A multi-constituent model for assessing the effect of impeller shroud on the thrombosis potential of a centrifugal blood pump.

Centrifugal blood pumps can be used for treating heart failure patients. However, pump thrombosis has remained one of the complications that trouble clinical treatment. This study analyzed the effect of impeller shroud on the thrombosis risk of the blood pump, and predicted areas prone to thrombosis. Multi-constituent transport equations were presented, considering mechanical activation and biochemical activation. It was found that activated platelets concentration can increase with shear stress and adenosine diphosphate(ADP) concentration increasing, and the highest risk of thrombosis inside the blood pump was under extracorporeal membrane oxygenation (ECMO) mode. Under the same condition, ADP concentration and thrombosis index of semi-shroud impeller can increase by 7.3% and 7.2% compared to the closed-shroud impeller. The main reason for the increase in thrombosis risk was owing to elevated scalar shear stress and more coagulation promoting factor-ADP released. The regions with higher thrombosis potential were in the center hole, top and bottom clearance. As a novelty, the findings revealed that impeller shroud can influence mechanical and biochemical activation factors. It is useful for identifying potential risk regions of thrombus formation based on relative comparisons.

Numerical investigation on the effect of impeller axial position on hemodynamics of an extracorporeal centrifugal blood pump.

Extracorporeal centrifugal blood pumps are used to treat cardiogenic shock. Owing to the imbalanced excitation or initial assembly configurations, the variation in the impeller axial position has the potential to affect the blood pump performance. This study compared the hydrodynamics and hemolysis outcomes at different impeller axial positions via numerical simulations. The result shows that pressure difference of the blood pump decreased with increasing impeller axial position, with decreasing by 4.5% at a flow rate of 2 L/min. Under axial impeller motion close to the top pump casing, average wall shear stress and scalar shear stress reached their maximum values (64.2 and 29.1 Pa, respectively). The residence time in the impeller center hole and bottom clearance were extended to 0.5 s by increasing impeller axial position. Compared to the baseline blood pump, hemolysis index increased by 12.3% and 24.3% when impeller axial position is 2.5 and 4.0 mm, respectively. As a novelty, the findings reveal that the impeller axial position adversely affects hemolysis performance when the impeller is close to the pump casing. Therefore, in the development process of centrifugal blood pumps, the optimal axial position of the impeller must be defined to ensure hemodynamic performance.

Synthesis and biological evaluation of thiazolidine-2-thione derivatives as novel xanthine oxidase inhibitors.

Xanthine oxidase (XO) is a key enzyme in the generation and development of hyperuricemia. Thiazolidine-2-thione, a typical heterocyclic compound, have been widely used in the field of drug synthesis. In this study, a series of novel thiazolidine-2-thione derivatives were synthesized as XO inhibitors, and the XO inhibitory potencies of obtained compounds were evaluated by in vitro enzyme catalysis. The result shown that compound 6k behaved the strongest XO inhibitory activity with an IC50 value of 3.56 µmol/L, which was approximately 2.5-fold more potent than allopurinol. The structure-activity relationship revealed that the phenyl-sulfonamide group was indispensable for thiazolidine-2-thione derivatives to produce XO inhibitory activity. The enzyme inhibition kinetics analyses confirmed that compound 6k exerted a mixed-type XO inhibition. Additionally, the molecular docking results suggested that the 4-fluorophenyl-sulfonyl moiety could interact with Gly260 and Ile264 in the innermost part of the active pocket through 2 hydrogen bonds, while the thiazolidinethione moiety could form two hydrogen bonds with Glu263 and Ser347 in hydrophobic pockets. In summary, the results described above suggested that compound 6k could be a valuable lead compound for the treatment of hyperuricemia as a novel XO inhibitor.

Discovery of N-(2-benzyl-4-oxochroman-7-yl)-2-(5-(ethylsulfonyl) pyridin-2-yl) acetamide (b12) as a potent, selective, and orally available novel retinoic acid receptor-related orphan receptor γt inverse agonist.

