Biomedical subjects

Lei Zhang

Publications and source records attributed to Lei Zhang.

At least 91 records · Page 5Linked to original sources

PubMed2006

An isoflavone metabolite reduces arterial stiffness and blood pressure in overweight men and postmenopausal women.

OBJECTIVES: Isoflavones reduce arterial stiffness, a predictor of cardiovascular events. Whether metabolites of isoflavones have similar bioactivity is unknown. The effect of supplemental trans-tetrahydrodaidzein (THD) a metabolite of daidzein on pulse wave velocity (PWV), a measure of arterial stiffness was tested in overweight men and postmenopausal women. METHODS: 25 subjects, 11 postmenopausal women, 14 men (age, 57 [7] years; body mass index, 30.3 [4.7]kg/m(2); mean [S.D.]) participated in a double-blind, randomized, cross-over trial of THD versus placebo. DESIGN: 2 weeks run-in followed by either THD 1g daily or placebo, each intervention 5 weeks. Aorta-femoral artery PWV, blood pressure and plasma lipids were measured after run-in, THD and placebo. RESULTS: PWV was significantly reduced (signifying diminished central arterial stiffness): medians (25th and 75th%), placebo 9.9 m/s (8.7, 11.1), THD 8.8m/s (7.9, 10.9); RM ANOVA P=0.023, with Tukey procedure P<0.05. Systolic blood pressure was significantly reduced: means (S.D.), placebo 125.6 (14.7), THD 121.3 (12.2)mmHg; Tukey P<0.05. Plasma cholesterol, triglyceride and LDL cholesterol did not differ significantly. Absorption of THD >80% substantially exceeded that of parent isoflavones. CONCLUSION: A metabolite normally formed after consumption of isoflavones (formononetin, daidezein), taken orally, reduced blood pressure and central arterial stiffness indicating reduced cardiovascular risk.

Arteries↗

PubMed2006

Distinct roles of CysLT1 and CysLT2 receptors in oxygen glucose deprivation-induced PC12 cell death.

Cysteinyl leukotrienes are involved in ischemic brain injury, and their receptors (CysLT(1) and CysLT(2)) have been cloned. To clarify which subtype mediates the ischemic neuronal injury, we performed permanent transfection to increase CysLT(1) and CysLT(2) receptor expressions in PC12 cells. Oxygen glucose deprivation (OGD)-induced cell death was detected by Hoechst 33258 and propidium iodide fluorescent staining as well as by flow cytometry. OGD induced late phase apoptosis mainly and necrosis minimally. Over-expression of CysLT(1) receptor decreased and over-expression of CysLT(2) receptor increased OGD-induced cell death. An agonist LTD(4) (10(-7)M) also induced apoptosis, especially in CysLT(2) receptor over-expressing cells. A selective CysLT(1) receptor antagonist montelukast did not affect OGD-induced apoptosis; while non-selective CysLT receptor antagonist Bay u9773 inhibited OGD-induced apoptosis, especially in CysLT(2) receptor over-expressing cells. Thus, CysLT(1) and CysLT(2) receptors play distinct roles in OGD-induced PC12 cell death; CysLT(1) attenuates while CysLT(2) facilitates the cell death.

Acetates↗

PubMed2006

Reduction of dopamine-related transcription factors Nurr1 and NGFI-B in the prefrontal cortex in schizophrenia and bipolar disorders.

Abnormal cortical and subcortical dopaminergic activities are among the most consistent neuropathological findings in schizophrenia. The molecular mechanisms remain unspecified. NGFI-B and Nurr1 are two closely related transcription factors involved in dopaminergic cell differentiation, maturation, and apoptosis. NGFI-B knockout mice show attenuated behavioral response to dopamine receptor agonists, whereas Nurr1 knockout disrupts midbrain dopaminergic neuron development. To further understand the role of Nurr1 and NGFI-B in schizophrenia and bipolar disorders, we measured Nurr1 and NGFI-B mRNA in the prefrontal cortex Brodmann's areas 9 (BA 9) and BA 46 by in situ hybridization, and the protein levels in BA 9 by Western blotting, of patients with schizophrenia, major depression, and bipolar disorders, and non-psychiatric control subjects (n=15 per group). NGFI-B mRNA (P<0.05) and protein (P<0.01) were significantly lower in patients with schizophrenia (BA 9), and NGFI-B mRNA was lower in bipolar disorder (BA 9 and BA 46) than in the controls. In the deep cortical layers of BA 46, Nurr1 mRNA was significantly (P<0.05) lower in patients with bipolar disorder and schizophrenia than in the controls. Nurr1 protein in BA 9 was significantly lower in major depression (P<0.05) and lower at a trend level in schizophrenia (P=0.056) than in the controls. These data show a deficient prefrontal NGFI-B and Nurr1 expression in schizophrenia and bipolar disorder. Further study may elucidate if and how these deficiencies could be associated with abnormal dopaminergic functions seen in both illnesses.

