Ophiopogonin D Inhibiting Epithelial NF-κB Signaling Pathway Protects Against Experimental Colitis in Mice.

The sustained activation of the nuclear factor κB (NF-κB) signaling pathway has been observed in human inflammatory bowel disease (IBD). Ophiopogonin D (OP-D) is a small molecular compound isolated from Ophiopogon japonicus, a widely used herbal remedy. In this study, dextran sodium sulfate was used to make a mouse model of experimental colitis and verify the effect of OP-D on the mouse model of experimental colitis. Small molecule-protein molecular docking approaches were also used to discover the mechanisms underlying the OP-D-induced regulation of colitis. In colitis, the OP-D can inhibit the apoptosis of intestinal mucosa cells, restore the intestinal barrier, and alleviate inflammation. The molecular docking simulations showed that OP-D had a high affinity with the REL-homology domain of NF-κB-p65 that affected its translocation to the nucleus. In a cell study, the effects of OP-D on inflammation and barrier dysfunction were significantly decreased by a small interfering RNA targeting NF-κB-p65. Further, the LPS-induced increase in NF-κB-p65 in the nucleus was also significantly inhibited by OP-D. OP-D alleviated experimental colitis by inhibiting NF-κB. New insights into the pathogenesis and treatment options of colitis are provided through this study.

The Metabolome of Carbapenem-Resistant Klebsiella pneumoniae Infection in Plasma.

AIM: Carbapenem-resistant Klebsiella pneumoniae- (CR-Kp-) mediated infections represent a challenge for clinical practitioners due to their expanding prevalence in hospital environments and antibiotic resistance. However, few studies have shown metabolic changes of carbapenem-resistant Klebsiella pneumoniae and CR-Kp-negative patients, and relevant studies are urgently needed. METHODS: In this study, we comprehensively profile the metabolites of 20 CR-Kp-positive and 18 CR-Kp-negative patients in plasma by using 2D gas chromatography-time-of-flight mass spectrometry (GC×GC-TOFMS). RESULTS: We identified 58 metabolites that were carbapenem-resistant Klebsiella pneumoniae-associated. N-Acetyl glucosamine, butanedioic acid, and myoinositol play a significant character in CR-Kp infection. CONCLUSIONS: Our study provides valuable data to serve as potential targets for developing therapies against CR-Kp infection.

Interaction of Serum Copper and Neurometabolites on Executive Dysfunction in Unmedicated Patients With Major Depressive Disorder.

Objective: The mechanism of executive function (EF) impairment in major depressive disorder (MDD) remains unclear. Previous studies have demonstrated that altered serum copper levels and neurometabolic alterations may be associated with the psychopathology and cognitive impairment of MDD. While, their inter-relationships in MDD remain uncertain. The present study aims to assess whether the interaction between serum copper levels and neurometabolic alterations is involved in the deficit of executive function (EF) in patients with unmedicated MDD. Methods: Serum copper levels and EFs were measured in 41 MDD patients and 50 control subjects. EFs were evaluated by Trail Making Test, Part-B (TMT-B), Digit Symbol Substitution Test (DSST), Wisconsin Card Sorting Task (WCST), and Semantic Verbal Fluency testing (SVFT). Additionally, 41 patients and 41 healthy controls underwent proton magnetic resonance spectroscopy (1H-MRS) to obtain ratios of N-acetyl aspartate to creatine (NAA/Cr) and choline-containing compounds to creatine (Cho/Cr) in the lenticular nucleus (LN) of basal ganglia (BG). Finally, association and interaction analysis were conducted to investigate their inter-relationships. Results: The results showed that patients performed worse in the DSST, WCST, TMT-B time and SVFT. Moreover, patients had higher serum copper levels, but lower NAA/Cr ratios in left LN of BG than healthy controls. In patients, serum copper levels were found to significantly negative associated with Categories Completed (CC) number of WCST (r = -0.408, p = 0.008), and positive associated with the Total Errors (TE) and Nonperseverative Errors (PE) number of WCST (r = 0.356, p = 0.023; r = -0.356, p = 0.022). In addition, the NAA/Cr ratios of left LN were found to significantly negative associated with VFS (r = -0.401, p = 0.009), as well as negative associated with serum copper levels (r = -0.365, p = 0.019). Finally, the interaction between copper and NAA may as influencing factors for SVFT and CC number of WCST in patients. Conclusion: Our results indicated that the interaction of abnormal copper levels and NAA/Cr neurometabolic disruption of the LN may impact executive dysfunction, and this may relevant to the pathophysiology of executive impairment in MDD patients.