The nuclear receptor retinoic acid receptor-related orphan receptor γ (RORγ, NR1F3, or RORc) exists in two isoforms, with one isoform (RORγ or RORc1) widely expressed in a variety of tissues, and the expression of the second isoform (RORγt or RORc2) restricted to the thymus and cells of the immune system. RORγt is a key regulator of the development and functions of T-helper 17 (Th17) cells. Clinical proof-of-concept (PoC) with small molecule inverse agonists of RORγt has been achieved with VTP-43742 (Phase II) for the treatment of psoriasis, and pre-clinical PoC for this mechanism has also been established for the treatment of autoimmune diseases. A series of aryl sulfonyl derivatives as novel RORγt inverse agonists were designed and synthesized based on VTP-43742. We conducted structural modifications that improved the activity profile. In pharmacodynamic (PD) studies, oral administration of compound b12 showed robust and dose-dependent inhibition of IL-6 and IL-17A cytokine expression. The ability of compound b12 to reduce the levels of IL-6 and IL-17A in vivo after oral dosing in mice, and a corresponding reduction in skin inflammation further supports the potential of small molecule RORγt modulation as a therapeutic target for the treatment of inflammatory diseases.

Discovery of 2H-chromone-4-one based sulfonamide derivatives as potent retinoic acid receptor-related orphan receptor γt inverse agonists.

Retinoic acid receptor related orphan receptor γt (RORγt), identified as the essential functional regulator of IL-17 producing Th17 cells, is an attractive drug target for treating autoimmune diseases. Starting from the reported GSK2981278 (Phase II), we structurally modified and synthesized a series of 2H-chromone-4-one based sulfonamide derivatives as novel RORγt inverse agonists, which significantly improved their human metabolic stabilities while maintaining a potent RORγt inverse agonist profile. Efforts in reducing the lipophilicity and improving the LLE values led to the discovery of c9, which demonstrated potent RORγt inverse agonistic activity and consistent metabolic stability. During in vivo studies, oral administration of compound c9 exhibited a robust and dose-dependent inhibition of IL-17A cytokine expression and significantly lessened the skin inflammatory symptoms in the mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that c9 can suitably occupy the active pocket, and the introduction of the morpholine pyridine group can interact with Leu396, His479, and Cys393. Thus, compound c9 was selected as a preclinical compound for treating Th17-driven autoimmune diseases.

Discovery of Chromane-6-Sulfonamide Derivative as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist.

Interleukin-17 (IL-17) is a proinflammatory cytokine that plays a dominant role in inflammation, autoimmunity, and host defense. RORγt is a key transcription factor mediating T helper 17 (Th17) cell differentiation and IL-17 production, which is able to activate CD8+ T cells and elicit antitumor efficacy. A series of sulfonamide derivatives as novel RORγt inverse agonists were designed and synthesized. Using GSK2981278 (phase II) as a starting point, we engineered structural modifications that significantly improved the activity and pharmacokinetic profile. In animal studies, oral administration of compound d3 showed a robust and dose-dependent inhibition of the IL-17A cytokine expression in a mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that the compound d3 occupied the active pocket suitably. Thus, compound d3 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.

The complete mitochondrial DNA sequence of Yimeng black goat (Capra hircus) and its potential application in mutton discrimination.

Yimeng black goat is one of the national breeds of geographical indication in China and is one of the key protected local livestock and poultry breeds of Shandong province. The complete mitochondrial genome sequence of Yimeng black goat was investigated in this study (GenBank accession no. MT134111). The mitogenome (16,640 bp) consisted of a non-coding control region (D-loop region), two ribosomal RNA (rRNA) genes, 13 protein-coding genes (PCGs), and 22 transfer RNA (tRNA) genes. The complete mitochondrial genome sequence and the neighbour-joining tree of the Yimeng black goat would contribute to further study in genetic mechanism and phylogenomic research of goats.

