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author:("Liu, duzhong")
1.  Survey of Tuberculosis Hospitals in China: Current Status and Challenges 
PLoS ONE  2014;9(11):e111945.
Background
Hospitals will play an increasingly important role in delivering TB services in China, however little is known in terms of the current landscape of the hospital system that delivers TB care.
Methodology/Principal Findings
In order to examine the status of TB hospitals we performed a study in which a total of 203 TB hospitals, with 30 beds or more, were enrolled from 31 provinces and Xinjiang Production and Construction Corps. Of the 203 hospitals, 93 (45.8%) were located in the eastern region of China, 84 (41.4%) in the central region, and 26 (12.8%) in the western region, while there were 34.6 million TB patients in western China, accounting for 34.6% of the TB burden nationwide. The total number of staff in these 203 hospitals was 83,011, of which 18,899 (22.8%) provided health services for TB patients, (physicians, nurses, lab technicians, etc). Although both the overall number of the health care workers and TB staff in the 203 hospitals increased from the year 1999 to 2009, the former increased by 52%, while the latter increased only by 34%, showing that the percentage of TB staff declined significantly (χ2 = 181.7, P<0.01). The total annual income of the 203 hospitals increased 5.5 fold from 1999 to 2009, while that from TB care increased 3.8 fold during the same period. TB care and control experienced a relatively slower development during this period as shown by the lower percentage of TB staff and the lesser increase in income from TB care in the hospitals.
Conclusions/Significance
In conclusion, our findings demonstrated that hospital resources are scarcer in western China as compared with eastern China. In view of the current findings, policymakers are urged to address the uneven distribution of medical resources between the underdeveloped west and the more affluent eastern provinces.
doi:10.1371/journal.pone.0111945
PMCID: PMC4218826  PMID: 25365259
2.  The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice 
Nature medicine  2014;20(5):524-530.
Acquisition of microbes by the neonate, which begins immediately during birth, is influenced by gestational age and mother’s microbiota and modified by exposure to antibiotics1. In neonates, prolonged duration of antibiotic therapy is associated with increased risk of sepsis after 4 days of life, known as late-onset sepsis (LOS)2, a disorder critically controlled by neutrophils3, but a role for the microbiota in regulating neutrophil behavior in the neonate has not been described. We exposed pregnant mouse dams to antibiotics in drinking water to limit transfer of maternal microbes to the neonates. Antibiotic exposure of dams decreased the total number of microbes in the intestine, altered the structure of intestinal microbiota and changed the pattern of microbial colonization. These changes were associated with decreased numbers of circulating and bone marrow neutrophils and granulocyte/macrophage restricted progenitor cells in the bone marrow. Antibiotic-exposure of dams attenuated the postnatal granulocytosis by reducing the number of interleukin (IL) 17-producing cells in intestine and consequent production of granulocyte colony stimulating factor (G-CSF). Relative granulocytopenia contributed to increased susceptibility of antibiotic-exposed neonatal mice to Escherichia coli K1 and Klebsiella pneumoniae sepsis, which could be partially reversed by administration of G-CSF. Restoration of normal microbiota, through TLR4- and MYD88-dependent mechanism, induced accumulation of IL17-producing type 3 innate lymphoid cells (ILC) in the intestine, promoted granulocytosis, and restored the IL17-dependent resistance to sepsis. Specific depletion of ILCs prevented the IL17- and G-CSF-dependent granulocytosis and resistance to sepsis. These data support a role for the intestinal microbiota in regulation of granulocytosis and host resistance to sepsis in the neonates.
doi:10.1038/nm.3542
PMCID: PMC4016187  PMID: 24747744
3.  Immuno-phenotypes and prognosis of acute leukemia in elderly patients 
Objective: This study is to provide reliable experimental treatment options for the diagnosis of acute leukemia, prognosis analysis and the detection of minimal residual disease. We observed the bone marrow CD123/CD117/CD34/HLA-DR antigen expression in 64 elderly patients with acute leukemia (AL). Methods: The immune phenotypes of 64 elderly AL patients were detected and the correlations of CD123, HLA-DR, CD34 and CD117 expression with the leukemia cell morphology were analyzed. The cell genetics, molecular biology and the prognostic stratification were compared based on flow cytometry. Results: In CDl23-positive patients, the complete remission (CR) rate was 21.5%. In CDl23-negative patients, the CR rate was 59.1%. The CR rate was 21.9% in HLA-DR-positive patients and 43.8% in HLA-DR-negative patients. The CR rate was 24.0% in CD34-positive patients and 41.1% in CD34-negative patients. The CR rate was 29.0% in CD117-positive patients and 42.3% in CD117-negative patients. The CR rate was 34.4% in CD38-positive patients and 0.00% in CD38-negative patients. Conclusions: These results suggest that CD123+, CD117+, CD34+, and HLA-DR+ are the factors related with the poor prognosis of elderly patients with acute leukemia.
