Publications by authors named "Miaomiao Fan"

25 Publications

  • Page 1 of 1

FNDC5/Irisin attenuates diabetic cardiomyopathy in a type 2 diabetes mouse model by activation of integrin αV/β5-AKT signaling and reduction of oxidative/nitrosative stress.

J Mol Cell Cardiol 2021 Jul 3;160:27-41. Epub 2021 Jul 3.

Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address:

Irisin, the cleaved form of the fibronectin type III domain containing 5 (FNDC5) protein, is involved in metabolism and inflammation. Recent findings indicated that irisin participated in cardiovascular physiology and pathology. In this study, we investigated the effects of FNDC5/irisin on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice. Downregulation of myocardial FNDC5/irisin protein expression and plasma irisin levels was observed in db/db mice compared to db/+ controls. Moreover, echocardiography revealed that db/db mice exhibited normal cardiac systolic function and impaired diastolic function. Adverse structural remodeling, including cardiomyocyte apoptosis, myocardial fibrosis, and cardiac hypertrophy were observed in the hearts of db/db mice. Sixteen-week-old db/db mice were intramyocardially injected with adenovirus encoding FNDC5 or treated with recombinant human irisin via a peritoneal implant osmotic pump for 4 weeks. Both overexpression of myocardial FNDC5 and exogenous irisin administration attenuated diastolic dysfunction and cardiac structural remodeling in db/db mice. Results from in vitro studies revealed that FNDC5/irisin protein expression was decreased in high glucose (HG)/high fat (HF)-treated cardiomyocytes. Increased levels of inducible nitric oxide synthase (iNOS), NADPH oxidase 2 (NOX2), 3-nitrotyrosine (3-NT), reactive oxygen species (ROS), and peroxynitrite (ONOO) in HG/HF-treated H9C2 cells provided evidence of oxidative/nitrosative stress, which was alleviated by treatment with FNDC5/irisin. Moreover, the mitochondria membrane potential (ΔΨm) was decreased and cytochrome C was released from mitochondria with increased levels of cleaved caspase-3 in HG/HF-treated H9C2 cells, indicating the presence of mitochondria-dependent apoptosis, which was partially reversed by FNDC5/irisin treatment. Mechanistic studies showed that activation of integrin αVβ5-AKT signaling and attenuation of oxidative/nitrosative stress were responsible for the cardioprotective effects of FNDC5/irisin. Therefore, FNDC5/irisin mediates cardioprotection in DCM by inhibiting myocardial apoptosis, myocardial fibrosis, and cardiac hypertrophy. These findings implicate that FNDC5/irisin as a potential therapeutic intervention for DCM, especially in type 2 diabetes mellitus (T2DM).
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http://dx.doi.org/10.1016/j.yjmcc.2021.06.013DOI Listing
July 2021

Branched chain amino acids exacerbate myocardial ischemia/reperfusion vulnerability via enhancing GCN2/ATF6/PPAR-α pathway-dependent fatty acid oxidation.

Theranostics 2020 27;10(12):5623-5640. Epub 2020 Apr 27.

Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi'an, China.

: Myocardial vulnerability to ischemia/reperfusion (I/R) injury is strictly regulated by energy substrate metabolism. Branched chain amino acids (BCAA), consisting of valine, leucine and isoleucine, are a group of essential amino acids that are highly oxidized in the heart. Elevated levels of BCAA have been implicated in the development of cardiovascular diseases; however, the role of BCAA in I/R process is not fully understood. The present study aims to determine how BCAA influence myocardial energy substrate metabolism and to further clarify the pathophysiological significance during cardiac I/R injury. : Parameters of glucose and fatty acid metabolism were measured by seahorse metabolic flux analyzer in adult mouse cardiac myocytes with or without BCAA incubation Chronic accumulation of BCAA was induced in mice receiving oral BCAA administration. A genetic mouse model with defective BCAA catabolism was also utilized. Mice were subjected to MI/R and the injury was assessed extensively at the whole-heart, cardiomyocyte, and molecular levels. : We confirmed that chronic accumulation of BCAA enhanced glycolysis and fatty acid oxidation (FAO) but suppressed glucose oxidation in adult mouse ventricular cardiomyocytes. Oral gavage of BCAA enhanced FAO in cardiac tissues, exacerbated lipid peroxidation toxicity and worsened myocardial vulnerability to I/R injury. Etomoxir, a specific inhibitor of FAO, rescued the deleterious effects of BCAA on I/R injury. Mechanistically, valine, leucine and their corresponding branched chain α-keto acid (BCKA) derivatives, but not isoleucine and its BCKA derivative, transcriptionally upregulated peroxisome proliferation-activated receptor alpha (PPAR-α). BCAA/BCKA induced PPAR-α upregulation through the general control nonderepresible-2 (GCN2)/ activating transcription factor-6 (ATF6) pathway. Finally, in a genetic mouse model with BCAA catabolic defects, chronic accumulation of BCAA increased FAO in myocardial tissues and sensitized the heart to I/R injury, which could be reversed by adenovirus-mediated PPAR-α silencing. : We identify BCAA as an important nutrition regulator of myocardial fatty acid metabolism through transcriptional upregulation of PPAR-α. Chronic accumulation of BCAA, caused by either dietary or genetic factors, renders the heart vulnerable to I/R injury via exacerbating lipid peroxidation toxicity. These data support the notion that BCAA lowering methods might be potentially effective cardioprotective strategies, especially among patients with diseases characterized by elevated levels of BCAA, such as obesity and diabetes.
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http://dx.doi.org/10.7150/thno.44836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196282PMC
May 2021

Luteolin attenuates sepsis‑induced myocardial injury by enhancing autophagy in mice.

Int J Mol Med 2020 May 11;45(5):1477-1487. Epub 2020 Mar 11.