Etomidate inhibits nuclear factor-κB through decreased expression of glucocorticoid receptor in septic rats.

The present study aimed to investigate the effect of etomidate administered prior to or following cecal ligation and puncture (CLP) on the expression of glucocorticoid receptor (GR) and lymphocyte apoptosis in septic rats. Right jugular vein catheterization was performed on female Sprague­Dawley rats under isoflurane anesthesia, and CLP surgery was performed to induce sepsis 3 days following catheterization. The rats were randomly divided into five groups. All groups were infused with 2 ml of either etomidate or 5‰ dimethyl sulfoxide (DMSO) at 1 ml/h for 2 h from 6 h post­surgery. The sham group received abdominal sham surgery and infusion with DMSO; the CLP control group received infusion with DMSO. Treatment group A received infusion with 2 mg/kg etomidate; group B received 0.6 mg/kg etomidate following CLP and an infusion of 2 mg/kg etomidate. Group C received 0.6 mg/kg etomidate 24 h prior to CLP and post­surgical etomidate infusion. The 10­day survival rates of the rats in the CLP, A, B and C groups were 60, 50, 55 and 40%, respectively. The serum mRNA expression levels of tumor necrosis factor­α, GR and glucocorticoid­induced leucine zipper were detected by reverse transcription­quantitative polymerase chain reaction, the abundance of inhibitor of nuclear factor (NF)-κB­α was measured by western blotting, and the apoptotic rates of the splenic lymphocytes were determined using flow cytometry. The results suggested that etomidate inhibited NF­κB by decreasing the expression of GR in the septic rats. The increased apoptosis of lymphocytes induced by etomidate may lead to a poor outcome during sepsis.

The pituitary adenylate cyclase-activating polypeptide (PACAP) protects adrenal function in septic rats administered etomidate.

BACKGROUND: Both hyperinflammation during sepsis and etomidate can suppress adrenal function. In this study, we explored whether treatment with pituitary adenylate cyclase-activating polypeptide (PACAP) relieves adrenal suppression in cecal ligation and puncture (CLP)-induced septic rats. MATERIALS AND METHODS: Female Sprague-Dawley rats were randomly divided into five groups (n=7 per group), including the sham group, sepsis group (CLP group), sepsis and etomidate group (CLP+ETO group), PACAP group, and etomidate alone group (ETO group). Rats were sacrificed on the third day of sepsis, and blood and adrenal gland samples were obtained for further testing. RESULTS: The PACAP reduced the apoptosis rate of adrenal cells and peripheral lymphocytes, improving adrenal function, inhibiting the secretion of interferon gamma (IFN-γ) from peripheral lymphocytes, and slightly relieving the suppression of the adrenal function induced by the injection of etomidate in sepsis. CONCLUSION: In septic conditions, the PACAP protects the adrenal gland by regulating peripheral inflammation, which slightly relieves the toxic effects of etomidate on adrenal function.

Parity and litter size effects on maternal behavior of Small Tail Han sheep in China.

The effects of parity and litter size on maternal behavior of Small Tail Han sheep was investigated at Linyi University, China. Sixty-eight ewes were observed from parturition to weaning. Continuous focal animal sampling was used to quantify the duration of maternal behaviors. Ewe feces were collected every 2 days and estradiol concentration was measured with an enzyme immunoassay kit. All lambs were weighed 24 h after parturition and again at 35 days of age. Parity increased sucking, following, grooming, low-pitched bleat, head-up and udder-refusal behavior and decreased aggressive behavior (P < 0.01, P < 0.01, P < 0.05, P < 0.05, P < 0.05, P < 0.05, P < 0.01, respectively), and litter size showed significant effect on sucking, following and low-pitched bleat behavior (P < 0.05, P < 0.01, P < 0.05, respectively). The lambs of multiparous ewes were significantly heavier than primiparous ewes at birth (P < 0.01) and were significantly heavier at weaning age (P < 0.01). Similar results were founded for birth weight and weaning weight gain in litter size (P < 0.01, P < 0.01, respectively). Estradiol concentration in feces was higher in multiparous ewes than primiparous ewes. Parity and litter size may have effects on maternal behavior during lactation. Ewes that have 2-3 lambs may be more suitable for production of Small Tail Han sheep in China.

