Biomedical subjects

Emily Ho

Publications and source records attributed to Emily Ho.

18 recordsLinked to original sources

PubMed2006

Dietary zinc restriction in rats alters antioxidant status and increases plasma F2 isoprostanes.

Approximately 12% of Americans do not consume the estimated average requirement for zinc and could be at risk for zinc deficiency. Since zinc has proposed antioxidant function, inadequate zinc consumption may lead to an enhanced susceptibility to oxidative stress through several mechanisms, including altered antioxidant defenses. In this study, we hypothesized that dietary zinc restriction would result in lower antioxidant status and increased oxidative damage. We fed weanling Sprague-Dawley rats (n=12 per group) a zinc-adequate (50 mg/kg of zinc) diet, a zinc-deficient (<0.05 mg/kg of zinc) diet or a pair-fed diet for 3 weeks and then assessed their antioxidant status and oxidative stress parameters. Rats were zinc deficient as indicated by a significant (P<.05) reduction in body weight (49%) and 19% lower (P<.05) hepatic zinc (20.6+/-2.1 mg/kg) as compared with zinc-adequate rats (24.6+/-2.2 mg/kg). Zinc deficiency resulted in elevated (P<.05) plasma F(2) isoprostanes. Zinc deficiency-mediated oxidative stress was accompanied by a 20% decrease (P<.05) in the ferritin-reducing ability of plasma assay and a 50% reduction in plasma uric acid (P<.05). No significant change in plasma ascorbic acid or in plasma alpha-tocopherol and gamma-tocopherol was observed. However, hepatic alpha-tocopherol and gamma-tocopherol concentrations were decreased by 38% and 27% (P<.05), respectively, as compared with those in zinc-adequate rats. Hepatic alpha-tocopherol transfer protein levels were unaltered (P>.05) by zinc deficiency, but cytochrome P450 (CYP) 4F2 protein levels were elevated (P<.05) as compared with those in zinc-adequate rats. Collectively, zinc deficiency increased oxidative stress, which may be partially explained by increased CYP activity and reductions in hepatic alpha-tocopherol and gamma-tocopherol and in plasma uric acid.

Animals↗

PubMed2006

Xanthohumol, a prenylflavonoid derived from hops induces apoptosis and inhibits NF-kappaB activation in prostate epithelial cells.

There is increasing evidence that certain natural compounds found in plants may be useful as cancer chemopreventive or chemotherapeutic agents. Limited in vitro studies indicate that several prenylated flavonoids present in the hop plant (Humulus lupulus) possess anticarcinogenic properties. The purpose of this study was to investigate the anti-tumorigenic effects of xanthohumol (XN), the major prenylflavonoid in hops, on prostate cancer and benign prostate hyperplasia. BPH-1 and PC3 cell lines were used in our study to represent both non-tumorigenic hyperplasia and malignant prostate cancer. In both BPH-1 and PC3 cells, XN and its oxidation product, XAL, decreased cell viability in a dose dependent manner (2.5-20 microM) as determined by MTT assay and caused an increase in the formation of early and late apoptotic cells as determined by Annexin V staining and multicaspase assays. XN and its oxygenated derivative also induced cell cycle changes in both cells lines, seen in an elevated sub G1 peak at 48h treatment. Western blot analysis was performed to confirm the activation of proapoptotic proteins, Bax and p53. XN and its derivative caused decreased activation of NFkappaB. This work suggests that XN and its oxidation product, XAL, may be potentially useful as a chemopreventive agent during prostate hyperplasia and prostate carcinogenesis, acting via induction of apoptosis and down-regulation of NFkappaB activation in BPH-1 cells.

Apoptosis↗

PubMed2006

Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc-minus mice.