Adult↗

PubMed2006

Blood rheological properties are strongly related to the metabolic syndrome in middle-aged Chinese.

The current investigation sought to evaluate the relation between hemorheological properties and the metabolic syndrome. 1400 office workers aged 35 to 59 years were enrolled in this study. Waist circumference and blood pressure were determined. Plasma high-density lipoprotein (HDL cholesterol), triglyceride, fasting blood glucose, plasma insulin and whole blood viscosity (WBV) at a high-shear rate of 200 s(-1) were measured at the attendance. Metabolic syndrome was defined according to National Cholesterol Education Program (NCEP)/ATP III guidelines. The metabolic syndrome was identified in 18% of this sedentary population. Mean WBV was 4.71+/-0.56 mPa s. One-way ANOVA indicated WBV increased across subjects with 0-4 metabolic syndrome components (F=3.86, p<0.01). The highest vs. lowest quartiles of WBV occurred significantly more often among subjects as the number of metabolic syndrome components increased. Across five categories of the metabolic syndrome, the frequencies of the occurrence of the highest vs. lowest quartiles were: 0.40, 0.87, 1.31, 1.92, and 4.80, respectively, showing a significant correlation (R=0.817, p<0.05). Univariate logistic regression analysis showed that the prevalence of hyperviscosity was predicted positively by waist circumference (OR=1.018, 95% CI: 1.002-1.035, p<0.05) and negatively by HDL cholesterol (OR=0.295, 95% CI: 0.133-0.680, p<0.01), independently of age, sex, and smoking status. In summary, this study has shown that WBV is strongly related to the severity of the metabolic syndrome. We suggest that the hemorheological parameters could potentially be used as an additional indicator of the metabolic syndrome.

Adult↗

PubMed2006

Effects of angiotensin converting enzyme inhibitor, angiotensin II type I receptor blocker and their combination on postinfarcted ventricular remodeling in rats.