Etomidate Mitigates Lipopolysaccharide-Induced CD14 and TREM-1 Expression, NF-κB Activation, and Pro-inflammatory Cytokine Production in Rat Macrophages.

This study was aimed at investigating the effect of etomidate on the viability of rat macrophages and the function of lipopolysaccharide (LPS)-stimulated macrophages as well as the potential mechanisms. Rat macrophages were isolated and treated with different doses of etomidate for 24 h, and their viability was determined by the CCK-8 assay. Furthermore, macrophages were treated with, or without, 1 µg/ml of LPS, and/or 2.5 or 5 µM etomidate in the presence or absence of a TREM-1 inhibitor (LP17, 100 ng/ml), and the levels of TNF-α, IL-6, CD14, and TREM-1 in the different groups of cells were determined by quantitative RT-PCR, ELISA, and Western blot assays. The levels of NF-κB activation in the different groups of cells were analyzed by an electrophoretic mobility shift assay (EMSA). Etomidate at 31.25 µM or a low dose did not affect the viability of rat macrophages, while etomidate at higher doses reduced the viability of macrophages in vitro. Treatment with 2.5 or 5 µM etomidate or with LP17 alone did not affect the levels of TNF-α, IL-6, CD-14, and TREM-1 in macrophages. Treatment with etomidate significantly mitigated LPS-stimulated TNF-α, IL-6, CD-14, and TREM-1 expression (p < 0.05 for all) and inhibited LPS-induced NF-κB activation in macrophages in vitro. However, treatment with both etomidate and LP17 did not enhance the inhibitory effects in macrophages. Hence, etomidate mitigates LPS-up-regulated pro-inflammatory cytokine production and inhibits LPS-enhanced CD14 and TREM-1 expression and NF-κB activation in macrophages.

Pretreatment with low dose etomidate prevents etomidate-induced rat adrenal insufficiency by regulating oxidative stress-related MAPKs and apoptosis.

Etomidate is frequently used as an anesthetic and sedation agent in the clinic setting. This study determined that a low-dose pre-infusion followed by a continuous dose infusion of etomidate could reduce etomidate-induced adrenal gland insufficiency. Sixty adult male Wistar rats were used, with six rats per group. Based on preliminary experiments, 0.6mg/kg etomidate was selected as the low dose for this study. Oxidative stress and apoptosis-related proteins in the adrenal glands were assayed using Western blot, and serum levels of CORT and 11ß-hydroxylase were detected using ELISA. Pretreatment with a single bolus of low dose etomidate significantly increased the levels of CORT and 11ß-hydroxylase as well as the activities of superoxide dismutase (SOD), catalase (CAT) and glutathioneperoxidase (GPx) in the adrenal glands, but reduced nitric oxide (NO) production when compared to the positive group. Furthermore, Western blot data showed that pretreatment with low dose etomidate increased extracellular signal-regulated kinase1/2 (ERK1/2), CREB and bcl-2 activation, but suppressed the p-p38, c-JunN-terminal kinase (JNK), inducible NO synthase (iNOS), cleaved-caspase3, cleaved-poly-ADP-ribose polymerase (PARP), bax, and AKT activation. The ERK inhibitor PD98059 and the p38MAPK inhibitor SB203580 abolished the protective effect of low dose etomidate pretreatment. These data demonstrated that pretreatment with low dose etomidate attenuated etomidate-induced adrenal insufficiency to rat adrenal glands. Oxidative stress-related MAPKs and apoptosis proteins might be responsible for mediating the etomidate preconditioning effect in rats.

