Effects of melatonin on spinal cord injury-induced oxidative damage in mice testis.

This study evaluated the effects of melatonin on spinal cord injury (SCI)-induced oxidative damage in testes. Adult male C57BL/6 mice were randomly divided into sham-, SCI- or melatonin (10 mg/kg, i.p.)-treated SCI groups. To induce SCI, a standard weight-drop method that induced a contusion injury at T10 was used. After 1 week, testicular blood flow velocity was measured using the Laser Doppler Line Scanner. Malondialdehyde (MDA), glutathione (GSH), oxidised glutathione (GSSG) and myeloperoxidase (MPO) were measured in testis homogenates. Microvascular permeability of the testes to Evan's Blue was examined by spectrophotometric and fluorescence microscopic quantitation. The tight junction protein zonula occludens-1 (ZO-1) and occludin in testes were assessed by immunoblot analysis. Melatonin increased the reduced blood flow and decreased SCI-induced permeability of capillaries. MDA levels and MPO activity were elevated in the SCI group compared with shams, which was reversed by melatonin. In contrast, SCI-induced reductions in GSH/GSSG ratio were restored by melatonin. Decreased expression of ZO-1 and occludin was observed, which was attenuated by melatonin. Overall, melatonin treatment protects the testes against oxidative stress damage caused by SCI.

Antipsychotic Medication Risk of Dementia and Death: A Propensity Matched Cohort Study.

OBJECTIVE: This study aimed to compare the incidence of dementia and all-cause mortality up to 20 years post-treatment in an index non-demented cohort between antipsychotic (AP) medication treatment and non-AP treatment groups. METHODS: All patients in Kaiser Permanente Northern California with a major psychiatric diagnosis between 01/01/1996 and 12/31/2000, age ≥ 50 years, and without dementia diagnosis were included. The study cohort was divided into a "user group", patients treated with AP for ≥ 365 days (n = 1,829), and a "non-user group", propensity score-matched on age, sex, and race (n = 9,145). The association between AP exposure and dementia or mortality during the follow-up period (01/01/2001-12/31/2015) was evaluated using Cox proportional hazard models adjusted for psychiatric diagnosis, comorbidities, and other medications. RESULTS: The user group had a hazard ratio (HR) of 2.2 (CI 1.8-2.7) for dementia and 1.3 (CI 1.2- 1.5) for death. The onset of dementia in the user group was significantly higher in patients aged ≤ 65 years (p < 0.001). The user group was sub-grouped into atypical, typical, and both; HR for dementia was 1.7 (CI 1.2-2.4), 2.5 (CI 1.9-3.1), and 1.8 (CI 1.4-2.4), respectively. Dementia and mortality were significantly higher in patients concurrently treated with benzodiazepine (HR 1.3; CI 1.2-1.5 and HR 1.4; CI 1.3-1.5) or tricyclic antidepressants (HR 1.2; CI 1.1-1.4 and HR 1.1; CI 1.0-1.2), respectively. CONCLUSION: Our preliminary results reveal an association between AP treatment and increased rates of both dementia and mortality. Future research is needed to substantiate our current findings.

Early brain response to low-dose radiation exposure involves molecular networks and pathways associated with cognitive functions, advanced aging and Alzheimer's disease.

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy and environmental nuclear contamination as well as for Earth-orbit and space missions. Analyses of transcriptome profiles of mouse brain tissue after whole-body irradiation showed that low-dose exposures (10 cGy) induced genes not affected by high-dose radiation (2 Gy) and that low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues and pathways that were specific for brain tissue. Low-dose genes clustered into a saturated network (P < 10(-53)) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified nine neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose irradiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down-regulated in normal human aging and Alzheimer's disease.

The antioxidant butylated hydroxytoluene prevents early cholesterol-induced microcirculatory changes in rabbits.