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

Sepsis‑induced cardiomyopathy (SIC) is a complication of severe sepsis and septic shock characterized by an invertible myocardial depression. This study sought to explore the potential effects and mechanism of luteolin, a flavonoid polyphenolic compound, in lipopolysaccharide (LPS)‑induced myocardial injury. Experimental mice were randomly allocated into 3 groups (25 mice in each group): The control group (NC), the LPS group (LPS) and the LPS + luteolin group (LPS + Lut). Before the SIC model was induced, luteolin was dissolved in DMSO and injected intraperitoneally for 10 days into LPS + Lut group mice. NC group and LPS group mice received an equal volume of DMSO for 10 days. On day 11, the animal model of sepsis‑induced cardiac dysfunction was induced by intraperitoneal injection of LPS. A total of 12 h after LPS injection, measurements and comparisons were made among the groups. Luteolin administration improved cardiac function, attenuated the inflammatory response, alleviated mitochondrial injury, decreased oxidative stress, inhibited cardiac apoptosis and enhanced autophagy. In addition, luteolin significantly decreased the phosphorylation of AMP‑activated protein kinase (AMPK) in septic heart tissue. The protective effect of luteolin was abolished by 3‑methyladenine (an autophagy inhibitor) and dorsomorphin (compound C, an AMPK inhibitor), as evidenced by decreased autophagic activity, destabilized mitochondrial membrane potential and increased apoptosis in LPS‑treated cardiomyocytes, but was mimicked by 5‑aminoimidazole‑4‑carboxamide ribonucleotide (an AMPK activator), suggesting that luteolin attenuates LPS‑induced myocardial injury by increasing autophagy through AMPK activation. Luteolin may be a promising therapeutic agent for treating SIC.
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http://dx.doi.org/10.3892/ijmm.2020.4536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138288PMC
May 2020

Branched-Chain Amino Acids Exacerbate Obesity-Related Hepatic Glucose and Lipid Metabolic Disorders via Attenuating Akt2 Signaling.

Diabetes 2020 06 17;69(6):1164-1177. Epub 2020 Mar 17.

Department of Cardiology, Xijing Hospital, Air Force Military Medical University, Xi'an, Shaanxi, China

Branched chain amino acids (BCAAs) are associated with the progression of obesity-related metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease. However, whether BCAAs disrupt the homeostasis of hepatic glucose and lipid metabolism remains unknown. In this study, we observed that BCAAs supplementation significantly reduced high-fat (HF) diet-induced hepatic lipid accumulation while increasing the plasma lipid levels and promoting muscular and renal lipid accumulation. Further studies demonstrated that BCAAs supplementation significantly increased hepatic gluconeogenesis and suppressed hepatic lipogenesis in HF diet-induced obese (DIO) mice. These phenotypes resulted from severe attenuation of Akt2 signaling via mTORC1- and mTORC2-dependent pathways. BCAAs/branched-chain α-keto acids (BCKAs) chronically suppressed Akt2 activation through mTORC1 and mTORC2 signaling and promoted Akt2 ubiquitin-proteasome-dependent degradation through the mTORC2 pathway. Moreover, the E3 ligase Mul1 played an essential role in BCAAs/BCKAs-mTORC2-induced Akt2 ubiquitin-dependent degradation. We also demonstrated that BCAAs inhibited hepatic lipogenesis by blocking Akt2/SREBP1/INSIG2a signaling and increased hepatic glycogenesis by regulating Akt2/Foxo1 signaling. Collectively, these data demonstrate that in DIO mice, BCAAs supplementation resulted in serious hepatic metabolic disorder and severe liver insulin resistance: insulin failed to not only suppress gluconeogenesis but also activate lipogenesis. Intervening BCAA metabolism is a potential therapeutic target for severe insulin-resistant disease.
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http://dx.doi.org/10.2337/db19-0920DOI Listing
June 2020

Tailorable Hydrogel Improves Retention and Cardioprotection of Intramyocardial Transplanted Mesenchymal Stem Cells for the Treatment of Acute Myocardial Infarction in Mice.

J Am Heart Assoc 2020 01 18;9(2):e013784. Epub 2020 Jan 18.

Department of Cardiology Xijing Hospital Fourth Military Medical University Xi'an China.

Background Poor engraftment of intramyocardial stem cells limits their therapeutic efficiency against myocardial infarction (MI)-induced cardiac injury. Transglutaminase cross-linked Gelatin (Col-Tgel) is a tailorable collagen-based hydrogel that is becoming an excellent biomaterial scaffold for cellular delivery in vivo. Here, we tested the hypothesis that Col-Tgel increases retention of intramyocardially-injected stem cells, and thereby reduces post-MI cardiac injury. Methods and Results Adipose-derived mesenchymal stem cells (ADSCs) were co-cultured with Col-Tgel in a 3-dimensional system in vitro, and Col-Tgel encapsulated ADSCs were observed using scanning electron microscopy and confocal microscopy. Vitality, proliferation, and migration of co-cultured ADSCs were evaluated. In addition, mice were subjected to MI and were intramyocardially injected with ADSCs, Col-Tgel, or a combination thereof. ADSCs engraftment, survival, cardiac function, and fibrosis were assessed. In vitro MTT and Cell Counting Kit-8 assays demonstrated that ADSCs survive and proliferate up to 4 weeks in the Col-Tgel. In addition, MTT and transwell assays showed that ADSCs migrate outside the edge of the Col-Tgel sphere. Furthermore, when compared with ADSCs alone, Col-Tgel-encapsulated ADSCs significantly enhanced the long-term retention and cardioprotective effect of ADSCs against MI-induced cardiac injury. Conclusions In the current study, we successfully established a 3-dimensional co-culture system using ADSCs and Col-Tgel. The Col-Tgel creates a suitable microenvironment for long-term retention of ADSCs in an ischemic area, and thereby enhances their cardioprotective effects. Taken together, this study may provide an alternative biomaterial for stem cell-based therapy to treat ischemic heart diseases.
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http://dx.doi.org/10.1161/JAHA.119.013784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033822PMC
January 2020

Endophytic fungi from the branches of Camellia taliensis (W. W. Smith) Melchior, a widely distributed wild tea plant.

World J Microbiol Biotechnol 2019 Jul 9;35(7):113. Epub 2019 Jul 9.