Etomidate increases mortality in septic rats through inhibition of nuclear factor kappa-B rather than by causing adrenal insufficiency.

BACKGROUND: Both hyperinflammation during sepsis and etomidate can suppress adrenal function. In this study, we explored whether pretreatment with etomidate can relieve adrenal suppression and its impact on outcomes of cecal ligation and puncture (CLP)-induced septic rats. MATERIALS AND METHODS: Rats (n = 18 per group) were divided in seven groups, including two control groups and treated with different combinations of a small pretreatment dose (0.6 mg/kg) and a large continuous dose (2 mg/kg/h over 2 h) of etomidate to evaluate the impact of the different administration combinations on the adrenal glands and outcomes in the septic rats. Animals (n = 8 per group) were euthanized at 24 h after CLP and blood samples and adrenal glands were then collected for further measurements. The remaining rats (n = 10 per group) were used to observe the 7-d survival rate post-CLP. RESULTS: The survival rate (30%) was much lower in the group pretreated with a small dose before CLP surgery and followed by a large dose of etomidate than in the other groups. Etomidate decreased serum corticosterone, but not adrenocorticotropic hormone levels in septic rats, and also decreased serum tumor necrosis factor-alpha and interleukin-6 levels. In rat pretreated with a small dose of etomidate, the toll-like receptor-4 expression level in the adrenal glands was decreased and nuclear factor kappa-B (NF-kappa B) translocation was inhibited. CONCLUSIONS: The mortality of septic rats and degree of adrenal injury caused by etomidate are not correlated. The etomidate-induced inhibition of inflammation and NF-kappa B translocation, which was more significant than adrenal suppression, may be responsible for the increased mortality in septic rats.

Establishment and biological characteristics of acquired gefitinib resistance in cell line NCI-H1975/gefinitib-resistant with epidermal growth factor receptor T790M mutation.

Non­small cell lung cancer (NSCLC) cells harboring mutations in the epidermal growth factor receptor (EGFR) gene initially respond well to EGFR tyrosine kinase inhibitors (TKI), including gefitinib. However the tumor cells will invariably develop acquired resistance to the drug. The EGFR T790M mutation is generally considered to be the molecular genetic basis of acquired TKI resistance. The present study aimed to explore how the T790M mutation induces tumor cells to escape inhibition by TKI treatment. An acquired gefitinib­resistant cell line (NCI­H1975/GR) was generated from the NCI­H1975 human NSCLC cell line, which harbors the sensitive L858R and resistant T790M mutations of EGFR. The resistant cell line was established by exposing the cells intermittently to increasing concentrations of gefitinib. The mechanisms by which NSCLC acquires resistance to TKIs based on the T790M mutation, were investigated by detecting the protein expression levels of the EGFR/Kirsten rat sarcoma viral oncogene homolog (KRAS)/v­Raf murine sarcoma viral oncogene homolog B (BRAF) transduction pathway, and epithelial­mesenchymal transition (EMT) with immunocytochemistry. The resistance of the NCI­H1975/GR cells to gefitinib was 2.009­fold, as compared with the parent cells; however, the protein expression levels of EGFR, KRAS and BRAF were lower in the resistant cells. Some mesenchymal morphology was observed in the NCI­H1975/GR cells, alongside a decreasing E­cadherin expression and increasing vimentin expression. These results suggest that the reactivation of the EGFR/KRAS/BRAF transduction pathway was not detected in the NCI­H1975/GR cells. EMT may have an important role in the development of acquired resistance to EGFR­TKIs in NSCLC cells with sensitivity and resistance mutations.

[The changes of p-Akt/MuRF1/FoxO1 proteins expressions in the conditions of training and immobilization in rats' gastrocnemius muscle].

