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Daniela Ortiz

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Vitamin E deficiency does not induce compensatory antioxidant increases in central nervous system tissue of apolipoprotein E-deficient mice

Journal of Alzheimer's Disease, 2003

Compensatory upregulation in endogenous antioxidants has been shown to accompany certain genetic ... more Compensatory upregulation in endogenous antioxidants has been shown to accompany certain genetic and dietary deficiencies that promote oxidative stress, including that related to Alzheimer's disease. We compared antioxidant levels in brain tissue of normal and transgenic mice lacking apolipoprotein E following dietary deprivation of vitamin E or folate. As described previously, ApoE-deficient mice displayed increased levels of the endogenous antioxidant glutathione as compared to normal mice, and increased these levels further following folate deprivation. By contrast, glutathione was depleted following vitamin E deprivation in brain tissue of normal and ApoE-deficient mice. TBAR analyses confirmed increased oxidative damage following vitamin E deprivation. However, combined deprivation of folate and vitamin E resulted in levels of glutathione intermediate between those observed following deprivation of either agent, indicating that the lack of compensatory increase in glutathione following vitamin E deprivation was not due to overt neurotoxicity. Similar results were observed for total antioxidant levels in brain tissue. The differential response to vitamin E and folate deprivation is consistent with the possibility that specific differences in oxidative damage may result from deficiencies in either of these agents. The lack of a compensatory response to vitamin E deprivation highlights the importance of dietary vitamin E in prevention of chronic neurodegeneration.

MRP3, a new ATP-binding cassette protein localized to the canalicular domain of the hepatocyte

American Journal of Physiology-Gastrointestinal and Liver Physiology, 1999

Bile secretion in liver is driven in large part by ATP-binding cassette (ABC)-type proteins that ... more Bile secretion in liver is driven in large part by ATP-binding cassette (ABC)-type proteins that reside in the canalicular membrane and effect ATP-dependent transport of bile acids, phospholipids, and non-bile acid organic anions. Canalicular ABC-type proteins can be classified into two subfamilies based on membrane topology and sequence identity: MDR1, MDR3, and SPGP resemble the multidrug resistance (MDR) P-glycoprotein, whereas MRP2 is similar in structure and sequence to the multidrug resistance protein MRP1 and transports similar substrates. We now report the isolation of the rMRP3 gene from rat liver, which codes for a protein 1522 amino acids in length that exhibits extensive sequence similarity with MRP1 and MRP2. Northern blot analyses indicate that rMRP3 is expressed in lung and intestine of Sprague-Dawley rats as well as in liver of Eisai hyperbilirubinemic rats and TR− mutant rats, which are deficient in MRP2 expression. rMRP3 expression is also transiently induced in li...

N-acteyl cysteine alleviates oxidative damage to central nervous system of ApoE-deficient mice following folate and vitamin E-deficiency

Journal of Alzheimer's Disease, 2005

Oxidative stress is an early neurodegenerative insult in Alzheimer's disease (AD). Antioxidant me... more Oxidative stress is an early neurodegenerative insult in Alzheimer's disease (AD). Antioxidant mechanisms, including elements of the glutathione (GSH) pathway, undergo at least a transient compensatory increase that is apparently insufficient due to continued oxidative damage during disease progression. Mice deficient in apolipoprotein E, which provide a model for some aspects of AD, undergo increased oxidative damage to brain tissue and cognitive decline when maintained on a folate-free diet, despite a compensatory increase in glutathione synthase transcription and activity as well as increased levels of GSH. Dietary supplementation with N-acetyl cysteine (1 g/kg diet), a cell-permeant antioxidant and GSH precursor, alleviated oxidative damage and cognitive decline, and restored glutathione synthase and GSH levels in ApoE-deficient mice deprived of folate to those of normal mice maintained in the presence of folate. These data support the administration of antioxidant precursors to buffer oxidative damage in neurodegenerative disorders.

