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author:("Zhang, habo")
1.  Breaking the Q-cycle: finding new ways to study Qo through thermodynamic manipulations 
Thirty years ago, Peter Mitchell won the Nobel Prize for proposing how electrical and proton gradients across bioenergetic membranes were the energy coupling intermediate between photosynthetic and respiratory electron transfer and cellular activities that include ATP production. A high point of his thinking was the development of the Q-cycle model that advanced our understanding of cytochrome bc1. While the principle tenets of his Q-cycle still hold true today, Mitchell did not explain the specific mechanism that allows the Qo site to perform this Q-cycle efficiently without undue energy loss. Though much speculation on Qo site mode of molecular action and regulation has been introduced over the 30 years after Mitchell collected his Prize, no single mechanism has been universally accepted. The mystery behind the Qo site mechanism remains unsolved due to elusive kinetic intermediates during Qo site electron transfer that have not been detected spectroscopically. Therefore, to reveal the Qo mechanism, we must look beyond traditional steady-state experimental approaches by changing cytochrome bc1 thermodynamics and promoting otherwise transient Qo site redox states.
PMCID: PMC4315942  PMID: 18956237
Cytochrome bc1; Q-cycle; Thermodynamics; Electron transfer; Quinones
2.  I-FABP as Biomarker for the Early Diagnosis of Acute Mesenteric Ischemia and Resultant Lung Injury 
PLoS ONE  2014;9(12):e115242.
Acute mesenteric ischemia (AMI) is a life-threatening condition that can result in multiple organ injury and death. A timely diagnosis and treatment would have a significant impact on the morbidity and mortality in high-risk patient population. The purpose of this study was to investigate if intestinal fatty acid binding protein (I-FABP) and α-defensins can be used as biomarkers for early AMI and resultant lung injury. C57BL/6 mice were subjected to intestinal ischemia by occlusion of the superior mesenteric artery. A time course of intestinal ischemia from 0.5 to 3 h was performed and followed by reperfusion for 2 h. Additional mice were treated with N-acetyl-cysteine (NAC) at 300 mg/kg given intraperitoneally prior to reperfusion. AMI resulted in severe intestinal injury characterized by neutrophil infiltrate, myeloperoxidase (MPO) levels, cytokine/chemokine levels, and tissue histopathology. Pathologic signs of ischemia were evident at 1 h, and by 3 h of ischemia, the full thickness of the intestine mucosa had areas of coagulative necrosis. It was noted that the levels of α-defensins in intestinal tissue peaked at 1 h and I-FABP in plasma peaked at 3 h after AMI. Intestinal ischemia also resulted in lung injury in a time-dependent manner. Pretreatment with NAC decreased the levels of intestinal α-defensins and plasma I-FABP, as well as lung MPO and cytokines. In summary, the concentrations of intestinal α-defensins and plasma I-FABP predicted intestinal ischemia prior to pathological evidence of ischemia and I-FABP directly correlated with resultant lung injury. The antioxidant NAC reduced intestinal and lung injury induced by AMI, suggesting a role for oxidants in the mechanism for distant organ injury. I-FABP and α-defensins are promising biomarkers, and may guide the treatment with antioxidant in early intestinal and distal organ injury.
PMCID: PMC4277349  PMID: 25541714
3.  The protective effects of glutamine in a rat model of ventilator-induced lung injury 
Journal of Thoracic Disease  2014;6(12):1704-1713.
The mortality rate of patients with acute respiratory distress syndrome (ARDS) is still high despite the use of protective ventilatory strategies. We sought to examine the pharmacological effects of glutamine (GLN) in a two-hit model of endotoxin-induced inflammation followed by ventilator-induced lung injury (VILI). We hypothesized that the administration of GLN ameliorates the VILI.
Sprague-Dawley rats were anesthetized and given lipopolysaccharide (LPS) intratracheally as a first hit to induce lung inflammation, followed 24 h later by a second hit of mechanical ventilation (MV) with either low tidal volume (6 mL/kg) with 5 cmH2O of positive end-expiratory pressure (PEEP) or high tidal volume (22 mL/kg) with zero PEEP for 4 h. GLN or lactated Ringer’s solution as the placebo was administered intravenously 15 min prior to MV.
In the LPS-challenged rats ventilated with high tidal volume, the treatment with GLN improved lung injury indices, lung mechanics and cytokine responses compared with the placebo group.
The administration of GLN given immediately prior to MV may be beneficial in the context of reducing VILI.