Microcirculation was studied during 10 wk in untreated rabbits (n = 13) and in rabbits treated with dietary addition of 1% cholesterol (n = 13), 1% cholesterol + 1% of the antioxidant BHT (butylated hydroxytoluene) (n = 11), or 1% BHT (n = 5). The studies were performed by direct intravital microscopic imaging of the left and right conjunctivae with the use of a stereo microscope and a high resolution television camera. Microvessel diameter, erythrocyte flow velocity, and microhemorheologic conditions were evaluated quantitatively via a computer-assisted digital image processing system. Significant and marked changes occurred in all the above variables as a consequence of cholesterol feeding. After 3 wk of feeding there was a dramatic decrease (approximately 30%) in blood flow velocity in arterioli of the third order (P < 0.0001), accompanied by aggregation of cells in 40-50% of the smaller conjunctival vessels (P < 0.0001). These changes were enhanced further during the following 7 wk of treatment. All the above changes in the microcirculation were markedly reduced by the addition of BHT treatment. The diameter of the above arterioli decreased in the purely cholesterol-fed group (P < 0.005), whereas this did not occur in the group fed both cholesterol and BHT. In rabbits fed BHT in the absence of cholesterol, there was no significant effect on any assessed microcirculatory variable. In conclusion, the results demonstrate that the antioxidant BHT prevented early cholesterol-induced microcirculatory changes. This prevention occurred in the absence of a reduction of blood lipid levels. The results provide strong support for the hypothesis that a considerable part of the effects on microcirculation in hypercholesterolemia may be due to cholesterol-induced oxidations and not to cholesterol itself. The results are discussed in relation to the previously demonstrated antiatherogenic effect of BHT and the possible use of antioxidants in the therapy and prophylaxis of atherosclerosis.

The expression of Troponin T1 gene is induced by ketamine in adult mouse brain.

The glutamatergic system has been implicated in neuropsychiatric disorders, such as schizophrenia, bipolar disorder and Alzheimer's disease, which also have a high prevalence of metabolic syndrome. Treatment with ketamine, a non-competitive glutamate N-methyl-d-aspartic acid (NMDA) receptor antagonist, is known to have paradoxical effects of neuroprotection and neurotoxicity. We investigated gene expression in brain tissue of adult mice treated with ketamine to characterize the expression profiles and to identify the affected metabolic pathways. Adult male mice were treated by a single intraperitoneal (i.p.) injection of either s(+)ketamine (80 mg/kg) or distilled water (as the control). Fifty genes were differentially expressed in ketamine-treated mouse brains compared with control mice using oligonucleotide microarray analysis, and the expression of Troponin T1 (Tnnt1) gene was consistently elevated (2- to 4-fold) (p<0.001). Ketamine-induced Tnnt1 expression was confirmed and characterized using RNA in situ hybridization techniques in paraffin embedded brain tissue sections. Tnnt1 expression was induced in the granule layer of the hippocampus, amygdala, hypothalamus, Purkinje cells of cerebellum (p<0.0001), and cerebral cortex. Tnnt1 gene is known to interact directly with FoxO1, which is involved in multiple peripheral metabolic pathways and central energy homeostasis. Our findings suggest that the induction of Tnnt1 gene expression in adult mouse brains by ketamine may illustrate the genes involved in the metabolic syndromes observed in neuropsychiatric disorders.

NOVP chemotherapy for Hodgkin's disease transiently induces sperm aneuploidies associated with the major clinical aneuploidy syndromes involving chromosomes X, Y, 18, and 21.

The objective of this research was to determine whether Novantrone, Oncovin, Velban, and Prednisone (NOVP) combination chemotherapy for Hodgkin's disease increases the frequencies of the specific types of aneuploid sperm that might elevate the risk of fathering a child with one of the major clinical aneuploidy syndromes, i.e., Down (disomy 21 sperm), Edward (disomy 18 sperm), Turner (nullisomy sex sperm), XYY (disomy Y sperm), triple X (disomy X sperm), or Klinefelter (XY sperm). A four-chromosome multicolor sperm fluorescence in-situ hybridization assay that simultaneously evaluates chromosomes 18, 21, X, and Y was applied to semen provided by four healthy men and to repeated samples of eight Hodgkin's disease patients before treatment, 35-50 days after treatment to examine the effects of treatment on male meiotic cells, and 1-2 years after treatment to measure the persistence of damage. There were chromosome-specific variations in baseline frequencies and significant inductions of all of the detectable types of sperm aneuploidies: XY sperm (14-fold increase), disomy 18 (7-fold), nullisomy sex (3-fold), disomy 21 (3-fold), and disomy X and Y (approximately 2-fold each). Disomy 21 was about twice as frequent as disomy 18, and neither showed a preferential segregation with a sex chromosome. Extrapolating across the genome, approximately 18% of sperm carried a numerical abnormality after NOVP treatment of meiotic cells. Induced effects did not persist to 1-2 years after treatment, suggesting that persistent spermatogonial stem cells were not sensitive to NOVP. These findings establish the hypothesis that conception shortly after certain chemotherapies can transiently increase the risks of fathering aneuploid pregnancies that terminate during development or result in the birth of children with major human aneuploidy syndromes.

Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters.