Key Laboratory for Forest Resources Conservation and Utilization in the Southwest Mountains of China, Ministry of Education, Southwest Forestry University, Kunming, 650224, People's Republic of China.

Camellia taliensis (W. W. Smith) Melchior is a wild tea plant endemic from the west and southwest of Yunnan province of China to the north of Myanmar and is used commonly to produce tea by the local people of its growing areas. Its chemical constituents are closely related to those of C. sinensis var. assamica, a widely cultivated tea plant. In this study, the α diversity and phylogeny of endophytic fungi in the branches of C. taliensis were explored for the first time. A total of 160 fungal strains were obtained and grouped into 42 species from 29 genera, which were identified based on rDNA internal transcribed spacer sequence analysis. Diversity analysis showed that the endophytic fungal community of the branches of C. taliensis had high species richness S (42), Margalef index D' (8.0785), Shannon-Wiener index H' (2.8494), Simpson diversity index D (0.8891), PIE index (0.8947) and evenness Pielou index J (0.7623) but a low dominant index λ (0.1109). By contrast, that in the branches of C. taliensis had abundant species and high species evenness. Diaporthe tectonigena, Acrocalymma sp. and Colletotrichum magnisporum were the dominant endophytic fungi. The phylogenetic tree was established by maximum parsimony analysis, and the 11 orders observed for endophytic fungi belonging to Ascomycota and Basidiomycota were grouped into 4 classes.
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http://dx.doi.org/10.1007/s11274-019-2686-xDOI Listing
July 2019

Thioredoxin-1 promotes macrophage reverse cholesterol transport and protects liver from steatosis.

Biochem Biophys Res Commun 2019 09 4;516(4):1103-1109. Epub 2019 Jul 4.

Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi'an, China. Electronic address:

Atherosclerosis is characterized by the accumulation of excess cholesterol in plaques. Reverse cholesterol transport (RCT) plays a key role in the removal of cholesterol. In the present study, we examined the effect of thioredoxin-1 (Trx-1) on RCT and explored the underlying mechanism. We found that Trx-1 promoted RCT in vivo, as did T0901317, a known liver X receptor (LXR) ligand. T0901317 also inhibited the development of atherosclerotic plaques but promoted liver steatosis. Furthermore, Trx-1 promoted macrophage cholesterol efflux to apoAI in vitro. Mechanistically, Trx-1 promoted nuclear translocation of LXRα and induced the expression of ATP-binding cassette transporter A1 (ABCA1). Apolipoprotein E knockout (apoE-/-) mice fed an atherogenic diet were daily injected intraperitoneally with saline or Trx-1 (0.33 mg/kg). Trx-1 treatment significantly inhibited the development of atherosclerosis and induced the expression of ABCA1 in macrophages retrieved from apoE-/- mice. Moreover, the liver steatosis was attenuated by Trx-1. Overall, we demonstrated that Trx-1 promotes RCT by upregulating ABCA1 expression through induction of nuclear translocation of LXRα, and protects liver from steatosis.
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http://dx.doi.org/10.1016/j.bbrc.2019.06.109DOI Listing
September 2019

Melatonin Ameliorates the Progression of Atherosclerosis via Mitophagy Activation and NLRP3 Inflammasome Inhibition.

Oxid Med Cell Longev 2018 4;2018:9286458. Epub 2018 Sep 4.

Department of Cardiology & National Clinical Research Center of Geriatrics Disease, Chinese PLA General Hospital, Beijing 100853, China.

The NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome-mediated inflammatory responses are critically involved in the progression of atherosclerosis (AS), which is the essential cause for cardiovascular diseases. Melatonin has anti-inflammatory properties. However, little is known about the potential effects of melatonin in the pathological process of AS. Herein, we demonstrate that melatonin suppressed prolonged NLRP3 inflammasome activation in atherosclerotic lesions by reactive oxygen species (ROS) scavenging via mitophagy in macrophages. The atherosclerotic mouse model was induced with a high-fat diet using ApoE mice. Melatonin treatment markedly attenuated AS plaque size and vulnerability. Furthermore, melatonin decreased NLRP3 inflammasome activation and the consequent IL-1 secretion within atherosclerotic lesions. Despite the unchanged protein expression, the silent information regulator 3 (Sirt3) activity was elevated in the atherosclerotic lesions in melatonin-treated mice. In ox-LDL-treated macrophages, melatonin attenuated the NLRP3 inflammasome activation and the inflammatory factors secretion, while this protective effect was abolished by either Sirt3 silence or autophagy inhibitor 3-MA. Mitochondrial ROS (mitoROS), which was a recognized inducer for NLRP3 inflammasome, was attenuated by melatonin through the induction of mitophagy. Both Sirt3-siRNA and autophagy inhibitor 3-MA partially abolished the beneficial effects of melatonin on mitoROS clearance and NLRP3 inflammasome activation, indicating the crucial role of Sirt3-mediated mitophagy. Furthermore, we demonstrated that melatonin protected against AS via the Sirt3/FOXO3a/Parkin signaling pathway. In conclusion, the current study demonstrated that melatonin prevented atherosclerotic progression, at least in part, via inducing mitophagy and attenuating NLRP3 inflammasome activation, which was mediated by the Sirt3/FOXO3a/Parkin signaling pathway. Collectively, our study provides insight into melatonin as a new target for therapeutic intervention for AS.
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http://dx.doi.org/10.1155/2018/9286458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142770PMC
November 2018

Dopamine Receptor Subtypes Mediate Opposing Effects on Form Deprivation Myopia in Pigmented Guinea Pigs.

Invest Ophthalmol Vis Sci 2018 09;59(11):4441-4448

School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Purpose: We reported previously that changes in dopamine receptor (DR) subtype activation modulate spontaneous myopia progression in albino guinea pigs. To determine if DR control of refractive error development is different than in its normal counterpart, we evaluated the contribution of dopaminergic pathways to emmetropization and form deprivation myopia (FDM) progression in pigmented guinea pigs.

