[Mechanism of piRNA in bisphenol A-promoted invasion and migration of prostate cancer cells].

Objective: To investigate the regulatory mechanisms of piwi-interacting RNA (piRNA) in bisphenol A (BPA)-induced prostate cancer cell invasion and migration. Methods: The Cancer Genome Atlas (TCGA) data was used to analyze and screen for piRNAs with significantly increased expression in prostate cancer tissues. PC-3 cells were treated with different concentrations of BPA for 12, 24, and 48 h, respectively, and the 20% inhibitory concentration (IC20) was measured using a CCK-8 assay. The expression levels of piRNAs before and after BPA treatment were determined by reverse transcription-quantitative PCR. Target genes regulated by BPA and associated with prostate cancer were screened in the Comparative Toxicogenomics Database (CTD). Dual-luciferase reporter gene assay was performed to verify the relationship between piRNA and target genes, and the expression change of the piRNA target gene was detected by Western blotting. Cell migration and invasion assays were used to determine the effects of piRNA on the malignant phenotype of prostate cancer cells. Results: After treatment of PC-3 cells with 160 µmol/L BPA, the expression of piR-sno48 was most significantly increased (P<0.05). Transfection of piR-sno48 antagomir resulted in decreased expression of endogenous piR-sno48 and a significant increase in the expression of its target gene GSTP1 (P<0.05). However, the expression of GSTP1 did not change significantly in BPA-treated PC-3 cells after transfection with piR-sno48 antagomir (P>0.05). The dual-luciferase reporter gene confirmed that piR-sno48 inhibited the expression of GSTP1 by forming an inversely complementary sequence with the 3'-UTR of GSTP1. The Transwell assay results showed that treatment with BPA significantly increased the invasion and migration ability of prostate cancer cells (P<0.01), whereas piR-sno48 antagonists significantly inhibited the effects above (P<0.01). Conclusion: BPA promotes the invasion and migration of prostate cancer cells by upregulating the expression of piR-sno48 and suppressing the expression of GSTP1. Interfering with the expression of endogenous piR-sno48 may inhibit the malignant phenotype of prostate cancer cells caused by BPA.

Integrative analysis reveals the recurrent genetic etiologies in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is increasingly recognized as a chronic, progressive and fatal lung disease with an unknown etiology. Current studies focus on revealing the genetic factors in the risk of IPF, making the integrative analysis of genetic variations and transcriptomic alterations of substantial value. AIM: This study aimed to improve the understanding of the molecular basis of IPF through an integrative analysis of whole-exome sequencing (WES), bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) data. METHODS: WES is a powerful tool for studying the genetic basis of IPF, allowing for the identification of genetic variants that may be associated with the development of the disease. RNA-seq data provide a comprehensive view of the transcriptional changes in IPF patients, while scRNA-seq data offer a more granule view of cell-type-specific alterations. RESULTS: In this study, we identified a comprehensive mutational landscape of recurrent genomic and transcriptomic variations, including single-nucleotide polymorphisms, CNVs and differentially expressed genes, in IPF populations, which may play a significant role in the development and progression of IPF. CONCLUSIONS: Our study provided valuable insights into the genetic and transcriptomic variations associated with IPF, revealing changes in gene expression that may contribute to disease development and progression. These findings highlight the importance of an integrative approach to understanding the molecular mechanisms underlying IPF and may pave the way for identifying potential therapeutic targets.

Protective effects of recombinant lactoferrin with different iron saturations on enteritis injury in young mice.