PMCID: PMC4238529  PMID: 25419423
Acute leukemia; CD123; elderly patients; flow cytometry
4.  Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice 
Recent studies have challenged the prevailing view that reduced mitochondrial function and increased oxidative stress are correlated with reduced longevity. Mice carrying a homozygous knockout (KO) of the Surf1 gene showed a significant decrease in mitochondrial electron transport chain Complex IV activity, yet displayed increased lifespan and reduced brain damage after excitotoxic insults. In the present study, we examined brain metabolism, brain hemodynamics, and memory of Surf1 KO mice using in vitro measures of mitochondrial function, in vivo neuroimaging, and behavioral testing. We show that decreased respiration and increased generation of hydrogen peroxide in isolated Surf1 KO brain mitochondria are associated with increased brain glucose metabolism, cerebral blood flow, and lactate levels, and with enhanced memory in Surf1 KO mice. These metabolic and functional changes in Surf1 KO brains were accompanied by higher levels of hypoxia-inducible factor 1 alpha, and by increases in the activated form of cyclic AMP response element-binding factor, which is integral to memory formation. These findings suggest that Surf1 deficiency-induced metabolic alterations may have positive effects on brain function. Exploring the relationship between mitochondrial activity, oxidative stress, and brain function will enhance our understanding of cognitive aging and of age-related neurologic disorders.
doi:10.1038/jcbfm.2013.116
PMCID: PMC3790931  PMID: 23838831
glucose metabolism; memory; mitochondrial complex IV; mitochondrial dysfunction; Surf1
5.  Altered Apoptosis-Related Signaling after Cardioplegic Arrest in Patients with Uncontrolled Type 2 Diabetes 
Circulation  2013;128(11 0 1):10.1161/CIRCULATIONAHA.112.000332.
Background
We investigated the effects of cardioplegic arrest and reperfusion (CP/Rep) on myocardial apoptosis and key apoptotic mediators, such as apoptosis-inducing factor (AIF), caspase 3, caspase 8, caspase 9, PARP, Bcl-2 family proteins and PKC in uncontrolled type 2 diabetic (UDM), controlled type 2 diabetic (CDM), and non-diabetic (ND) patients.
Methods and Results
Right atrial tissue was harvested pre- and post-CP/Rep from UDM patients (HbA1C = 9.6 ± 0.25), CDM patients (HbA1C = 6.5 ± 0.15) and ND patients (HbA1C = 5.4 ± 0.12) undergoing coronary artery bypass grafting (n = 8/group). TUNEL staining was used for identification of apoptotic cells. Total and modified AIF, Bcl-2 family proteins, phospho-PKC-α phosphor-PKC β1 and PARP were quantified by immunoblotting or immuno-histochemistry. At baseline, the number of apoptotic cells and expression of total AIF, Bcl-2, Bak and Bax in the pre-CP/Rep atrial tissue from the UDM patients were significantly increased as compared with those of ND or CDM patients (P<0.05). After CP/Rep, the amount of apoptotic cells, AIF, phospho-Bad, phospho-PKC-alpha, phospho-PKC beta-1, and cleaved PARP in post-CP/Rep atrial tissue were increased in all three groups as compared to pre-CP/Rep. These increases after CP/Rep were more pronounced in the UDM group. In addition, there were significant increases in expression of cleaved caspase 8 and caspase 9 in the basal and post-CP/Rep atrium of UDM group as compared to ND or CDM group.
Conclusions
Uncontrolled diabetes is associated with increases in myocardial apoptosis and expression of key apoptosis mediators at baseline and in the setting of CP/Rep.
doi:10.1161/CIRCULATIONAHA.112.000332
PMCID: PMC3815526  PMID: 24030399
apoptosis; cardioplegia; diabetes mellitus; cardiopulmonary bypass; bypass surgery
6.  Ethanol Promotes Arteriogenesis and Restores Perfusion to Chronically Ischemic Myocardium 
Circulation  2013;128(11 0 1):S136-S143.
Background
Moderate alcohol consumption is known to be cardioprotective as compared to either heavy drinking or complete abstinence. We assessed the hypothesis that ethanol supplementation would improve myocardial function in the setting of chronic ischemia.
Methods and Results
Sixteen male Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Post-operatively animals were supplemented with either 90 ml of ethanol daily (50%/V, EtOH) or 80 g of sucrose of equal caloric value (SUC) serving as controls. Seven weeks after ameroid placement, arteriolar density (1.74 ± 0.210 vs. 3.11 ± 0.368 % area of arterioles per low-powered field in SUC vs. EtOH, p = 0.004), myocardial perfusion (ratio of blood flow to the at-risk myocardium compared to the normal ventricle during demand pacing was 0.585 ± 0.107 vs. 1.08 ± 0.138 for SUC vs. EtOH, p = 0.014), and microvascular reactivity were significantly increased in the ethanol-treated animals compared to controls in the at-risk myocardium. Analysis of VEGF and NOTCH pathway signaling suggested pro-neovascular and proliferative activity in the ischemic area. The average peak blood alcohol level in the treatment group was 40 ± 4 mg/dL consistent with levels of moderate drinking in humans.
Conclusions
Ethanol supplementation increased arteriolar density and significantly improved myocardial perfusion and endothelium-dependent vasorelaxation in chronically ischemic myocardium. These findings suggest that at moderate doses, ethanol directly promotes vasculogenesis and improves microvascular function resulting in significant improvements in myocardial perfusion in the setting of chronic ischemia.
doi:10.1161/CIRCULATIONAHA.112.000207
PMCID: PMC3983870  PMID: 24030397
alcohol; angiogenesis; chronic ischemia; myocardial perfusion; microvascular dysfunction
7.  Altered expression and activation of mitogen-activated protein kinases in diabetic heart during cardioplegic arrest and cardiopulmonary bypass 
Surgery  2013;154(3):436-443.