This study was aimed to investigate the changes of muscle protein synthesis and degradation under different movement conditions, so as to provide theoretical basis for muscle atrophy mechanism. Sprague Dawley (SD) rats were randomly divided into control, endurance training (treadmill training), hind limb overhanging and eccentric training (treadmill training, angle -16º) groups. The gastrocnemius muscles of rats were taken and weighed. The muscle was sectioned, and HE staining was employed to determine the cell's cross-sectional area. Protein expression of p-Akt was measured by immunohistochemistry; and the expressions of MuRF1 and FoxO1 were determined by Western blot. The results showed that, compared with control group, hind limb overhanging and eccentric training groups exhibited decreased muscle weight and cross-sectional area, but endurance training group did not show any changes. The expressions of p-Akt in endurance and eccentric training groups, not in hind limb overhanging group, were significantly higher than that in control group. Compared with that of control, MuRF1 protein remained unchanged in endurance training groups, but was increased in eccentric training and hind limb overhanging groups; FoxO1 protein was decreased in endurance training group, but was increased in eccentric training and hind limb overhanging groups. These results indicate that movement (endurance and eccentric training) can activate Akt expression, but does not increase muscle weight, whereas eccentric training and hind limb overhanging can increase the expressions of MuRF1 and FoxO1, and induce amyotrophy, suggesting MuRF1 and FoxO1 are major determinant factors in muscle atrophy.

The reverse effect of X-ray irradiation on acquired gefitinib resistance in non-small cell lung cancer cell line NCI-H1975 in vitro.

The clinical efficacy of gefitinib in the treatment of non-small cell lung cancer (NSCLC) with mutations in exon 18, 19 or 21 of epidermal growth factor receptor (EGFR) is limited by the acquired resistance to the drug. To explore whether X-ray irradiation could reverse the acquired gefitinib resistance in NSCLC cell in vitro. We chose a human NSCLC cell line NCI-H1975 to establish acquired gefitinib-resistant cell line named as NCI-H1975/GR. NCI-H1975/GR was irradiated with X-ray and then named as NCI-H1975/GR/XR. In the three cell lines, subsequently cell growth curves and cell population doubling time were calculated by cell proliferation assay, the changes of cell viability were evaluated by trypan blue dye exclusion method and MTT assay, the cell cycle distribution and apoptosis were investigated by flow cytometry, the expressions of E-cadherin and vimentin used to indicate epithelial-mesenchymal transition (EMT) were determined by western blot analysis, the protein expressions in EGFR/KRAS/BRAF transduction pathway were detected by immunocytochemistry, and the mutations of EGFR, KRAS and BRAF were detected by high resolution melting analysis and direct sequencing. We found that the X-ray irradiation enhanced the growth inhibitory effects of gefitinib on the acquired gefitinib-resistant cell line. Of NCI-H1975/GR/XR following gefitinib treatment, the IC50 decreased significantly, the cell proportion of phase G0/G1 was slightly higher, and the apoptosis cell proportion was significantly higher than those of NCI-H1975/GR. In addition, the reversal of EMT being present in NCI-H1975/GR cells was likely appearing in NCI-H1975/GR/XR cells. These results indicated that the acquired gefitinib resistance could be reversed by X-ray irradiation in NSCLC cell line NCI-H1975 harboring both the L858R and T790M mutation in vitro.

Utility of BRAF protein overexpression in predicting the metastasis potential of papillary thyroid carcinoma.

