Methimazole and α-lipoic acid as metallo-ß-lactamases inhibitors.

The emergence of bacterial resistance poses a serious threat to public health. One of the most important resistance mechanisms against ß-lactam antibiotics is the production of metallo-ß-lactamases (MBLs). In this study, α-lipoic acid (LA) and methimazole (MMI), which have been used in clinical practice as non-antibacterial drugs and as a supplement, were chosen to explore their potential to be metallo-ß-lactamases inhibitors (MBLIs). Enzyme inhibition assays showed that LA and MMI had moderate inhibitory activity against NDM-1 but no activity against VIM-2 and IMP-7. Antibacterial assays to determine synergy, demonstrated that the combination of LA or MMI with meropenem (MER) reduced the MIC value of MER against NDM-1 producing E. coli 16 times and 4 times, respectively, lower than that of MER alone. The fractional inhibitory concentration index (FICI) values were calculated to be less than 0.5, indicating that both LA and MMI had synergistic antibacterial effects with MER against all three MBLs expressing E. coli strains. The time-kill studies also suggested that LA and MMI were effective in restoring the antibacterial effect of MER. These findings revealed that LA and MMI are potential carbapenem enhancers, and provide a starting point for the development of potent MBLIs.

Correlation analysis of omega-3 fatty acids and mortality of sepsis and sepsis-induced ARDS in adults: data from previous randomized controlled trials.

OBJECTIVE: This study aimed to investigate the possible effect of omega-3 fatty acids on reducing the mortality of sepsis and sepsis-induced acute respiratory distress syndrome (ARDS) in adults. METHODS: Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI) database, WangFang database, and Chinese BioMedical Literature Database from their inception to March 6, 2017, were searched using systematic review researching methods. Five factors were analyzed to investigate the correlation between omega-3 fatty acids (either parenteral or enteral supplementation) and mortality rate. RESULTS: Forty randomized controlled trials (RCTs) were initially included, but only 25 of them assessed mortality. Of these RCTs, nine used enteral nutrition (EN) and 16 used parenteral nutrition (PN). The total mortality rate in the omega-3 fatty acid group was lower than that in the control group. However, the odds ratio (OR) value was not significantly different in the EN or PN subgroup. Eighteen RCTs including 1790 patients with similar severity of sepsis and ARDS were also analyzed. The OR value was not significantly different in the EN or PN subgroup. Omega-3 fatty acids did not show positive effect on improving mortality of sepsis-induced ARDS (p = 0.39). But in EN subgroup, omega-3 fatty acids treatment seemed to have some benefits in reducing mortality rate (p = 0.04). In the RCTs including similar baseline patients, partial correlation analysis found that the concentration ratio of n-6 to n-3 fatty acids had positive correlation with reduction of mortality (RM) (γ = 0.60, P = 0.02), whereas the total number of each RCT had negative correlation with RM (γ = - 0.54, P = 0.05). CONCLUSIONS: This review found that omega-3 fatty acid supplementation could reduce the mortality rate of sepsis and sepsis-induced ARDS. However, further investigation based on suitable concentrations and indications is needed to support the findings.

[Cerebral injury induced by heat stroke and the therapeutic effect of hyperbaric oxygen therapy].

OBJECTIVE: With the global warming, the incidence of heat stroke was significantly higher than before. Severe heat stroke has a high mortality, high morbidity and consolidated central nervous system injury characteristics. The main features of severe heat stroke cerebral injury include cognitive impairment, delirium, convulsions and coma. Its mechanism is related with heat shock induced cerebral tissue ischemia and hypoxia, vascular dysfunction, secondary cascade inflammation and so on. Currently, the main treatment of heat stroke cerebral injury is the hypothermia therapy, dehydration for the reduction of intracranial pressure, naloxone and other cerebral protection and nutrition treatments. Hyperbaric oxygen therapy (HBOT) is effective in treating brain injury. HBOT can alleviate tissue ischemia and hypoxia, improve circulation, reduce cerebral edema, and anti-inflammatory, anti-oxidative damage, anti-apoptosis and other molecular biological effects. HBOT also play a wake up-promoting effect of nerve repair in the cerebral injury. The treatment of cerebral injury has been the difficulty and weakness of heat stroke research. Therefore, this article reviewed the epidemiology, pathogenesis, the therapeutic effect and mechanism of hyperbaric oxygen on cerebral injury in severe heat stroke to clarify the advantages of HBOT and to provide experimental basis for further research.