Nanosphere-mediated delivery of vitamin E increases its efficacy against oxidative stress resulting from exposure to amyloid beta

Journal of Alzheimer's Disease, 2005

Oxidative stress is an early hallmark of affected neurons in Alzheimer's disease (AD). The antiox... more Oxidative stress is an early hallmark of affected neurons in Alzheimer's disease (AD). The antioxidant vitamin E provided limited neuroprotection in AD, which may have derived from its lipophilic nature and resultant inability to quench cytosolic reactive oxygen species (ROS), including those generated from antecedent membrane oxidative damage. We examined herein whether or not encapsulation into polyethylene glycol (PEG)-based nanospheres, which can enter the cytosol, improved the efficacy of vitamin E against amyloid-β (Aβ)-induced ROS. Unexcapsulated vitamin E prevented Aβ-induced ROS in cultured SH-SY-5Y human neuroblastoma cells only if present prior to, or applied simultaneously with, Aβ treatment. By contrast, encapsulated vitamin E was equally effective if administered 1 hr after Aβ exposure. These findings suggest suggests that nanosphere-mediated delivery methods may be a useful adjunct for antioxidant therapy in AD.

Apple juice concentrate prevents oxidative damage and impaired maze performance in aged mice

Journal of Alzheimer's Disease, 2005

Oxidative stress contributes to age-related cognitive decline. In some instances, consumption of ... more Oxidative stress contributes to age-related cognitive decline. In some instances, consumption of fruits and vegetables rich in antioxidant can provide superior protection than supplementation with purified antioxidants. Our prior studies have shown that supplementation with apple juice concentrate (AJC) alleviates oxidative damage and cognitive decline in a transgenic murine model compromised in endogenous antioxidant potential when challenged with a vitamin-deficient, oxidative stresspromoting diet. Herein, we demonstrate that AJC, administered in drinking water, is neuroprotective in normal, aged mice. Normal mice aged either 9-10 months or 2-2.5 years were maintained for 1 month on a complete diet or a diet lacking folate and vitamin E and containing iron as a pro-oxidant, after which oxidative damage was assayed by thiobarbituric acid-reactive substances and cognitive decline as assayed by performance in a standard Y-maze. Mice 9-12 months of age were unaffected by the deficient diet, while older mice demonstrated statistically-increased oxidative damage and poorer performance in a Y maze test. Supplementation with AJC prevented these neurodegenerative effects. These data are consistent with normal aged individuals being susceptible to neurodegeneration following dietary compromise such as folate deficiency, and a hastened onset of neurodegeneration in those individuals harboring a genetic risk factor such as ApoE deficiency. These findings also support the efficacy of antioxidant supplementation, including consumption of antioxidant-rich foods such as apples, in preventing the decline in cognitive performance that accompanies normal aging.

Differential susceptibity of transgenic mice lacking one or both apolipoprotein alleles to folate and vitamin E deprivation

Journal of Alzheimer's Disease, 2004

The E4 allele of apolipoprotein E (ApoE) is associated with neurodegeneration in part due to incr... more The E4 allele of apolipoprotein E (ApoE) is associated with neurodegeneration in part due to increased oxidative stress. Transgenic mice lacking ApoE (−/−) represent a model for the consequences of deficiencies in ApoE function. Dietary deficiency in folate and vitamin E has previously been shown to potentiate the impact of ApoE deficiency; ApoE−/− mice deprived of folate and vitamin E for 1 month demonstrated increased oxidative damage in brain tissue and impaired cognitive performance as compared to ApoE+/+ mice. Since individuals homozygous for E4 can demonstrate more increased risk for neurodegeneration and an earlier age of onset than individuals heterozygous for E4, we tested the impact of folate and vitamin E deprivation on ApoE+/− mice. Thiobarbituric acid-reactive substances in brain tissue of ApoE+/− were significantly increased compared to ApoE+/+ mice, but this increase was less than that observed in ApoE−/− mice.