V-raf murine sarcoma viral oncogene homolog B1 (BRAF) is a significant member of the MAPK pathway, the point mutation (V600E) of which is a common genetic event in papillary thyroid carcinoma (PTC). Investigators showed that the variations in BRAF expression levels were independent of the V600E mutation. These variations were involved in the pathogenesis of thyroid carcinomas. This study evaluated the feasibility of BRAF, proliferating cell nuclear antigen (PCNA) and hMSH2 as markers for the prediction of the metastatic potential of PTC. Using immunohistochemistry, the expression of BRAF, PCNA and hMSH2 proteins was studied in 70 PTC and 29 nodular goiter (NG) tissues. The results indicated that i) the positive rate of BRAF, PCNA and hMSH2 expression in PTCs was significantly higher than that in NGs (P=0.000, P=0.000 and P=0.003, respectively), ii) the positive rate of BRAF expression in the lymph node metastasis (LNM) group was significantly higher than that in the non-LNM group (P=0.019), iii) the age at diagnosis of PTC patients with LNM was significantly older compared to that without LNM (P=0.021) and iv) the positive rate of BRAF expression significantly correlated with that of PCNA and hMSH2 expression (P=0.000 and P=0.019, respectively). In conclusion, BRAF, PCNA and hMSH2 overexpression appeared to be molecular events of PTC carcinogenesis. Older patients with BRAF overexpression appear to be a high-risk group for PTC metastasis. Detection of BRAF expression is likely to aid in the prediction of the metastatic potential of the carcinoma.

Metabonomics study of liver cancer based on ultra performance liquid chromatography coupled to mass spectrometry with HILIC and RPLC separations.

In this study, urinary metabolites from liver cancer patients and healthy volunteers were studied by a metabonomic method based on ultra performance liquid chromatography coupled to mass spectrometry. Both hydrophilic interaction chromatography (HILIC) and reversed-phase liquid chromatography (RPLC) were used to separate the urinary metabolites. Principle component analysis (PCA) and partial least squares to latent structure-discriminant analysis (PLS-DA) models were built to separate the healthy volunteers from the liver cancer patients and to find compounds that are expressed in significantly different amounts between the two populations. 21 metabolite ions were considered as potential biomarkers according to the Variable importance in the Project (VIP) value and S-plot. Compared with RPLC, a more sensitive and stable response can be recorded in HILIC mode due to the high content of organic solvent used. Moreover, the liver cancer group and the healthy volunteers can be better separated based on the data from the HILIC separation, which indicates that HILIC is suitable for urinary metabonomic analysis. In HILIC mode, several polar compounds related to arginine and proline metabolism, alanine and aspartate metabolism, lysine degradation, nicotinate and nicotinamide metabolism were found to be significantly changed in the concentrations of the two different populations: healthy and cancer. In contrast, in RPLC mode, these changed compounds are related to fatty acids oxidation.

Differential impairment of spatial and nonspatial cognition in a mouse model of brain aging.

AIMS: Chronic exposure to d-galactose (D-Gal), which causes acceleration in aging and simulated symptoms of natural senescence, has been used as a reliable animal model of aging. However, the different influences of D-Gal on spatial and nonspatial cognition are as yet unclear. MAIN METHODS: In the present study, the object recognition test (ORT), object location test (OLT) and Y-maze test were carried out to assess the cognitive performance of mice after 8 weeks of chronic D-Gal exposure. The expression of oxidative-stress biomarkers in the prefrontal cortex (PFC) and caspase-3 in the hippocampus (HIP) were also determined. KEY FINDINGS: The results of the behavioral tests indicated that after chronic D-Gal exposure, the spatial memory of mice was seriously impaired, whereas nonspatial cognition remained intact. D-Gal exposure also induced more significant changes in malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activities in the HIP than in the PFC. Furthermore, chronic D-Gal exposure triggered more substantial caspase-3 overexpression in the HIP than in the PFC. SIGNIFICANCE: Together, these findings suggest the impairment of spatial, but not nonspatial, cognitive ability after chronic D-Gal exposure. The differential nature of this impairment might be due to the more substantial reduction of antioxidant enzyme activities and more severe neuronal apoptosis mediated by caspase-3 in the HIP. The present results also indicate that the HIP and HIP-dependent spatial cognition might be more susceptible to oxidative stress during senescence or other pathological processes.