A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration.

Zebrafish and mammalian neonates possess robust cardiac regeneration via the induction of endogenous cardiomyocyte (CM) proliferation, but adult mammalian hearts have very limited regenerative potential. Developing small molecules for inducing adult mammalian heart regeneration has had limited success. We report a chemical cocktail of five small molecules (5SM) that promote adult CM proliferation and heart regeneration. A high-content chemical screen, along with an algorithm-aided prediction of small-molecule interactions, identified 5SM that efficiently induced CM cell cycle re-entry and cytokinesis. Intraperitoneal delivery of 5SM reversed the loss of heart function, induced CM proliferation, and decreased cardiac fibrosis after rat myocardial infarction. Mechanistically, 5SM potentially targets α1 adrenergic receptor, JAK1, DYRKs, PTEN, and MCT1 and is connected to lactate-LacRS2 signaling, leading to CM metabolic switching toward glycolysis/biosynthesis and CM de-differentiation before entering the cell-cycle. Our work sheds lights on the understanding CM regenerative mechanisms and opens therapeutic avenues for repairing the heart.

Cell-Wide Survey of Amide-Bonded Lysine Modifications by Using Deacetylase CobB.

BACKGROUND: Lysine post-translational modifications are important regulators of protein function. Proteomic and biochemical approaches have resulted in identification of several lysine modifications, including acetylation, crotonylation, and succinylation. Here, we developed an approach for surveying amide-bonded lysine modifications in the proteome of human tissues/cells based on the observation that many lysine modifications are amide-bonded and that the Salmonella enterica deacetylase, CobB, is an amidase. RESULTS: After the proteome of human tissues/cells was denatured and the non-covalently bonded metabolites were removed by acetone washes, and the amide-bonded modifiers were released by CobB and analyzed using liquid- and/or gas chromatography/mass spectrometry metabolomic analysis. This protocol, which required 3-4 days for completion, was used to qualitatively identify more than 40 documented and unreported lysine modifications from the human proteome and to quantitatively analyze dynamic changes in targeted amide-bonded lysine modifications. CONCLUSIONS: We developed a method that was capable of monitoring and quantifying amide-bonded lysine modifications in cells of different origins.

[The impact of early restrictive positive fluid balance strategy on the prognosis of patients with severe trauma].

OBJECTIVE: To observe the impact of early restrictive positive fluid balance strategy on the prognosis of patients with trauma. METHODS: A prospective controlled study was conducted. The patients with severe post-trauma capillary leak syndrome (PTCLS) admitted to department of critical care medicine of the Fifth Center Hospital in Tianjin were considered as study object. Fluid treatment was adjusted according to intra-thoracic blood volume index (ITBVI), mean arterial pressure (MAP), cardiac index (CI) and oxygen saturation of central vein (ScvO2) at leakage stage of PTCLS. Patients were divided into two groups according to different fluid therapy volume, restrictive positive fluid balance group (restrictive group) and non-restrictive positive fluid balance group (non-restrictive group), 30 patients were enrolled into each group. The fluid balance volume and index of prognosis between two groups were analyzed within 7 days of treatment. RESULTS: During the leakage stage of PTCLS, compared with non-restrictive group, fluid positive volume of the restrictive group were decreased at 1-6 days of the treatment (1 day: 5968.8±1818.0 ml/d vs. 7109.7±2186.41 ml/d, 2 days: 3653.7±1525.1 ml/d vs. 6080.3±1538.8 ml/d, 3 days: 1953.6±621.3 ml/d vs. 3223.3±875.1 ml/d, 4 days: -2808.7±888.0 ml/d vs. -4169.9±1302.5 ml/d, 5 days: -5969.1±1470.8 ml/d vs. -6896.5±1619.4 ml/d, 6 days: -1938.1±746.0 ml/d vs. -4964.0±1389.6 ml/d, P<0.05 or P<0.01), ITBVI and extravascular lung water index (EVLWI) were decreased at 2 days and 3 days of the treatment (ITBVI 2 days: 689.2±60.6 ml/m(2) vs. 807.7±67.8 ml/m(2), 3 days: 729.6±43.3 ml/m(2) vs. 825.5±71.5 ml/m(2); EVLWI 2 days: 6.9±2.0 ml/kg vs. 8.3±2.1 ml/kg, 3 days: 7.6±2.0 ml/kg vs. 8.9±1.9 ml/kg, P<0.05 or P<0.01). Compared with non-restrictive group, the occurrence of respiratory dysfunction (46.7% vs. 76.7%), gastrointestinal dysfunction (33.3% vs. 60.0%) and the occurrence of intracranial hypertension (26.7% vs. 56.7%) at 7 days of treatment in restrictive group were decreased (all P<0.05), the time of mechanical ventilation (3.6±1.1 days vs. 5.1±1.5 days) and intensive care unit (ICU) stay time (5.5±1.5 days vs. 7.0±1.9 days) were shortened (both P<0.01). There were no differences in the occurrence of dysfunction of cardiovascular, blood coagulation, hepatic and renal function, the percentage of patients receiving renal-replacement therapy and the number of days with dialysis, as well as the mortality during the first 28 days between two groups (all P>0.05). CONCLUSION: Using restrictive positive fluid balance strategy in the leakage stage of PTCLS, fluid positive balance volume, occurrence of dysfunction of some organs, mechanical ventilation and ICU stay time can be decreased.