The characteristic of cognitive impairments in patients with bipolar II depression and its association with N-acetyl aspartate of the prefrontal white matter.

BACKGROUND: Cognitive deficit is acknowledged as a core feature of clinical manifestations of bipolar disorder (BD). However, the underlying mechanism of cognitive impairment in bipolar II depression has remained uncertain. We aim to determine the association of cognitive impairments with biochemical metabolism using proton magnetic resonance spectroscopy (1H-MRS) and a battery of neuropsychological testing. METHODS: The current study was designed to assess four cognitive domains in a sample of 110 patients with bipolar II depression and 110 healthy controls, using a battery of 6 cognitive tests, including the Digit Symbol Substitution Test (DSST), Wisconsin Cart Sorting Test (WCST), Trail Making Test Part B (TMT-B), Digit Span Test (DST), TMT-part A (TMT-A) and Verbal Fluency Test (VFT). Metabolite levels were obtained in the following brain regions of interest: bilateral prefrontal white matter (PWM), bilateral anterior cingulate cortex (ACC), bilateral lenticular nucleus (LN), and bilateral thalamus. N-acetyl aspartate (NAA)/creatine (Cr) and choline-containing compounds (Cho)/Cr ratios are analyzed. RESULTS: Patients with bipolar II depression performed significantly worse on DSST (score), TMT (completion time), DSB (score), and VFT (valid word number) when compared with healthy controls. In the bilateral PWM, NAA/Cr ratios in the PWM were significantly reduced (bilaterally) than those in healthy controls. Correlation analysis was conducted with data from patients with bipolar II depression, we found that the NAA/Cr ratio of the left PWM was positively correlated with the score of DS and DSB, and the NAA/Cr ratio of the right PWM was negatively correlated with the completion time of TMT-B. CONCLUSIONS: Our findings suggested that psychomotor speed, executive function, working memory, and verbal fluency are impaired in patients with BD II depression. Hypoactivity NAA/Cr in bilateral PWM may be associated with BD II depression's pathophysiology and results in cognitive dysfunction.

Alleviation of cognitive deficits and high copper levels by an NMDA receptor antagonist in a rat depression model.

BACKGROUND: Major depressive disorder (MDD) is frequently associated with cognitive deficits and high copper levels. Dysfunction of N-methyl-d-aspartate (NMDA) receptors has been postulated to underlie MDD pathogenesis. This study sought to investigate the curative effect of the NMDA receptor antagonist memantine on cognitive deficits in depression and the underlying mechanisms. METHODS: Adult male Sprague-Dawley rats received corticosterone (CORT) (20 mg/kg) bi-weekly via subcutaneous injection and/or copper gluconate (7 mg/kg) via daily intragastric administration. After 3 weeks, sucrose preference tests and open field tests showed anhedonia and high anxiety in both the CORT and CORT+Cu groups. Memantine intervention (20 mg/kg daily via intragastric administration for 14 days) led to recovery of anhedonia and anxiety behaviors. Memantine also remarkably suppressed serum copper ion levels. Moreover, memantine treatment effectively rescued depression-related spatial memory deficits as shown by the Morris water maze task. RESULTS: Compared to the pre-memantine treatment results, the results of behavioral tests and cognitive function after memantine treatment were significantly normalized, and the copper concentration was decreased in all groups. CONCLUSIONS: Collectively, our findings suggest that the NMDA receptor antagonist memantine may improve symptoms of anhedonia and anxiety and the cognitive deficits associated with depression, likely be related to suppress serum copper ion levels.