Background
We investigated whether mitogen-activated protein kinases (MAPKs) are changed in the hearts of patients with diabetes after cardioplegia and cardiopulmonary bypass (CP/CPB) operations.
Methods
Biopsies from the right atrial appendage were harvested pre- and post-CP/CPB from nondiabetic (ND) patients (n = 8, hemoglobin A1c (HbA1c) = 5.4 ± 0.12); patients with controlled diabetes (CDM) (n = 8, HbA1c = 6.5 ± 0.15); and patients with uncontrolled diabetes (UDM) (n = 8, HbA1c = 9.6 ± 0.3) undergoing coronary artery bypass grafting. The expression and/or activation of the p38-MAPK, ERK1/2, JNK, and MKP-1 in the right-atrial tissues were analyzed by Western blotting. The vasomotor function of coronary arterioles was measured by videomicroscopy.
Results
The post-CP/CPB levels of total p38-MAPK were decreased in the 3 groups as compared with their pre-CP/CPB levels (P < .05). There were increases in phospho-p38-MAPK, phospho-ERK1/2, and MKP-1 in UDM patients as compared with ND and CDM patients at baseline (P < .05). Compared to pre-CP/CPB, the post-CP/CPB levels of phospho-p38-MAPK decreased in the UDM group but were unaltered in the ND and CDM groups; however, the post-CP/CPB levels of phospho-p38-MAPK still remained greater than the post-CP/CPB levels of the other 2 groups. Post-CP/CPB levels of phospho-ERK1/2 were increased in the ND and CDM groups but were decreased in the UDM group compared to their pre-CP/CPB levels, respectively (P < .05). There were no significant differences in phospho-JNK in 3 groups at baseline. Post-CP/CPB levels of phospho-JNK, however, were increased in the 3 groups and were more pronounced in the myocardia of the UDM group (P < .05). After CP/CPB, the protein levels of MKP-1 were unchanged in the 3 groups when compared with their pre-CP/CPB levels. Post-CP/CPB levels of MKP-1, however, remained greater in the UDM group than in the ND and CDM groups. The post-CP/CPB contractile responses to the thromboxane A2 analog U46619 were significantly impaired in all 3 groups compared with pre-CP/CPB contractile responses. These impairments were more pronounced in the UDM group.
Conclusion
Uncontrolled diabetes is associated with changes in expression of and activation of MAPKs and vasomotor dysfunction in the setting of CP/CPB.
doi:10.1016/j.surg.2013.05.016
PMCID: PMC3793891  PMID: 23972649
8.  Rapamycin-induced metabolic defects are reversible in both lean and obese mice 
Aging (Albany NY)  2014;6(9):742-754.
The inhibition of mTOR (mechanistic target of rapamycin) by the macrolide rapamycin has many beneficial effects in mice, including extension of lifespan and reduction or prevention of several age-related diseases. At the same time, chronic rapamycin treatment causes impairments in glucose metabolism including hyperglycemia, glucose intolerance and insulin resistance. It is unknown whether these metabolic effects of rapamycin are permanent or whether they can be alleviated. Here, we confirmed that rapamycin causes glucose intolerance and insulin resistance in both inbred and genetically heterogeneous mice fed either low fat or high fat diets, suggesting that these effects of rapamycin are independent of genetic background. Importantly, we also found that these effects were almost completely lost within a few weeks of cessation of treatment, showing that chronic rapamycin treatment does not induce permanent impairment of glucose metabolism. Somewhat surprisingly, chronic rapamycin also promoted increased accumulation of adipose tissue in high fat fed mice. However, this effect too was lost when rapamycin treatment was ended suggesting that this effect of rapamycin is also not permanent. The reversible nature of rapamycin's alterations of metabolic function suggests that these potentially detrimental side-effects might be managed through alternative dosing strategies or concurrent treatment options.
PMCID: PMC4221917  PMID: 25324470
rapamycin; glucose; insulin; obesity; mTOR
9.  Oxidative damage associated with obesity is prevented by overexpression of CuZn- or Mn-superoxide dismutase 
The development of insulin resistance is the primary step in the etiology of type 2 diabetes mellitus. There are several risk factors associated with insulin resistance, yet the basic biological mechanisms that promote its development are still unclear. There is growing literature that suggests mitochondrial dysfunction and/or oxidative stress play prominent roles in defects in glucose metabolism. Here, we tested whether increased expression of CuZn-superoxide dismutase (Sod1) or Mn-superoxide dismutase (Sod2) prevented obesity-induced changes in oxidative stress and metabolism. Both Sod1 and Sod2 overexpressing mice were protected from high fat diet-induced glucose intolerance. Lipid oxidation (F2-isoprostanes) was significantly increased in muscle and adipose with high fat feeding. Mice with increased expression of either Sod1 or Sod2 showed a significant reduction in this oxidative damage. Surprisingly, mitochondria from the muscle of high fat diet-fed mice showed no significant alteration in function. Together, our data suggest that targeting reduced oxidative damage in general may be a more applicable therapeutic target to prevent insulin resistance than by improving mitochondrial function.
