department of Immunology, School of Basic Medicine, The Fourth Military Medical University, Xi'an, China.

When endoplasmic reticulum (ER) homeostasis is disrupted, known as ER stress (ERS), the ER generates an adaptive signaling pathway called the unfolded protein response to maintain the homeostasis of this organelle. However, if homeostasis is not restored, the ER initiates death signaling pathways, which contribute to the pathogenesis of various disorders. The activation of inflammatory mechanisms is also emerging as a crucial component of cardiovascular and metabolic disorders. Furthermore, the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome has attracted more attention than others and is the best-characterized member of the NLR family of inflammasomes to date. ERS intersects with many different inflammatory pathways, particularly the NLRP3 inflammasome. In this review, we focus on the interactions between ERS and the NLRP3 inflammasome. The pharmacologic and nonpharmaceutical manipulation of these two processes may offer novel opportunities for the treatment of cardiovascular and metabolic disorders.
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http://dx.doi.org/10.1002/jcp.28275DOI Listing
February 2019

Total arch repair with open placement of a novel double-branched stent graft for acute Type A aortic dissection: a single-centre experience with 21 consecutive patients.

Interact Cardiovasc Thorac Surg 2019 02;28(2):262-269

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.

Objectives: The aim of this study was to evaluate the safety and feasibility of total arch repair with open placement of a novel double-branched stent graft for acute Type A aortic dissection (TAAD).

Methods: We retrospectively analysed the effect of the double-branched stent graft for total aortic arch placement with acute TAAD from December 2013 to February 2015. The effectiveness of the open placement of the double-branched stent graft was estimated by complete thrombus obliteration of the false lumen surrounding it on computed tomography angiography. Follow-up was performed at 6 months postoperatively and annually thereafter.

Results: The double-branched stent graft was successfully placed into the true lumen of the descending aorta, aortic arch, left subclavian artery and left common carotid artery through the delivery system in 21 patients with acute TAAD. The mean cardiopulmonary bypass time was 210.2 ± 32.4 min, the mean aortic cross-clamp time was 94.9 ± 18.0 min, and the selective cerebral perfusion and deep hypothermia cardiopulmonary arrest time was 27.0 ± 10.4 min. The in-hospital mortality rate was 4.8%. The mean follow-up duration was 38.2 ± 12.5 months. No severe complications related to the surgery or residual dissection occurred during the follow-up. All survivors resumed normal activities.

Conclusions: The novel double-branched stent graft is proved to be safe and effective for total arch repair with acute TAAD in this study. It would be a new selective method for total arch repair in patients with acute TAAD.

Clinical Registration Number: Research on pathogenic risk factors or characteristic features and clinical treatment of aortic dissection in Chinese Population (20120216-4).
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http://dx.doi.org/10.1093/icvts/ivy243DOI Listing
February 2019

Noninvasive Cerebral Imaging and Monitoring Using Electrical Impedance Tomography During Total Aortic Arch Replacement.

J Cardiothorac Vasc Anesth 2018 12 3;32(6):2469-2476. Epub 2018 May 3.

Department of Biomedical Engineering, Fourth Military Medical University, Xi'an, China. Electronic address:

Objective: To explore the feasibility of using electrical impedance tomography (EIT) to provide noninvasive cerebral imaging and monitoring in total aortic arch replacement (TAAR).

Design: A prospective, observational study.

Setting: Department of cardiovascular surgery in a university hospital.

Participants: Forty-two patients undergoing TAAR using hypothermic circulatory arrest and unilateral antegrade cerebral perfusion.

Interventions: None.

Measurements And Main Results: Cerebral impedances of the patients were monitored intraoperatively by an EIT system. The prognostic information of the patients, including postoperative neurological dysfunction, was collected during their hospitalizations. Eight (19.0%) subjects had at least 1 postoperative neurological dysfunction complication. The results show that cerebral impedance was related negatively to perfusion flow, and the gradual increase in cerebral resistivity might reflect the evolving process of brain tissue caused by hypoxia. Maximum resistivity asymmetry index was extracted from the reconstructed images to quantify the pathological changes of the brain. The area under the receiver operating characteristic curve of maximum resistivity asymmetry index for postoperative neurological dysfunction was 0.864. In multivariate logistic regression, maximum resistivity asymmetry index was the strongest independent predictor of neurological dysfunction with an odds ratio of 24.3.