Infant intestinal development is immature and, thus, is vulnerable to bacterial and viral infections, which damage intestinal development and even induce acute enteritis. Numerous studies have investigated that lactoferrin (LF) has protective effects on the intestine and may play a role in preventing intestinal inflammation in infants. Lactoferrin is divided into 2 types, namely apo-LF and holo-LF, depending on the degree of iron saturation, which may affect its bioactivities. However, the role of LF iron saturation in protecting infant intestinal inflammation has not been clearly clarified. Therefore, in this study, young mice models with intestinal damage induced by lipopolysaccharides (LPS) in vivo and primary intestinal epithelial cells in vitro were constructed to enteritis injury in infants for investigation. The apo-LF and holo-LF were subsequently applied to the mouse models to investigate and compare their levels of protection in the intestinal inflammatory injury, as well as to identify which LF was most active. Moreover, the specific mechanism of the LF with optimal iron saturation was further investigated through Western blot assay. Results demonstrated that disease activity index, shortened length of colon tissue, and histopathological score were significantly decreased in the apo-LF group compared with those of the LPS group and the holo-LF group. In the apo-LF group, the concentration of LPS in the intestinal tract and the number of gram-negative bacteria colonies decreased significantly and the expression levels of proinflammatory factors in the colon tissue were downregulated, in comparison with those in the LPS group. The findings of this study thus verify that apo-LF can significantly alleviate enteritis injury caused by LPS, through regulating the PPAR-γ/PFKFB3/NF-κB inflammatory pathway.

[Study on the diet balance index and its relationship with blood uric acid of smoking adults in Tianjin].

Objective: Diet balance index (DBI_16) was used to evaluate the dietary status of smoking adults in Tianjin, and the relationship between DBI_16 and serum uric acid was analyzed. Methods: A total of 1 478 inhabitants aged 18 and above were enrolled. The dietary status was obtained with a 3-day dietary recall and condiment weighing method. And their fasting venous blood was collected to detect uric acid. Food intake and DBI_16 scores of smokers and non-smokers were described, and the relationship among smoking, diet quality distance (DQD-DBI), and serum uric acid was analyzed. Results: The intake of vegetables, fruits, and milk of smokers in Tianjin was lower than while the salt, oil, cereals, and aquatic products were higher than that of non-smokers. The DBI_16 scores of vegetables and fruits, food types, milk, and beans of smokers were lower than those of non-smokers in Tianjin, and the scores of pure energy foods and condiments were higher than those of the non-smokers. The DQD-DBI, high bound score and low bound score of smokers in Tianjin were 42.0, 14.0, and 29.0 respectively, which were all higher than those of non-smokers. The main problems appeared as moderately inadequate intake (accounting for 67.0%), low, excessive intake (accounting for 70.9%), and moderate imbalance of intake (accounting for 67.2%). The serum uric acid of smokers was higher than in the non-smokers, and there the same result appeared under the conditions of "not suitable" in DQD-DBI. Conclusions: In Tianjin, the dietary imbalance was more evident in smokers than the non-smokers, and the serum uric acid was significantly higher than the non-smokers. Strategies as strengthening the nutrition education and intervention targeted for smokers were in urgent need.

[Study of influence of birth weight on risk of chronic diseases and blood uric acid in adulthood].

Objective: To understand the influence of birth weight on the risk of chronic diseases, such as hypertension and diabetes, and the relationship between birth weight and serum uric acid in adulthood. Methods: According to the Chinese Adult Chronic Disease and Nutrition Surveillance Program, a total of 1 131 residents aged 18 years and above were enrolled from Hexi, Nankai, Hongqiao, Wuqing, Jinnan, Baodi and Jizhou districts of Tianjin. The data of birth weight and blood pressure of the residents were collected, and fasting venous blood samples were collected from them to detect uric acid, blood glucose and blood lipids levels. The distribution of birth weight of the surveyed population was described, and the relationship between birth weight and chronic diseases, such as hypertension and diabetes, and the blood uric acid level in adulthood were analyzed. Results: The average birth weight of the surveyed population in Tianjin was 3.37 kg, which was higher in males than in females. No matter overweight/obesity, hypertension or diabetes, the prevalence rate of normal birth weight was the lowest in adulthood. After univariate logistic regression analysis and adjusting for age, sex, smoking and drinking status, it was found that compared with normal birth weight, low birth weight had a stronger correlation with diabetes (OR=2.91,95%CI:1.46-5.76) and dyslipidemia (OR=1.79,95%CI:1.01-3.19) in adulthood. Macrosomia was strongly associated with overweight/obesity in adulthood (OR=1.47, 95%CI:1.08-2.01). There was no significant difference in serum uric acid level among the residents with different birth weights. Conclusions: The low birth weight of the surveyed population in Tianjin was closely related to the risk of diabetes and dyslipidemia in adulthood, and the macrosomia was closely related to the risk of overweight/obesity in adulthood.