Deregulation of the MYC oncogene produces Myc protein that regulates multiple aspects of cancer cell metabolism, contributing to the acquisition of building blocks essential for cancer cell growth and proliferation. Therefore, disabling Myc function represents an attractive therapeutic option for cancer treatment. However, pharmacological strategies capable of directly targeting Myc remain elusive. Here, we identified that 3-bromopyruvate (3-BrPA), a drug candidate that primarily inhibits glycolysis, preferentially induced massive cell death in human cancer cells overexpressing the MYC oncogene, in vitro and in vivo, without appreciable effects on those exhibiting low MYC levels. Importantly, pharmacological inhibition of glutamine metabolism synergistically potentiated the synthetic lethal targeting of MYC by 3-BrPA due in part to the metabolic disturbance caused by this combination. Mechanistically, we identified that the proton-coupled monocarboxylate transporter 1 (MCT1) and MCT2, which enable efficient 3-BrPA uptake by cancer cells, were selectively activated by Myc. Two regulatory mechanisms were involved: first, Myc directly activated MCT1 and MCT2 transcription by binding to specific recognition sites of both genes; second, Myc transcriptionally repressed miR29a and miR29c, resulting in enhanced expression of their target protein MCT1. Of note, expressions of MCT1 and MCT2 were each significantly elevated in MYCN-amplified neuroblastomas and C-MYC-overexpressing lymphomas than in tumors without MYC overexpression, correlating with poor prognosis and unfavorable patient survival. These results identify a novel mechanism by which Myc sensitizes cells to metabolic inhibitors and validate 3-BrPA as potential Myc-selective cancer therapeutics.

Low temperature fabrication & photocatalytical activity of carbon fiber-supported TiO2 with different phase compositions.

Crystalline TiO2 nanoparticles with different phase compositions were fabricated on carbon fibers. The fabrication is achieved at low temperature. The process includes the treatment of Ti(OH)4 with hydrogen peroxide in the presence of carbon fibers. Neither additional acids nor bases, or additives are used during the process. Carbon fibers prior to and after TiO2 loading are characterized by FE-SEM, XRD, and UV-vis absorption spectroscopy. The photocatalytic activity was assessed via photocatalytic degradation of methyl orange solution, and found to be phase composition-dependent & pH dependent. Carbon fibers loaded with mixed-phase TiO2 led to the best photocatalytic performance. HRTEM reveals the anatase/rutile heterojunction which helps explain the high efficiency of photocatalysis. They have been demonstrated to be re-usable in the continuous photocatalytic degradation process.

Concentration-driven phase control for low temperature synthesis of phase-pure anatase and rutile titanium oxide.

It is highly desirable to develop controlled synthetic methods at low temperature (<100 °C) for defined phases of titanium oxide nanoparticle. We present here a simple low temperature approach which is based on the peroxide route. This approach allows the preparation of phase-pure rutile and anatase without the use of any additives or surfactants or external acids. The formation of crystalline phases is found to be dependent on reaction temperature and highly dependent on concentration. Phase-pure rutile is obtained in two concentration zones while phase-pure anatase is obtained in one concentration zone. The relationship between phases and reaction conditions (concentration and temperature) fits well with the nucleation diffusion rate model.

Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

Y-shaped two-photon absorbing molecules with an imidazole-thiazole core.

Two new classes of two-photon absorbing Y-shaped molecules have been developed to possess an imidazole-thiazole core and a stilbene-type conjugation pathway with either nitro or sulfonyl as terminal electron-accepting group.

N-acetylcysteine improves microcirculatory flow during smoking: new effects of an old drug with possible benefits for smokers.

BACKGROUND: Cigarette smoking provokes marked acute changes in the microcirculatory vasculature, including a reduced blood flow velocity. In accordance with the hypothesis that the reduced blood flow is due to an imbalance between pro-oxidants and oxidants, we recently showed that most of the reduction could be reversed by a high dose of vitamin C. HYPOTHESIS: In the present work we tested the hypothesis that N-acetylcysteine, a mucolyticum and an antioxidant, may have an effect on the smoking-induced changes observed by vital capillary microscopy of the nailfold. METHODS: In all, 37 healthy volunteers of both genders and with varied smoking habits were treated with N-acetylcysteine 200 mg t.i.d. for 2 weeks. In vivo investigation of the microcirculation by capillaroscopy was performed before and after treatment. RESULTS: Treatment with N-acetylcysteine significantly reduced the smoking-induced relative decrease in capillary blood flow velocity in a group of volunteers with varied smoking habits (p = 0.0016). The preventive effect was clearly significant in smokers (p = 0.003). CONCLUSION: Treatment with N-acetylcysteine has a positive impact on microcirculatory flow during smoking, particularly in habitual smokers.