Conclusion: EIT is a promising technique to provide noninvasive cerebral imaging and monitoring in TAAR.
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http://dx.doi.org/10.1053/j.jvca.2018.05.002DOI Listing
December 2018

Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery.

Am J Respir Crit Care Med 2018 11;198(10):1279-1287

2 Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Rationale: No medical intervention has been identified that decreases acute kidney injury and improves renal outcome at 1 year after cardiac surgery.

Objectives: To determine whether administration of nitric oxide reduces the incidence of postoperative acute kidney injury and improves long-term kidney outcomes after multiple cardiac valve replacement requiring prolonged cardiopulmonary bypass.

Methods: Two hundred and forty-four patients undergoing elective, multiple valve replacement surgery, mostly due to rheumatic fever, were randomized to receive either nitric oxide (treatment) or nitrogen (control). Nitric oxide and nitrogen were administered via the gas exchanger during cardiopulmonary bypass and by inhalation for 24 hours postoperatively.

Measurements And Main Results: The primary outcome was as follows: oxidation of ferrous plasma oxyhemoglobin to ferric methemoglobin was associated with reduced postoperative acute kidney injury from 64% (control group) to 50% (nitric oxide group) (relative risk [RR], 0.78; 95% confidence interval [CI], 0.62-0.97; P = 0.014). Secondary outcomes were as follows: at 90 days, transition to stage 3 chronic kidney disease was reduced from 33% in the control group to 21% in the treatment group (RR, 0.64; 95% CI, 0.41-0.99; P = 0.024) and at 1 year, from 31% to 18% (RR, 0.59; 95% CI, 0.36-0.96; P = 0.017). Nitric oxide treatment reduced the overall major adverse kidney events at 30 days (RR, 0.40; 95% CI, 0.18-0.92; P = 0.016), 90 days (RR, 0.40; 95% CI, 0.17-0.92; P = 0.015), and 1 year (RR, 0.47; 95% CI, 0.20-1.10; P = 0.041).

Conclusions: In patients undergoing multiple valve replacement and prolonged cardiopulmonary bypass, administration of nitric oxide decreased the incidence of acute kidney injury, transition to stage 3 chronic kidney disease, and major adverse kidney events at 30 days, 90 days, and 1 year. Clinical trial registered with ClinicalTrials.gov (NCT01802619).
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http://dx.doi.org/10.1164/rccm.201710-2150OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290943PMC
November 2018

Honokiol Ameliorates Myocardial Ischemia/Reperfusion Injury in Type 1 Diabetic Rats by Reducing Oxidative Stress and Apoptosis through Activating the SIRT1-Nrf2 Signaling Pathway.

Oxid Med Cell Longev 2018 20;2018:3159801. Epub 2018 Feb 20.

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.

Reducing oxidative stress is a crucial therapeutic strategy for ameliorating diabetic myocardial ischemia/reperfusion (MI/R) injury. Honokiol (HKL) acts as an effective cardioprotective agent for its strong antioxidative activity. However, its roles and underlying mechanisms against MI/R injury in type 1 diabetes (T1D) remain unknown. Since SIRT1 and Nrf2 are pivotal regulators in diabetes mellitus patients suffering from MI/R injury, we hypothesized that HKL ameliorates diabetic MI/R injury via the SIRT1-Nrf2 signaling pathway. Streptozotocin-induced T1D rats and high-glucose-treated H9c2 cells were exposed to HKL, with or without administration of the SIRT1 inhibitor EX527, SIRT1 siRNA, or Nrf2 siRNA, and then subjected to I/R operation. We found that HKL markedly improved the postischemic cardiac function, decreased the infarct size, reduced the myocardial apoptosis, and diminished the reactive oxygen species generation. Intriguingly, HKL remarkably activated SIRT1 signaling, enhanced Nrf2 nuclear translocation, increased antioxidative signaling, and decreased apoptotic signaling. However, these effects were largely abolished by EX527 or SIRT1 siRNA. Additionally, our cellular experiments showed that Nrf2 siRNA blunted the cytoprotective effects of HKL, without affecting SIRT1 expression and activity. Collectively, these novel findings indicate that HKL abates MI/R injury in T1D by ameliorating myocardial oxidative damage and apoptosis via the SIRT1-Nrf2 signaling pathway.
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http://dx.doi.org/10.1155/2018/3159801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838504PMC
September 2018

Snapshots: Endoplasmic Reticulum Stress in Lipid Metabolism and Cardiovascular Disease.