17 β-Estradiol alleviates synergistic oxidative stress resulting from folate deprivation and amyloid-β treatment

Journal of Alzheimer's Disease, 2003

Oxidative stress is thought to be a pivotal factor in Alzheimer's disease (AD). Amyloid-β (Aβ) in... more Oxidative stress is thought to be a pivotal factor in Alzheimer's disease (AD). Amyloid-β (Aβ) induces oxidative damage, which is likely to be compounded by deficiencies in endogenous antioxidant capacity. Indeed, folate deprivation, which has been associated with AD, potentiates generation of reactive oxygen species (ROS) by Aβ. We examined whether the antioxidant 17-β-estradiol could attenuate ROS generation following Aβ treatment in the presence and absence of folate using differentiated SH-SY-5Y human neuroblastoma cells. Folate-deprivation and Aβ treatment each induced an increase in ROS, and treatment of folate-deprived cultures with Aβ induced a synergistic increase in ROS. 17-β-estradiol reduced ROS levels in Aβ-treated, folate-deprived cultures to ROS levels observed in cultures treated with Aβ in the presence of folate, suggesting that this antioxidant was able to prevent the synergistic impact of Aβ and folate deprivation on ROS generation. 17-β-estradiol also completely prevented neuronal death induced by both Aβ and folate deprivation individually, and reduced neuronal death following Aβ treatment along with folate deprivation. These findings suggest that therapeutic approaches utilizing antioxidants may be particularly important in conditions such as AD, where multiple factors, including compromises in endogenous antioxidants, promote oxidative stress.

Amyloid-β promotes calcium influx and neurodegeneration via stimulation of L voltage-sensitive calcium channels rather than NMDA channels in cultured neurons

Journal of Alzheimer's Disease, 2001

Communicated by Garth Hall Exposure of cultured neurons and neuronal cells to aggregated amyloid-... more Communicated by Garth Hall Exposure of cultured neurons and neuronal cells to aggregated amyloid-β (Aβ) induces multiple neurodegenerative events including accumulation of cytosolic calcium, generation of reactive oxygen species, abnormal levels of phosphorylation of the microtubule-associated protein tau, and apoptosis. Prevention of accumulation of calcium within the cytosol also prevents all other events, suggesting that calcium accumulation is an early and pivotal event in Aβ neurotoxicity. Calcium influx has been suggested to occur via L voltagesensitive calcium channels or NMDA channels. Calcium influx into differentiated human neuroblastoma cells has been previously attributed to the L voltage-sensitive calcium channel, but the contribution of the NMDA channel was not examined. In the present study, treatment of these cells with MK-801, an antagonist of NMDA channels, failed to attenuate Aβ-induced calcium influx or neurodegeneration, while nimopridine, an antagonist of the L voltage-sensitive calcium channel, blocked Aβ-induced calcium influx. Our findings suggest that NMDA channels do not contribute significantly to Aβ neurotoxicity in these acute cell culture analyses.

Apple juice prevents oxidative stress induced by amyloid-beta in culture

Journal of Alzheimer's Disease, 2004

Increased oxidative stress contributes to the decline in cognitive performance during normal agin... more Increased oxidative stress contributes to the decline in cognitive performance during normal aging and in neurodegerative conditions such as Alzheimer's disease. Dietary supplementation with fruits and vegetables that are high in antioxidant potential have in some cases compensated for oxidative stress. Herein, we examined whether apple juice could alleviate the neurotoxic consequences of exposure of cultured neuronal cells to amyloid-β (Aβ), since at least a portion of the neurotoxicity of Aβ is due to oxidative stress. Apple juice concentrate (AJC; 70 degree brix) was diluted into culture medium of SH-SY-5Y human neuroblastoma cells that had been differentiated for 7 days with 5 µM retinoic acid concurrent with the addition of 20 µM Aβ. AJC prevented the increased generation of reactive oxygen species (ROS) normally induced by Aβ treatment under these conditions. AJC also prevented Aβ-induced calcium influx and apoptosis, each of which results in part due to increased ROS. These findings suggest that the antioxidant potential of apple products can prevent Aβ-induced oxidative damage.