Effect of Temperature on the Composition of a Synthetic Hydrocarbon Aviation Lubricating Oil.

Synthetic hydrocarbon aviation lubricating oils (SHALOs) gradually degrade over time when subjected to high temperatures, resulting in their composition and properties varying over the operation lifetime. Therefore, understanding the SHALO degradation properties by elucidating the mechanism on a molecular level, as a function of high temperature, is of interest. A SHALO was subjected to thermal treatment (TT) at 180, 200, 230, 250, 270, or 300 °C for 2 h. The chemical compositions of six TT samples and one fresh oil were analyzed by fourier transform infrared F spectroscopy, advanced polymer chromatography, and gas chromatography/mass spectrometry. Furthermore, the physicochemical properties, such as kinematic viscosity, pour point, and acid number, of seven samples were determined. The oil samples were grouped by cluster analysis (CA) using a statistical method. The SHALO was identified to comprise 20 functional groups, including comb-like alkanes, long-chain diesters, amines, phenols, and other compounds. TT at <230 °C caused partial cracking of the SHALO base oils, with a concomitant change in the antioxidant content and type, and the polycondensation reactions were dominant. The observed antioxidant changes were not obvious from TT at >230 °C. A large number of small-molecule compounds were detected, including n-alkanes and olefins. TT at 250 °C was shown to be an important threshold for the kinematic viscosity, pour point, and acid number of the samples. Below 250 °C, the sample properties were relatively stable; but at elevated TT temperatures (>250 °C), the properties were observed to dramatically degrade. As the sample color was highly sensitive to temperature, the TT temperature induced rapid and significant color changes. The CA analysis results for the oil compounds at the molecular level were in good agreement with observed changes in the physicochemical properties at the macro level.

Inhibition of lung cancer cells and Ras/Raf/MEK/ERK signal transduction by ectonucleoside triphosphate phosphohydrolase-7 (ENTPD7).

BACKGROUND: The aim of this study was to investigate the effects and mechanisms of ectonucleoside triphosphate phosphohydrolase-7 (ENTPD7) on lung cancer cells. METHODS: The expression characteristics of ENTPD7 and its effect on the survival of lung cancer patients were analyzed by referring to The Cancer Genome Atlas (TCGA). Streptavidin-peroxidase (SP) staining was performed to detect the ENTPD7 protein in tumor tissues and adjacent tissues. Plasmid transfection technology was also applied to silence ENTPD7 gene. Crystal violet staining and flow cytometry were performed to determine cell proliferation and apoptosis. Tumor-bearing nude mice model was established to investigate the effect of sh-ENTPD7 on tumors. RESULTS: The results showed that patients with low levels of ENTPD7 had higher survival rates. ENTPD7 was up-regulated in lung cancer tissues and cells. Down-regulation of the expression of ENTPD7 inhibited proliferation but promoted apoptosis of lung cancer cell. Silencing ENTPD7 also inhibited the expression levels of Ras and Raf proteins and the phosphorylation of mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK). Tumor-bearing nude mice experiments showed that silencing ENTPD7 had an inhibitory effect on lung cancer cells. CONCLUSIONS: ENTPD7 was overexpressed in lung cancer cells. Down-regulating ENTPD7 could inhibit lung cancer cell proliferation and promote apoptosis via inhibiting the Ras/Raf/MEK/ERK pathway.

Similar profiles of cognitive domain deficits between medication-naïve patients with bipolar II depression and those with major depressive disorder.