doi:10.1016/j.bbrc.2013.07.029
PMCID: PMC3768142  PMID: 23872067
diabetes; mitochondria; F2-isoprostane; oxidative stress
10.  Dietary restriction attenuates the accelerated aging phenotype of Sod1−/− mice 
Dietary restriction is a powerful aging intervention that extends the life span of diverse biological species ranging from yeast to invertebrates to mammals, and it has been argued that the anti-aging action of dietary restriction occurs through reduced oxidative stress/damage. Using Sod1−/− mice, which have previously been shown to have increased levels of oxidative stress associated with a shorter life span and a high incidence of neoplasia, we were able to test directly the ability of dietary restriction to reverse an aging phenotype due to increased oxidative stress/damage. We found that dietary restriction increased the life span of Sod1−/− mice 30%, returning it to that of wild type, control mice fed ad libitum. Oxidative damage in Sod1−/− mice was markedly reduced by dietary restriction, as indicated by a reduction in liver and brain F2-isoprostanes, a marker of lipid peroxidation. Analysis of end of life pathology showed that dietary restriction significantly reduced the overall incidence of pathological lesions in the Sod1−/− mice fed the dietary restricted-diet compared to Sod1−/− mice fed ad libitum, including the incidence of lymphoma (27 vs 5%) and overall liver pathology. In addition to reduced incidence of overall and liver specific pathology, the burden and severity of both neoplastic and non-neoplastic lesions was also significantly reduced in the Sod1−/− mice fed the dietary restricted-diet. These data demonstrate that dietary restriction can significantly attenuate the accelerated aging phenotype observed in Sod1−/− mice that arises from increased oxidative stress/damage.
doi:10.1016/j.freeradbiomed.2013.02.026
PMCID: PMC3696984  PMID: 23459073
dietary restriction; aging oxidative stress; CuZnSOD
11.  The Lack of CuZnSOD Leads to Impaired Neurotransmitter Release, Neuromuscular Junction Destabilization and Reduced Muscle Strength in Mice 
PLoS ONE  2014;9(6):e100834.
Elevated reactive oxygen species (ROS) production and ROS-dependent protein damage is a common observation in the pathogenesis of many muscle wasting disorders, including sarcopenia. However, the contribution of elevated ROS levels to –a breakdown in neuromuscular communication and muscle atrophy remains unknown. In this study, we examined a copper zinc superoxide dismutase [CuZnSOD (Sod1)] knockout mouse (Sod1−/−), a mouse model of elevated oxidative stress that exhibits accelerated loss of muscle mass, which recapitulates many phenotypes of sarcopenia as early as 5 months of age. We found that young adult Sod1−/− mice display a considerable reduction in hind limb skeletal muscle mass and strength when compared to age-matched wild-type mice. These changes are accompanied by gross alterations in neuromuscular junction (NMJ) morphology, including reduced occupancy of the motor endplates by axons, terminal sprouting and axon thinning and irregular swelling. Surprisingly however, the average density of acetylcholine receptors in endplates is preserved. Using in vivo electromyography and ex vivo electrophysiological studies of hind limb muscles in Sod1−/− mice, we found that motor axons innervating the extensor digitorum longus (EDL) and gastrocnemius muscles release fewer synaptic vesicles upon nerve stimulation. Recordings from individually identified EDL NMJs show that reductions in neurotransmitter release are apparent in the Sod1−/− mice even when endplates are close to fully innervated. However, electrophysiological properties, such as input resistance, resting membrane potential and spontaneous neurotransmitter release kinetics (but not frequency) are similar between EDL muscles of Sod1−/− and wild-type mice. Administration of the potassium channel blocker 3,4-diaminopyridine, which broadens the presynaptic action potential, improves both neurotransmitter release and muscle strength. Together, these results suggest that ROS-associated motor nerve terminal dysfunction is a contributor to the observed muscle changes in Sod1−/− mice.
doi:10.1371/journal.pone.0100834
PMCID: PMC4074103  PMID: 24971750
12.  Soil Characteristic Comparison of Fenced and Grazed Riparian Floodplain Wetlands in the Typical Steppe Region of the Inner Mongolian Plateau, China 
The Scientific World Journal  2014;2014:765907.
In recent decades, degradation of ecosystem in the steppe region of the Inner Mongolia Plateau, especially in riparian floodplain wetlands, has become a significant ecological crisis. Not uncommonly, with the increasing of livestock in the Inner Mongolian steppe region, a riparian floodplain wetland is becoming a hotspot area of grazing for local herdsmen. Hence, it is essential to understand degradation mechanisms of riparian floodplain wetland ecosystems caused by extensive grazing. In this study, the spatial distribution of soil compaction, salinity, total nitrogen, total phosphorus, organic carbon, and microbial biomass C and N were investigated. The results showed that grazing led to an increase in soil compaction and soil surface salinity, which significantly lowered levels of total N, P, and TOC in the soil surface. Grazing decreased soil microbial biomass C and N concentration in the lower riparian floodplain wetland, whereas it significantly increased soil microbial biomass C and N concentration in the higher riparian floodplain wetland. Elevation differences in the riparian floodplain wetland increased spatial heterogeneity in the soil and thus resulted in different influence of grazing on wetland soils and ecosystem. Therefore, elevation differences and grazing intensity were the main factors controlling soil characteristics in the riparian floodplain wetland of this region.
doi:10.1155/2014/765907
PMCID: PMC4052528  PMID: 24959627
13.  Increased mitochondrial matrix directed superoxide production by fatty acid hydroperoxides in skeletal muscle mitochondria 
Free radical biology & medicine  2010;50(5):592-601.