PMCID: PMC4283323  PMID: 25589963
Acute respiratory distress syndrome (ARDS); mechanical ventilation (MV); glutamine (GLN); cytokines
4.  Reperfusion times of ST-Segment elevation myocardial infarction in hospitals 
Pakistan Journal of Medical Sciences  2014;30(6):1367-1371.
Objective: To investigate the reperfusion time in patients with ST-segment elevation myocardial infarction (STEMI) in Henan Province, China, and discuss the strategies for shortening that period.
Methods: The reperfusion times of 1556 STEMI cases in 30 hospitals in Henan Province were analyzed from January 2008 to August 2012, including 736 cases from provincial hospitals, 462 cases from municipal hospitals and 358 cases from country hospitals. The following data: Time period 1 (from symptom onset to first medical contact), Time period 2 (from first medical contact to diagnosis), Time period 3 (from the diagnosis to providing consent), Time period 4 (from the time of providing consent to the beginning of treatment) and Time period 5 (from the beginning of treatment to the patency) were recorded and analyzed.
Results: In patients receiving primary percutaneous coronary intervention, the door-to-balloon time of provincial hospitals and municipal hospitals was 172±13 minutes and 251±14 minutes, respectively. The hospitals at both levels had a delay comparison of 90 minutes largely caused by the delay in the time for obtaining consent. In patients receiving thrombolysis treatment, the door-to-needle times of provincial hospitals, municipal hospitals and country hospitals were 86±7, 91±7 and 123±11 minutes, respectively. The hospitals at all levels had delays lasting more than 30 minutes, which was mainly attributed to the delay in the time for providing consent. Compared with the time required by the guidelines, the reperfusion time of patients with STEMI in China is evidently delayed. In terms of China's national conditions, the door-to-balloon time is too general. Therefore, we suggest refining this time as the first medical contact–diagnosis time, consent provision time, therapy preparation time and the start of therapy balloon time.
Conclusion: Compared to the time required by the guidelines, the reperfusion time of patients with STEMI in China was obviously greater. In terms of China's national conditions, the door to balloon time is not applicable. So it is suggested to refine it as the first medical contact-diagnosis time, providing consent time, therapy prepare time and the start of therapy – balloon time.
PMCID: PMC4320732
Henan Province; ST-segment elevation myocardial infarction; Reperfusion time; Study
5.  Construction and management of ARDS/sepsis registry with REDCap 
Journal of Thoracic Disease  2014;6(9):1293-1299.
The study aimed to construct and manage an acute respiratory distress syndrome (ARDS)/sepsis registry that can be used for data warehousing and clinical research.
The workflow methodology and software solution of research electronic data capture (REDCap) was used to construct the ARDS/sepsis registry. Clinical data from ARDS and sepsis patients registered to the intensive care unit (ICU) of our hospital formed the registry. These data were converted to the electronic case report form (eCRF) format used in REDCap by trained medical staff. Data validation, quality control, and database management were conducted to ensure data integrity.
The clinical data of 67 patients registered to the ICU between June 2013 and December 2013 were analyzed. Of the 67 patients, 45 (67.2%) were classified as sepsis, 14 (20.9%) as ARDS, and eight (11.9%) as sepsis-associated ARDS. The patients’ information, comprising demographic characteristics, medical history, clinical interventions, daily assessment, clinical outcome, and follow-up data, was properly managed and safely stored in the ARDS/sepsis registry. Data efficiency was guaranteed by performing data collection and data entry twice weekly and every two weeks, respectively.
The ARDS/sepsis database that we constructed and manage with REDCap in the ICU can provide a solid foundation for translational research on the clinical data of interest, and a model for development of other medical registries in the future.
PMCID: PMC4178117  PMID: 25276372
Acute respiratory distress syndrome (ARDS)/sepsis registry; research electronic data capture (REDCap); data quality; data management
6.  Pharmacokinetics and Biodistribution of Zinc-Enriched Yeast in Rats 
The Scientific World Journal  2014;2014:217142.
Zinc-enriched yeast (ZnY) and zinc sulfate (ZnSO4) are considered zinc (Zn) supplements currently available. The purpose of the investigation was to compare and evaluate pharmacokinetics and biodistribution of ZnY and ZnSO4 in rats. ZnY or ZnSO4 were orally administered to rats at a single dose of 4 mg Zn/kg and Zn levels in plasma and various tissues were determined using inductively coupled plasma-optical emission spectrometry. Maximum plasma concentration values were 3.87 and 2.81 μg/mL for ZnY and ZnSO4, respectively. Both ZnY and ZnSO4 were slowly eliminated with a half-life of over 7 h and bone had the highest Zn level in all tissues. Compared to ZnSO4, the relative bioavailability of ZnY was 138.4%, indicating that ZnY had a significantly higher bioavailability than ZnSO4.