BACKGROUND: Bipolar disorder (BD) II is more likely to be misdiagnosed as major depressive disorder (MDD) than other types of BD, leading to incorrect treatment and poor outcomes. Previous studies have shown inconsistent results regarding the differences in cognitive deficits between the two disorders. To eliminate the compounding effects of medication and aging, we sought to investigate changes in cognitive function in medication-naïve, non-late-life patients with BDII and MDD. METHODS: Three subject groups were enrolled: 30 depressed BDII patients, 30 depressed MDD patients and 30 healthy controls. All subjects underwent a battery of cognitive tests to assess 8 cognitive domains. The cognitive domains were compared between the three subject groups. In BDII and MDD, the effect sizes were computed as evaluation parameters, weighing the degree of the cognitive deficits and the correlations between cognitive test deficits and clinical variables were also computed. RESULTS: Compared with the controls, the BDII and MDD patients were characterized by similar deficits in psychomotor speed, working memory, visual memory, attention switching and verbal fluency. Moderate to severe deficits in the majority of cognitive tests were observed in the BDII and MDD patients. Furthermore, correlations between the modified Wisconsin Card Sorting Test total errors and age of onset in the BDII patients and between correct digit span responses (backward and total) and depressive severity were found in the MDD patients. CONCLUSIONS: Our findings suggest that BDII and MDD patients may suffer from similar profiles of cognitive domain deficits that may not assist in distinguishing between the two disorders. In addition, cognitive deficits may be correlated with the age of onset and depressive severity in mood disorders.

Synthesis and Evaluation of 1,5-Dithia-d-laminaribiose, Triose, and Tetraose as Truncated ß-(1→3)-Glucan Mimetics.

The preparation and characterization of a series of di-, tri-, and tetrasaccharide analogues of ß-(1→3)-glucans is described in which each pyranoside ring is replaced by a 5-thiopyranosyl ring and each glycosidic oxygen by a thioether. These oligomeric 1,5-dithio-d-glucopyranose derivatives were shown to inhibit the staining of human neutrophils and of mouse macrophages by fluorescent anti-CR3 and anti-Dectin-1 antibodies, respectively. The compounds were also demonstrated to stimulate phagocytosis and pinocytosis indicative of binding to the carbohydrate binding domains of complement receptor 3 (CR3) and Dectin-1. Activity in all three assays was optimum at the level of the trisaccharide mimic, suggesting that, while the replacement of ethereal oxygens by thioethers results in a greater affinity for the aromatic lined hydrophobic binding pockets, the presence of multiple longer C-S bonds eventually results in a mismatch and a loss of affinity.

Associations between executive function impairment and biochemical abnormalities in bipolar disorder with suicidal ideation.

BACKGROUND: Executive dysfunction and biochemical abnormalities using proton magnetic resonance spectroscopy (1H-MRS) have been reported in bipolar disorder (BD). Much less is known about the information from BD with suicidal ideation (SI). This study aimed to assess alterations of execution function and biochemical metabolism in BD with SI, in BD without SI, and in healthy controls. The associations between execution function and biochemical metabolism in the two BD patient groups were also been studied. METHODS: 92 patients with bipolar disorder during a depressive episode (50 with current SI, and 42 without SI), as well as, 43 healthy controls were recruited in our study. Executive function was assessed by Wisconsin Card Sorting Test (WCST). Bilateral metabolite levels of prefrontal cortex (PFC), anterior cingulated cortex (ACC), lenticular nucleus (LN) of basal ganglia and thalamus were obtained by 1H-MRS at 3.0 T, then determined the ratios of N-acetyl aspartate (NAA), choline-containing compounds (Cho), myo-inositol (mI) to creatine (Cr). RESULTS: Number of categories completed (CC) in BD with SI was significantly less than healthy controls. NAA/Cr ratios of left PFC in the two BD patient groups (with or without SI) were significantly lower than healthy controls, and NAA/Cr ratios of left thalamus were significantly higher than healthy controls. Moreover, NAA/Cr ratio of right LN in BD without SI was higher than BD with SI and healthy controls. For BD with SI, NAA/Cr ratio of left thalamus was negatively correlated with number of CC. CONCLUSIONS: These results suggested that BD with or without SI may have abnormal NAA metabolism, and NAA/Cr ratio of right LN may distinguish SI from the BD patients. Further, BD with SI may have executive function impairment, which may be associated with the abnormal NAA metabolism in the left thalamus.

Biochemical abnormalities in basal ganglia and executive dysfunction in acute- and euthymic-episode patients with bipolar disorder: A proton magnetic resonance spectroscopy study.