Curr Issues Mol Biol 2018 1;28:14-28. Epub 2018 Feb 1.

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.

The endoplasmic reticulum (ER) is an organelle present in most eukaryotic cells and plays a pivotal role in lipid metabolism. ER dysfunction, specifically ER stress (ERS), is a pathophysiological response involved in lipid metabolism and cardiovascular lesions. Therefore, suppression of ERS may improve lipid metabolic disorders and reduce cardiovascular risk. Herein, we focus on novel breakthroughs regarding the roles of ERS in lipid metabolism and cardiovascular disease (CVD), as well as the internal mechanisms of ERS and its status as a potential therapeutic target. This review highlights recent advances in ERS, the regulation of which might be helpful for both basic research and clinical drug design for lipid metabolic disorders and CVD.
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http://dx.doi.org/10.21775/cimb.028.014DOI Listing
April 2019

SIRT6 protects against hepatic ischemia/reperfusion injury by inhibiting apoptosis and autophagy related cell death.

Free Radic Biol Med 2018 02 10;115:18-30. Epub 2017 Nov 10.

Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China; Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. Electronic address:

Silent information regulator 6 (SIRT6), a class III histone deacetylase, has been revealed to participate in multiple metabolic processes in the liver, and it plays important roles in protecting against ischemia/reperfusion (I/R) injury in multiple organs. In this study, we explored whether SIRT6 is protective against hepatic I/R injury and elucidated the underlying mechanisms. The expression of SIRT6 was significantly decreased during reperfusion compared with the control group. SIRT6-LKO mice exhibited significantly aggravated oxidative stress, mitochondrial dysfunction, inflammatory responses, mitogen-activated protein kinase (MAPK) signaling activation, and apoptosis and autophagy related hepatocyte death compared with control mice. In vitro studies in SIRT6-KO hepatocytes exhibited similar results. In contrast, SIRT6 upregulation alleviated liver damage during hepatic I/R injury. Our study demonstrated for the first time that SIRT6 upregulation effectively protects against hepatic I/R injury. The underlying mechanisms involve the maintenance of oxidative homeostasis and mitochondrial function, which subsequently inhibit the inflammatory responses and MAPK signaling, and finally attenuate apoptosis and autophagy related hepatocyte death. These results suggest that the activation of SIRT6 exerts multifaceted protective effects during hepatic I/R injury, which can provide a novel therapeutic target for hepatic I/R injury.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.11.005DOI Listing
February 2018

Melatonin protects against the pathological cardiac hypertrophy induced by transverse aortic constriction through activating PGC-1β: In vivo and in vitro studies.

J Pineal Res 2017 Oct 16;63(3). Epub 2017 Aug 16.

Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Melatonin, a circadian molecule secreted by the pineal gland, confers a protective role against cardiac hypertrophy induced by hyperthyroidism, chronic hypoxia, and isoproterenol. However, its role against pressure overload-induced cardiac hypertrophy and the underlying mechanisms remains elusive. In this study, we investigated the pharmacological effects of melatonin on pathological cardiac hypertrophy induced by transverse aortic constriction (TAC). Male C57BL/6 mice underwent TAC or sham surgery at day 0 and were then treated with melatonin (20 mg/kg/day, via drinking water) for 4 or 8 weeks. The 8-week survival rate following TAC surgery was significantly increased by melatonin. Melatonin treatment for 8 weeks markedly ameliorated cardiac hypertrophy. Compared with the TAC group, melatonin treatment for both 4 and 8 weeks reduced pulmonary congestion, upregulated the expression level of α-myosin heavy chain, downregulated the expression level of β-myosin heavy chain and atrial natriuretic peptide, and attenuated the degree of cardiac fibrosis. In addition, melatonin treatment slowed the deterioration of cardiac contractile function caused by pressure overload. These effects of melatonin were accompanied by a significant upregulation in the expression of peroxisome proliferator-activated receptor-gamma co-activator-1 beta (PGC-1β) and the inhibition of oxidative stress. In vitro studies showed that melatonin also protects against angiotensin II-induced cardiomyocyte hypertrophy and oxidative stress, which were largely abolished by knocking down the expression of PGC-1β using small interfering RNA. In summary, our results demonstrate that melatonin protects against pathological cardiac hypertrophy induced by pressure overload through activating PGC-1β.
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http://dx.doi.org/10.1111/jpi.12433DOI Listing
October 2017

Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis.

J Pineal Res 2017 Sep 20;63(2). Epub 2017 Jun 20.