Crystal structure of 4,5-bis(4-dimethylaminophenyl)-2-(4-nitrophenyl)imidazole.

A nonlinear optical chromophore, 4,5-bis(4-dimethylaminophenyl)-2-(4-nitrophenyl)imidazole, was investigated by X-ray crystallography. The study focused on coplanarity among several aromatic rings, including phenyls and imidazole. Two phenyl rings with NMe2 groups are twisted by 46.39(3) degrees from each other. However, they are twisted by 23.05(5) degrees and 46.84(3) degrees from the imidazole, respectively. These unequal twists were elucidated by different conjugation pathways from the donors to the acceptor. The phenyl ring with the NO2 group is twisted by only 6.76(6) degrees from the imidazole.

Microvascular medicine in Asia.

The frontiers of microcirculatory research in the present world is reviewed in relation to the development of genomics and post-genomics.

The role of the microlymphatic valve in the propagation of spontaneous rhythmical lymphatic motion in rat.

Male Wistar rats (n = 12) with the mesenteric preparation were used to quantitatively investigate the characteristics of wave-like propagation of spontaneous rhythmical lymphatic motion and to explore the mechanism of microlymphatic valve on the activity of lymphatic motion. The dynamical behaviors of collecting lymphatics were visualized by a closed circuit TV system. The frequency, amplitude, and phase angle of the diameter oscillation, the spreading speed of peristaltic wave and the contractile index (CI) of rhythmical lymphatic motion were measured and calculated by the image processing system. The lymphatic segment between two adjacent valves, named by lymphangion, was a basic unit of microlymphatic activity. The present results revealed that there was a wave-like propelling of the contractile activity progressively from one lymphangion to the next. No significant characteristic differences were observed from the two adjacent lymphangion units except the increasing contractile index. The motion wave propagation from upstream over a valve to down stream led to a significant phase angle change. The pacemaker site of lymphatic motion seemed to be at the inlet side of the valve in each lymphangion unit. The contractile motion wave propagated just within each lymphangion unit. The lymph flow over the valve converted the pressure changes between two adjacent lymphangions and stimulated a new contraction wave at the next inlet site of valve. The endothelium response to wall tension and shear stress alteration near the inlet valve site might be one of the pacemaking mechanisms of lymphatic motion.

Gene transfer of vascular endothelial growth factor plasmid/liposome complexes in glioma cells in vitro: the implication for the treatment of cerebral ischemic diseases.

Vascular endothelial growth factor (VEGF) is most promising in therapeutic angiogenesis for ischemic vascular disease. This paper aimed to study VEGF gene therapy for the treatment of cerebral ischemia. The glial cell was chosen as the target cell for gene transfer, and the expression of VEGF was studied in vitro. VEGF plasmid/liposome complexes were constructed by mixing VEGF plasmid with liposome, and then cultured C6 glioma cells were transfected with these complexes by lipofectamine method. As control, the same kind of cells were exposed to liposome only. Immunohistochemistry was performed to both groups at 24, 48 and 72 hours after transfection. The transfected cells expressed VEGF significantly higher than the control. The present result demonstrated the feasibility of choosing the glial cell as the target cell for VEGF gene transfer, and found the rationale for the cerebral VEGF gene therapy.

The therapeutic effect of Ginkgo biloba extract in SHR rats and its possible mechanisms based on cerebral microvascular flow and vasomotion.

This paper aimed to investigate the therapeutic effect of an extract of Ginkgo biloba leaves (EGb 761) on hypertension and its possible mechanisms in the view of cerebral microcirculation. Twenty normotensive rats and 24 SHR rats were used. Surgical preparation was made to produce a cranial window for observation of the capillary network on the cerebral cortex. The intravital videomicroscopy equipped with digital image processing system and laser Doppler flowmeter were used for this study. The arterial blood pressure, red cell velocity (V), microvacular diameter (D), number of open capillaries (OCN), circulating endothelial cells (CEC) in blood, relative blood flow (Flow) and frequency (Fc), amplitude (AMP) of vasomotion were measured. The obtained data were compared between EGb-treated rats that received per os 100 mg/kg/d for 9 days and placebo control rats. Untreated SHR rats showed very severe dysfunction in the microcirculation with high blood pressure (213 +/- 16.7 mmHg). The blood pressure decreased significantly to 153 +/- 20 mmHg in EGb-treated SHRs group, compared with those of untreated rats (p < 0.01). Both normotensive and hypertensive rats increased the blood flow velocity and LDF flow after EGb-treatment. The vasomotion property, the CEC and OCN changed greatly in EGb-treated SHR rats, but no significant difference was observed in normotensive rats. It was suggested that EGb 761 had therapeutic effect on SHR rats by increasing blood perfusion, regulating vasomotion function, opening efficiently capillaries and releasing the peripheral resistance. The injured vascular endothelium of SHR rats was also partly reversed by EGb-treatment. It was concluded that EGb 761 could be used to regulate hypertension and to protect the cerebral microcirculatory function.