BACKGROUND: Transforming growth factor (TGF) beta(1)-Smads signal plays an important role in cardiac remodeling following myocardial infarction (MI). In addition, both angiotensin converting enzyme inhibitor (ACEI) and angiotensin II type I receptor blocker (ARB) can effectively prevent left ventricular remodeling. The current study focused on whether the combination of ACEI and ARB is more beneficial for preventing ventricular remodeling and whether Smad proteins mediate this beneficial effect. METHODS: MI was induced by ligating the left anterior descending coronary artery in rats. Twenty-four hours after ligation, the survived rats were randomly divided into five groups and treated for 8 weeks: placebo group, ACEI group (benazepril 10 mg.kg(-1).d(-1)), ARB group (irbesartan 50 mg.kg(-1).d(-1)), ACEI + ARB group (benazepril 10 mg.kg(-1).d(-1) + irbesartan 50 mg.kg(-1).d(-1)) and control group (sham-operated rats). After 8 weeks, we examined the following indexes: the ratio of ventricular weight to body weight (VW/BW), left ventricular end diastolic dimension (LVDd), ejection fraction (EF), fractional shortening (FS), ratio of E-wave to A-wave velocity, collagen of noninfarcted zone, the mRNA expression of TGFbeta(1), Smad 2, and Smad 3 by RT-PCR in noninfarcted zone, the protein expression of Smad 2 and Smad 3 in noninfarcted zone by Western blot. RESULTS: VW/BW significantly increased in the placebo groups compared with that in the control group (P < 0.01). This increase was limited in ACEI, ARB, and combined groups (P < 0.01 compared with placebo group). There was no significant difference among the three actively treated groups. Collagen was increased in placebo group (5.68 +/- 0.5)% compared with that in control group (P < 0.01). ACEI, ARB and combined treatment attenuated this increase of collagen [(4.3 +/- 0.5)%, (3.5 +/- 0.5)%, (3.2 +/- 0.4)%] in comparison with that in placebo group (P < 0.01 respectively). Combined treatment showed more significant effect on collagen deposition. EF and FS significantly decreased, LVDd and E/A significantly increased in placebo group compared with that in control group (P < 0.01 respectively). ACEI, ARB and combined treatment ameliorated these indexes (P < 0.01 compared with placebo group). The mRNA expression of TGFbeta(1), Smad 2, and Smad 3 (0.700 +/- 0.045, 0.959 +/- 0.037 and 0.850 +/- 0.051) increased in placebo group compared with that in control group (P < 0.01). ACEI, ARB and combined treatment normalized the increase (P < 0.01). Furthermore, ARB and combined treatment proved to be more effective in decreasing TGF beta(1) and Smad mRNA expression than ACEI treatment (P < 0.01). The expression of Smad 2 and Smad 3 protein increased in placebo group compared with that in control group (P < 0.01). ACEI, ARB and combined treatment normalized the increase (P < 0.01). Furthermore, ARB and combined treatment proved to be more effective than ACEI alone (P < 0.01). CONCLUSIONS: TGFbeta(1)-Smads signal activation is correlated with ventricular remodeling following MI. ACEI and ARB treatment prevents ventricular remodeling by inhibiting expression of Smad 2 and Smad 3. ARB and combined treatment are more effective than ACEI alone.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2006

Activation of 5-lipoxygenase after oxygen-glucose deprivation is partly mediated via NMDA receptor in rat cortical neurons.

5-Lipoxygenase (5-LOX) is the enzyme metabolizing arachidonic acid to produce pro-inflammatory leukotrienes. We have reported that 5-LOX is translocated to the nuclear envelope after ischemic-like injury in PC12 cells. In the present study, we determined whether 5-LOX is activated (translocation and production of leukotrienes) after oxygen-glucose deprivation (OGD) in primary rat cortical neurons; if so, whether this activation is mediated by NMDA receptor. After OGD, 5-LOX was translocated to the nuclear envelope as detected by immunoblotting, immunostaining and green fluorescent protein-5-LOX transfection. 5-LOX metabolites, cysteinyl-leukotrienes (CysLTs) but not leukotriene B4, in the culture media were increased 0.5-1.5 h after recovery. Similarly, NMDA (100 microm) also induced 5-LOX translocation, and increased the production of CysLTs during 0.5-1 h NMDA exposure. Both OGD and NMDA reduced neuron viability. NMDA receptor antagonist MK-801 inhibited almost all the responses to OGD and NMDA; whereas 5-LOX activating protein inhibitor MK-886 and 5-LOX inhibitor caffeic acid inhibited the reduction of neuron viability and the production of CysLTs, but did not affect 5-LOX translocation. From these results, we conclude that OGD can activate 5-LOX in primary rat cortical neurons, and that this activation may be partly mediated via activating NMDA receptor.

Active Transport, Cell Nucleus↗

PubMed2006

Fluorogold labeling of descending brain neurons in larval lamprey does not cause cell death.

In our previous double-labeling studies, the fluorescent anatomical tracers Fluorogold (FG) and Texas red dextran amine (TRDA) were used to demonstrate that descending brain neurons, approximately 80% of which are reticulospinal (RS) neurons, in spinal cord-transected larval lamprey regenerate their axons. However, the numbers of FG-labeled descending brain neurons decreased significantly with increasing recovery times, from 2 to 16 weeks. For some FG-labeled mammalian neurons, FG appears to degrade and/or be lost over time, while in other neurons this tracer can kill neurons. In the present study, these possibilities were examined in larval lamprey for FG-labeled descending brain neurons. As in our previous studies, FG was applied to the spinal cord at 40% body length (BL, relative distance from the head) to retrogradely labeled descending brain neurons, and after recovery times of 2, 8, or 16 weeks, HRP, a non-toxic retrograde tracer, was applied to the spinal cord at 20% BL to determine if the numbers of HRP-labeled neurons were reduced. At these three recovery times, the numbers of HRP-labeled descending brain neurons were not significantly different than the numbers of HRP-labeled neurons in control animals that were not labeled with FG. Furthermore, the size and morphology of cell bodies and dendritic trees were not noticeably different in descending brain neurons with and without FG. Thus, in larval lamprey, FG does not appear to kill these neurons, but some FG probably is degraded and/or lost from neurons with increasing recovery times.