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

Sirtuins are a family of highly evolutionarily conserved nicotinamide adenine nucleotide-dependent histone deacetylases. Sirtuin-3 (SIRT3) is a member of the sirtuin family that is localized primarily to the mitochondria and protects against oxidative stress-related diseases, including myocardial ischemia/reperfusion (MI/R) injury. Melatonin has a favorable effect in ameliorating MI/R injury. We hypothesized that melatonin protects against MI/R injury by activating the SIRT3 signaling pathway. In this study, mice were pretreated with or without a selective SIRT3 inhibitor and then subjected to MI/R operation. Melatonin was administered intraperitoneally (20 mg/kg) 10 minutes before reperfusion. Melatonin treatment improved postischemic cardiac contractile function, decreased infarct size, diminished lactate dehydrogenase release, reduced the apoptotic index, and ameliorated oxidative damage. Notably, MI/R induced a significant decrease in myocardial SIRT3 expression and activity, whereas the melatonin treatment upregulated SIRT3 expression and activity, and thus decreased the acetylation of superoxide dismutase 2 (SOD2). In addition, melatonin increased Bcl-2 expression and decreased Bax, Caspase-3, and cleaved Caspase-3 levels in response to MI/R. However, the cardioprotective effects of melatonin were largely abolished by the selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl)pyridine (3-TYP), suggesting that SIRT3 plays an essential role in mediating the cardioprotective effects of melatonin. In vitro studies confirmed that melatonin also protected H9c2 cells against simulated ischemia/reperfusion injury (SIR) by attenuating oxidative stress and apoptosis, while SIRT3-targeted siRNA diminished these effects. Taken together, our results demonstrate for the first time that melatonin treatment ameliorates MI/R injury by reducing oxidative stress and apoptosis via activating the SIRT3 signaling pathway.
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http://dx.doi.org/10.1111/jpi.12419DOI Listing
September 2017

Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling.

Sci Rep 2017 01 25;7:41337. Epub 2017 Jan 25.

Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, 83 Wenhua Road, Shenyang, Liaoning 110016, China.

Enhancing mitochondrial biogenesis and reducing mitochondrial oxidative stress have emerged as crucial therapeutic strategies to ameliorate diabetic myocardial ischemia/reperfusion (MI/R) injury. Melatonin has been reported to be a safe and potent cardioprotective agent. However, its role on mitochondrial biogenesis or reactive oxygen species (ROS) production in type 1 diabetic myocardium and the underlying mechanisms remain unknown. We hypothesize that melatonin ameliorates MI/R injury in type 1 diabetic rats by preserving mitochondrial function via AMPK-PGC-1α-SIRT3 signaling pathway. Both our in vivo and in vitro data showed that melatonin reduced MI/R injury by improving cardiac function, enhancing mitochondrial SOD activity, ATP production and oxidative phosphorylation complex (II, III and IV), reducing myocardial apoptosis and mitochondrial MDA, HO generation. Importantly, melatonin also activated AMPK-PGC-1α-SIRT3 signaling and increased SOD2, NRF1 and TFAM expressions. However, these effects were abolished by Compound C (a specific AMPK signaling blocker) administration. Additionally, our cellular experiment showed that SIRT3 siRNA inhibited the cytoprotective effect of melatonin without affecting p-AMPK/AMPK ratio and PGC-1α expression. Taken together, we concluded that melatonin preserves mitochondrial function by reducing mitochondrial oxidative stress and enhancing its biogenesis, thus ameliorating MI/R injury in type 1 diabetic state. AMPK-PGC1α-SIRT3 axis plays an essential role in this process.
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http://dx.doi.org/10.1038/srep41337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264601PMC
January 2017

Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia-reperfusion injury: role of RISK and SAFE pathways interaction.

Apoptosis 2016 07;21(7):809-24

Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China.