Sulforaphane (SFN) is an isothiocyanate from broccoli that induces phase 2 detoxification enzymes. We recently reported that SFN acts as a histone deacetylase (HDAC) inhibitor in human colon cancer cells in vitro, and the present study sought to extend these findings in vivo. In mice treated with a single oral dose of 10 mumol SFN, there was significant inhibition of HDAC activity in the colonic mucosa after 6 h, and immunoblots revealed a concomitant increase in acetylated histones H3 and H4, which returned to control levels by 48 h. Longer-term treatment with SFN in the diet resulted in levels of acetylated histones and p21(WAF1) in the ileum, colon, prostate, and peripheral blood mononuclear cells that were elevated compared with controls. Consistent with these findings, SFN suppressed tumor development in Apc(min) mice, and there was an increase in acetylated histones in the polyps, including acetylated histones specifically associated with the promoter region of the P21 and bax genes. These results provide the first evidence for HDAC inhibition by SFN in vivo and imply that such a mechanism might contribute to the cancer chemoprotective and therapeutic effects of SFN, alone or in combination with other HDAC inhibitors currently undergoing clinical trials.

Acetylation↗

PubMed2006

Dietary agents as histone deacetylase inhibitors.

In cancer cells, an imbalance often exists between histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities, and various drug companies are actively seeking competitive HDAC inhibitors for chemotherapeutic intervention. Cancer cells appear to be more sensitive than nontransformed cells to HDAC inhibitors, which disrupt the cell cycle and induce apoptosis via derepression of genes such as P21 and BAX. However, in the search for potent HDAC inhibitors with cancer therapeutic potential, a tendency exists to overlook or dismiss weak ligands that could prove effective in cancer prevention. Butyrate, diallyl disulfide (DADS), and sulforaphane (SFN) are three dietary agents that exhibit HDAC inhibitory activity in vitro and/or in vivo, and other such dietary agents probably will be discovered that affect HDAC activity. We make the distinction between 'pharmacologic' agents that potently derepress gene expression, during therapeutic intervention, and dietary HDAC inhibitors that, as weak ligands, might subtly regulate the expression of genes involved in cell growth and apoptosis. An important issue for future study is to determine the extent to which dietary HDAC inhibitors, by modulating genes such as p21 and Bax, enable normal, nontransformed cells to respond most effectively to external stimuli and toxic insults.

Diet↗

PubMed2006

Synthesis and characterization of an injectable hydrogel with tunable mechanical properties for soft tissue repair.

Injectable polymers are attractive materials for the fixation or augmentation of soft tissues. Thermosensitive hydrogels, especially poly(N-isopropylacryamide), have been investigated for these applications to exploit the lower critical solution temperature (LCST) which falls between room and body temperatures. One limitation to the material is the ability to withstand loading. In this work, we evaluated an injectable material system, poly(N-isopropylacryamide)-co-poly(ethyleneglycol) dimethacrylate, with the addition of trimethacryloxypropyltrimethoxysilane (MPS). Our goal was to investigate the potential to tune the mechanical behavior of the injectable hydrogel. Addition of MPS to the hydrogel increased the compressive modulus but did not affect the LCST of the hydrogel. An increase in ion concentration of the immersion media resulted in less solution uptake by the hydrogels, regardless of MPS presence in the system. The challenge of this material system is to balance the network-forming and modulus-enhancing MPS while maintaining an injectable hydrogel for potential soft tissue repair.

Biocompatible Materials↗

PubMed2006

The role of interfacial mechanics in the prediction of global mechanical behavior of a bioactive composite: an in vitro study.

A bioactive bone-tissue substitute, hydroxyapatite (HA)-polymethylmethacrylate (PMMA) with the addition of a copolymer coupling agent, was examined in vitro to determine the influence of the coupling agent on the local mechanical properties of the system before and after simulated biologic conditions. Nano-indentation of the cross-sectional interface between the HA and PMMA of the composite was studied. The fracture mechanism and position of each indent mark were analyzed at up to 5000x magnification under field-emission, environmental-scanning electron microscopy. The local interfacial results were compared with global quasistatic compression test results. It was found that nano-indentation of the interface could predict changes in global mechanical behavior of the composite. Both interfacial and global Young's moduli were reduced after immersion in the simulated biologic media. Although the coupling agent improved the interfacial and global mechanical properties before and after 24 hours in in vitro immersion, it did not affect the surface bioactivity of the system, as shown in the measurement of calcium and phosphate concentration uptake. Thus, nano-indentation is a sensitive technique for examining interfacial mechanics and mechanical consequences of biologic reactivity of composite materials.