PMCID: PMC4151581  PMID: 25215316
7.  Monocyte interaction accelerates HCl-induced lung epithelial remodeling 
BMC Pulmonary Medicine  2014;14:135.
Acute respiratory distress syndrome (ARDS) is characterized by overwhelming inflammatory responses and lung remodeling. We hypothesized that leukocyte infiltration during the inflammatory response modulates epithelial remodeling through a mechanism of epithelial-mesenchymal transition (EMT).
Human lung epithelial cells were treated for 30 min with hydrochloric acid (HCl). Human monocytes were then cocultured with the epithelial cells for up to 48 h, in the presence or absence of blocking peptides against lymphocyte function-associated antigen-1 (LFA-1), or tyrphostin A9, a specific inhibitor for platelet-derived growth factor (PDGF) receptor tyrosine kinase.
Exposure of lung epithelial cells to HCl resulted in increased expression of intercellular adhesion molecule-1 (ICAM-1) and production of interleukin (IL)-8 at 24 h. The expression of the epithelial markers E-cadherin decreased while the mesenchymal markers vimentin and α-smooth muscle actin (α-SMA) increased at 24 h and remained high at 48 h. The addition of monocytes augmented the profiles of lower expression of epithelial markers and higher mesenchymal markers accompanied by increased collagen deposition. This EMT profile was associated with an enhanced production of IL-8 and PDGF. Treatment of the lung epithelial cells with the LAF-1 blocking peptides CD11a237–246 or/and CD18112–122 suppressed monocyte adhesion, production of IL-8, PDGF and hydroxyproline as well as EMT markers. Treatment with tyrphostin A9 prevented the EMT profile shift induced by HCl stimulation.
The interaction between epithelial cells and monocytes enhanced epithelial remodelling after initial injury through EMT signalling that is associated with the release of soluble mediators, including IL-8 and PDGF.
PMCID: PMC4141266  PMID: 25108547
ARDS; PDGF; Chemokine; EMT
8.  Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence 
Aging Cell  2014;13(4):669-678.
Cellular senescence, which is known to halt proliferation of aged and stressed cells, plays a key role against cancer development and is also closely associated with organismal aging. While increased insulin-like growth factor (IGF) signaling induces cell proliferation, survival and cancer progression, disrupted IGF signaling is known to enhance longevity concomitantly with delay in aging processes. The molecular mechanisms involved in the regulation of aging by IGF signaling and whether IGF regulates cellular senescence are still poorly understood. In this study, we demonstrate that IGF-1 exerts a dual function in promoting cell proliferation as well as cellular senescence. While acute IGF-1 exposure promotes cell proliferation and is opposed by p53, prolonged IGF-1 treatment induces premature cellular senescence in a p53-dependent manner. We show that prolonged IGF-1 treatment inhibits SIRT1 deacetylase activity, resulting in increased p53 acetylation as well as p53 stabilization and activation, thus leading to premature cellular senescence. In addition, either expression of SIRT1 or inhibition of p53 prevented IGF-1-induced premature cellular senescence. Together, these findings suggest that p53 acts as a molecular switch in monitoring IGF-1-induced proliferation and premature senescence, and suggest a possible molecular connection involving IGF-1-SIRT1-p53 signaling in cellular senescence and aging.
PMCID: PMC4118446  PMID: 25070626
aging; IGF-1; p53; senescence; SIRT1
Journal of the American Chemical Society  2013;135(30):11322-11329.
Pauses regulate the rhythm of ribosomal protein synthesis. Mutations disrupting even minor pauses can give rise to improperly formed proteins and human disease. Such minor pauses are difficult to characterize by ensemble methods, but can be readily examined by single-molecule (sm) approaches. Here we use smFRET to carry out real-time monitoring of the expression of a full-length protein, the green fluorescent protein variant Emerald GFP. We demonstrate significant correlations between measured elongation rates and codon and isoacceptor tRNA usage, and provide a quantitative estimate of the effect on elongation rate of replacing a codon recognizing an abundant tRNA with a synonymous codon cognate to a rarer tRNA. Our results suggest that tRNA selection plays an important general role in modulating the rates and rhythms of protein synthesis, potentially influencing simultaneous co-translational processes such as folding and chemical modification.