Anticancer treatment of endostatin gene therapy by targeting tumor neovasculature in C57/BL mice.

Antiangiogenesis strategy has been widely recognized as a viable approach to fight cancer. Considering the high cost and inconvenience of protein therapy of endostatin (ES), which is a potent antiangiogenic protein, we attempted to explore the inhibitory effect of ES gene therapy on tumor growth and metastasis. In this experiment, Lewis lung carcinoma (LLC)-bearing C57/BL mice were used to evaluate the antitumor effect of ES gene therapy and its impairment of tumor neovasculature. The data showed that the ectopic ES in circulation expressed by intramuscular administration of formulated ES-encoding plasmid DNA significantly suppressed primary tumor growth and lung metastasis in LLC-bearing C57/BL mice. Hence, our results demonstrated the inhibitory effect of ES gene therapy on angiogenesis-dependent tumor growth and metastasis.

[Angiogenesis induced by SP2/0 and HeLa tumor cells].

Cheek pouches of Syrian golden hamsters and transparent access chambers of BALB/C mice were implanted with SP2/0 and HeLa tumor cells separately. Observation was done by continual photo and video from D 1 through the D 10 after implantation. It was found by the development of angiogenesis and the density of microvessels that both kinds of tumor cells could induce angiogenesis. On D 2 after implantation, there appeared leakage and hemorrhage from the microvessels near the tumor cells. On D 3 and D 4, there was an increased density of new capillaries which formed a very fine, tortuous and basketlike vascular plexus of irregular diameter. Most of the new microvessels came from the venules on the edge of the implant mass and they grew toward the tumor cells to penetrate the tumor tissue on D 4 to D 5. On D 7, the density of new microvessels reached the maximum and they began to extend outside the tumor which was surrounded by dense new capillaries. Compound 36 has been proved an effective substance against some tumors in clinical applications in this country. Also proved by our experiments, a drug effective in inhibition of angiogenesis induced by SP2/0 tumor cells.

[An animal experiment and clinical investigation on the protective effect of selenium on the microcirculation induced by free radical damaged RBCs].

UNLABELLED: Fluorescent labeling image analysis was used to evaluate the changes in cerebral arteriole and veinlet diameters (D), circulation velocities (FV) and permeability (VP) in rats; while in clinics, a laser-doppler device was used for assessing changes of skins and muscles microcirculation. The results show that in control rats, equal volume perfusion of free radical damaged RBCs resulted in decreases of D and FV significantly but VP was increased, whereas in the case when free radical damaged RBCs were perfused together with selenium, no disturbances in the D and VP were observed with FV even improved. In the human control group, either average skin microcirculative perfusions (ASMP) at 25 degrees C or maximal skin microcirculative perfusions (MSMP) at 42 degrees C were evidently decreased during myocardial ischemia/reperfusion period, while ASMP at 24th hour of post-surgery was kept reducing. At the same time, the changes in muscles microcirculative perfusions (MMP) tended to be similar to the skin, but overloaded than the pre-surgery levels at 24th hour of post-surgery period. In the selenium group before surgery, the ratio of MSMP to ASMP was obviously increased than the control group (3.95 in Se group vs 1.74 in control group, P < 0.05), but did not have significantly differences in ASMP, MSMP and MMP between the two groups during surgery period. RBC deformabilities were not changed. At 24th hour post-surgery, the ASMP were almost restored to pre-surgery levels. However, MMP were still lower than the pre-surgery levels. CONCLUSIONS: (1) free radical damaged RBC perfusion leads to damage of microcirculation; (2) selenium is highly efficient in protecting microcirculation from free radical damaged RBC disturbance; and (3) Oral administration of selenium may improve pre-surgery maximal skin microcirculative perfusion and promote recovery of the worsened skin microcirculation in addition to prevent the occurrence of RBC deformability.