[Clinical study on pulmonary circulation changes in patients with acute respiratory distress syndrome induced by lung contusion].

OBJECTIVE: To analyze the variation and significance of pulmonary circulation in patients with acute respiratory distress syndrome (ARDS) induced by lung contusion by means of Swan-Ganz catheter and the pulse index continuous cardiac output (PiCCO) monitoring. METHODS: A prospective, randomized, non-blinded clinical trial was conducted. All patients admitted hospital from August 2009 to August 2011 met the inclusion criteria, were divided into the group with ARDS induced by lung contusion (contusion group, n = 18) and the group without lung contusion and ARDS (control group, n = 22). The measured parameters included pulmonary artery systolic pressure (PAS), pulmonary artery diastolic pressure (PAD), pulmonary artery wedge pressure (PAWP), pulmonary artery diastolic-pulmonary wedge pressure gradient (PAD-PAWP), and extravascular lung water index (ELWI) of each group at 0 hour after placing the catheter and at 12, 24, 36, 48, 60, 72 hours after contusion. The differences of all the parameters were compared within a group and among the different groups. RESULTS: In the survivors with ARDS induced by lung contusion, PAS, PAD and PAD-PAWP were significantly higher than those in the control group and then gradually declined. PAS and PAD returned to the level of control group at 60 hours after contusion, and the PAD-PAWP restored to the level of control group at 48 hours after contusion. For the patients in the control group, there were no significant differences in PAS and PAD from the 0 hour after placing catheter to 72 hours after contusion, but PAD-PAWP increased at 72 hours after contusion compared with at 48 hours. Compared with the control group, the ELWI in contusion group increased significantly, and peaked at 12 hours after contusion and then gradually declined, and restored to the level of control group at 60 hours after contusion. For the patients in the control group, ELWI were lower at 60 hours and 72 hours after contusion than at 48 hours. Compared with control group, PAWP in contusion group decreased at 0 hour, and returned to the level of control group at 48 hours after contusion. For the patients in the control group, there were no significant differences in PAWP from the 0 hour after placing the catheter to 72 hours after contusion. The positive correlation were found between ELWI and PAS, PAD, PAD-PAWP from 0 hour after placing the catheter to 48 hours after contusion in contusion group (r value, 0.554, 0.498, 0.629, respectively, all P < 0.01). CONCLUSION: Among the patients with ARDS induced by lung contusion, it appears that changes in PAS, PAD and PAD-PAWP, as well as ELWI play important roles in assessing fluid status, guiding mechanical ventilation and severity.

[The application of "expiration holding" in measuring end expiration pulmonary artery wedge pressure in patients undergoing mechanical ventilation].

OBJECTIVE: To find an accurate and convenient method of measuring end expiratory pulmonary artery wedge pressure (eePAWP) by "expiration holding" function of ventilator and "pulmonary artery wedge pressure (PAWP) Review" software of monitor. METHODS: Twelve patients with introduction of pulmonary artery catheter and undergoing mechanical ventilation were selected. Fifty measurements were randomly selected for the comparison of the differences between automatic measurement and expiration holding method in each patient. There were 21 cases underwent single positive pressure ventilation and 29 cases with positive pressure ventilation mixed with spontaneous breathing. All measurements were first divided into <8 mm Hg (1 mm Hg=0.133 kPa) or ≥8 mm Hg groups according to respiratory variability (RV). They were then divided into automatic measurement group and expiration holding group according to PAWP measurement, and the difference in the results between two groups were recorded. RESULTS: In 21 cases with single positive pressure ventilation, in 12 cases PAWP (mm Hg) of automatic measurement group was higher than that of expiration holding group (12-16 vs. 9-14) when RVP<8 mm Hg, but the difference between two groups was not obvious, and measurements were similar occasionally. In automatic measurement group PAWP (mm Hg) was higher than that of expiration holding group (13-20 vs. 9-15) in 9 cases when RV≥8 mm Hg, the difference was obvious. Neither RVP<8 mm Hg nor RV≥8 mm Hg, the statistical difference was significant (all P<0.01). In 29 cases, when positive pressure ventilation was mixed with spontaneous breathing, RVP<8 mm Hg (n=13), RV≥8 mm Hg (n=16), most of the results in automatic measurement group were higher than those of expiration holding group (11-18 vs. 10-17), and only 4 of them were lower than expiration holding group (11-20 vs. 14-23). There was no statistically significant difference between two groups (all P>0.05). CONCLUSION: Expiration holding measurement is a better method that can identify the eePAWP, and it reflects the true hemodynamic status more accurately and quickly whether positive pressure ventilation only or positive pressure ventilation mixed with spontaneous breathing is given.