PMCID: PMC3768011  PMID: 23822614
10.  Late outcomes for the surgical management of absent pulmonary valve syndrome in infants 
Absent pulmonary valve syndrome (APVS) is a rare cardiac malformation that is usually associated with aneurysmal dilatation of pulmonary arteries and respiratory distress. The surgical mortality of neonates and infants with APVS has decreased tremendously, from 60% in 1980s to 10–20% recently. This study retrospectively reviews surgical outcomes of our 10-year experience in patients with APVS.
From 2002 to 2012, 42 patients with APVS underwent surgical correction. Thirty-seven patients had APVS as a variant of tetralogy of Fallot, 4 with double outlet right ventricle and 1 with ventricular septal defect. Respiratory distress was present in 12 infants. Four patients needed continuous positive airway pressure and 5 required intubation with mechanical ventilation before surgery.
There was no hospital death and 3 late deaths. The mean follow-up time was 62.71 ± 34.31 months. Significant differences were found in the duration of postoperative ventilation between patients with or without respiratory distress (P = 0.009) and patients with left or right aortic arch (P = 0.012). The Kaplan–Meier curve indicated that overall survival at 5 and 10 years was 92.4%. The survival rates between patients with or without respiratory distress were 72.7 and 100%, respectively (P = 0.003). Overall mortality was associated with longer cardiopulmonary bypass time (P = 0.004) and lower weight at operation (P = 0.042). There were no significant differences in survival and postoperative data such as the duration of ventilation or intensive care unit stay and New York Heart Association class among the three methods of right ventricular outflow tract (RVOT) reconstruction.
Surgical treatment of APVS has got favourable outcomes in terms of mortality and reoperation rate. Different methods of RVOT reconstruction do not affect the surgical outcome. Patients required long-term follow-up for postoperative respiratory complications secondary to persistent bronchomalacia.
PMCID: PMC3653468  PMID: 23439440
Congenital heart disease; Pulmonary valve; Surgery
11.  Apocynin attenuates ventilator-induced lung injury in an isolated and perfused rat lung model 
Intensive care medicine  2011;37(8):1360-1367.
Apocynin suppresses the generation of reactive oxygen species (ROS) that are implicated in ventilator-induced lung injury (VILI). We thus hypothesized that apocynin attenuates VILI.
VILI was induced by mechanical ventilation with tidal volume (Vt) of 15 ml/kg in isolated and perfused rat lung. Apocynin was administered in the perfusate at onset of mechanical ventilation. A group ventilated with low Vt of 5 ml/kg served as control. Hemodynamics, lung injury indices, inflammatory responses, and activation of apoptotic pathways were determined upon completion of mechanical ventilation.
There was an increase in lung permeability and lung weight gain after mechanical ventilation with high Vt, compared with low Vt. Levels of inflammatory cytokines including interleukin-1b (IL-1b), tumor necrosis factor-alpha (TNF-a), and macrophage inflammatory protein-2 (MIP-2) increased in lung lavage fluids; concentrations of carbonyl, thiobarbituric acid reactive substances, and H2O2 were higher in perfusates and lung lavage fluids, and expression of myeloperoxidase, JNK, p38, and caspase-3 in lung tissue was greater in the high-Vt than in the low-Vt group. Administration of apocynin attenuated these inflammatory responses and lung permeability associated with decreased activation of nuclear factor-κB.
VILI is associated with inflammatory responses including generation of ROS, cytokines, and activation of mitogen-activated protein kinase cascades. Administration of apocynin at onset of mechanical ventilation attenuates inflammatory responses and VILI in the isolated, perfused rat lung model.
PMCID: PMC4020846  PMID: 21618001 CAMSID: cams4110
ARDS; Inflammation; NADPH; MAPK; NF-κB
12.  Electrospun gelatin/PCL and collagen/PLCL scaffolds for vascular tissue engineering 
Electrospun hybrid nanofibers prepared using combinations of natural and synthetic polymers have been widely investigated in cardiovascular tissue engineering. In this study, electrospun gelatin/polycaprolactone (PCL) and collagen/poly(l-lactic acid-co-ε-caprolactone) (PLCL) scaffolds were successfully produced. Scanning electron micrographs showed that fibers of both membranes were smooth and homogeneous. Water contact angle measurements further demonstrated that both scaffolds were hydrophilic. To determine cell attachment and migration on the scaffolds, both hybrid scaffolds were seeded with human umbilical arterial smooth muscle cells. Scanning electron micrographs and MTT assays showed that the cells grew and proliferated well on both hybrid scaffolds. Gross observation of the transplanted scaffolds revealed that the engineered collagen/PLCL scaffolds were smoother and brighter than the gelatin/PCL scaffolds. Hematoxylin and eosin staining showed that the engineered blood vessels constructed by collagen/PLCL electrospun membranes formed relatively homogenous vessel-like tissues. Interestingly, Young’s modulus for the engineered collagen/PLCL scaffolds was greater than for the gelatin/PCL scaffolds. Together, these results indicate that nanofibrous collagen/PLCL membranes with favorable mechanical and biological properties may be a desirable scaffold for vascular tissue engineering.