Recently, we demonstrated that melatonin reduced protein kinase RNA (PKR)-like ER kinase (PERK)-eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor-4 (ATF4)-mediated myocardial endoplasmic reticulum (ER) stress and apoptosis during myocardial ischemia-reperfusion (MI/R) injury. However, the underlying mechanisms are still not clear. Myocardial reperfusion injury salvage kinase (RISK) pathway as well as survivor activating factor enhancement (SAFE) pathway are two pivotal intrinsic pro-survival signaling cascades. In this study, we performed in vivo and in vitro experiment to investigate the ameliorative effect of melatonin on ER stress with a focus on RISK and SAFE pathways interaction. Male C57Bl/6 mice received melatonin (300 μg/25 g/day, 3 days before MI/R surgery; 300 μg/25 g, 25 min before the onset of ischemia) pre-treatment with or without the administration of LY294002 (a PI3K/Akt inhibitor), U0126 (an ERK1/2 inhibitor) or AG490 (a STAT3 pathway inhibitor). H9c2 cells were pre-treated with melatonin (100 μM, 8 h) in the presence or absence of LY294002, U0126 or AG490. Compared with the I/R-injured group, melatonin effectively reduced myocardial apoptosis, oxidative stress and improved cardiac function. In addition, melatonin pre-treatment also increased the phosphorylation of Akt, GSK-3β, ERK1/2 and STAT3 and reduced PERK-eIF2α-ATF4-mediated ER stress. However, these effects were blocked by LY294002, U0126 or AG490. Additionally, either LY294002 or U0126 treatment could inhibit STAT3 phosphorylation, whereas AG490 administration also reduced both Akt and ERK1/2 phosphorylation, indicating an interplay exists between RISK and SAFE pathways in melatonin's cardioprotective effect. In summary, our study demonstrates that RISK and SAFE pathways mediate the cardioprotective effect of melatonin against MI/R injury. Melatonin pre-treatment attenuates PERK-eIF2α-ATF4-mediated ER stress and apoptosis during MI/R injury via RISK and SAFE pathways interaction.
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http://dx.doi.org/10.1007/s10495-016-1246-1DOI Listing
July 2016

Bakuchiol attenuates myocardial ischemia reperfusion injury by maintaining mitochondrial function: the role of silent information regulator 1.

Apoptosis 2016 May;21(5):532-45

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China.

Ischemia reperfusion (IR) injury (IRI) is associated with poor prognoses in the settings of both cardiac surgery and ischemic heart disease and causes mitochondrial oxidative stress and cell death. Silent information regulator 1 (SIRT1), a member of the histone deacetylase family, exerts anti-IRI effects. Bakuchiol (BAK), an analog of resveratrol and a monoterpene phenol isolated from the seeds of Psoralea corylifolia (Leguminosae), protects tissues from injury. This study was designed to investigate the protective effects of BAK treatment in the setting of myocardial IRI and to elucidate the potential mechanism of those effects. Prior to induction of IR, isolated rat hearts or cardiomyocytes were exposed to BAK in either the absence or presence of the SIRT1 inhibitors Sirtinol and SIRT1 siRNA. BAK exerted cardioprotective effects, as evidenced by the improvements noted in cardiac function following ischemia, attenuated myocardial apoptosis, and changes in several biochemical parameters (including increases in the level of the anti-apoptotic protein Bcl2, decreases in the level of the pro-apoptotic protein Bax, and decreases in the cleaved Caspase 3 level). However, Sirtinol and SIRT1 siRNA each blocked BAK-induced cardioprotection by inhibiting SIRT1 signaling. Additionally, BAK significantly increased the activities of mitochondrial succinate dehydrogenase, cytochrome c oxidase, and mitochondrial superoxide dismutase and decreased the production of malondialdehyde. These findings suggested that BAK significantly attenuated IR-induced mitochondrial oxidative damage. However, Sirtinol and SIRT1 siRNA abolished BAK-dependent mitochondrial function. In summary, our results demonstrate that BAK treatment attenuates IRI by attenuating IR-induced mitochondrial oxidative damage via the activation of SIRT1/PGC-1α signaling.
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http://dx.doi.org/10.1007/s10495-016-1225-6DOI Listing
May 2016

Protective role of silent information regulator 1 against hepatic ischemia: effects on oxidative stress injury, inflammatory response, and MAPKs.

Expert Opin Ther Targets 2016 9;20(5):519-31. Epub 2016 Mar 9.

a Department of Cardiovascular Surgery, Xijing Hospital , The Fourth Military Medical University , Xi'an , China.

Objective: Previous studies have verified that silent information regulator 1 (SIRT1), a class III histone deacetylase, protects against ischemia reperfusion (IR) injury (IRI) in some organs. In this study, we examined whether SIRT1 could protect against hepatic IRI and explored the potential mechanisms.

Research Design And Methods: We examined whether SIRT1 could protect against hepatic IRI in vivo and in vitro using hepatic-specific SIRT1(-/-) mice, SIRT1 siRNA-transfected hepatocytes and SIRT1(+/+) hepatocytes.