[Pretreatment with Xuebijing injection alleviates systemic inflammatory response induced by severe heat-stroke via ameliorating intestinal injury in rats].

OBJECTIVE: To observe the effect of Xuebijing injection pretreatment on systemic inflammatory response induced by severe heat-stroke, and to investigate the mechanism of alleviation of intestinal injury in rats. METHODS: Thirty-six healthy adult male Wistar rats with grade SPF were randomly assigned into three groups with randomized number method, namely sham group, severe heat-stroke model group, and Xuebijing pretreatment group ( XBJ group ), with 12 rats in each group. The animals were placed in a pre-warm chamber [ temperature ( 40±2 ) centigrade, humidity ( 65±5 )% ] in order to induce typical heat-stroke. The duration of heat-stress was 60 minutes, while the animals in sham group were exposed to ambient temperature of 25 centigrade. Arterial blood samples were collected at the beginning and the end of heat-stress, the concentrations of tumor necrosis factor-α( TNF-α), interleukins ( IL-1ß, IL-6 ), and lipopolysaccharide ( LPS ) in peripheral blood were determined by enzyme linked immunosorbent assay ( ELISA ). The intestinal tissues were harvested after heat-stress, and the pathological changes in intestine tissues were observed after hematoxylin-eosin ( HE ) staining and under optical microscope. The pathological injury scores were calculated. Immunohistochemistry was performed to determine inducible nitric oxide synthase ( iNOS ) expression in intestinal tissue. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling ( TUNEL ) staining. Western Blot was used to measure the tight junction protein occludin expression. RESULTS: The concentrations of TNF-α, IL-1ß, IL-6 and LPS in blood of the rats after heat-stress in model group were significantly higher than those of sham group [ TNF-α ( µg/L ): 443.00±110.10 vs. 98.36±44.61, IL-1ß ( µg/L ): 436.37±163.64 vs.64.24±16.15, IL-6 ( µg/L ): 342.70±92.42 vs. 54.40±13.22, LPS ( µg/L ): 0.68±0.22 vs. 0.09±0.02, all P < 0.01 ], but the levels of these parameters in XBJ group were significantly lower than those of model group [ TNF-α ( µg/L ): 340.45±68.57 vs. 443.00±110.10, IL-1ß ( µg/L ): 191.33±82.78 vs. 436.37±163.64, IL-6 ( µg/L ): 192.21±37.89 vs. 342.70±92.42, LPS ( µg/L ): 0.43±0.17 vs. 0.68±0.22, all P < 0.01 ]. Infiltration of inflammatory cells, necrosis and hemorrhage in intestinal mucosa were found in the intestine of heat-stroke animals in model group. The pathological lesions in XBJ group were milder than those of model group, with a decreased pathological injury score compared with model group ( 2.10±1.15 vs. 3.20±0.67, P < 0.01 ). The expression of iNOS and apoptosis of cells in intestinal tissue in model group were increased compared with that of sham group, but they were significantly less marked in XBJ group compared with model group [ iNOS ( adjusted A value ): 0.32±0.15 vs. 0.74±0.17, apoptotic index: 0.23±0.08 vs. 0.56±0.07, both P < 0.01 ]. The order of expression for occludin protein from high to low was sham group, XBJ group and model group ( A value was 0.96±0.25, 0.62±0.20, 0.33±0.11, respectively ). Furthermore, there was significant difference in the expression of occludin protein between model group and both XBJ group and sham group ( both P < 0.01 ). CONCLUSIONS: Xuebijing injection alleviates inflammation and endotoxemia produced by severe heat-stroke in rats. The mechanism may be related to amelioration of oxidative injury, apoptosis, and dysfunction of tight junction protein occludin expression.