PMCID: PMC4026554  PMID: 24872696
electrospinning; gelatin; collagen; polycaprolactone; poly(l-lactic acid-co-ε-caprolactone)
13.  Cortisol Is an Associated-Risk Factor of Brain Dysfunction in Patients with Severe Sepsis and Septic Shock 
BioMed Research International  2014;2014:712742.
Objectives. To investigate cortisol levels in brain dysfunction in patients with severe sepsis and septic shock. Methods. In 128 septic and sedated patients, we studied brain dysfunction including delirium and coma by the evaluation of Richmond Agitation Sedation Scale (RASS), the Confusion Method Assessment in the ICU (CAM-ICU) after sedation withdrawal and the measurement of serum S100B biomarker of brain injury. Serum cortisol and S100B were measured within 12 hours after ICU admission and daily over the next four days. Results. Brain dysfunction was observed in 50% (64/128) before but in 84% (107/128) of patients after sedation withdrawal, and was more common in the patients older than 57 years (P = 0.009). Both cortisol (P = 0.007) and S100B levels (P = 0.028) were higher in patients with than patients without brain dysfunction. Cortisol levels were associated with ICU mortality (hazard ratio = 1.17, P = 0.024). Multivariate logistic regression showed that cortisol (odds ratio (OR): 2.34, 95% CI (2.01, 3.22), P = 0.02) and the combination effect of cortisol with age (OR: 1.004, 95% CI (1.002, 1.93), P = 0.038) but not S100B were associated with brain dysfunction. Conclusions. Cortisol was an associated-risk factor of brain dysfunction in patients with severe sepsis and septic shock.
PMCID: PMC4022165  PMID: 24883321
14.  De-novo synthesis of 2-phenylethanol by Enterobacter sp. CGMCC 5087 
BMC Biotechnology  2014;14:30.
2-phenylethanl (2-PE) and its derivatives are important chemicals, which are widely used in food materials and fine chemical industries and polymers and it’s also a potentially valuable alcohol for next-generation biofuel. However, the biosynthesis of 2-PE are mainly biotransformed from phenylalanine, the price of which barred the production. Therefore, it is necessary to seek more sustainable technologies for 2-PE production.
A new strain which produces 2-PE through the phenylpyruvate pathway was isolated and identified as Enterobacter sp. CGMCC 5087. The strain is able to use renewable monosaccharide as the carbon source and NH4Cl as the nitrogen source to produce 2-PE. Two genes of rate-limiting enzymes, chorismate mutase p-prephenate dehydratase (PheA) and 3-deoxy-d-arabino-heptulosonic acid 7-phosphate synthase (DAHP), were cloned from Escherichia coli and overexpressed in E. sp. CGMCC 5087. The engineered E. sp. CGMCC 5087 produces 334.9 mg L-1 2-PE in 12 h, which is 3.26 times as high as the wild strain.
The phenylpyruvate pathway and the substrate specificity of 2-keto-acid decarboxylase towards phenylpyruvate were found in E. sp. CGMCC 5087. Combined with the low-cost monosaccharide as the substrate, the finding provides a novel and potential way for 2-PE production.
PMCID: PMC4005845  PMID: 24766677
2-Phenylethanol; Biosynthesis; Ehrlich pathway; Enterobacter sp
15.  Production of free monounsaturated fatty acids by metabolically engineered Escherichia coli 
Monounsaturated fatty acids (MUFAs) are the best components for biodiesel when considering the low temperature fluidity and oxidative stability. However, biodiesel derived from vegetable oils or microbial lipids always consists of significant amounts of polyunsaturated and saturated fatty acids (SFAs) alkyl esters, which hampers its practical applications. Therefore, the fatty acid composition should be modified to increase MUFA contents as well as enhancing oil and lipid production.