BACKGROUND: Recent studies found abnormal biochemical metabolism and executive cognitive deficits in acute bipolar disorder (BD). However, the evidence concerning in euthymic BD is limited. Thus, a comparison between acute and euthymic BD is conductive to better understanding the association between cognition and the outcome of neuroimaging. This study sought to investigate the relationship between the executive function and the biochemical metabolism in acute- and euthymic-episode BD patients and delineate the prominent endophenotype of BD. METHODS: Three groups of participants were recruited in this study: 30 BD patients with an acute depressive episode, 22 euthymic BD patients, and 31 healthy controls. All participants were interviewed using the Structured Clinical Interview for DSM-IV, and underwent two-dimensional multivoxel proton magnetic resonance spectroscopy (1H-MRS) to obtain the bilateral metabolite levels in the lenticular nucleus of basal ganglia(BG). The ratios of N-acetylaspartate (NAA)/creatine (Cr) and Choline-containing compounds (Cho) /Cr ratios were calculated. Executive function was assessed by using the Wisconsin Card Sorting Test (WCST) and Trail Making Test, Part-B(TMT-B). RESULTS: The comparison of biochemical changes showed that the NAA/Cr ratios in bilateral lenticular nucleus in both acute and euthymic BD patients was significantly lower than that in healthy controls at a confidence level of p<0.05. In the comparison of executive function, both acute and euthymic BD patients showed significantly decreased numbers of categories completed, and increased numbers of total errors, perseverative and noperseverative errors, and TMT-B uptake compared to the healthy controls at a confidence level of p<0.05. There were no significant differences between the acute BD and euthymic BD groups in the biochemical metabolite ratios and executive function. We found that the NAA/Cr ratio in the left in BG in the acute -episode BD patients was positively correlated with the number of categories completed, whereas it was negatively correlated with the total errors and TMT-B uptake. There was no correlation between the NAA/Cr and Cho/Cr ratios in the bilateral BG and the scores of SWCT and TMT-B in euthymic-episode BD patients. LIMITATION: The sample size was relatively small and not all the euthymic-episode patients are the ones with an acute episode. CONCLUSIONS: Our findings suggest that biochemical abnormalities in the lenticular nucleus and the executive dysfunction may occur early in the course of BD, and persist during remission, and are the most likely markers of endophenotypes of BD. The dysfunction of the neuronal function in the lenticular nucleus may be correlated with the cold dysfunction in patients with acute BD.

A comparison of neurometabolites between remitted bipolar disorder and depressed bipolar disorder: A proton magnetic resonance spectroscopy study.

BACKGROUND: Recent many studies found the abnormal neurometabolites in the acute bipolar disorder (BD). However, limited studies were to detect neurometabolites in remitted BD, comparison between acute and remitted BD is conductive to understand the outcome of neurometabolites. This study sought to investigate the differences in neurometabolites between remitted and depressed BD patients using proton magnetic resonance spectroscopy (1H-MRS). METHODS: Three subject groups were enrolled: 22 remitted BD patients, 22 depressed BD patients and 24 healthy controls. All subjects underwent 1H-MRS to measure N-acetylaspartate (NAA), Choline (Cho), myo-Inositol (mI) and Creatine (Cr) of several bilateral areas potentially involved in BD: prefrontal whiter matter (PWM), thalamus and putamen. The neurometabolite ratios were compared among three groups. The correlations between abnormal neurometabolite ratios and clinical data were computed. RESULTS: The lower bilateral PWM NAA/Cr ratios were found in depressed BD patients than remitted BD patients and healthy controls, no differences were found between the remitted BD patients and controls. For depressed BD patients, left PWM NAA/Cr ratios showed negative correlation with age of onset, right PWM NAA/Cr ratios showed positive correlation with duration of illness. CONCLUSIONS: Our findings suggest the abnormal neurometabolites in the prefrontal lobe whiter may occur in the depressed BD. The remitted BD may resemble healthy subjects in terms of neurometabolites. In addition, abnormal neurometabolites in prefrontal lobe whiter may correlate with the age of onset and illness length.

A Meta-Analysis of Oxidative Stress Markers in Depression.