Animals↗

PubMed2006

High-fat emulsion-induced rat model of nonalcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is emerging as a common medical problem. Nonalcoholic steatohepatitis (NASH) is the critical turning point at which NAFLD progresses to more advanced stages such as hepatic fibrosis, cirrhosis and even hepatocellular carcinoma. However, the study of the pathogenic or therapeutic factors involved in NASH has been hampered by the absence of a suitable experimental model. The aim of the present work was to establish a high-fat emulsion-induced rat model of NASH. Male Sprague-Dawley rats were fed a high-fat emulsion via gavage for 6 weeks. Animals were examined for weight gain, serum and hepatic biochemistry, insulin sensitivity, hepatic malondialdehyde (MDA), superoxide dismutase (SOD) and tissue morphology, as well as cytochrome P-450 2E1 (CYP2E1) and peroxisome proliferator-activated receptor alpha (PPARalpha) expression in the liver. The results showed that rats treated with high-fat emulsion became obese, demonstrated abnormal aminotransferase activity, hyperlipoidemia, hyperinsulinemia, hyperglycemia and insulin resistance. The model rats exhibited an increased concentration of serum TNF-alpha, total cholesterol (TC), triglyceride (TG), MDA and reduced SOD levels in the liver. Immunoblot analysis showed that the expression of CYP2E1 was increased, whereas PPARalpha was reduced in the NASH model rat liver. Moreover, morphological evaluation revealed that hepatic steatosis, inflammation and mitochondrial lesions were also reproduced in this model. In conclusion, a practical and repeatable new rat model of steatohepatitis was established by feeding with high-fat emulsion via gavage. This model provides a valuable research tool and reproduces many of the clinical indices of human NASH.

Animals↗

PubMed2006

Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo.

PURPOSE: Papillary thyroid carcinomas are associated with nonoverlapping activating mutations of RET, NTRK, RAS and BRAF, which altogether are present in approximately 70% of cases. We postulated that compounds that inhibit a distal effector in the mitogen-activated protein kinase (MAPK) pathway would inhibit growth and tumorigenicity of human thyroid cancer cell lines with mutations of RET or BRAF. EXPERIMENTAL DESIGN AND RESULTS: We first examined the effects of AAL-881 and LBT-613, two inhibitors of RAF kinase activity, on RAF-MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK activation in thyroid PCCL3 cells after conditional induction of expression of H-RAS(G12V) or BRAF(V600E). Both compounds blocked RAS and RAF-dependent MEK and ERK phosphorylation. They also potently blocked MEK phosphorylation in human thyroid cancer cell lines with either RET/PTC1 (TPC1) or BRAF(V600E) (NPA, ARO, and FRO) mutations. Inhibition of ERK phosphorylation was transient in TPC1 and ARO cells, with recovery of ERK phosphorylation associated with concomitant down-regulation of the MAPK phosphatases MKP-3 and DUSP5. Both compounds inhibited growth of all cell lines, with LBT-613 being approximately 10-fold more potent than AAL-881. TPC1 cells were more sensitive to growth inhibition (IC50 0.1-0.25 and approximately 0.05 micromol/L for AAL-881 and LBT-613, respectively) than BRAF + lines (IC50 2.5-5 and 0.1-0.5 micromol/L, respectively). Growth inhibition was associated with G1 arrest, and induction of cell death. Growth of ARO and NPA tumor xenografts was inhibited by LBT-613 or AAL-881. MEK and ERK phosphorylation was inhibited by both compounds in ARO but not in NPA cell xenografts. CONCLUSIONS: Compounds that inhibit kinase activity are effective growth inhibitors for poorly differentiated thyroid cancer cell lines with either RET or RAF mutations, and hold promise for treatment of most forms of papillary thyroid carcinoma.