Methods: Monocular myopia was induced by unilateral form-deprivation (FD). The effects of agonists of D1R (SKF38393) and D2R (quinpirole), the corresponding antagonists (SCH23390 and sulpiride), and vehicle were tested by peribulbar injection around FD or untreated control eyes. High-performance liquid chromatography with electrochemical detection quantified retinal and vitreous dopamine (DA) and 4-dihydroxyphenylacetic acid (DOPAC) levels. Ocular refraction and axial dimensions were measured using eccentric infrared photoretinoscopy (EIR) and A-scan ultrasonography, respectively, initially and after 2 or 4 weeks of treatment.

Results: After treatment with any of these four agents for 2 weeks, retinal and vitreal DA and DOPAC levels were not significantly different in drug- and vehicle-treated eyes. Neither agonism nor antagonism of D1R or D2R activity affected emmetropization. In contrast, D1R activation by SKF38393 inhibited FDM progression, while D2R activation by quinpirole augmented this response. On the other hand, D2R antagonism with sulpiride slowed FDM progression while D1R antagonism with SCH23390 had no effect.

Conclusions: In pigmented guinea pigs, D1R activation inhibited, whereas D2R activation enhanced, FDM. These results closely mirror previous findings in albino animals and offer further evidence that DA and its cognate receptors affect refractive error regulation in guinea pigs.
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http://dx.doi.org/10.1167/iovs.17-21574DOI Listing
September 2018

Precise theranostic nanomedicines for inhibiting vulnerable atherosclerotic plaque progression through regulation of vascular smooth muscle cell phenotype switching.

Theranostics 2018 12;8(13):3693-3706. Epub 2018 Jun 12.

Department of Cardiology & National Clinical Research Center of Geriatrics Disease, Chinese PLA General Hospital, Beijing 100853, China.

Coronary heart disease is a prevalent and fatal killer caused by vulnerable atherosclerotic plaques (VASPs). However, the precise detection and treatment of VASPs remains a difficult challenge. Here, we present the development of noninvasive human serum albumin (HSA)-based theranostic nanomedicines (NMs) for the specific diagnosis and effective therapy of VASPs. The ICG/[email protected] NMs were formulated to contain payloads of the near-infrared (NIR) fluorescent dye indocyanine green (ICG) and the sirtuin 1 (Sirt1) activator SRT1720, and modified with a peptide moiety targeting osteopontin (OPN). The atherosclerotic mouse model was established with the high-fat diet (HFD). The vascular smooth muscle cells (VSMCs) phenotypic switching was induced using the ox-LDL stimulation. Due to the overexpression of OPN in activated VSMCs and VASPs, the targeted NMs specifically accumulated within the VASPs region after intravenous injection into the atherosclerotic mice, achieving the precise detection of VASPs. In addition, in the presence of SRT1720, the NMs could activate intracellular Sirt1 and activate an antiatherogenesis effect by inhibiting the phenotypic switching of VSMCs, which is an essential contributor to the vulnerability and progression of atherosclerotic plaques. After therapeutic administration of the ICG/[email protected] NMs for two weeks, the physiological sizes and plaque compositions of VASPs were markedly improved. Furthermore, ICG/[email protected] NMs-treated mice presented a more favorable plaque phenotype than that was observed in free SRT1720-treated mice, suggesting the enhanced delivery of pharmaceutical agents to the atherosclerotic lesions and improved therapeutic efficacy of NMs compared with free SRT1720. The theranostic ICG/[email protected] NMs showed great potential for the precise identification and targeted treatment of atherosclerotic diseases.
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http://dx.doi.org/10.7150/thno.24364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037040PMC
August 2019

A Novel Mechanism of Mesenchymal Stromal Cell-Mediated Protection against Sepsis: Restricting Inflammasome Activation in Macrophages by Increasing Mitophagy and Decreasing Mitochondrial ROS.

Oxid Med Cell Longev 2018 13;2018:3537609. Epub 2018 Feb 13.

Department of Cardiology & National Clinical Research Center of Geriatrics Disease, Chinese PLA General Hospital, Beijing 100853, China.

Sepsis, a systemic inflammatory response to infection, is the leading cause of death in the intensive care unit (ICU). Previous studies indicated that mesenchymal stromal cells (MSCs) might have therapeutic potential against sepsis. The current study was designed to investigate the effects of MSCs on sepsis and the underlying mechanisms focusing on inflammasome activation in macrophages. The results demonstrated that the bone marrow-derived mesenchymal stem cells (BMSCs) significantly increased the survival rate and organ function in cecal ligation and puncture (CLP) mice compared with the control-grouped mice. BMSCs significantly restricted NLRP3 inflammasome activation, suppressed the generation of mitochondrial ROS, and decreased caspase-1 and IL-1 activation when cocultured with bone marrow-derived macrophages (BMDMs), the effects of which could be abolished by Mito-TEMPO. Furthermore, the expression levels of caspase-1, IL-1, and IL-18 in BMDMs were elevated after treatment with mitophagy inhibitor 3-MA. Thus, BMSCs exert beneficial effects on inhibiting NLRP3 inflammasome activation in macrophages primarily via both enhancing mitophagy and decreasing mitochondrial ROS. These findings suggest that restricting inflammasome activation in macrophages by increasing mitophagy and decreasing mitochondrial ROS might be a crucial mechanism for MSCs to combat sepsis.
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http://dx.doi.org/10.1155/2018/3537609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831900PMC
September 2018

Highly Uniform Hollow GdF3 Ellipsoids: Controllable Synthesis, Characterization and Up-Conversion Luminescence Properties.

J Nanosci Nanotechnol 2018 Aug;18(8):5822-5827

The Key Laboratory of Inorganic Molecule-Based Chemistry of Liaoning Province, College of Applied Chemistry, Shenyang University of Chemical Technology, Shenyang 110142, China.