Inhibitory effects of lactoferrin on pulmonary inflammatory processes induced by lipopolysaccharide by modulating the TLR4-related pathway.

This study tested the ability of lactoferrin to modulate pulmonary inflammation. To construct in vitro and in vivo inflammatory lung models, cells from the human lung adenocarcinoma cell line (A549) were exposed to lipopolysaccharide (LPS, 1 µg/mL), and mice (CD-1) were intratracheally administered LPS [10 mg/kg of body weight (BW), tracheal lumen injection], respectively. The A549 cells were preincubated with lactoferrin (10 mg/mL), and the mice were intraperitoneally injected with lactoferrin (100 mg/kg of BW), followed by LPS treatment. The concentrations of proinflammatory cytokines (IL-1ß and TNF-α) in culture medium of A549 cells and in bronchoalveolar lavage fluid of the mice were determined using enzyme-linked immunosorbent assays. The toll-like receptor 4-related pathway (TLR4/MyD88/IRAK1/TRAF6/NFκB) was determined at gene and protein expression levels in A549 cells and mouse lung tissue. Results showed that LPS treatment significantly elevated the concentrations of IL-1ß and TNF-α in the A549 cell culture medium and in bronchoalveolar lavage fluid of the mice; it also elevated both the mRNA and protein expressions of TLR4 and the TLR4 downstream factors in A549 cells and mouse lung tissue. Nevertheless, lactoferrin apparently depressed the releases of IL-1ß and TNF-α from A549 cells and lung tissues stimulated by LPS, and significantly suppressed the TLR4 signaling pathway. Lactoferrin also promoted the enhancement of miR-146a expression in A549 cells and mouse lung tissue. Moreover, 100°C heating for 3 min caused total loss of the previously listed bioactivity of lactoferrin. Collectively, we proved that lactoferrin intervened in LPS-induced inflammation in the pulmonary cell model and in the mouse model, through inhibiting the TLR4-related pathway.

[Study on the relationship between preoperative evaluation, operation and prognosis of microvascular decompression for the treatment of hemifacial spasm].

Objective: To investigate the relationship between preoperative evaluation, surgery and prognosis of microvascular decompression (MVD) for the treatment of hemifacial spasm (HFS). Methods: The clinical data of 128 HFS patients treated with MVD in the department of neurosurgery of Taizhou Hospital of Zhejiang Province were retrospectively analyzed. According to the SMC grading system, the patients were divided into general spasm group and severe spasm group, and the clinical characteristics, offending vessel, prognosis and surgical complications of the two groups were compared. Results: In the general spasm group,the age at MVD was (48.6±10.6) years, the disease duration was (4.2±3.3) years;while in the severe spasm group,the age at MVD was (51.8±9.9) years, the disease duration was (8.1±4.5) years;the differences of age and disease duration between the two groups were statistically significant (P<0.05).In the general spasm group, there were 41 cases in which the offending vessel were AICA, 21 cases were PICA, 1 case was VA, 63 cases were single offending vessel, and 7 cases were multiple offending vessels. In the severe spasm group, there were 29 cases in which the offending vessel were AICA, 13 cases were PICA, 2 cases were VA, the total of 44 cases were single offending vessel and 14 cases were multiple offending vessels.There was a significant difference in the proportion of multiple offending vessels in the two groups, and the difference was statistically significant (P<0.05).Patients in the two groups were followed up for 12 to 32 months after surgery, and the difference in effective rate and recurrence rate was not statistically significant (P>0.05).Some kinds of postoperative complications were different between the two groups, the incidence of postoperative delayed facial paralysis was statistically significant (P<0.05), and the other complications were not statistically significant (P>0.05). Conclusion: Compared with the general spasm group, the patients in the severe spasm group were older, with longer disease duration, higher probability of multiple offending vessels and higher incidence of postoperative delayed facial paralysis. Therefore, preoperative SMC grading is helpful for the evaluation and prediction of intraoperative and postoperative conditions, which is worthy of wide clinical application.