Previous studies have shown that muscle atrophy is associated with mitochondrial dysfunction and an increased rate of mitochondrial reactive oxygen species production. We recently demonstrated that fatty acid hydroperoxides (FA-OOH) are significantly elevated in mitochondria isolated from atrophied muscles. The purpose of the current study is to determine whether FA-OOH can alter skeletal muscle mitochondrial function. We found that FA-OOH (at low micromolar concentrations) induces mitochondrial dysfunction assessed by decrease in the rate of ATP production, oxygen consumption and activity of respiratory chain complexes I and III. Using methods to distinguish superoxide release towards the matrix and inter-membrane space, we demonstrate that FA-OOH significantly elevates oxidative stress in the mitochondrial matrix (and not the inter-membrane space) with complex I as the major site of superoxide production (most likely from a site upstream of the ubiquinone binding site but downstream from the flavin binding site-the iron sulfur clusters). Our results are the first to indicate that FA-OOH’s are important modulators of mitochondrial function and oxidative stress in skeletal muscle mitochondria and may play an important role in muscle atrophies that are associated with increased generation of FA-OOH’s, e.g., denervation-induced muscle atrophy.
doi:10.1016/j.freeradbiomed.2010.12.014
PMCID: PMC4017321  PMID: 21172427
Oxidative stress; superoxide; fatty acid hydroperoxides; hydrogen peroxide; mitochondria
14.  Effects of Different Vegetation Zones on CH4 and N2O Emissions in Coastal Wetlands: A Model Case Study 
The Scientific World Journal  2014;2014:412183.
The coastal wetland ecosystems are important in the global carbon and nitrogen cycle and global climate change. For higher fragility of coastal wetlands induced by human activities, the roles of coastal wetland ecosystems in CH4 and N2O emissions are becoming more important. This study used a DNDC model to simulate current and future CH4 and N2O emissions of coastal wetlands in four sites along the latitude in China. The simulation results showed that different vegetation zones, including bare beach, Spartina beach, and Phragmites beach, produced different emissions of CH4 and N2O in the same latitude region. Correlation analysis indicated that vegetation types, water level, temperature, and soil organic carbon content are the main factors affecting emissions of CH4 and N2O in coastal wetlands.
doi:10.1155/2014/412183
PMCID: PMC4032685  PMID: 24892044
15.  Atorvastatin increases oxidative stress and modulates angiogenesis in Ossabaw swine with the metabolic syndrome 
Objective
The purpose of the present study was to evaluate the effect of atorvastatin on oxidative stress and angiogenesis in ischemic myocardium in a clinically relevant porcine model of the metabolic syndrome.
Methods
Sixteen Ossabaw pigs were fed either a high-fat diet alone or a high-fat diet supplemented with atorvastatin (1.5 mg/kg daily) for 14 weeks. Chronic myocardial ischemia was induced by ameroid constrictor placement around the circumflex artery. After 6 months of the diet, myocardial perfusion was measured at rest and with demand pacing. The heart was harvested for analysis of perfusion, microvessel relaxation, protein expression, and oxidative stress.
Results
Both groups had similar endothelium-dependent microvessel relaxation to adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside. Myocardial perfusion in the ischemic territory was also not significantly different either at rest or with demand pacing. Atorvastatin treatment increased total myocardial protein oxidation and serum lipid peroxidation. However, the expression of markers of oxidative stress, including NOX2, RAC1, myeloperoxidase, and superoxide dismutase 1, 2, and 3, were not statistically different. The expression of proangiogenic proteins endothelial nitric oxide synthase, phosphorylated endothelial nitric oxide synthase (Ser 1177), phosphorylated adenosine monophosphate kinase (Thr 172), phosphorylated extracellular signal-regulated kinase (T202, Y204), and vascular endothelial growth factor were all upregulated in the atorvastatin group.
Conclusions
Atorvastatin increased the capillary and arteriolar density and upregulated the proangiogenic proteins endothelial nitric oxide synthase and phosphorylated endothelial nitric oxide synthase, phosphorylated adenosine monophosphate kinase, phosphorylated extracellular signal-regulated kinase, and vascular endothelial growth factor in a swine model of the metabolic syndrome. However, it failed to increase myocardial perfusion. Atorvastatin treatment was associated with increased myocardial and serum oxidative stress, which might contribute to the lack of collateral-dependent perfusion in the setting of angiogenesis.
doi:10.1016/j.jtcvs.2012.08.065
PMCID: PMC3592386  PMID: 22995723
16.  Dietary restriction attenuates age-associated muscle atrophy by lowering oxidative stress in mice even in complete absence of CuZnSOD 
Aging cell  2012;11(5):770-782.
Age-related loss of muscle mass and function, sarcopenia, has a major impact on the quality of life in the elderly. Among the proposed causes of sarcopenia are mitochondrial dysfunction and accumulated oxidative damage during aging. Dietary restriction (DR), a robust dietary intervention that extends lifespan and modulates age-related pathology in a variety of species has been shown to protect from sarcopenia in rodents. Although the mechanism(s) by which DR modulates aging are still not defined, one potential mechanism is through modulation of oxidative stress and mitochondrial dysfunction. To directly test the protective effect of DR against oxidative stress induced muscle atrophy in vivo, we subjected mice lacking a key antioxidant enzyme, CuZnSOD (Sod1) to DR (40% of ad libitum fed diet). We have previously shown that the Sod1−/− mice exhibit an acceleration of sarcopenia associated with high oxidative stress, mitochondrial dysfunction, and severe neuromuscular innervation defects. Despite the dramatic atrophy phenotype in the Sod1−/− mice, DR led to a reversal or attenuation of reduced muscle function, loss of innervation and muscle atrophy in these mice. DR improves mitochondrial function as evidenced by enhanced Ca2+ regulation and reduction of mitochondrial reactive oxygen species (ROS). Furthermore, we show upregulation of SIRT3 and MnSOD in DR animals, consistent with reduced mitochondrial oxidative stress and reduced oxidative damage in muscle tissue measured as F2- isoprostanes. Collectively, our results demonstrate that DR is a powerful mediator of mitochondrial function, mitochondrial ROS production, and oxidative damage, providing a solid protection against oxidative stress induced neuromuscular defects and muscle atrophy in vivo even under conditions of high oxidative stress.