In this paper, the hollow GdF3 ellipsoids were successfully synthesized through a facile hydrothermal approach. The results indicated that the as-obtained GdF3 sample has an orthorhombic structure and the average length and diameter of the hollow ellipsoids are 750 nm and 350 nm, respectively. The possible formation mechanism of the hollow GdF3 ellipsoids has been presented. The upconversion (UC) luminescence properties of the hollow GdF3: Yb3+/Ln3+ (Ln3+ = Er3+, Tm3+, Ho3+) ellipsoids were systematically investigated, which showed green (Er3+, 4S3/2, 2H11/2 → 4I15/2), blue (Tm3+, 1G4 → 3H6), and green (Ho3+, 5S2 → 5I8) luminescence under 980 nm NIR excitation, respectively. Furthermore, the UC white light was successfully obtained in the GdF3: Yb3+/Er3+/Tm3+ sample through adjusting relative doping concentration of Yb3+, Er3+ and Tm3+ ions. These findings may reveal potential applications in the fields of laser, bioanalysis, optoelectronic and nanoscale devices due to multicolor emissions in the visible region.
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http://dx.doi.org/10.1166/jnn.2018.15422DOI Listing
August 2018

SIRT1 Activation by Resveratrol Alleviates Cardiac Dysfunction via Mitochondrial Regulation in Diabetic Cardiomyopathy Mice.

Oxid Med Cell Longev 2017 13;2017:4602715. Epub 2017 Aug 13.

Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.

Background: Diabetic cardiomyopathy (DCM) is a major threat for diabetic patients. Silent information regulator 1 (SIRT1) has a regulatory effect on mitochondrial dynamics, which is associated with DCM pathological changes. Our study aims to investigate whether resveratrol, a SRIT1 activator, could exert a protective effect against DCM.

Methods And Results: Cardiac-specific SIRT1 knockout (SIRT1) mice were generated using Cre-loxP system. SIRT1 mice displayed symptoms of DCM, including cardiac hypertrophy and dysfunction, insulin resistance, and abnormal glucose metabolism. DCM and SIRT1 hearts showed impaired mitochondrial biogenesis and function, while SIRT1 activation by resveratrol reversed this in DCM mice. High glucose caused increased apoptosis, impaired mitochondrial biogenesis, and function in cardiomyocytes, which was alleviated by resveratrol. SIRT1 deletion by both SIRT1 and shRNA abolished the beneficial effects of resveratrol. Furthermore, the function of SIRT1 is mediated via the deacetylation effect on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), thus inducing increased expression of nuclear respiratory factor 1 (NRF-1), NRF-2, estrogen-related receptor-α (ERR-α), and mitochondrial transcription factor A (TFAM).

Conclusions: Cardiac deletion of SIRT1 caused phenotypes resembling DCM. Activation of SIRT1 by resveratrol ameliorated cardiac injuries in DCM through PGC-1α-mediated mitochondrial regulation. Collectively, SIRT1 may serve as a potential therapeutic target for DCM.
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http://dx.doi.org/10.1155/2017/4602715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572590PMC
May 2018

Endothelial deletion of mTORC1 protects against hindlimb ischemia in diabetic mice via activation of autophagy, attenuation of oxidative stress and alleviation of inflammation.

Free Radic Biol Med 2017 07 1;108:725-740. Epub 2017 May 1.

Department of Cardiology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing 100853, China; Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address:

Peripheral arterial disease (PAD) complicated with diabetes mellitus (DM) still remains a thorny issue due to lack of effective strategies. Our previous study has demonstrated that inhibition of mTORC1 protected adipose-derived stromal cells from hindlimb ischemic injury in PAD mice. However, whether inhibition of mTORC1 could protect against PAD in diabetes mellitus and the underlying mechanisms remained elusive. In this study, we employed endothelial-specific raptor (an essential component of the mTORC1 signaling complex) knockout (KO) mice (Tie2-mTORC1) to investigate whether and how mTORC1 downregulation could alleviate hindlimb ischemic injury in diabetic mice. Tie2-mTORC1 mice and their wild-type littermates were intraperitoneally injected with streptozocin to induce type 1 diabetic model, after which the hyperglycemic mice were randomly allocated to sham operation or PAD operation (femoral artery ligation). The restoration of hindlimb blood perfusion and recovery of limb functions were improved in diabetic Tie2-mTORC1 PAD mice with significant improvements of autophagy, angiogenesis and vascular integrity as well as attenuation of apoptosis, inflammation and oxidative stress. In vitro, high glucose combining with hypoxia/serum deprivation treatment (HG+H/SD) significantly triggered apoptosis, reactive oxygen species generation and inflammation while inhibited autophagy and tube formation in HUVECs. The effect could be accentuated and attenuated by mTORC1 over-expression (TSC2 siRNA) and mTORC1 silencing (raptor siRNA), respectively. Moreover, autophagy inhibitor 3-MA could simulate the effects of TSC2 siRNA while autophagy inducer rapamycin could mimic the effects of raptor siRNA, suggesting that the beneficial effects of mTORC1 deletion were associated with autophagy induction. In conclusion, our present study demonstrates that endothelial mTORC1 deletion protects against hindlimb ischemic injury in diabetic mice possibly via activation of autophagy, attenuation of oxidative stress and alleviation of inflammation. Therapeutics targeting mTORC1 may therefore represents a promising strategy to rescue limb ischemia in diabetes mellitus.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.05.001DOI Listing
July 2017

Dihydromyricetin Protects against Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetic Mice.

Biomed Res Int 2017 21;2017:3764370. Epub 2017 Mar 21.

Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Diabetic cardiomyopathy (DCM) is an important cause of heart failure in diabetic patients. The present study sought to explore the potential effects of dihydromyricetin (DHM) on DCM and its possible mechanism. A diabetic model was induced by intraperitoneal injection of streptozotocin (STZ) in C57BL/6J mice. Two weeks after the STZ injection, mice were randomly allocated into the following 4 groups for treatment: the control group (CON), the control treated with DHM group (CON + DHM), the diabetes group (DM), and the diabetes treated with DHM group (DM + DHM). DHM was dissolved in distilled water and administered daily by gavage. For 14 weeks, the CON + DHM group and DM + DHM group were given a dose of 100 mg/kg/day DHM (Sigma-Aldrich), while the CON and DM groups were intragastrically given equivalent volumes of distilled water. Assessments and comparisons were made among the groups based on cardiac function and structural changes, inflammation factors, markers of oxidative stress, mitochondria function, apoptosis, and autophagy. The DHM treatment normalized body weight, preserved cardiac function, attenuated oxidative stress (MDA, SOD, and GSH-Px), reduced the levels of inflammation factors (IL-6, TNF-), alleviated pathological changes, improved mitochondrial function (ATP content, CS activity, and complex Ι/ΙΙ/ΙΙΙ/ΙV/V activities), inhibited cardiac apoptosis, and restored autophagy in diabetic mice. DHM may have a great therapeutic potential in the treatment of DCM.
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http://dx.doi.org/10.1155/2017/3764370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379084PMC
May 2017

Activation of Cannabinoid Receptor Type II by AM1241 Ameliorates Myocardial Fibrosis via Nrf2-Mediated Inhibition of TGF-β1/Smad3 Pathway in Myocardial Infarction Mice.