Animals↗

PubMed2006

Preliminary study on health risk from mercury exposure to residents of Wujiazhan town on the Di'er Songhua river, Northeast China.

Mercury concentrations in hair are typically used as a biomarker to assess exposure to mercury. A total of 108 hair samples were collected from residents (age range 5-73 years) of Wujiazhan town, northeast China, to determine total mercury concentrations. Hair mercury concentrations ranged from 0.16 to 199 mg kg(-1) with an average value of 3.41 mg kg(-1). The relationships between mercury concentration and gender and between hair mercury concentration and age were not significant. Overall, 16.7% of all samples were above the RfD value published by the United States Environmental Protection agency. The results indicate that there may be some been health risk from mercury exposure to the residents in the study area.

Adolescent↗

PubMed2006

Short- and long-term regulation of adenylyl cyclase activity by delta-opioid receptor are mediated by Galphai2 in neuroblastoma N2A cells.

Activation of the opioid receptor results in short-term inhibition of intracellular cAMP levels followed by receptor desensitization and subsequent increase of cAMP above the control level (adenylyl cyclase superactivation). Using adenovirus to deliver pertussis toxin-insensitive mutants of the alpha-subunits of G(i/o) that are expressed in neuroblastoma Neuro2A cells (Galpha(i2), Galpha(i3), and Galpha(o)), we examined the identities of the G proteins involved in the short- and long-term action of the delta-opioid receptor (DOR). Pertussis toxin pretreatment completely abolished the ability of [d-Pen(2), d-Pen(5)]-enkephalin (DPDPE) to inhibit forskolin-stimulated intracellular cAMP production. Expression of the C352L mutant of Galpha(i2), and not the C351L mutants of Galpha(i3) or Galpha(o), rescued the short-term effect of DPDPE after pertussis toxin treatment. The ability of Galpha(i2) in mediating DOR inhibition of adenylyl cyclase activity was also reflected in the ability of Galpha(i2), not Galpha(i3) or Galpha(o), to coimmunoprecipitate with DOR. Coincidently, after long-term DPDPE treatment, pertussis toxin treatment eliminated the antagonist naloxone-induced superactivation of adenylyl cyclase activity. Again, only the C352L mutant of Galpha(i2) restored the adenylyl cyclase superactivation after pertussis toxin treatment. More importantly, the C352L mutant of Galpha(i2) remained associated with DOR after long-term agonist and pertussis toxin treatment whereas the wild-type Galpha(i2) did not. These data suggest that Galpha(i2) serves as the signaling molecule in both DOR-mediated short- and long-term regulation of adenylyl cyclase activity.

Adenoviridae↗

PubMed2006

Sol-gel template synthesis and photoluminescence of n- and p-type semiconductor oxide nanowires.

A sol-gel template technique has been put forward to synthesize single-crystalline semiconductor oxide nanowires, such as n-type SnO2 and p-type NiO. Scanning electron microscopy and transmission electron microscopy observations show that the oxide nanowires are single-crystal with average diameters in the range of 100-300 nm and lengths of over 10 microm. Photoluminescence (PL) spectra show a PL emission peak at 401 nm for n-type semiconductor SnO2, and a PL emission at 407 nm for p-type semiconductor NiO nanowires, respectively. Correspondingly, the observed violet-light emission at room temperature is attributed to near-band-edge emission for SnO2 nanowires and the 3d(7)4s-->3d8 transition of Ni2+ for NiO nanowires.

Journal Article↗

PubMed2006

Synthesis of variable-aspect-ratio, single-crystalline ZnO nanostructures.

Variable-aspect-ratio (length/diameter), one-dimensional (1-D) ZnO nanostructures (nanorods and nanowires) were prepared in alcohol/water solution by reacting a Zn2+ precursor with an organic weak base, tetramethylammonium hydroxide (Me4NOH). The effect of the experimental parameters (temperature, base concentration, reaction time, and water content) on nucleation, growth, and the final morphology of the ZnO nanostructures was investigated. The low-temperature syntheses (75-150 degrees C) yielded aspect ratios of the 1-D ZnO nanostructures that depended on the water content. The individual ZnO nanorods and nanowires were determined to be perfect, single crystals with their c axes as the primary growth direction.