doi:10.1111/j.1474-9726.2012.00843.x
PMCID: PMC3444532  PMID: 22672615
17.  Delayed Resolution of Lung Inflammation in Il-1rn−/− Mice Reflects Elevated IL-17A/Granulocyte Colony–Stimulating Factor Expression 
IL-1 has been associated with acute lung injury (ALI) in both humans and animal models, but further investigation of the precise mechanisms involved is needed, and may identify novel therapeutic targets. To discover the IL-1 mediators essential to the initiation and resolution phases of acute lung inflammation, knockout mice (with targeted deletions for either the IL-1 receptor–1, i.e., Il-1r1−/−, or the IL-1 receptor antagonist, i.e., Il-1rn−/−) were exposed to aerosolized LPS, and indices of lung and systemic inflammation were examined over the subsequent 48 hours. The resultant cell counts, histology, protein, and RNA expression of key cytokines were measured. Il-1r1−/− mice exhibited decreased neutrophil influx, particularly at 4 and 48 hours after exposure to LPS, as well as reduced bronchoalveolar lavage (BAL) expression of chemokines and granulocyte colony–stimulating factor (G-CSF). On the contrary, Il-1rn−/− mice demonstrated increased BAL neutrophil counts, increased BAL total protein, and greater evidence of histologic injury, all most notably 2 days after LPS exposure. Il-1rn−/− mice also exhibited higher peripheral neutrophil counts and greater numbers of granulocyte receptor-1 cells in their bone marrow, potentially reflecting their elevated plasma G-CSF concentrations. Furthermore, IL-17A expression was increased in the BAL and lungs of Il-1rn−/− mice after exposure to LPS, likely because of increased numbers of γδ T cells in the Il-1rn−/− lungs. Blockade with IL-17A monoclonal antibody before LPS exposure decreased the resultant BAL neutrophil counts and lung G-CSF expression in Il-1rn−/− mice, 48 hours after exposure to LPS. In conclusion, Il-1rn−/− mice exhibit delayed resolution in acute lung inflammation after exposure to LPS, a process that appears to be mediated via the G-CSF/IL-17A axis.
doi:10.1165/rcmb.2012-0104OC
PMCID: PMC3488622  PMID: 22592923
IL-1 receptor antagonist; IL-17A; IL-1 receptor–1; acute lung injury
18.  Effects of red wine and vodka on collateral-dependent perfusion and cardiovascular function in hypercholesterolemic swine 
Circulation  2012;126(11 Suppl 1):S65-S72.
Background
Moderate consumption of alcohol, particularly red wine, has been shown to decrease cardiac risk. We used a hypercholesterolemic swine model of chronic ischemia to examine the effects of two alcoholic beverages on the heart.
Methods and Results
Yorkshire swine fed a high-cholesterol diet underwent left circumflex ameroid constrictor placement to induce chronic ischemia at 8 weeks of age. One group (HCC, n=9) continued on the diet alone, the second (HCW, n=8) was supplemented with red wine (pinot noir, 12.5% alcohol, 375 mL daily), and the third (HCV, n=9) was supplemented with vodka (40% alcohol, 112 mL daily). After 7 weeks, cardiac function was measured, and ischemic myocardium was harvested for analysis of perfusion, myocardial fibrosis, vessel function, protein expression, oxidative stress, and capillary density. Platelet function was measured by aggregometry. Perfusion to the ischemic territory as measured by microsphere injection was significantly increased in both HCW and HCV compared to HCC at rest, but in only the HCW group under ventricular pacing. Microvessel relaxation response to adenosine 5’-diphosphate was improved in the HCW group alone, as was regional contractility in the ischemic territory, though myocardial fibrosis was decreased in both HCW and HCV. Expression of pro-angiogenic proteins phospho-eNOS and VEGF was increased in both HCW and HCV, while phospho-mTOR was increased only in the HCV group. Expression of Sirt-1 and downstream antioxidant phospho-FoxO1 was increased only in the HCW group. Protein oxidative stress was decreased in the HCW group alone, while capillary density was increased only in the HCV group. There was no significant difference in platelet function between groups.
Conclusion
Moderate consumption of red wine and vodka may reduce cardiovascular risk by improving collateral-dependent perfusion via different mechanisms. Red wine may offer increased cardioprotection related to its antioxidant properties.
doi:10.1161/CIRCULATIONAHA.111.082172
PMCID: PMC3448932  PMID: 22965995
Ischemia; myocardial perfusion; antioxidants; alcohol; animal model
19.  Changes in Microvascular Reactivity after Cardiopulmonary Bypass in Patients with Poorly Controlled versus Controlled Diabetes 
Circulation  2012;126(11 Suppl 1):S73-S80.