Cell Physiol Biochem 2016 12;39(4):1521-36. Epub 2016 Sep 12.

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

Aims: Myocardial interstitial fibrosis is a major histologic landmark resulting in cardiac dysfunction after myocardial infarction (MI). Activation of cannabinoid receptor type II (CB2 receptor) have been demonstrated to reduce fibrosis in hepatic cirrhotic rat. However, the anti-fibrotic effect of CB2 receptor activation in infarcted hearts was still unclear. In this study, we aimed to investigate the effects of a CB2 receptor selective agonist AM1241 on myocardial fibrosis post MI in mice.

Methods: Echocardiograph was conducted to assess cardiac function. Fibrosis markers such as type I and type III collagen, fibronectin, Plasminogen activator inhibitor(PAI)-1 and tissue inhibitor of metalloprotease(TIMP)-1 were examined by Western blot, while collagens were directly observed by Sirius-red staining. Primary cultured cardiac fibroblasts(CFs) were subjected to hypoxia/serum deprivation (H/SD) injury to simulate ischemic conditions in vivo. Nrf2 siRNA were applied to explore the role of Nrf2 and TGF-β1/Smad3 pathway in this process.

Results: Echocardiography showed that AM1241 significantly improved cardiac function, suppressed the expression of fibrosis markers such as collagen I and collagen III, fibronectin, PAI-1 and TIMP-1 in mice with MI. In cardiac fibroblasts subjected to H/SD injury, AM1241 reduced the elevated levels of α-SMA, collagen I and collagen III, which were partially abrogated by the Nrf2 siRNA transfection. Furthermore, AM1241 not only activated and accelerated the translocation of Nrf2 to nucleus, but also inhibited TGF-β1/ Smad3 pathway in an Nrf2 dependent manner.

Conclusion: CB2 receptor agonist AM1241 alleviated myocardial interstitial fibrosis via Nrf2 -mediated down-regulation of TGF-β1/Smad3 pathway, which suggested that CB2 receptor activation might represent a promising target for retarding cardiac fibrosis after MI.
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http://dx.doi.org/10.1159/000447855DOI Listing
January 2017

Quaternized Chitosan/Alginate-Fe3O4 Magnetic Nanoparticles Enhance the Chemosensitization of Multidrug-Resistant Gastric Carcinoma by Regulating Cell Autophagy Activity in Mice.

J Biomed Nanotechnol 2016 May;12(5):948-61

Multidrug resistance (MDR) and targeted therapies present major challenges in tumor chemotherapy. Nanoparticles (NPs) hold promise for use in cancer theranostics due to their advantages in terms of tumor-targeted cytotoxicity and imaging. In this study, we developed N-((2-hydroxy-3-trimethylammonium) propyl) chitosan chloride (HTCC)/alginate-encapsulated Fe3O4 magnetic NPs (HTCC-MNPs) and applied them to MDR gastric cancer both in vivo and in vitro. HTCC-MNPs were fabricated from sodium alginate (ALG), Fe3O4 and HTCC using an ionic gelation method. The sizes and physical characteristics of the NPs were determined using dynamic light scattering, transmission electron microscopy (TEM) and zeta potential analysis. The HTCC-MNPs exhibited excellent water solubility and biocompatibility as well as significantly reduced cell viability in the drug-resistant cancer cell line SGC7901/ADR, but not in normal gastric cells (P < 0.05). An analysis of LC3 expression demonstrated the involvement of autophagy in HTCC-MNP cytotoxicity. Additionally, apoptosis was verified using a DNA content assay. HTCC-MNPs led to mitochondrial membrane potential loss, decreased ATP production and excessive reactive oxygen species (ROS) generation compared to a control group (P < 0.05). Magnetic resonance imaging showed enrichment of HTCC-MNPs in tumor-bearing mice. In vivo bioluminescence imaging and tumor volume measurements revealed that HTCC-MNPs markedly inhibited in vivo tumor growth (P < 0.05). In conclusion, HTCC-MNPs significantly inhibited MDR gastric tumor growth and reduced tumor volume via the induction of cellular autophagy and apoptosis, which was attributed to mitochondrial dysfunction and excessive ROS accumulation.
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http://dx.doi.org/10.1166/jbn.2016.2232DOI Listing
May 2016

Therapeutic efficacy of apelin on transplanted mesenchymal stem cells in hindlimb ischemic mice via regulation of autophagy.

Sci Rep 2016 Feb 23;6:21914. Epub 2016 Feb 23.

Department of Cardiology, Chinese PLA General Hospital, Beijing, 100853, China.