The Mul maize transposable element induces tissue-specific aberrant splicing and polyadenylation in two Adhl mutants

Molecular and Cellular Biology, 1990

Tissue of Apolipoprotein E-Deficient Mice

Amyloid- promotes calcium influx and

Journal of Alzheimer's disease: JAD

ABSTRACT

Bone Augmentation, Presurgical Expectations and Outcomes in Dental Implant Therapy

Objective: to assess expectations about implant therapy among women who required alveolar bone au... more Objective: to assess expectations about implant therapy among women who required alveolar bone augmentation and how expectations shape post-surgical outcomes. Methods: This is an observational study of postmenopausal women receiving implants with bone augmentation focused on the relationship between osteopenia/osteoporosis and augmentation outcomes. The augmentation procedures included: expansion, particulate graft, expansion+particulate graft or block graft. Inclusion criteria: age between 45 and 85; 12 teeth; edentulous area with a narrow alveolar ridge. Participants completed questionnaires prior to treatment, at one week, eight weeks and nine months. Data were collected on demographics, implant location and bone density. Expectations and perceived outcomes were measured using a 15-item scale on symptoms, oral and social function. Items were rated on a 7-point scale from 1 being no discomfort to 7 being much discomfort. Results: The mean age of participants (n=80) was 62 years (s...

Bone Health in Postmenopausal Women Undergoing Bone Augmentation and Implantation

Objective: No reports to date have evaluated specific measures of bone metabolism, bone health pa... more Objective: No reports to date have evaluated specific measures of bone metabolism, bone health parameters and success of alveolar bone augmentation procedures. This ongoing best practice descriptive study, in response to an NIDCR initiative, is designed to evaluate surgical bone augmentation and dental implant placement outcomes among postmenopausal women of varying bone health. This abstract reports preliminary descriptive bone health findings for the first 31 participants. Methods: Participants (mean=61.2 yrs) were recruited from the University of Connecticut Health Center clinics and the population at large. Bone mineral density (BMD) at lumbar spine, femoral neck and total hip as well as 25-hydroxyvitamin D was determined at baseline. Bone turnover markers, including C-telopeptide (sCTX) and procollagen peptide (P1NP), were measured at baseline, 1 week and 8 weeks post-procedure. Results: All participants had augmentation simultaneous with dental implant placement. Sixteen parti...

Expectations about dental implant treatment among postmenopausal women

Objectives: to assess expectations about treatment among postmenopausal women who received alveol... more Objectives: to assess expectations about treatment among postmenopausal women who received alveolar bone augmentation and dental implants Methods: This is an observational study of women receiving one of three bone augmentation procedures during implant placement: expansion, dehiscence repair, or block graft. Inclusion criteria: age between 55 and 80; twelve remaining teeth; one intra-oral edentulous area with a narrow alveolar ridge. Participants completed questionnaires prior to treatment; data were collected on demographic characteristics, medical/dental history and clinical assessment of the implant. Patient expectations were measured using a 15-item scale assessing expectations about oral function, aesthetics, general health, social function and well-being. Each item was rated on a 7-point scale from 1 being no discomfort, 4 being so-so and 7 being much discomfort. Results: Data are available on 54 women. Mean age of participants was 61.9 (sd=5.4), most were married (54%), had ...

Increased Alveolar Bone Width In Postmenopausal Women Following Implant Placement

Objective: To evaluate the fate of the buccal cortical plate and width of the alveolar bone resul... more Objective: To evaluate the fate of the buccal cortical plate and width of the alveolar bone resulting from surgical augmentation simultaneous with dental implant placement after 9 months using cone beam CT. Method: A subset of 14 patients, who were participants in a best-practice study of postmenopausal women receiving dental implants with horizontal ridge augmentation were analyzed. Cases with a single implant in the posterior mandible with a 6-inch field of view CBCT scan done preoperatively, immediately post-implant placement and at 9 month recalls were selected for this analysis. All implant study sites received a particulate graft or buccal plate expansion. Cross sectional images of the region of interest were created using CB works software version-3.0 with a pitch distance of 1.5mm and a slice thickness of 5mm. The width of the implant site was measured at the center of the implant at a standardized point on the cross sectional images generated at the aforementioned time poin...