Results: The expression and activity of SIRT1 were significantly reduced during reperfusion compared with that observed in the control group. Hepatic-specific SIRT1(-/-) mice exhibited significant increase of hepatic damage markers and augment of oxidative stress and inflammatory response compared with control mice. In vitro studies demonstrated similar results. Furthermore, SIRT1 upregulation protects against hepatic IRI, through the overexpression of p-JNK, p-p38MAPK, and p-ERK. The protection of SIRT1 can be effectively reversed by the inhibitors of p38MAPK, JNK, and ERK.

Conclusion: The activation of SIRT1 significantly inhibits the oxidative stress and inflammatory response during hepatic IRI, which can be developed as a novel method to protect against hepatic IRI.
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http://dx.doi.org/10.1517/14728222.2016.1153067DOI Listing
December 2016

Berberine Attenuates Myocardial Ischemia/Reperfusion Injury by Reducing Oxidative Stress and Inflammation Response: Role of Silent Information Regulator 1.

Oxid Med Cell Longev 2016 14;2016:1689602. Epub 2015 Dec 14.

Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.

Berberine (BBR) exerts potential protective effect against myocardial ischemia/reperfusion (MI/R) injury. Activation of silent information regulator 1 (SIRT1) signaling attenuates MI/R injury by reducing oxidative damage and inflammation response. This study investigated the antioxidative and anti-inflammatory effects of BBR treatment in MI/R condition and elucidated its potential mechanisms. Sprague-Dawley rats were treated with BBR in the absence or presence of the SIRT1 inhibitor sirtinol (Stnl) and then subjected to MI/R injury. BBR conferred cardioprotective effects by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase levels, upregulating SIRT1, Bcl-2 expressions, and downregulating Bax and caspase-3 expressions. Stnl attenuated these effects by inhibiting SIRT1 signaling. BBR treatment also reduced myocardium superoxide generation, gp91(phox) expression, malondialdehyde (MDA) level, and cardiac inflammatory markers and increased myocardium superoxide dismutase (SOD) level. However, these effects were also inhibited by Stnl. Consistently, BBR conferred similar antioxidative and anti-inflammatory effects against simulated ischemia reperfusion injury in cultured H9C2 cardiomyocytes. SIRT1 siRNA administration also abolished these effects. In summary, our results demonstrate that BBR significantly improves post-MI/R cardiac function recovery and reduces infarct size against MI/R injury possibly due to its strong antioxidative and anti-inflammatory activity. Additionally, SIRT1 signaling plays a key role in this process.
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http://dx.doi.org/10.1155/2016/1689602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691633PMC
October 2016

Melatonin reverses flow shear stress-induced injury in bone marrow mesenchymal stem cells via activation of AMP-activated protein kinase signaling.

J Pineal Res 2016 Mar;60(2):228-41

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

Tissue-engineered heart valves (TEHVs) are a promising treatment for valvular heart disease, although their application is limited by high flow shear stress (FSS). Melatonin has a wide range of physiological functions and is currently under clinical investigation for expanded applications; moreover, extensive protective effects on the cardiovascular system have been reported. In this study, we investigated the protection conferred by melatonin supplementation against FSS-induced injury in bone marrow mesenchymal stem cells (BMSCs) and elucidated the potential mechanism in this process. Melatonin markedly reduced BMSC apoptotic death in a concentration-dependent manner while increasing the levels of transforming growth factor β (TGF-β), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and B-cell lymphoma 2 (Bcl2), and decreasing those of Bcl-2-associated X protein (Bax), p53 upregulated modulator of apoptosis (PUMA), and caspase 3. Notably, melatonin exerted its protective effects by upregulating the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), which promotes acetyl-CoA carboxylase (ACC) phosphorylation. Further molecular experiments revealed that luzindole, a nonselective antagonist of melatonin receptors, blocked the anti-FSS injury (anti-FSSI) effects of melatonin. Inhibition of AMPK by Compound C also counteracted the protective effects of melatonin, suggesting that melatonin reverses FSSI in BMSCs through the AMPK-dependent pathway. Overall, our findings indicate that melatonin contributes to the amelioration of FSS-induced BMSC injury by activating melatonin receptors and AMPK/ACC signaling. Our findings may provide a basis for the design of more effective strategies that promote the use of TEHCs in patients.
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http://dx.doi.org/10.1111/jpi.12306DOI Listing
March 2016

Association of genetic polymorphisms on BTNL2 with susceptibility to and prognosis of dilated cardiomyopathy in a Chinese population.