Mesenchymal stem cells (MSCs)-based therapy provides a promising avenue for the management of peripheral arterial disease (PAD). However, engrafted MSCs are subjected to acute cell death in the ischemic microenvironment. Apelin has been shown to protect bone marrow MSCs against apoptosis although the mechanism of action remains elusive. Here we demonstrated that apelin promoted functional survival of AD-MSCs in ischemic hindlimbs and provoked a synergetic effect with AD-MSCs to restore hindlimb blood perfusion and limb functions. Further in vitro studies revealed that a biphasic response in autophagy was induced by apelin in AD-MSCs during hypoxia and hypoxia/reoxygenation (H/R) stages to exert cytoprotective effects against H/R injury. Mechanistically, apelin increased the viability of AD-MSCs via promoting protective autophagy during hypoxia, which was accompanied with activation of AMPK and inhibition of mammalian target of rapamycin (mTOR). To the contrary, apelin suppressed autophagic cell death during reoxygenation, which was accompanied with activation of Akt and inhibition of Beclin1. Our findings indicated that apelin facilitated AD-MSCs-based therapy in PAD, possibly through promoting survival of AD-MSCs by way of autophagy regulation. Our data support the promises of apelin as a novel strategy to improve MSC-based therapy for PAD, possibly through autophagy modulation in MSCs.
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http://dx.doi.org/10.1038/srep21914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763210PMC
February 2016

Ghrelin improves functional survival of engrafted adipose-derived mesenchymal stem cells in ischemic heart through PI3K/Akt signaling pathway.

Biomed Res Int 2015 24;2015:858349. Epub 2015 Mar 24.

Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China ; Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.

Mesenchymal stem cells (MSCs) have been proposed as a promising cell population for cell therapy and regenerative medicine applications. However, the low retention and poor survival of engrafted cells hampered the therapeutic efficacy of engrafted MSCs. Ghrelin is a 28-amino-acid peptide hormone and is proved to exert a protective effect on the cardiovascular system. This study is designed to investigate the protective effects of ghrelin on engrafted adipose-derived mesenchymal stem cells (ADMSCs) and its beneficial effects with cellular therapy in mice myocardial infarction (MI). Results showed that intramyocardial injection of ADMSCs combining with ghrelin administration inhibited host cardiomyocyte apoptosis, reduced fibrosis, and improved cardiac function. To reveal possible mechanisms, ADMSCs were subjected to hypoxia/serum deprivation (H/SD) injury to simulate ischemic conditions in vivo. Ghrelin (10(-8) M, 33,712 pg/ml) improved ADMSCs survival under H/SD condition. Western blot assay revealed that ghrelin increased AKT phosphorylation both in vivo and in vitro, decreased the proapoptotic protein Bax, and increased the antiapoptotic protein Bcl-2 in vitro, while these effects were abolished by PI3K inhibitor LY294002. These revealed that ghrelin may serve as a promising candidate for hormone-driven approaches to improve the efficacy of mesenchymal stem cell-based therapy for cardiac ischemic disease via PI3K/AKT pathway.
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http://dx.doi.org/10.1155/2015/858349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387976PMC
December 2015

Cellular microRNAs up-regulate transcription via interaction with promoter TATA-box motifs.

RNA 2014 Dec 21;20(12):1878-89. Epub 2014 Oct 21.

Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.

The TATA box represents one of the most prevalent core promoters where the pre-initiation complexes (PICs) for gene transcription are assembled. This assembly is crucial for transcription initiation and well regulated. Here we show that some cellular microRNAs (miRNAs) are associated with RNA polymerase II (Pol II) and TATA box-binding protein (TBP) in human peripheral blood mononuclear cells (PBMCs). Among them, let-7i sequence specifically binds to the TATA-box motif of interleukin-2 (IL-2) gene and elevates IL-2 mRNA and protein production in CD4(+) T-lymphocytes in vitro and in vivo. Through direct interaction with the TATA-box motif, let-7i facilitates the PIC assembly and transcription initiation of IL-2 promoter. Several other cellular miRNAs, such as mir-138, mir-92a or mir-181d, also enhance the promoter activities via binding to the TATA-box motifs of insulin, calcitonin or c-myc, respectively. In agreement with the finding that an HIV-1-encoded miRNA could enhance viral replication through targeting the viral promoter TATA-box motif, our data demonstrate that the interaction with core transcription machinery is a novel mechanism for miRNAs to regulate gene expression.
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http://dx.doi.org/10.1261/rna.045633.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4238354PMC
December 2014

Optimizations of siRNA design for the activation of gene transcription by targeting the TATA-box motif.

PLoS One 2014 24;9(9):e108253. Epub 2014 Sep 24.

Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.

Small interfering RNAs (siRNAs) are widely used to repress gene expression by targeting mRNAs. Some reports reveal that siRNAs can also activate or inhibit gene expression through targeting the gene promoters. Our group has found that microRNAs (miRNAs) could activate gene transcription via interaction with the TATA-box motif in gene promoters. To investigate whether siRNA targeting the same region could upregulate the promoter activity, we test the activating efficiency of siRNAs targeting the TATA-box motif of 16 genes and perform a systematic analysis to identify the common features of the functional siRNAs for effective activation of gene promoters. Further, we try various modifications to improve the activating efficiency of siRNAs and find that it is quite useful to design the promoter-targeting activating siRNA by following several rules such as (a) complementary to the TATA-box-centered region; (b) UA usage at the first two bases of the antisense strand; (c) twenty-three nucleotides (nts) in length; (d) 2'-O-Methyl (2'-OMe) modification at the 3' terminus of the antisense strand; (e) avoiding mismatches at the 3' end of the antisense strand. The optimized activating siRNAs potently enhance the expression of interleukin-2 (IL-2) gene in human and mouse primary CD4+ T cells with a long-time effect. Taken together, our study provides a guideline for rational design the promoter-targeting siRNA to sequence-specifically enhance gene expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108253PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176967PMC
June 2015

Necroptosis takes place in human immunodeficiency virus type-1 (HIV-1)-infected CD4+ T lymphocytes.

PLoS One 2014 8;9(4):e93944. Epub 2014 Apr 8.

Institute of Human Virology, Sun Yatsen University, Guangzhou, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yatsen University, Guangzhou, China.