[The expression of programmed death receptor 1 in non-small cell lung cancer and its clinicopathological features and prognosis showed a connection with epidermal growth factor receptor gene mutations].

Objective: To investigate the relationships between the expression of programmed death 1 (PD-1) and the epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer (NSCLC). The study also attempted to investigate the clinicopathological features and prognosis in NSCLC patients. Methods: The expression of PD-1 protein in 88 cases of NSCLC tumor tissues and adjacent tissues was detected by immunohistochemistry. The mutations of EGFR in NSCLC were detected by Polymerase Chain Reaction-Amplification Refractory Mutation System(PCR-ARMS) method. The expression of PD-1 and patients' clinical characteristics and prognosis were analyzed. Results: PD-1 was positive in 63.6%(56/88) NSCLC tumor tissues, which was significantly higher than that in adjacent normal tissues (21.6%, 19/88) (P<0.05). EGFR gene mutations were found in 43 cases (48.9%), in which 30 cases (69.8%)were PD-1 positive expression. 45 cases had the wild types of EGFR gene, in which 26 cases (57.8%) were PD-1 positive. There were 24 cases of 19Del EGFR mutations, including 20 cases (83.3%) of PD-1 positive expression. 19 patients had 21L858 EGFR mutations, including 10 cases (52.6%) of PD-1 positive expression. The expression of PD-1 in NSCLC was related to patients' smoking status, lymph node metastasis and EGFR gene mutations (P<0.05). The median progression-free survival time of patients with PD-1 positive and negative expression was 7.03 and 18.66 months, respectively (P=0.007). In patients with wild-type EGFR gene, the median progression-free survival time of PD-1 positive and negative expression was 25.21 and 38.24 months, respectively. The difference was statistically significant (P=0.024). The median progression-free survival time in 43 cases of EGFR mutant patients with PD-1 positive and negative expression was 21.23 and 31.44 months. The difference was not statistically significant (P=0.128). Conclusions: PD-1 expresses in both EGFR mutant and wild-type NSCLC, and its expression levelis different with various EGFR mutations. The expression of PD-1 in NSCLC is related to the prognosis of patients, and the prognosis of patients with positive PD-1 expression was poor.

In vitro effect of IL-17D on human ovarian carcinoma cells and inherent immunity.

This study explored the expression of interleukin 17D (IL-17D) secreted by human ovariancarcinoma cells and the effect of exogenous IL-17D transfection on MICA, which is the ligand of NKG2D, on the surface of ovary carcinoma cells. Human ovarian papillary serous adenocarcinoma cell line SKOV3, empty vector control cell line SKOV3/vector, exogenous human IL-17D stable-transfected cell line SKOV3/IL-17D, as well as cisplatin (CDDP)-resistant cell SKOV/CDDP were cultured; ovarian adenocarcinoma cell line OVCAR-3, empty vector control cell line OVCAR3/vector and OVCAE3/IL- 17D were observed under a microscope. In the study, methyl-thiazolyl-tetrazolium (MTT) method was used to detect the inhibition rate, resistance index and proliferation of SKOV3 and SKOV3/CDDP. It was found that the expression of IL-17 D in SKOV3/CDDP was much higher than that of its parent cell line SKOV3; IL-17D might be correlated to the drug resistance of cells; the proliferation of SKOV3 transfected with IL-17D was significantly accelerated, indicating IL-17D may be effective in promoting the growth of oncocyte.

Development of a NanoString assay to detect leukemogenic fusion transcripts in acute myeloid leukemia.