Biocompatible Materials↗

PubMed2006

Troponin T elevation after coronary bypass surgery: clinical relevance and correlation with perioperative variables.

OBJECTIVE: Elevation in markers of myocardial necrosis is a common feature following coronary artery bypass surgery, but its relevance is unclear. The objective of this study was to evaluate the association between postoperative troponin T elevation, perioperative variables and clinical outcomes. METHODS: We evaluated 100 low-risk patients undergoing first-time elective on-pump coronary artery bypass surgery. The mean age was 62 +/- 9.8 years and 83% were male; patients with diabetes mellitus, renal failure and impaired left ventricular function (ejection fraction < 40%) were excluded. Troponin levels were measured at baseline and 12 and 24 h following the onset of cardiopulmonary bypass. Predefined clinical endpoints included death, new Q waves on 12-lead electrocardiogram and inotropic requirement. RESULTS: Postoperative troponin elevation occurred in 95%. Troponin T elevation was related to the duration of cardiopulmonary bypass (P = 0.0001) and aortic cross-clamp time (P = 0.0003). There was also an inverse relationship with perioperative core temperature (P = 0.0001). There was no association between postoperative troponin elevation and clinical outcomes. CONCLUSIONS: Postoperative troponin T elevation occurs in the majority of patients undergoing elective on-pump coronary artery bypass surgery. In this low-risk cohort, troponin T elevation was associated with procedural duration but not with clinical outcome.

Aged↗

PubMed2005

Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells.

Sulforaphane (SFN), an isothiocyanate first isolated from broccoli, exhibits chemopreventive properties in prostate cancer cells through mechanisms that are poorly understood. We recently reported on a novel mechanism of chemoprotection by SFN in human colon cancer cells, namely the inhibition of histone deacetylase (HDAC). Here, we show that addition of 15 microM SFN also inhibited HDAC activity by 40, 30 and 40% in BPH-1, LnCaP and PC-3 prostate epithelial cells, respectively. The inhibition of HDAC was accompanied by a 50-100% increase in acetylated histones in all three prostate cell lines, and in BPH-1 cells treated with SFN there was enhanced interaction of acetylated histone H4 with the promoter region of the P21 gene and the bax gene. A corresponding 1.5- to 2-fold increase was seen for p21Cip1/Waf1 and Bax protein expression, consistent with previous studies using HDAC inhibitors, such as trichostatin A. The downstream events included cell cycle arrest and activation of apoptosis, as evidenced by changes in cell cycle kinetics and induction of multi-caspase activity. These findings provide new insight into the mechanisms of SFN action in benign prostate hyperplasia, androgen-dependent prostate cancer and androgen-independent prostate cancer cells, and they suggest a novel approach to chemoprotection and chemotherapy of prostate cancer through the inhibition of HDAC.

Androgens↗

PubMed2005

Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention?

There is growing interest in the various mechanisms that regulate chromatin remodeling, including modulation of histone deacetylase (HDAC) activities. Competitive HDAC inhibitors disrupt the cell cycle and/or induce apoptosis via de-repression of genes such as P21 and BAX, and cancer cells appear to be more sensitive than non-transformed cells to trichostatin A and related HDAC inhibitory compounds. This apparent selectivity of action in cancer cells makes HDAC inhibitors an attractive avenue for drug development. However, in the search for potent HDAC inhibitors with cancer therapeutic potential there has been a tendency to overlook or dismiss weak ligands that could prove effective in cancer prevention, including agents present in the human diet. Recent reports have described butyrate, diallyl disulfide and sulforaphane as HDAC inhibitors, and many other dietary agents will be probably discovered to attenuate HDAC activity. Here we discuss 'pharmacologic' agents that potently de-repress gene expression (e.g. during therapeutic intervention) versus dietary HDAC inhibitors that, as weak ligands, might subtly regulate the expression of genes involved in cell growth and apoptosis. An important question is the extent to which dietary HDAC inhibitors, and other dietary agents that affect gene expression via chromatin remodeling, modulate the expression of genes such as P21 and BAX so that cells can respond most effectively to external stimuli and toxic insults.