Int J Clin Exp Pathol 2015 1;8(9):10488-99. Epub 2015 Sep 1.

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University Xi'an 710032, China.

Background: Dilated cardiomyopathy (DCM) is one type of primary myocardial disease, partly caused by immunity dysfunctions. BTNL2 (butyrophilin-like 2) has already been confirmed to be involved in the etiology of autoimmune disorders and GWAS (genome wide association study) has also identified mutants of a SNP (single nucleotide polymorphism) near BTNL2 could modulate risk of coronary heart disease (also cardiomyopathy). The current study, therefore, was aimed to investigate whether polymorphisms within or around BTNL2 would be correlated with susceptibility to and prognosis of DCM.

Material And Methods: Peripheral blood samples were gathered from 82 DCM patients and 75 healthy controls. Nine tag-SNPs within or near BTNL2 were obtained from HapMap Database and previously published studies. Eligible haplotypes were gained on the basis of SHesis software. Genotyping of SNPs was implemented with aid of Sequenom MassArray iPLEX platform and subsequently analyzed via MALDI-TOF mass spectrometry. The odd ratios and their 95% confidence interval (95% CI) were utilized to evaluate the correlations between SNPs/haplotypes and DCM risks. Finally, Cox proportional hazard models and Kaplan-Meier curves were performed to assess association of SNPs/haplotypes with prognosis of DCM patients. The statistical analyses were conducted with SPSS 19.0 software.

Results: Under the allelic model, rs3763313 (A > C), rs9268494 (C > A), rs9268492 (C > G) and rs9268402 (A > G) were remarkably associated with susceptibility to grade IV of DCM classified by NYHA (New York heart association) (OR = 0.43, 95% CI: 0.22-0.84; P = 0.018; OR = 0.49, 95% CI: 0.27-0.91; P = 0.024; OR = 0.50, 95% CI: 0.27-0.94; P = 0.035; OR = 0.53, 95% CI: 0.28-0.97; P = 0.048). Haplotype C-C-A-T (rs9268492, rs9268494, rs3763313 and rs3763317 synthesized) was also regarded as a protective factor for DCM patients compared with carriers of other haplotypes (OR = 0.50, 95% CI: 0.26-0.97, P = 0.038). Moreover, the univariate survival analysis and multivariate Cox regression analysis both indicated noticeable correlations between rs9268402 and haplotype C-C-A-T and prognosis of DCM patients (NYHA IV), respectively (Long-Rank P = 0.029, HR: 0.241, 95% CI: 0.089-0.650, P = 0.005; Long-Rank P = 0.036; HR = 0.126, 95% CI: 0.035-0.457, P = 0.002). Nonetheless, rs3763313 was found only associated with prognosis of DCM patients (NYHA IV) expressed in the Kaplan-Meier curve (P = 0.009).

Conclusion: The genetic mutations within or around BTNL2 (rs3763313, rs9268494, rs9268492 and rs9268402) could alter susceptibility to grade IV of DCM in a Chinese population, and the 2 SNPs (rs3763313 and rs9268402) therein added with haplotype C-C-A-T might separately predict the prognosis of DCM patients. However, additional studies regarding diverse ethnicities need to be furthered to validate our results.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637574PMC
September 2016

Resveratrol attenuates inflammation and oxidative stress induced by myocardial ischemia-reperfusion injury: role of Nrf2/ARE pathway.

Int J Clin Exp Med 2015 15;8(7):10420-8. Epub 2015 Jul 15.

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University Xi'an, China.

The protective role of resveratrol in myocardial ischemia/reperfusion is not well understood. The aim of this study was to investigate whether resveratrol modulates inflammation and oxidative stress and the possible role of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway in an ischemia/reperfusion injured rat heart model. Rats were randomly exposed to sham operation, myocardial ischemia/reperfusion (MI/R) alone, and MI/R + resveratrol. The results demonstrated that compared to MI/R, resveratrol improved cardiac function, reduced myocardial infarction area, myocardial myeloperoxidase (MPO) levels, serum creatinine kinase (CK) and lactate dehydrogenase (LDH) levels. Resveratrol also markedly enhanced the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and reduced the level of malondialdehyde (MDA) in MI/R rats. Resveratrol also enhanced levels of Nrf2 and heme oxygenase-1. In summary, these results demonstrated that resveratrol exerted significant antioxidant and cardioprotective effects following myocardial ischemia, possibly through the activation of the Nrf2/ARE signaling pathway.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565215PMC
September 2015

Reduced silent information regulator 1 signaling exacerbates myocardial ischemia-reperfusion injury in type 2 diabetic rats and the protective effect of melatonin.