INTRODUCTION: Detection of leukemogenic fusion transcripts in acute myeloid leukemia (AML) is critical for AML diagnosis. NanoString nCounter system is a novel probe-based gene expression platform capable of measuring up to 800 targets with advantages of reproducibility, accuracy, and sample type flexibility. To study the potential application of NanoString in leukemia at clinic, we used this technology to detect AML leukemogenic fusion transcripts and compared the performances with clinical molecular assays. METHODS: We developed a NanoString assay to detect seven leukemogenic fusion transcripts, namely RUNX1-RUNX1T1 (e5e12), PML-RARA (bcr1, bcr2, and bcr3), and CBFB-MYH11 (e5e12, e5e8, and e5e7). We set up the cut-off value for each fusion transcript and tested 42 de novo AML samples. We compared the results with reverse transcriptase-polymerase chain reaction (RT-PCR) and TaqMan reverse quantitative-polymerase chain reaction (RQ-PCR), the molecular methods standardly used at clinic. RESULTS: We demonstrated that the NanoString and RT-PCR results correlate well (P < 0.0001) and are highly concordant (95.2%). Using TaqMan RQ-PCR as a validation method and gold standard, we demonstrated superior accuracy and sensitivity of NanoString compared to RT-PCR and comparable specificity. Furthermore, we showed that NanoString is not as sensitive as TaqMan RQ-PCR in detecting very low level of fusion transcripts. CONCLUSIONS: NanoString can serve as a reliable and alternative molecular method to multiplexed RT-PCR for diagnosis of de novo AML with the perspective of screening/quantitation of a large number of leukemogenic fusion transcripts and prognostic genes. However, NanoString may not be an alternative method for monitoring minimal residual disease in AML.

Lysine-specific demethylase 1 promotes the stemness and chemoresistance of Lgr5(+) liver cancer initiating cells by suppressing negative regulators of ß-catenin signaling.

Cancer initiating cells (CICs) are responsible for the unrestrained cell growth and chemoresistance of malignant tumors. Histone demethylation has been shown to be crucial for self-renewal/differentiation of stem cells, but it remains elusive whether lysine-specific demethylase 1 (LSD1) regulates the stemness properties of CICs. Here we report that the abundant expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is associated with the progression of hepatocellular carcinoma (HCC). Lgr5(+) HCC cells behave similarly to CICs and are highly tumorigenic and resistant to chemotherapeutic agents. Importantly, Lgr5(+) cells express higher levels of LSD1, which in turn regulates Lgr5 expression and promotes the self-renewal and drug resistance of Lgr5(+) CICs. Mechanistically, LSD1 promotes ß-catenin activation by inhibiting the expression of several suppressors of ß-catenin signaling, especially Prickle1 and APC in Lgr5(+) CICs, by directly regulating the levels of mono- and di-methylation of histone H3 lysine-4 at the promoters of these genes. Furthermore, LSD1-associated activation of the ß-catenin signaling is essential for maintaining the activity of Lgr5(+) CICs. Together, our findings unravel the LSD1/Prickle1/APC/ß-catenin signaling axis as a novel molecular circuit regulating the stemness and chemoresistance of hepatic Lgr5(+) CICs and provide potential targets to improve chemotherapeutic efficacies against HCC.

The role of hepatic liver X receptor α- and sterol regulatory element binding protein-1c-mediated lipid disorder in the pathogenesis of non-alcoholic steatohepatitis in rats.

Liver X receptor α (LXRα) and sterol regulatory element binding protein-1c (SREBP-1c) were studied in rats with non-alcoholic steatohepatitis (NASH) induced by a high-fat diet. Forty 5-week-old rats were fed either a high-fat diet (n = 30) or a normal diet (n = 10) for 9, 13 or 17 weeks. The mRNA and protein levels for LXRα and SREBP-1c were measured at each time point, as was fatty acid synthase (FAS) activity and the serum levels of free fatty acid (FFA) and triglyceride (TG). The mRNA and protein levels for LXRα and SREBP-1c, FAS activity and serum levels of FFA and TG all significantly increased from week 9 in the high-fat diet rats versus controls. In conclusion, a high-fat diet upregulates LXRα which, in turn, upregulates SREBP-1c, increasing the activity of FAS and FFA and accumulation of TG in hepatocytes. Thus, LXRα and SREBP-1c contribute to the development of NASH.

Serum KL-6 differentiates neuroendocrine cell hyperplasia of infancy from the inborn errors of surfactant metabolism.