Quality of life impacts of dental implant among postmenopausal women

Purpose: to assess quality of life impacts among postmenopausal women who receive alveolar bone a... more Purpose: to assess quality of life impacts among postmenopausal women who receive alveolar bone augmentation and dental implants Methods: This is an observational study of women receiving one of three bone augmentation procedures during implant placement: expansion, dehiscence repair, or block graft. Inclusion criteria: age between 55 and 80; twelve remaining teeth; one intra-oral edentulous area with a narrow alveolar ridge. Participants completed questionnaires prior to treatment, at 1 and 8 weeks and at 9 months post implant placement. Data were collected on demographic characteristics, medical/dental history, clinical assessment of the implant and quality of life impacts using the 14-item Oral Health Impact Profile (OHIP). Two scores were calculated: number of items checked occurring more than occasionally and total severity score. Results: Sixty-three women have enrolled in the study and 28 have been followed for 9 months post-implant placement. Mean age of participants was 61....

Relationship between bisphosphonate exposure, implant stability and serum CTX

Objectives: The effect of bone health and bisphosphonate (BSP) exposure on dental implant outcome... more Objectives: The effect of bone health and bisphosphonate (BSP) exposure on dental implant outcomes is an important issue. This analysis, part of an ongoing best practice investigation of bone health and bone augmentation techniques for implant surgery, assessed the relationship between BSP exposure, implant stability and serum (s)CTX, a biochemical marker of systemic bone resorption. Methods: One SLActive implant site was evaluated in each of 57 postmenopausal women. Each implant placement included a previous or simultaneous bone augmentation procedure. BSP exposure was assessed at time of enrollment and documented as either never or past/current exposure. Current users discontinued BSPs for three months prior to and up to three months after surgery. Implant stability was assessed by resonance frequency analysis at the time of surgery and eight weeks following implant placement (ISQ value). sCTX measurements were obtained by fasting blood collections at treatment planning, as well a...

Bone quality evaluation: Comparison of CBCT and subjective surgical assessment

Objectives: The assessment of local bone quantity and quality is crucial for implant treatment pl... more Objectives: The assessment of local bone quantity and quality is crucial for implant treatment planning. Bone quality depends on the thickness of cortical bone, the abundance of trabecular bone and the overall degree of mineralization. Cone beam computed tomography (CBCT) is an essential diagnostic tool for implant treatment planning. CBCT offers the opportunity to more quantitatively assess bone quality. However, whether these radiological assessments correlate with subjective assessments at surgery is unknown. In this study, we evaluated the relationship between CBCT gray scale values at the implant site and the subjective clinical bone quality assessed at surgery. Methods: Our sample comprised 37 female patients, representing the initial patients enrolled in a large clinical study to evaluate the outcome of bone augmentation procedures for implant placement. All patients were examined by CBCT for treatment planning and immediately after implant placement. The gray values of the c...

CBCT evaluation of buccal bone regeneration in postmenopausal women with and without osteopenia or osteoporosis undergoing dental implant therapy