Alcohols↗

PubMed2006

Adipocyte enhancer-binding protein 1 is a potential novel atherogenic factor involved in macrophage cholesterol homeostasis and inflammation.

Peroxisome proliferator-activated receptor gamma1 (PPARgamma1) and liver X receptor alpha (LXRalpha) play pivotal roles in macrophage cholesterol homeostasis and inflammation, key biological processes in atherogenesis. Herein we identify adipocyte enhancer-binding protein 1 (AEBP1) as a transcriptional repressor that impedes macrophage cholesterol efflux, promoting foam cell formation, via PPARgamma1 and LXRalpha down-regulation. Contrary to AEBP1 deficiency, AEBP1 overexpression in macrophages is accompanied by decreased expression of PPARgamma1, LXRalpha, and their target genes ATP-binding cassette A1, ATP-binding cassette G1, apolipoprotein E, and CD36, with concomitant elevation in IL-6, TNF-alpha, monocyte chemoattractant protein 1, and inducible NO synthase levels. AEBP1, but not the C-terminally truncated DNA-binding domain mutant (AEBP1DeltaSty), represses PPARgamma1 and LXRalpha in vitro. Expectedly, AEBP1-overexpressing transgenic (AEBP1TG) macrophages accumulate considerable amounts of lipids compared with AEBP1 nontransgenic macrophages, making them precursors for foam cells. Indeed, AEBP1-overexpressing transgenic macrophages exhibit diminished cholesterol efflux compared with AEBP1 nontransgenic macrophages, whereas AEBP1-knockout (AEBP1-/-) macrophages exhibit enhanced cholesterol efflux compared with wild-type (AEBP1+/+) macrophages. Our in vitro and ex vivo experimental data strongly suggest that AEBP1 plays critical regulatory roles in macrophage cholesterol homeostasis, foam cell formation, and proinflammation. Thereby, we speculate that AEBP1 may be critically implicated in the development of atherosclerosis, and it may serve as a molecular target toward developing antiinflammatory, antiatherogenic therapeutic approaches.

Animals↗

PubMed2006

A genetic model for muscle-eye-brain disease in mice lacking protein O-mannose 1,2-N-acetylglucosaminyltransferase (POMGnT1).

Protein O-mannose beta1,2-N-acetyglucosaminyltransferase 1 (POMGnT1) is an enzyme involved in the synthesis of O-mannosyl glycans. Mutations of POMGnT1 in humans result in the muscle-eye-brain (MEB) disease. In this study, we have characterized a null mutation generated by gene trapping with a retroviral vector inserted into the second exon of the mouse POMGnT1 locus. Expression of POMGnT1 mRNA was abolished in mutant mice. Glycosylation of alpha-dystroglycan was also reduced. POMGnT1 mutant mice were viable with multiple developmental defects in muscle, eye, and brain, similar to the phenotypes observed in human MEB disease. The present study provides the first genetic animal model to further dissect the roles of POMGnT1 in MEB disease.

Animals↗

PubMed2006

Possible role of potassium channel, big K in etiology of schizophrenia.

Schizophrenia (SZ), a common severe mental disorder, affecting about 1% of the world population. However, the etiology of SZ is still largely unknown. It is believed that molecules that are in an association with the etiology and pathology of SZ are neurotransmitters including dopamine, 5-HT and gamma-aminobutyric acid (GABA). But several lines of evidences indicate that potassium large conductance calcium-activated channel, known as BK channel, is likely to be included. BK channel belongs to a group of ion channels that plays an important role in regulating neuronal excitability and transmitter releasing. Its involvement in SZ emerges as a great interest. For example, commonly used neuroleptics, in clinical therapeutic concentrations, alter calcium-activated potassium conductance in central neurons. Diazoxide, a potassium channel opener/activator, showed a significant superiority over haloperidol alone in the treatment of positive and general psychopathology symptoms in SZ. Additionally, estrogen, which regulates the activity of BK channel, modulates dopaminergic D2 receptor and has an antipsychotic-like effect. Therefore, we hypothesize that BK channel may play a role in SZ and those agents, which can target either BK channel functions or its expression may contribute to the therapeutic actions of SZ treatment.