BACKGROUND: The study was conducted in order to determine if the glycoprotein KL-6 is a useful biomarker in differentiating neuroendocrine cell hyperplasia of infancy (NEHI), a benign form of children's interstitial lung disease, from the more severe inborn errors of surfactant metabolism (IESM), since their clinical presentation can be similar. METHODS: Serum KL-6 levels were measured in 10 healthy control children, 6 with NEHI and 13 with IESM (4 with surfactant protein C (SP-C) and 9 with ABCA3 mutations). The initial clinical presentation, findings on previous CT scans and interstitial lung disease (ILD) scores at the time of KL-6 testing were compared. Correlations of KL-6 levels with age and with interval from lung biopsy were evaluated. RESULTS: The median (range) KL-6 levels were 265 (1-409), 194 (47-352), 1149 (593-4407) and 3068 (726-9912) U/ml for the control, NEHI, SP-C and ABCA3 groups, respectively. When compared with the control and NEHI groups, median KL-6 levels were significantly higher in the SP-C (p<0.01; p = 0.01, respectively) and ABCA3 groups (p<0.001; p = 0.001, respectively); however, there was no difference between the control and NEHI groups (p = 0.91). An inverse relationship was seen between KL-6 levels and age in the IESM groups, but not in the NEHI or control groups. Children with NEHI had similar presenting clinical features and were equally symptomatic at the time of KL-6 measurement as those with IESM. CONCLUSIONS: Children with NEHI have normal KL-6 levels, in contrast to those with IESM, who have elevated serum KL-6 levels; serum KL-6 may be a useful biomarker in distinguishing between these entities when their clinical presentations overlap.

Clinical, radiological and pathological features of ABCA3 mutations in children.

BACKGROUND: Mutations in the ABCA3 gene can result in fatal surfactant deficiency in term newborn infants and chronic interstitial lung disease in older children. Previous studies on ABCA3 mutations have focused primarily on the genetic abnormalities and reported limited clinical information about the resultant disease. A study was undertaken to analyse systematically the clinical presentation, pulmonary function, diagnostic imaging, pathological features and outcomes of children with ABCA3 mutations. METHODS: The records of nine children with ABCA3 mutations evaluated at Texas Children's Hospital between 1992 and 2005 were reviewed and their current clinical status updated. Previous diagnostic imaging studies and lung biopsy specimens were re-examined. The results of DNA analyses were confirmed. RESULTS: Age at symptom onset ranged from birth to 4 years. Cough, crackles, failure to thrive and clubbing were frequent findings. Mean lung function was low but tended to remain static. CT scans commonly revealed ground-glass opacification, septal thickening, parenchymal cysts and pectus excavatum. Histopathological patterns included pulmonary alveolar proteinosis, desquamative interstitial pneumonitis and non-specific interstitial pneumonitis, and varied with age. Dense abnormalities of lamellar bodies, characteristic of ABCA3 mutations, were seen by electron microscopy in all adequate specimens. Outcomes varied with the age at which the severity of lung disease warranted open lung biopsy, and some patients have had prolonged survival without lung transplantation. CONCLUSIONS: The presentation and course of interstitial lung disease due to ABCA3 mutations are variable, and open lung biopsy and genetic testing are warranted early in the evaluation of children with a consistent clinical picture.

Selective inhibition of inducible nitric oxide in ischemia-reperfusion of rat small intestine.

PURPOSE: We investigated the role of constitutive and inducible nitric oxide (NO) synthases in intestinal ischemia-reperfusion (I/R) injury by observing the alterations in hemodynamics and intestinal microcirculation in response to I/R in rats, with or without inhibitors of NO synthases. METHODS: Adult male Sprague-Dawley rats (n = 9/group) received a standard I/R procedure alone: I/R plus intravenous administration of aminoguanidine (an inhibitor of inducible NO synthase); I/R plus L-NAME (NG-nitro-L-arginine methyl ester, an inhibitor of constitutive and inducible NO synthase); IR + L-Arg (L-arginine, an NO precursor); or a sham operation plus the vehicle. The I/R procedure was performed by clamping the perfusion vessels of a segment of the terminal ileum, and medication was administered intravenously before and after intestinal ischemia. The intestinal perfusion and leukocyte-endothelial interactions were evaluated with in vivo microscopy and laser Doppler flowmetry. Surface expression of CD11b (an adhesion molecule) of circulating granulocytes was measured with flow cytometry. RESULTS: Intestinal I/R produced circulatory alterations, intestinal microcirculatory derangement, energy depletion, and lipid peroxidation. Aminoguanidine significantly attenuated the reperfusion-related depression of mean arterial pressure (MAP), the decrease in intestinal perfusion index, the decrease in tissue ATP preservation, the increase in tissue malondialdehyde (MDA) level, and the expression of CD11b of circulating granulocytes. Administration of L-NAME had only minor and transient effects on reperfusion-related changes of MAP, intestinal flux, numbers of adherent leukocytes, and CD11b expression, but had some protective effects on tissue MDA and adenosine triphosphate levels and flow velocity. L-Arg further decreased the MAP but did not affect reperfusion-related variables. CONCLUSIONS: Our results show that the selective inhibition of inducible NO synthase by aminoguanidine attenuates the hemodynamic and microcirculatory derangement that results from intestinal I/R.