Apoptosis↗

PubMed2005

Protection by dietary zinc in ALS mutant G93A SOD transgenic mice.

Mutations to the copper, zinc superoxide dismutase (SOD) gene are responsible for 2-3% of amyotrophic lateral sclerosis (ALS) cases. These mutations result in the protein having a reduced affinity for zinc. SOD becomes toxic to motor neurons when zinc is missing from its active site. Recently, high dosages of zinc (75 and 375 mg/kg/day) have been paradoxically reported to increase the death of G93A-mutant SOD transgenic mice [G.J. Groeneveld, J. de Leeuw van Weenen, F.L. van Muiswinkel, H. Veldman, J.H. Veldink, J.H. Wokke, P.R. Bar, L.H. van den Berg, Zinc amplifies mSOD1-mediated toxicity in a transgenic mouse model of amyotrophic lateral sclerosis, Neurosci. Lett. 352 (2003) 175-178]. In contrast, we have found that moderate supplementation of zinc (approximately 12 mg/kg/day) delayed death in G93A-mutant SOD mice by 11 days compared to mice on a zinc-deficient diet. Supplementing zinc with even 18 mg/kg/day resulted in a more rapid death of some mice, consistent with the results of Groenevelt et al. However, large amounts of zinc competitively inhibit copper absorption, which inhibits the copper-dependent ceruloplasmin, and can cause a lethal anemia. We found that supplementing the 18 mg/kg/day dosage of zinc with 0.3 mg/kg/day of copper prevented the early death from zinc treatment alone. These data support a role for moderate levels of dietary zinc potentially protecting against the toxicity of ALS-associated SOD and the protection does not result from depleting copper.

Amyotrophic Lateral Sclerosis↗

PubMed2005

Human hippocampal theta activity during virtual navigation.

This study examines whether 4-8-Hz theta oscillations can be seen in the human hippocampus, and whether these oscillations increase during virtual movement and searching, as they do in rodents. Recordings from both hippocampal and neocortical depth electrodes were analyzed while six epileptic patients played a virtual taxi-driver game. During the game, the patients alternated between searching for passengers, whose locations were random, and delivering them to stores, whose locations remained constant. In both hippocampus and neocortex, theta increased during virtual movement in all phases of the game. Hippocampal and neocortical theta activity were also significantly correlated with each other, but this correlation did not differ between neocortex and hippocampus and within disparate neocortical electrodes. Our findings demonstrate the existence of movement-related theta oscillations in human hippocampus, and suggest that both cortical and hippocampal oscillations play a role in attention and sensorimotor integration.

Adult↗

PubMed2005

Effect of coupling agents on the local mechanical properties of bioactive dental composites by the nano-indentation technique.

OBJECTIVES: To examine the use of nano-indentation as a method of determining the interfacial mechanics of bioactive composites for mandibular bone substitutes. METHODS: Three coupling agents (PMMA-MAA, PMMA-MA and silane) were used to treat hydroxyapatite (HA) particles before incorporation into a polymethylmethacrylate (PMMA) matrix. Nano-indentation was used to determine the hardness and Young's modulus on the HA particle surface, at the HA/PMMA interface and in the PMMA matrix region for each of the four groups. In addition bulk four-point bending tests were conducted on each of the four groups as a comparison. RESULTS: The findings resulted in significant differences in the local interfacial Young's modulus between the polymer-treated composites and the uncoupled control specimens with a marked improvement (50%) in modulus with either polymertreated group. Similarly, the bending modulus of the polymer-treated groups was significantly higher than the un-treated control group; however, these differences were not as pronounced (approximately 15%). SIGNIFICANCE: The co-polymer-treated composites resulted in improved interfacial modulus as compared to the un-treated controls and that the nano-indentation technique is a powerful tool for understanding the local interfacial mechanics of bioactive composites.

Analysis of Variance↗

PubMed2005

Aortic hypoplasia and right ventricular outflow tract obstruction in a young man with uncontrolled hypertension.