J Pineal Res 2015 Oct 11;59(3):376-90. Epub 2015 Sep 11.

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

Diabetes mellitus (DM) increases myocardial oxidative stress and endoplasmic reticulum (ER) stress. Melatonin confers cardioprotective effect by suppressing oxidative damage. However, the effect and mechanism of melatonin on myocardial ischemia-reperfusion (MI/R) injury in type 2 diabetic state are still unknown. In this study, we developed high-fat diet-fed streptozotocin (HFD-STZ) rat, a well-known type 2 diabetic model, to evaluate the effect of melatonin on MI/R injury with a focus on silent information regulator 1 (SIRT1) signaling, oxidative stress, and PERK/eIF2α/ATF4-mediated ER stress. HFD-STZ treated rats were exposed to melatonin treatment in the presence or the absence of sirtinol (a SIRT1 inhibitor) and subjected to MI/R surgery. Compared with nondiabetic animals, type 2 diabetic rats exhibited significantly decreased myocardial SIRT1 signaling, increased apoptosis, enhanced oxidative stress, and ER stress. Additionally, further reduced SIRT1 signaling, aggravated oxidative damage, and ER stress were found in diabetic animals subjected to MI/R surgery. Melatonin markedly reduced MI/R injury by improving cardiac functional recovery and decreasing myocardial apoptosis in type 2 diabetic animals. Melatonin treatment up-regulated SIRT1 expression, reduced oxidative damage, and suppressed PERK/eIF2α/ATF4 signaling. However, these effects were all attenuated by SIRT1 inhibition. Melatonin also protected high glucose/high fat cultured H9C2 cardiomyocytes against simulated ischemia-reperfusion injury-induced ER stress by activating SIRT1 signaling while SIRT1 siRNA blunted this action. Taken together, our study demonstrates that reduced cardiac SIRT1 signaling in type 2 diabetic state aggravates MI/R injury. Melatonin ameliorates reperfusion-induced oxidative stress and ER stress via activation of SIRT1 signaling, thus reducing MI/R damage and improving cardiac function.
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http://dx.doi.org/10.1111/jpi.12269DOI Listing
October 2015

Membrane receptor-dependent Notch1/Hes1 activation by melatonin protects against myocardial ischemia-reperfusion injury: in vivo and in vitro studies.

J Pineal Res 2015 Nov 11;59(4):420-33. Epub 2015 Sep 11.

Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

Melatonin confers profound protective effect against myocardial ischemia-reperfusion injury (MI/RI). Activation of Notch1/Hairy and enhancer of split 1 (Hes1) signaling also ameliorates MI/RI. We hypothesize that melatonin attenuates MI/RI-induced oxidative damage by activating Notch1/Hes1 signaling pathway with phosphatase and tensin homolog deleted on chromosome 10 (Pten)/Akt acting as the downstream signaling pathway in a melatonin membrane receptor-dependent manner. Male Sprague Dawley rats were treated with melatonin (10 mg/kg/day) for 4 wk and then subjected to MI/R surgery. Melatonin significantly improved cardiac function and decreased myocardial apoptosis and oxidative damage. Furthermore, in cultured H9C2 cardiomyocytes, melatonin (100 μmol/L) attenuated simulated ischemia-reperfusion (SIR)-induced myocardial apoptosis and oxidative damage. Both in vivo and in vitro study demonstrated that melatonin treatment increased Notch1, Notch1 intracellular domain (NICD), Hes1, Bcl-2 expressions, and p-Akt/Akt ratio and decreased Pten, Bax, and caspase-3 expressions. However, these protective effects conferred by melatonin were blocked by DAPT (the specific inhibitor of Notch1 signaling), luzindole (the antagonist of melatonin membrane receptors), Notch1 siRNA, or Hes1 siRNA administration. In summary, our study demonstrates that melatonin treatment protects against MI/RI by modulating Notch1/Hes1 signaling in a receptor-dependent manner and Pten/Akt signaling pathways are key downstream mediators.
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http://dx.doi.org/10.1111/jpi.12272DOI Listing
November 2015
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