OBJECT: Studies have suggested that depression was accompanied by oxidative stress dysregulation, including abnormal total antioxidant capacity (TAC), antioxidants, free radicals, oxidative damage and autoimmune response products. This meta-analysis aims to analyse the clinical data quantitatively by comparing the oxidative stress markers between depressed patients and healthy controls. METHODS: A search was conducted to collect the studies that measured the oxidative stress markers in depressed patients. Studies were searched in Embase, Medline, PsychINFO, Science direct, CBMDisc, CNKI and VIP from 1990 to May 2015. Data were subjected to meta-analysis by using a random effects model for examining the effect sizes of the results. Bias assessments, heterogeneity assessments and sensitivity analyses were also conducted. RESULTS: 115 articles met the inclusion criteria. Lower TAC was noted in acute episodes (AEs) of depressed patients (p<0.05). Antioxidants, including serum paraoxonase, uric acid, albumin, high-density lipoprotein cholesterol and zinc levels were lower than controls (p<0.05); the serum uric acid, albumin and vitamin C levels were increased after antidepressant therapy (p<0.05). Oxidative damage products, including red blood cell (RBC) malondialdehyde (MDA), serum MDA and 8-F2-isoprostanes levels were higher than controls (p<0.05). After antidepressant medication, RBC and serum MDA levels were decreased (p<0.05). Moreover, serum peroxide in free radicals levels were higher than controls (p<0.05). There were no differences between the depressed patients and controls for other oxidative stress markers. CONCLUSION: This meta-analysis supports the facts that the serum TAC, paraoxonase and antioxidant levels are lower, and the serum free radical and oxidative damage product levels are higher than controls in depressed patients. Meanwhile, the antioxidant levels are increased and the oxidative damage product levels are decreased after antidepressant medication. The pathophysiological relationships between oxidative stress and depression, and the potential benefits of antioxidant supplementation deserve further research.

The correlation between biochemical abnormalities in frontal white matter, hippocampus and serum thyroid hormone levels in first-episode patients with major depressive disorder.

BACKGROUND: Previous neuroimaging studies found evidence of potential brain biochemical abnormalities in patients with major depressive disorder (MDD). Abnormal serum thyroid hormone levels were also found in MDD patients, which may correlated with the abnormal biochemical metabolism of brain. However, they rarely excluded the compounding effects of medication, and brain degeneration. This study sought to investigate the relationship between the biochemical metabolism and the serum thyroid hormone levels in first-episode, treatment-naive, non-late-life patients with MDD. METHODS: 26 first-episode, treatment-naive, non-late-life patients with MDD and 13 healthy controls were enrolled in this study. Participants underwent two-dimensinal multivoxel proton magnetic resonance spectroscopy ((1)H MRS) [repetition time (TR)=1000ms; echo-time (TE)=144ms] at 1.5T to obtain bilateral metabolite levels from the white matter in prefrontal (WMP) lobe, anterior cingulate cortex (ACC), and hippocampus. The ratios of N-acetylaspartate (NAA)/creatine (Cr) and choline containg compounds (Cho)/creatine (Cr) were calculated. Morning serum free triiodothyronine (FT3), free thyroxin (FT4), total triiodothyronine (T3), total thyroxin (T4), and thyroid-stimulating hormone (TSH) were measured before antidepressant treatment. RESULTS: On the comparison of brain biochemical changes, MDD patients had a significantly lower NAA/Cr ratio in the left WMP, and lower NAA/Cr and Cho/Cr ratios in the right WMP when compared to the controls. There were no significant differences in the metabolite ratios in the bilateral ACC, and hippocampus. On the comparison of serum thyroid hormone levels, MDD patients had a significantly decreased T3 and TSH levels. On the comparison of correlation of brain biochemical changes and serum thyroid hormone levels in patients with MDD, the NAA/Cr ratio in the right WMP was positively correlated with the level of TSH. CONCLUSION: These findings suggest that biochemical abnormalities and thyroid dysfunction may emerge early in the course of MDD. Dysfunction of neuronal function in the WMP may correlate with the abnormal TSH in patients with MDD, which may be related to the neuropathology of depression.