Animals↗

PubMed2006

Stress-induced change of mitochondria membrane potential regulated by genomic and non-genomic GR signaling: a possible mechanism for hippocampus atrophy in PTSD.

Posttraumatic stress disorder (PTSD) is a common psychiatric disorder often accompanied by morphologic changes in the hippocampus. Brain imaging studies have demonstrated a strong relationship between PTSD and a reduction in the volume of the hippocampus; however, the mechanisms that cause such atrophy are not well understood. In an attempt to expand our knowledge of these mechanisms, our theory has focused on the role of mitochondria in cell death, which may be associated with atrophy of the hippocampus. In addition to their function in respiration, mitochondria play an important role in the regulation of cytochrome c, an apoptotic signaling element. Normally, cytochrome c resides in the intermembrane space of mitochondria, where membrane potential exists-negative inside of about 180-200mV. In response to a variety of apoptotic stimuli, mitochondria membrane potential can be changed by genomic and non-genomic cortisol action. For the non-genomic action, stress increases cortisol levels, which activates the glucocorticoid receptor (GR). Stress-activated GR directly binds to mitochondrial membranes to regulate membrane potential. The GR will also produce a genomic action, in which GR, in interacting with several other molecules (such as heat shock proteins 90/70/40, etc.), translocates into the nucleus of the cell, where it binds to DNA and exerts transcriptional action. As one of the downstream modulaters of GR activation, Bax can be up regulated and translocated to the mitochondria, where it binds to modulator of apoptosis-1 (MAP-1), a mitochondrial effector of BAX to cause change Deltapsi. These non-genomic and genomic cortisol-induced changes of the mitochondrial membrane potential can result in the release of cytochrome c from the mitochondria to the cytoplasm where the cytochrome c promotes of the action of caspases which leads to apoptosis. Therefore, we hypothesis that stress-induced changes of mitochondrial membrane potential are regulated by non-genomic and genomic actions of cortisol in hippocampal neurons. Understanding the molecular mechanism for stress-induced cell death in the hippocampus may shed a new light on developing a mitochondrial membrane potential related therapeutic drug and/or diagnostic tool for PTSD.

Animals↗

PubMed2006

Citrate transporters play a critical role in aluminium-stimulated citrate efflux in rice bean (Vigna umbellata) roots.

BACKGROUND AND AIMS: Aluminium (Al) stimulates the efflux of citrate from apices of rice bean (Vigna umbellata) roots. This response is delayed at least 3 h when roots are exposed to 50 microm Al, indicating that some inducible processes leading to citrate efflux are involved. The physiological bases responsible for the delayed response were examined here. METHODS: The effects of several antagonists of anion channels and citrate carriers, and of the protein synthesis inhibitor, cycloheximide (CHM) on Al-stimulated citrate efflux and/or citrate content were examined by high-pressure liquid chromatography (HPLC) or an enzymatic method. KEY RESULTS: Both anion channel inhibitors and citrate carrier inhibitors can inhibit Al-stimulated citrate efflux, with anthracene-9-carboxylic acid (A-9-C, an anion channel inhibitor) and phenylisothiocyanate (PI, a citrate carrier inhibitor) the most effective inhibitors. A 6 h pulse of 50 microm Al induced a significant increase of citrate content in root apices and release of citrate. However, the increase in citrate content preceded the efflux. Furthermore, the release of citrate stimulated by the pulse treatment was inhibited by both A-9-C and PI, indicating the importance of the citrate carrier on the mitochondrial membrane and the anion channel on the plasma membrane for the Al-stimulated citrate efflux. CHM (20 microm) also significantly inhibited Al-stimulated citrate efflux, confirming that de novo protein synthesis is required for Al-stimulated citrate efflux. CONCLUSIONS: These results indicate that the activation of genes possibly encoding citrate transporters plays a critical role in Al-stimulated citrate efflux.

Aluminum↗