We report the case of a 35-year-old man who presented to hospital with symptomatic uncontrolled hypertension. He had no other conventional cardiovascular risk factors, but did have previous cataract surgery and patent ductus arteriosus repair. Echocardiography revealed normal valves, right ventricular outflow tract obstruction, and heavy calcification of the aortic root compromising luminal diameter. Pulmonary angiography confirmed supravalvular and subvalvular pulmonary stenosis. Aortography showed hypoplasia of the entire aortic trunk extending into the iliac arteries, but without involvement of other major branches. A possible unifying diagnosis, with the combination of aortic hypoplasia, pulmonary artery stenosis, patent ductus arteriosus, and cataracts, was believed to have been congenital rubella syndrome. Although associated with numerous cardiovascular abnormalities, aortic hypoplasia is an extremely rare manifestation of congenital rubella that, to our knowledge, has been reported in only two cases in the literature to date.

Adult↗

PubMed2004

A simple assay for frequency of chromosome breaks and loss (micronuclei) by flow cytometry of human reticulocytes.

Exposure to environmental stress, such as radiation, poor nutrition, or smoking, can cause hazardous lesions in DNA, including double-strand breaks. In red blood cells, a DNA fragment or lagging chromosome forms a micronucleus when left behind after the main nucleus is extruded to form the mature reticulocyte during erythropoiesis. Reticulocytes with micronuclei in human peripheral blood are not generally available for analysis because the spleen removes aberrant cells. We have developed a simple and rapid method to isolate and analyze immature reticulocytes in the peripheral blood for the presence of micronuclei before these cells are removed by the spleen. This method applies single-laser flow-cytometry to measure micronuclei in an enriched transferrin-positive reticulocyte population. Abramsson-Zetterberg et al. (Abramsson-Zetterberg, L., Zetterberg, G., Bergqvist, M., and Grawe, J. Environ. Mol. Mutagen. 36, 22-31, 2000) have described a method to measure micronuclei in an enriched reticulocyte population using a dual-laser flow cytometry. Unlike the beads used in their magnetic-immunoseparation procedures, the beads used in this study do not require a prelabeling step and are compatible with the flow cell, sparing the need to release the cells from the beads and avoiding the potentially confounding DNase-treatment step. Dertinger et al. (Dertinger, S. D., Torous, D. K., Hall, N. E., Murante, F. G., Gleason, S. E., Miller, R. K., and Tometsko, C. R. Mutat. Res. 515, 3-14, 2002; Dertinger, S. D., Chen, Y., Miller, R. K., Brewer, K. J., Smudzin, T., Torous, D. K., Hall, N. E., Olvany, K. A., Murante, F. G., and Tometsko, C. R. (2003) Mutat. Res. 542, 77-87, 2003) further improved the scoring of micronuclei to enable the use of bench-top instruments in analyzing samples of unenriched reticulocyte-populations. The present method is distinct from flow cytometric assays, such as reported by Dertinger et al., which enable scoring of limited numbers of reticulocytes per sample and require lengthy data acquisition times. We assessed DNA damage in smokers using this novel flow-cytometry based micronuclei-assay. The results show that this assay can effectively detect micronuclei in human blood samples. This method, unlike available micronuclei assays, allows rapid evaluation of a large number of cells and therefore should prove to be useful in monitoring of human populations for genetic damage.

Adult↗

PubMed2004

Dietary influences on endocrine-inflammatory interactions in prostate cancer development.

Prostate cancer is the most frequently diagnosed non-cutaneous cancer and is the second leading cause of cancer death in American men. The focus of this review is to define the relationship between hormonal (testosterone/estrogens) stimulation of chronic inflammation, generation of reactive oxygen species (ROS), and uncontrolled prostate cell proliferation, and review putative dietary chemoprevention strategies that focus on these processes. It has been proposed that elevated estrogen in men who already have high blood testosterone are at high risk for prostate cancer. We hypothesized that elevated estrogen, in the presence of testosterone, causes prolonged activation of a redox-sensitive transcription factor, nuclear factor kappa B (NF kappa B), that initiates and amplifies an inflammatory cascade within the prostate and results in sustained oxidative and nitrative damage. The inflammatory cascade is proposed to link with uncontrolled proliferation through up-regulated Wnt signal and abnormal catenin accumulation in the prostate. Finally, a strategy that emphasizes a "whole food" based approach to cancer prevention by selecting food products that bear anti-inflammatory and anti-proliferative properties may be most promising as an effective dietary chemopreventive strategy.