Background
We investigated the effects of cardiopulmonary bypass (CPB) on peripheral arteriolar reactivity and associated signaling pathways in poorly controlled (UDM), controlled (CDM), and case-matched non-diabetic (ND) patients undergoing coronary artery bypass grafting.
Methods and Results
Skeletal muscle arterioles were harvested pre- and post-CPB from the UDM patients (hemoglobin A1c [HbA1c] = 9.0 ± 0.3), the CDM patients (HbA1c = 6.3 ± 0.15) and the ND patients (HbA1c = 5.2 ± 0.1) undergoing CABG surgery (n = 10/group). In vitro relaxation responses of pre-contracted arterioles to endothelium-dependent vasodilators adenosine 5’-diphosphate (ADP) and substance P and the endothelium-independent vasodilator sodium nitroprusside (SNP) were examined. The baseline responses to ADP, substance P and SNP of arterioles from the UDM patients were decreased as compared to microvessels from the ND or CDM patients (P <0.05). The post-CPB relaxation responses to ADP and substance P were significantly decreased in all three groups compared to pre-CPB responses (P <0.05). However, these decreases were more pronounced in the UDM group (P <0.05). The post-CPB response to SNP was significantly decreased only in the UDM group, not in the other two groups compared to pre-CPB. The expression of PKC-α, PKC-β, protein oxidation and nitrotyrosine in the skeletal muscle were significantly increased in the UDM group as compared with those of ND or CDM groups (P<0.05).
Conclusion
Poorly controlled diabetes results in impaired arteriolar function before and after CPB. These alterations are associated with the increased expression/activation of PKC-α and PKC-β, and enhanced oxidative and nitrosative stress.
doi:10.1161/CIRCULATIONAHA.111.084590
PMCID: PMC3448935  PMID: 22965996
Microvascular Reactivity; Cardiopulmonary Bypass; Diabetes; Coronary Artery Bypass Grafting
20.  CXCL5 Regulates Chemokine Scavenging and Pulmonary Host Defense to Bacterial Infection 
Immunity  2010;33(1):106-117.
Summary
The chemokine sink hypothesis pertaining to erythrocyte Duffy Antigen Receptor for Chemokines (DARC) during inflammation has received considerable attention, but lacks direct in vivo evidence. Here we demonstrate, using mice with a targeted deletion in CXCL5, that CXCL5 bound erythrocyte DARC and impaired its chemokine scavenging in blood. CXCL5 increased the plasma concentrations of CXCL1 and CXCL2 in part through inhibiting chemokine scavenging, impairing chemokine gradients and desensitizing CXCR2, which led to decreased neutrophil influx to the lung, increased lung bacterial burden and mortality in an Escherichia coli pneumonia model. In contrast, CXCL5 exerted a predominant role in mediating neutrophil influx to the lung during inflammation after LPS inhalation. Platelets and lung resident cells were the sources of homeostatic CXCL5 in blood and inflammatory CXCL5 in the lung respectively. This study presents a paradigm whereby platelets and red cells alter chemokine scavenging and neutrophil-chemokine interaction during inflammation.
doi:10.1016/j.immuni.2010.07.009
PMCID: PMC3748840  PMID: 20643340
21.  Longitudinal transcriptomic dysregulation in the peripheral blood of transgenic Huntington’s disease monkeys 
BMC Neuroscience  2013;14:88.
Background
Huntington’s Disease (HD) is a progressive neurodegenerative disorder caused by an expansion in the polyglutamine (polyQ) region of the Huntingtin (HTT) gene. The clinical features of HD are characterized by cognitive, psychological, and motor deficits. Molecular instability, a core component in neurological disease progression, can be comprehensively evaluated through longitudinal transcriptomic profiling. Development of animal models amenable to longitudinal examination enables distinct disease-associated mechanisms to be identified.
Results
Here we report the first longitudinal study of transgenic monkeys with genomic integration of various lengths of the human HTT gene and a range of polyQ repeats. With this unique group of transgenic HD nonhuman primates (HD monkeys), we profiled over 47,000 transcripts from peripheral blood collected over a 2 year timespan from HD monkeys and age-matched wild-type control monkeys.
Conclusions
Messenger RNAs with expression patterns which diverged with disease progression in the HD monkeys considerably facilitated our search for transcripts with diagnostic or therapeutic potential in the blood of human HD patients, opening up a new avenue for clinical investigation.
doi:10.1186/1471-2202-14-88
PMCID: PMC3751855  PMID: 23957861
Transcriptome; Huntington’s disease; Longitudinal; Monkeys; Blood; mRNA
22.  Decreased Coronary Microvascular Reactivity after Cardioplegic Arrest in Patients with Poorly Controlled Diabetes 
Surgery  2012;152(2):262-269.
Background
We investigated the effects of cardioplegic arrest and reperfusion (CP/Rep) on coronary arteriolar responses to endothelium-dependent and -independent vasodilators and associated signaling pathways in poorly controlled diabetic, well controlled diabetic and case-matched non-diabetic patients undergoing coronary artery bypass grafting (CABG).