The Journal of Prosthetic Dentistry, 2015

Because alveolar bone augmentation in osteopenic/osteoporotic women has an uncertain prognosis, o... more Because alveolar bone augmentation in osteopenic/osteoporotic women has an uncertain prognosis, objective and reliable methods should be used to study standard surgical approaches. The purpose of this study was to evaluate bone regeneration 9 months after bone augmentation and implant placement in postmenopausal women with different levels of systemic bone health by using cone beam computed tomography (CBCT) and to test proof of concept for this measurement approach. A subset of 14 participants was analyzed in a best practice study of postmenopausal women receiving dental implants and simultaneous horizontal ridge augmentation. Women were categorized as osteopenic/osteoporotic or normal based on the results of preoperative dual-energy x-ray absorptiometry. All implant study sites received a particulate graft and/or buccal plate expansion. The study sites were evaluated with CBCT preoperatively, immediately postoperatively, and 9 months postoperatively. Nonparametric statistics were used for all analyses. The related samples Wilcoxon signed rank test was used to assess the differences in bone width between time points (α=.05 for all tests). After 9 months, 13 out of 14 participants showed increased bone width compared to the preoperative baseline measurements. The increase was statistically significant for the osteopenic/osteoporotic participants (P=.007), but not for those with normal bone health (P=.066). The CBCT scans showed that mineralized tissue buccal to the implant surface had the radiographic appearance of mature bone. CBCT showed evidence of bone regeneration, with an increase in alveolar ridge width in postmenopausal osteopenic/osteoporotic women subsequent to surgical reconstruction.

Vitamin E deficiency does not induce compensatory antioxidant increases in central nervous system tissue of apolipoprotein E-deficient mice

Journal of Alzheimer's Disease, 2003

Compensatory upregulation in endogenous antioxidants has been shown to accompany certain genetic ... more Compensatory upregulation in endogenous antioxidants has been shown to accompany certain genetic and dietary deficiencies that promote oxidative stress, including that related to Alzheimer's disease. We compared antioxidant levels in brain tissue of normal and transgenic mice lacking apolipoprotein E following dietary deprivation of vitamin E or folate. As described previously, ApoE-deficient mice displayed increased levels of the endogenous antioxidant glutathione as compared to normal mice, and increased these levels further following folate deprivation. By contrast, glutathione was depleted following vitamin E deprivation in brain tissue of normal and ApoE-deficient mice. TBAR analyses confirmed increased oxidative damage following vitamin E deprivation. However, combined deprivation of folate and vitamin E resulted in levels of glutathione intermediate between those observed following deprivation of either agent, indicating that the lack of compensatory increase in glutathione following vitamin E deprivation was not due to overt neurotoxicity. Similar results were observed for total antioxidant levels in brain tissue. The differential response to vitamin E and folate deprivation is consistent with the possibility that specific differences in oxidative damage may result from deficiencies in either of these agents. The lack of a compensatory response to vitamin E deprivation highlights the importance of dietary vitamin E in prevention of chronic neurodegeneration.

MRP3, a new ATP-binding cassette protein localized to the canalicular domain of the hepatocyte

American Journal of Physiology-Gastrointestinal and Liver Physiology, 1999

Bile secretion in liver is driven in large part by ATP-binding cassette (ABC)-type proteins that ... more Bile secretion in liver is driven in large part by ATP-binding cassette (ABC)-type proteins that reside in the canalicular membrane and effect ATP-dependent transport of bile acids, phospholipids, and non-bile acid organic anions. Canalicular ABC-type proteins can be classified into two subfamilies based on membrane topology and sequence identity: MDR1, MDR3, and SPGP resemble the multidrug resistance (MDR) P-glycoprotein, whereas MRP2 is similar in structure and sequence to the multidrug resistance protein MRP1 and transports similar substrates. We now report the isolation of the rMRP3 gene from rat liver, which codes for a protein 1522 amino acids in length that exhibits extensive sequence similarity with MRP1 and MRP2. Northern blot analyses indicate that rMRP3 is expressed in lung and intestine of Sprague-Dawley rats as well as in liver of Eisai hyperbilirubinemic rats and TR− mutant rats, which are deficient in MRP2 expression. rMRP3 expression is also transiently induced in li...