[Preventive effect of cardiomyopeptidin on rat heart injured by ischemia-reperfusion].

OBJECTIVE: To investigate the preventive effect of cardiomyopeptidin of small molecular weight polypeptide on rat hearts injured by ischemia-reperfusion. METHODS: In a rat model injured by ischemia-reperfusion in the heart, observation was made on the influence of cardiomyopeptidin on the activities of creatine kinase (CK) and lactate dehydrogenase(LDH), as well as on the content of MDA in plasma after the preventive drug was used. RESULTS: Cardiomyopeptidin could obviously prevent the injury caused by ischemia-reperfusion, reduce the activities of CK and LDH and the content of MDA in a dose-dependent manner. CONCLUSION: Cardiomyopeptidin has a preventive effect on myocardium injured by ischemia-reperfusion and this may be related to its reducing the release of myocardial enzyme and anti-lipoperoxidation.

Neutrophil elastase inhibitor (ONO-5046) attenuates reperfusion-induced hepatic microcirculatory derangement, energy depletion and lipid peroxidation in rats.

UNLABELLED: Microcirculatory derangement, energy depletion, and lipid peroxidation are associated with the development of ischemia-reperfusion injury in the liver. This study investigated the effects of a neutrophil elastase inhibitor (ONO-5046) on hepatic ischemia-reperfusion injury. Adult, male Sprague-Dawley rats were divided into four treatment groups: 1) sham-operated control (laparotomy only, no ischemia) and saline injection (1 mL/kg), n = 6; 2) ischemia control (1-h ischemia, 2-h reperfusion) and saline injection (1 mL/kg), n = 6; 3) intravenous injection with ONO-5046 at a dose of 1 mg/kg 5 min before ischemia and immediately after reperfusion plus 1-h ischemia and 2-h reperfusion, n = 6; and 4) intravenous injection with ONO-5046 at a dose of 10 mg/kg 5 min before ischemia and immediately after reperfusion plus 1-h ischemia and 2-h reperfusion, n = 6. A laser-Doppler flowmeter and in vivo microscopy were used to investigate hepatic microcirculation. Tissue malondialdehyde (MDA) and adenosine triphosphate (ATP) levels were determined at the end of the experiment. RESULTS: Compared with ischemia alone, ONO-5046 significantly reduced the extent of microcirculatory and hemodynamic derangement after ischemia-reperfusion. ONO-5046 at both doses significantly attenuated decreases in mean arterial pressure. ONO-5046 lessened adherent leukocyte count and improved flow velocity in the sinusoids and postsinusoidal venules. ONO-5046 at the dose of 10m/kg reduced MDA (1.97 +/- 0.54 micromol/g protein vs. 3.58 +/- 1.21 micromol/g protein in the ischemia and reperfusion group) and increased ATP levels (2.62 +/- 0.19 micromol/g wet wt vs. 0.57 +/- 0.37 pmol/g wet wt in the ischemia and reperfusion group), whereas ONO-5046 at a smaller dose (1 mg/kg) had lesser but significant effects on MDA and ATP alterations. This study demonstrates that treatment with ONO-5046, a neutrophil elastase inhibitor, can ameliorate ischemia-reperfusion injury of the rat liver.