Diet Therapy↗

PubMed2004

Zinc deficiency, DNA damage and cancer risk.

A large body of evidence suggests that a significant percentage of deaths resulting from cancer in the United States could be avoided through greater attention to proper and adequate nutrition. Although many dietary compounds have been suggested to contribute to the prevention of cancer, there is strong evidence to support the fact that zinc, a key constituent or cofactor of over 300 mammalian proteins, may be of particular importance in host defense against the initiation and progression of cancer. Remarkably, 10% of the U.S. population consumes less than half the recommended dietary allowance for zinc and are at increased risk for zinc deficiency. Zinc is known to be an essential component of DNA-binding proteins with zinc fingers, as well as copper/zinc superoxide dismutase and several proteins involved in DNA repair. Thus, zinc plays an important role in transcription factor function, antioxidant defense and DNA repair. Dietary deficiencies in zinc can contribute to single- and double-strand DNA breaks and oxidative modifications to DNA that increase risk for cancer development. This review will focus on potential mechanisms by which zinc deficiency impairs host protective mechanisms designed to protect against DNA damage, enhances susceptibility to DNA-damaging agents and ultimately increases risk for cancer.

Apoptosis↗

PubMed2003

Zinc deficiency induces oxidative DNA damage and increases p53 expression in human lung fibroblasts.

Poor zinc nutrition may be an important risk factor in oxidant release and the development of DNA damage and cancer. Approximately 10% of the United States population ingests <50% of the recommended daily allowance for zinc, a cofactor in proteins involved in antioxidant defenses, electron transport, DNA repair and p53 protein expression. This study examined the effects of zinc deficiency on oxidative stress, DNA damage and the expression of DNA repair enzymes in primary human lung fibroblasts by the use of DNA microarrays and functional assays. Cellular zinc was depleted by 1) growing cells in a zinc-deficient medium and 2) exposuring cells to an intracellular zinc chelator, N,N,N',N'-tetrakis-(2-pyridylmethyl)ethylenediamine. Array data revealed upregulation of genes involved in oxidative stress and DNA damage/repair and downregulation of other DNA repair genes. Zinc deficiency in cells caused an increase in oxidant production (dichlorofluoroscein fluorescence) and a significant induction of single-strand breaks (Comet assay) and p53 protein expression (Western blot analysis). Thus, zinc deficiency not only caused oxidative stress and DNA damage, but also compromised the cells' ability to repair this damage. Zinc adequacy appears to be necessary for maintaining DNA integrity and may be important in the prevention of DNA damage and cancer.

Blotting, Western↗

PubMed2002

Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFkappa B, and AP1 DNA binding, and affects DNA repair in a rat glioma cell line.

Approximately 10% of the U.S. population ingests <50% of the current recommended daily allowance for zinc. We investigate the effect of zinc deficiency on DNA damage, expression of DNA-repair enzymes, and downstream signaling events in a cell-culture model. Low zinc inhibited cell growth of rat glioma C6 cells and increased oxidative stress. Low intracellular zinc increased DNA single-strand breaks (comet assay). Zinc-deficient C6 cells also exhibited an increase in the expression of the zinc-containing DNA-repair proteins p53 and apurinic endonuclease (APE). Repletion with zinc restored cell growth and reversed DNA damage. APE is a multifunctional protein that not only repairs DNA but also controls DNA-binding activity of many transcription factors that may be involved in cancer progression. The ability of the transcription factors p53, nuclear factor kappaB, and activator protein 1 (AP1) to bind to consensus DNA sequences was decreased markedly with zinc deficiency, as assayed by electrophoretic mobility-shift assays. Thus, low intracellular zinc status causes oxidative DNA damage and induces DNA-repair protein expression, but binding of p53 and important downstream signals leading to proper DNA repair are lost without zinc.

Animals↗