The model microorganism Escherichia coli was engineered to produce free MUFAs. The fatty acyl-ACP thioesterase (AtFatA) and fatty acid desaturase (SSI2) from Arabidopsis thaliana were heterologously expressed in E. coli BL21 star(DE3) to specifically release free unsaturated fatty acids (UFAs) and convert SFAs to UFAs. In addition, the endogenous fadD gene (encoding acyl-CoA synthetase) was disrupted to block fatty acid catabolism while the native acetyl-CoA carboxylase (ACCase) was overexpressed to increase the malonyl coenzyme A (malonyl-CoA) pool and boost fatty acid biosynthesis. The finally engineered strain BL21ΔfadD/pE-AtFatAssi2&pA-acc produced 82.6 mg/L free fatty acids (FFAs) under shake-flask conditions and FFAs yield on glucose reached about 3.3% of the theoretical yield. Two types of MUFAs, palmitoleate (16:1Δ9) and cis-vaccenate (18:1Δ11) made up more than 75% of the FFA profiles. Fed-batch fermentation of this strain further enhanced FFAs production to a titer of 1.27 g/L without affecting fatty acid compositions.
This study demonstrated the possibility to regulate fatty acid composition by using metabolic engineering approaches. FFAs produced by the recombinant E. coli strain consisted of high-level MUFAs and biodiesel manufactured from these fatty acids would be more suitable for current diesel engines.
PMCID: PMC4021618  PMID: 24716602
Free monounsaturated fatty acids; Thioesterase; Fatty acid desaturase; acyl-CoA synthetase; acetyl-CoA carboxylase
16.  Circadian rhythms: From basic mechanisms to the intensive care unit 
Critical care medicine  2012;40(1):246-253.
Circadian rhythms are intrinsic timekeeping mechanisms that allow for adaptation to cyclic environmental changes. Increasing evidence suggests that circadian rhythms may influence progression of a variety of diseases as well as effectiveness and toxicity of drugs commonly used in the intensive care unit. In this perspective, we provide a brief review of the molecular mechanisms of circadian rhythms and its relevance to critical care.
Data Sources, Study Selection, Data Extraction, and Data Synthesis
Articles related to circadian rhythms and organ systems in normal and disease conditions were searched through the PubMed library with the goal of providing a concise review.
Critically ill patients may be highly vulnerable to disruption of circadian rhythms as a result of the severity of their underlying diseases as well as the intensive care unit environment where noise and frequent therapeutic/diagnostic interventions take place. Further basic and clinical research addressing the importance of circadian rhythms in the context of critical care is warranted to develop a better understanding of the complex pathophysiology of critically ill patients as well as to identify novel therapeutic approaches for these patients.
PMCID: PMC3977926  PMID: 21926587 CAMSID: cams2913
clock gene; diurnal variation; inflammation
17.  Protective effects of adenosine A2A receptor agonist in ventilator-induced lung injury in rats 
Critical care medicine  2009;37(7):2235-2241.
Mechanical ventilation is associated with overwhelming inflammatory responses that are associated with ventilator- induced lung injury (VILI) in patients with acute respiratory distress syndrome. The activation of adenosine A2A receptors has been reported to attenuate inflammatory cascades.
The administration of A2A receptors agonist ameliorates VILI.
Rats were subjected to hemorrhagic shock and resuscitation as a first hit to induce systemic inflammation. The animals randomly received the selective A2A receptor agonist CGS-21680 or a vehicle control in a blinded fashion at the onset of resuscitation phase. They were then randomized to receive mechanical ventilation as a second hit with a high tidal volume of 20 mL/kg and zero positive end-expiratory pressure, or a low tidal volume of 6 mL/kg with positive end-expiratory pressure of 5 cm H2O.
The administration of CGS-21680 attenuated lung injury as evidenced by a decrease in respiratory elastance, lung edema, lung injury scores, neutrophil recruitment in the lung, and production of inflammatory cytokines, compared with the vehicle treated animals.
The selective A2A receptor agonist may have a place as a novel therapeutic approach in reducing VILI.
PMCID: PMC3951985  PMID: 19487932 CAMSID: cams2915
acute respiratory distress syndrome; inflammation; neutrophils
18.  The Wnt Signaling Pathway Effector TCF7L2 Controls Gut and Brain Proglucagon Gene Expression and Glucose Homeostasis 
Diabetes  2013;62(3):789-800.