Human immunodeficiency virus type 1 (HIV-1) infection is characterized by progressive depletion of CD4+ T lymphocytes and dysfunction of the immune system. The numbers of CD4+ T lymphocytes in the human body are maintained constantly by homeostatic mechanisms that failed during HIV-1 infection, resulting in progressive loss of CD4+ T cells mainly via apoptosis. Recently, a non-apoptotic form of necrotic programmed cell death, named necroptosis, has been investigated in many biological and pathological processes. We then determine whether HIV-1-infected cells also undergo necroptosis. In this report, we demonstrate that HIV-1 not only induces apoptosis, but also mediates necroptosis in the infected primary CD4+ T lymphocytes and CD4+ T-cell lines. Necroptosis-dependent cytopathic effects are significantly increased in HIV-1-infected Jurkat cells that is lack of Fas-associated protein-containing death domain (FADD), indicating that necroptosis occurs as an alternative cell death mechanism in the absence of apoptosis. Unlike apoptosis, necroptosis mainly occurs in HIV-infected cells and spares bystander damage. Treatment with necrostatin-1(Nec-1), a RIP1 inhibitor that specifically blocks the necroptosis pathway, potently restrains HIV-1-induced cytopathic effect and interestingly, inhibits the formation of HIV-induced syncytia in CD4+ T-cell lines. This suggests that syncytia formation is mediated, at least partially, by necroptosis-related processes. Furthermore, we also found that the HIV-1 infection-augmented tumor necrosis factor-alpha (TNF-α) plays a key role in inducing necroptosis and HIV-1 Envelope and Tat proteins function as its co-factors. Taken together,necroptosis can function as an alternative cell death pathway in lieu of apoptosis during HIV-1 infection, thereby also contributing to HIV-1-induced cytopathic effects. Our results reveal that in addition to apoptosis, necroptosis also plays an important role in HIV-1-induced pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093944PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979729PMC
January 2015

A novel HIV-1-encoded microRNA enhances its viral replication by targeting the TATA box region.

Retrovirology 2014 Mar 12;11:23. Epub 2014 Mar 12.

Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.

Background: A lot of microRNAs (miRNAs) derived from viral genomes have been identified. Many of them play various important roles in virus replication and virus-host interaction. Cellular miRNAs have been shown to participate in the regulation of HIV-1 viral replication, while the role of viral-encoded miRNAs in this process is largely unknown.

Results: In this report, through a strategy combining computational prediction and deep sequencing, we identified a novel HIV-1-encoded miRNA, miR-H3. MiR-H3 locates in the mRNA region encoding the active center of reverse transcriptase (RT) and exhibits high sequence conservation among different subtypes of HIV-1 viruses. Overexpression of miR-H3 increases viral production and the mutations in miR-H3 sequence significantly impair the viral replication of wildtype HIV-1 viruses, suggesting that it is a replication-enhancing miRNA. MiR-H3 upregulates HIV-1 RNA transcription and protein expression. A serial deletion assay suggests that miR-H3 targets HIV-1 5' LTR and upregulates the promoter activity. It interacts with the TATA box in HIV-1 5' LTR and sequence-specifically activates the viral transcription. In addition, chemically-synthesized small RNAs targeting HIV-1 TATA box activate HIV-1 production from resting CD4+ T cells isolated from HIV-1-infected patients on suppressive highly active antiretroviral therapy (HAART).

Conclusions: We have identified a novel HIV-1-encoded miRNA which specifically enhances viral production and provide a specific method to activate HIV-1 latency.
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http://dx.doi.org/10.1186/1742-4690-11-23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007588PMC
March 2014

Facile synthesis of monodisperse LuPO4:Eu3+/Tb3+ hollow nanospheres and their luminescence properties.

J Nanosci Nanotechnol 2013 Oct;13(10):6644-52

College of Materials Science and Engineering, Shenyang University of Chemical Technology, Shenyang 110142, PR China.

Highly uniform and well-dispersed LuPO4 hollow nanospheres were successfully synthesized via a facile solution-phase method by utilizing the colloidal spheres of Lu(OH)CO3 as a sacrificial template and NH4H2PO4 as a phosphorus source. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transformed infrared (FT-IR), photoluminescence (PL) spectra, and cathodoluminescence (CL) spectra were employed to characterize the samples. The result indicates that the hollow LuPO4 spheres can be indexed to the tetragonal phase. The hollow LuPO4 spheres with diameter of about 300 nm become larger with respect to the sacrificial template. The shell of the hollow microspheres consists of numerous nanorods with the thickness of approximately 10 nm. Moreover, the possible formation mechanism of the evolution from Lu(OH)CO3 spheres to the final hollow LuPO4 hollow spheres has been proposed. In addition, upom ultraviolet (UV) and low-voltage electron beams excitation, 5 mol% Eu3+ and 5 mol% Tb3+ doped LuPO4 samples exhibit strong orange-red and green emission, corresponding to the characteristic lines of Eu3+ and Tb3+ under UV excitation, respectively, which may find potential application in the fields of color display and biomedicine.
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http://dx.doi.org/10.1166/jnn.2013.7448DOI Listing
October 2013

[Effect of overexpressing Nisin A structural gene nisA on Nisin A production].

Sheng Wu Gong Cheng Xue Bao 2012 Oct;28(10):1175-83

State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei, China.

Nisin is an antimicrobial peptide widely used in food industry. In this study, Nisin A production in Lactococcus lactis ATCC 11454 was improved by overexpression of Nisin A structural gene nisA through introducing a shuttle expression vector pMG36ek-nisA and an integrated vector pDG780-nisA into the host strain. The differences of growth profiles and Nisin A production level between the two obtained genetic engineering strains FMM1/FMM2 and the parent strain were investigated. Our results show that while the growth profile (the growth rate, biomass and pH) of FMM1 was similar to the parent strain, its Nisin A production increased 31%. In contrast, the biomass of FMM2 was notably lower than the parent strain, while its yield of Nisin A enhanced slightly. The transcription level of genes involved in Nisin A biosynthesis in both engineering strains was further detected by RT-PCR. We found that all the 11 Nisin A biosynthetic genes in FMM1 and FMM2 had a higher transcription level than those in the parent strain, and these genes exhibited more significant increasing degree of transcription level in FMM1 which hosted the autonomous replicating nisA gene. These data suggest that expression of nisA may act as a rate-limit factor in Nisin A biosynthesis. In conclusion, this work provides a new method to improve Nisin A production by increasing the transcription level of nisA, paving the way to further large-scale industrial production of Nisin A.
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October 2012
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