Xuebijing injection alleviates liver injury by inhibiting secretory function of Kupffer cells in heat stroke rats.

OBJECTIVE: To evaluate the effects of Xuebijing (XBJ) injection in heat stroke (HS) rats and to investigate the mechanisms underlying these effects. METHODS: Sixty anesthetized rats were randomized into three groups and intravenously injected twice daily for 3 days with 4 mL XBJ (XBJ group) or phosphate buffered saine (HS and Sham groups) per kg body weight. HS was initiated in the HS and XBJ groups by placing rats in a simulated climate chamber (ambient temperature 400C, humidity 60% ). Rectal temperature, aterial pressure, and heart rate were monitored and recorded. Time to HS onset and survival were determined, and serum concentrations of tumor necrosis factor (TNF)-alpha interleukin (IL)-1beta, IL-6, alanine-aminotransferase (ALT), and aspartate-aminotransferase (AST) were measured. Hepatic tissue was harvested for pathological examination and electron microscopic examination. Kupffer cells (KCs) were separated from liver at HS initiation, and the concentrations of secreted TNF-a, IL-beta and IL-6 were measured. RESULTS: Time to HS onset and survival were significantly longer in the XBJ than in the HS group. Moreover, the concentrations of TNF-alpha, IL-1beta, IL-6, ALT and AST were lower and liver injury was milder in the XBJ than in the HS group. Heat-stress induced structural changes in KCs and hepatic cells were more severe in the HS than in the XBJ group and the concentrations of TNF-alpha, IL-beta and IL-6 secreted by KCs were lower in the XBJ than in the HS group. CONCLUSION: XBJ can alleviate HS-induced systemic inflammatory response syndrome and liver injury in rats, and improve outcomes. These protective effects may be due to the ability of XBJ to inhibit cytokine secretion by KCs.

Curative effect of Xuebijing injection on severe pulmonary contusion.

OBJECTIVE: To investigate the curative effects of Xuebijing (XBJ) injection, a Chinese patent medicine, on severe pulmonary contusion (PC). METHODS: Sixty-three patients with PC were randomized to conventional therapy plus XBJ injection (n = 33) or conventional therapy alone (n = 30). Between groups differences in corticosteroid treatment, immune regulation therapy, hemofiltration, infusion volume, transfusion volume and antibiotic period were measured, as were intensive care unit (ICU)-free time, ventilation time, 28-day mortality rate and incidence of ventilation-associated pneumonia (VAP). Serum concentrations of procalcitonin (PCT), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-10, white blood cell (WBC) counts and percentages of human leukocyte antigen DR/ CD14+ (HLA-DR/CD14+) peripheral blood mononuclear cells were compared. Markers of ventilation were determined by blood gas analysis and ventilator parameters. RESULTS: WBC counts and serum concentrations of PCT, TNF-alpha, IL-6 and IL-10 were reduced significantly more quickly, and CD14+ percentage was increased significantly earlier, in the XBJ group than in the control group (P < 0.05 each).The level of ventilation and oxygenation index were ameliorated earlier in the XBJ than in the control group (P < 0.05). XBJ treatment significantly reduced ICU-free time, ventilation time and incidence of VAP (P < 0.05 each), but had no effect on 28-day mortality rate CONCLUSION: XBJ treatment can shorten ICU-free and ventilation times and reduce the incidence of VAP, improving outcomes in patients with severe PC. XBJ may act by regulating inflammation and immunity, alleviating systemic inflammatory response syndrome induced by trauma.