The type 2 diabetes risk gene TCF7L2 is the effector of the Wnt signaling pathway. We found previously that in gut endocrine L-cell lines, TCF7L2 controls transcription of the proglucagon gene (gcg), which encodes the incretin hormone glucagon-like peptide-1 (GLP-1). Whereas peripheral GLP-1 stimulates insulin secretion, brain GLP-1 controls energy homeostasis through yet-to-be defined mechanisms. We aim to determine the metabolic effect of a functional knockdown of TCF7L2 by generating transgenic mice that express dominant-negative TCF7L2 (TCF7L2DN) specifically in gcg-expressing cells. The gcg-TCF7L2DN transgenic mice showed reduced gcg expression in their gut and brain, but not in pancreas. Defects in glucose homeostasis were observed in these mice, associated with attenuated plasma insulin levels in response to glucose challenge. The defect in glucose disposal was exacerbated with high-fat diet. Brain Wnt activity and feeding-mediated hypothalamic AMP-activated protein kinase (AMPK) repression in these mice were impaired. Peripheral injection of the cAMP-promoting agent forskolin increased brain β-cat Ser675 phosphorylation and brain gcg expression and restored feeding-mediated hypothalamic AMPK repression. We conclude that TCF7L2 and Wnt signaling control gut and brain gcg expression and glucose homeostasis and speculate that positive cross-talk between Wnt and GLP-1/cAMP signaling is an underlying mechanism for brain GLP-1 in exerting its metabolic functions.
PMCID: PMC3581223  PMID: 22966074
19.  Microbial production of sabinene—a new terpene-based precursor of advanced biofuel 
Sabinene, one kind of monoterpene, accumulated limitedly in natural organisms, is being explored as a potential component for the next generation of aircraft fuels. And demand for advanced fuels impels us to develop biosynthetic routes for the production of sabinene from renewable sugar.
In this study, sabinene was significantly produced by assembling a biosynthetic pathway using the methylerythritol 4-phosphate (MEP) or heterologous mevalonate (MVA) pathway combining the GPP and sabinene synthase genes in an engineered Escherichia coli strain. Subsequently, the culture medium and process conditions were optimized to enhance sabinene production with a maximum titer of 82.18 mg/L. Finally, the fed-batch fermentation of sabinene was evaluated using the optimized culture medium and process conditions, which reached a maximum concentration of 2.65 g/L with an average productivity of 0.018 g h-1 g-1 dry cells, and the conversion efficiency of glycerol to sabinene (gram to gram) reached 3.49%.
This is the first report of microbial synthesis of sabinene using an engineered E. coli strain with the renewable carbon source as feedstock. Therefore, a green and sustainable production strategy has been established for sabinene.
PMCID: PMC3923588  PMID: 24512040
Sabinene; Geranyl diphosphate synthase; Sabinene synthase; Escherichia coli
20.  Reliability of intramyocardial electrogram for the noninvasive diagnosis of acute allograft rejection after heart transplantation in rats 
Journal of Thoracic Disease  2014;6(2):126-133.
To examine the reliability of the QRS amplitude of the autonomous intramyocardial electrogram (IMEG) and the maximum slope of the descending T wave (Tslew) of the ventricular evoked response (VER) for surveillance of acute allograft rejection (AR) after heart transplantation in rats.
Forty rats underwent heterotopic heart transplantation, including ten isograft (isograft group) and 30 allograft (allograft group) recipients. Autonomous IMEG and VER were recorded with epicardiac pacing leads. Isograft recipients were sacrificed on postoperative day 7 and allograft recipients on postoperative days 3, 5 and 7. Graft heart histopathological examinations were performed at the corresponding time points.
Postoperative QRS amplitude and Tslew gradually decreased in the allograft group, but were unaltered in the isograft group. Decreases in the allograft group QRS amplitudes and Tslew values correlated with the histopathological results. At the optimal cutoff point of 90%, Tslew had 94.74% sensitivity, 81.82% specificity, 82.61% positive and 90% negative predictive values. QRS had 68.42% sensitivity, 90.91% specificity, 92.86% positive and 62.50% negative predictive values at its optimal cutoff point of 72.3%.
The QRS amplitude of the autonomous IMEG and Tslew of VER are reliable markers for monitoring AR after heart transplantation in rats.
PMCID: PMC3944186  PMID: 24605226
Heart transplantation; acute allograft rejection; intramyocardial electrogram (IMEG)
21.  Lung protection during non-invasive synchronized assist versus volume control in rabbits 
Critical Care  2014;18(1):R22.
Experimental work provides insight into potential lung protective strategies. The objective of this study was to evaluate markers of ventilator-induced lung injury after two different ventilation approaches: (1) a “conventional” lung-protective strategy (volume control (VC) with low tidal volume, positive end-expiratory pressure (PEEP) and paralysis), (2) a physiological approach with spontaneous breathing, permitting synchrony, variability and a liberated airway. For this, we used non-invasive Neurally Adjusted Ventilatory Assist (NIV-NAVA), with the hypothesis that liberation of upper airways and the ventilator’s integration with lung protective reflexes would be equally lung protective.