Methods and Results
Coronary arterioles from harvested right-atrial tissues were dissected pre- and post-CP/Rep from poorly controlled diabetic (n = 10, hemoglobin A1c [HbA1c] = 9.3 ± 0.3), well controlled diabetic (n = 10, HbA1c = 6.2 ± 0.2) and non-diabetic patients (n = 10, HbA1c = 5.1 ± 0.1) undergoing CABG surgery. The baseline microvascular response to ADP, substance P and SNP of arterioles from poorly controlled diabetic patients were decreased as compared to the respective response from non-diabetic or well controlled diabetic patients (P < 0.05). The vasodilatory responses to ADP, and substance P after CP/Rep were significantly decreased in all three groups compared to pre-CP/Rep responses (P < 0.05). However, these decreases were more pronounced in the poorly controlled diabetic group (P < 0.05). The expression of protein kinase C-α (PKC-α), PKC-β, and protein oxidation in atrial tissues was significantly increased in the poorly controlled diabetic group as compared with those of non-diabetes or controlled diabetes.
Conclusion
Poorly controlled is associated with endothelium-dependent and -independent vascular dysfunction of coronary arterioles. Additionally, poorly controlled diabetes worsens the recovery of coronary arteriolar function after CP/Rep. These alterations are associated with the increased expression/activation of PKC-α and PKC-β, and enhanced oxidative stress.
doi:10.1016/j.surg.2012.04.009
PMCID: PMC3407967  PMID: 22828147
23.  The E3 ubiquitin ligase adaptor Ndfip1 regulates TH17 differentiation by limiting the production of pro-inflammatory cytokines1 
Ndfip1 is an adaptor for the E3 ubiquitin ligase Itch. Both Ndfip1- and Itch-deficient T cells are biased towards TH2 cytokine production. Here we demonstrate that lungs from Ndfip1−/− mice showed increased numbers of neutrophils and TH17 cells. This was not because Ndfip1−/− T cells are biased towards Th17 differentiation. In fact, fewer Ndfip1−/− T cells differentiated into TH17 cells in vitro due to high IL-4 production. Rather, TH17 differentiation was increased in Ndfip1−/− mice due to increased numbers of IL-6 producing eosinophils. IL-6 levels in mice that lacked both Ndfip1 and IL-4 were similar to WT controls and these mice had fewer TH17 cells in their lungs. These results indicate that TH2 inflammation, such as that observed in Ndfip1−/− mice, can increase TH17 differentiation by recruiting IL-6 producing eosinophils into secondary lymphoid organs and tissues. This may explain why TH17 cells develop within an ongoing TH2 inflammatory response.
doi:10.4049/jimmunol.1102779
PMCID: PMC3713491  PMID: 22403444
24.  Toward a noninvasive automatic seizure control system in rats with transcranial focal stimulations via tripolar concentric ring electrodes 
Epilepsy affects approximately one percent of the world population. Antiepileptic drugs are ineffective in approximately 30% of patients and have side effects. We are developing a noninvasive, or minimally invasive, transcranial focal electrical stimulation system through our novel tripolar concentric ring electrodes to control seizures. In this study we demonstrate feasibility of an automatic seizure control system in rats with pentylenetetrazole-induced seizures through single and multiple stimulations. These stimulations are automatically triggered by a real-time electrographic seizure activity detector based on a disjunctive combination of detections from a cumulative sum algorithm and a generalized likelihood ratio test. An average seizure onset detection accuracy of 76.14% was obtained for the test set (n = 13). Detection of electrographic seizure activity was accomplished in advance of the early behavioral seizure activity in 76.92% of the cases. Automatically triggered stimulation significantly (p = 0.001) reduced the electrographic seizure activity power in the once stimulated group compared to controls in 70% of the cases. To the best of our knowledge this is the first closed-loop automatic seizure control system based on noninvasive electrical brain stimulation using tripolar concentric ring electrode electrographic seizure activity as feedback.
doi:10.1109/TNSRE.2012.2197865
PMCID: PMC3525521  PMID: 22772373
brain stimulation; electrographic seizure feedback control; transcranial focal stimulation; tripolar concentric ring electrodes; seizure detection
25.  Oxidative stress improves coronary endothelial function through activation of the pro-survival kinase AMPK 
Aging (Albany NY)  2013;5(7):515-530.
Age-associated decline in cardiovascular function is believed to occur from the deleterious effects of reactive oxygen species (ROS). However, failure of recent clinical trials using antioxidants in patients with cardiovascular disease, and the recent findings showing paradoxical role for NADPH oxidase-derived ROS in endothelial function challenge this long-held notion against ROS. Here, we examine the effects of endothelium-specific conditional increase in ROS on coronary endothelial function. We have generated a novel binary (Tet-ON/OFF) conditional transgenic mouse (Tet-Nox2:VE-Cad-tTA) that induces endothelial cell (EC)-specific overexpression of Nox2/gp91 (NADPH oxidase) and 1.8±0.42-fold increase in EC-ROS upon tetracycline withdrawal (Tet-OFF). We examined ROS effects on EC signaling and function. First, we demonstrate that endothelium-dependent coronary vasodilation was significantly improved in Tet-OFF Nox2 compared to Tet-ON (control) littermates. Using EC isolated from mouse heart, we show that endogenous ROS increased eNOS activation and nitric oxide (NO) synthesis through activation of the survival kinase AMPK. Coronary vasodilation in Tet-OFF Nox2 animals was CaMKKβ-AMPK-dependent. Finally, we demonstrate that AMPK activation induced autophagy and thus, protected ECs from oxidant-induced cell death. Together, these findings suggest that increased ROS levels, often associated with cardiovascular conditions in advanced age, play a protective role in endothelial homeostasis by inducing AMPK-eNOS axis.
PMCID: PMC3765580  PMID: 24018842
Endothelial function; signal transduction; NADPH oxidase; reactive oxygen species; autophagy; aging

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