In this controlled and randomized in vivo laboratory study, 25 adult White New Zealand rabbits were studied, including five non-ventilated control animals. The twenty animals with aspiration-induced lung injury were randomized to ventilation with either VC (6 mL/kg, PEEP 5 cm H2O, and paralysis) or NIV-NAVA for six hours (PEEP = zero because of leaks). Markers of lung function, lung injury, vital signs and ventilator parameters were assessed.
At the end of six hours of ventilation (n = 20), there were no significant differences between VC and NIV-NAVA for vital signs, PaO2/FiO2 ratio, lung wet-to-dry ratio and broncho-alveolar Interleukin 8 (Il-8). Plasma IL-8 was higher in VC (P <0.05). Lung injury score was lower for NIV-NAVA (P = 0.03). Dynamic lung compliance recovered after six hours in NIV-NAVA but not in VC (P <0.05). During VC, peak pressures increased from 9.2 ± 2.4 cm H2O (hour 1) to 12.3 ± 12.3 cm H2O (hour 6) (P <0.05). During NIV-NAVA, the tracheal end-expiratory pressure was similar to the end-expiratory pressure during VC. Two animals regurgitated during NIV-NAVA, without clinical consequences, and survived the protocol.
In experimental acute lung injury, NIV-NAVA is as lung-protective as VC 6 ml/kg with PEEP.
PMCID: PMC4057206  PMID: 24456613
22.  Correction: Long-Term Results of a Minimally Invasive Surgical Pulmonary Vein Isolation and Ganglionic Plexi Ablation for Atrial Fibrillation 
PLoS ONE  2014;9(1):10.1371/annotation/c46d8841-f33e-45ea-9c17-b754e1017641.
PMCID: PMC3880343
23.  Intensive Care Unit-Acquired Bacteremia in Mechanically Ventilated Patients: Clinical Features and Outcomes 
PLoS ONE  2013;8(12):e83298.
Intensive care unit (ICU)-acquired bacteremia (IAB) is associated with high medical expenditure and mortality. Mechanically ventilated patients represent one third of all patients admitted to ICU, but the clinical features and outcomes in mechanically ventilated patients who develop IAB remain unknown. We conducted a 3-year retrospective observational cohort study, and 1,453 patients who received mechanical ventilation on ICU admission were enrolled. Among patients enrolled, 126 patients who had developed IAB ≧48 hours after ICU admission were identified. The study patients were divided into IAB and no IAB groups, and clinical characteristics of IAB based on specific bacterial species were further analyzed. The multivariate Cox regression analysis showed that ventilator support for chronic obstructive pulmonary disease and congestive heart failure, and patients admitted from nursing home were the independent risk factors for developing IAB. Patients with IAB were significantly associated with longer length of ICU stay, prolonged ventilator use, lower rate of successful weaning, and higher rate of ventilator dependence and ICU mortality as compared to those without IAB. IAB was the independent risk factor for ICU mortality (HR, 1.510, 95% CI 1.054–1.123; p = 0.010). The clinical characteristics of IAB related to specific bacterial species included IAB due to Pseudomonas aeruginosa being likely polymicrobial, lung source and prior antibiotic use; Escherichia coli developing earlier and from urinary tract source; methicillin-resistant Staphylococcus aureus related to central venous catheter and multiple sets of positive hemoculture; and Elizabethkingia meningoseptica significantly associated with delayed/inappropriate antibiotic treatment. In summary, IAB was significantly associated with poor patient outcomes in mechanically ventilated ICU patients. The clinical features related to IAB and clinical characteristics of IAB based on specific bacterial species identified in our study may be utilized to refine the management of IAB.
PMCID: PMC3871544  PMID: 24376683
24.  Correction: Rapamycin Inhibits IGF-1-Mediated Up-Regulation of MDM2 and Sensitizes Cancer Cells to Chemotherapy 
PLoS ONE  2013;8(12):10.1371/annotation/f1a4d192-57b9-43fb-a248-379e0f5a46ca.
PMCID: PMC3866301
25.  Year in review 2011: Critical Care - respirology 
Critical Care  2012;16(6):243.
Management of acute respiratory failure is an important component of intensive care. In this review, we analyze 21 original research articles published last year in Critical Care in the field of respiratory and critical care medicine. The articles are summarized according to the following topic categories: acute respiratory distress syndrome, mechanical ventilation, adjunctive therapies, and pneumonia.
PMCID: PMC3672547

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