N-acteyl cysteine alleviates oxidative damage to central nervous system of ApoE-deficient mice following folate and vitamin E-deficiency

Journal of Alzheimer's Disease, 2005

Oxidative stress is an early neurodegenerative insult in Alzheimer's disease (AD). Antioxidant me... more Oxidative stress is an early neurodegenerative insult in Alzheimer's disease (AD). Antioxidant mechanisms, including elements of the glutathione (GSH) pathway, undergo at least a transient compensatory increase that is apparently insufficient due to continued oxidative damage during disease progression. Mice deficient in apolipoprotein E, which provide a model for some aspects of AD, undergo increased oxidative damage to brain tissue and cognitive decline when maintained on a folate-free diet, despite a compensatory increase in glutathione synthase transcription and activity as well as increased levels of GSH. Dietary supplementation with N-acetyl cysteine (1 g/kg diet), a cell-permeant antioxidant and GSH precursor, alleviated oxidative damage and cognitive decline, and restored glutathione synthase and GSH levels in ApoE-deficient mice deprived of folate to those of normal mice maintained in the presence of folate. These data support the administration of antioxidant precursors to buffer oxidative damage in neurodegenerative disorders.

Nanosphere-mediated delivery of vitamin E increases its efficacy against oxidative stress resulting from exposure to amyloid beta

Journal of Alzheimer's Disease, 2005

Oxidative stress is an early hallmark of affected neurons in Alzheimer's disease (AD). The antiox... more Oxidative stress is an early hallmark of affected neurons in Alzheimer's disease (AD). The antioxidant vitamin E provided limited neuroprotection in AD, which may have derived from its lipophilic nature and resultant inability to quench cytosolic reactive oxygen species (ROS), including those generated from antecedent membrane oxidative damage. We examined herein whether or not encapsulation into polyethylene glycol (PEG)-based nanospheres, which can enter the cytosol, improved the efficacy of vitamin E against amyloid-β (Aβ)-induced ROS. Unexcapsulated vitamin E prevented Aβ-induced ROS in cultured SH-SY-5Y human neuroblastoma cells only if present prior to, or applied simultaneously with, Aβ treatment. By contrast, encapsulated vitamin E was equally effective if administered 1 hr after Aβ exposure. These findings suggest suggests that nanosphere-mediated delivery methods may be a useful adjunct for antioxidant therapy in AD.

Apple juice concentrate prevents oxidative damage and impaired maze performance in aged mice

Journal of Alzheimer's Disease, 2005

Oxidative stress contributes to age-related cognitive decline. In some instances, consumption of ... more Oxidative stress contributes to age-related cognitive decline. In some instances, consumption of fruits and vegetables rich in antioxidant can provide superior protection than supplementation with purified antioxidants. Our prior studies have shown that supplementation with apple juice concentrate (AJC) alleviates oxidative damage and cognitive decline in a transgenic murine model compromised in endogenous antioxidant potential when challenged with a vitamin-deficient, oxidative stresspromoting diet. Herein, we demonstrate that AJC, administered in drinking water, is neuroprotective in normal, aged mice. Normal mice aged either 9-10 months or 2-2.5 years were maintained for 1 month on a complete diet or a diet lacking folate and vitamin E and containing iron as a pro-oxidant, after which oxidative damage was assayed by thiobarbituric acid-reactive substances and cognitive decline as assayed by performance in a standard Y-maze. Mice 9-12 months of age were unaffected by the deficient diet, while older mice demonstrated statistically-increased oxidative damage and poorer performance in a Y maze test. Supplementation with AJC prevented these neurodegenerative effects. These data are consistent with normal aged individuals being susceptible to neurodegeneration following dietary compromise such as folate deficiency, and a hastened onset of neurodegeneration in those individuals harboring a genetic risk factor such as ApoE deficiency. These findings also support the efficacy of antioxidant supplementation, including consumption of antioxidant-rich foods such as apples, in preventing the decline in cognitive performance that accompanies normal aging.

Differential susceptibity of transgenic mice lacking one or both apolipoprotein alleles to folate and vitamin E deprivation

Journal of Alzheimer's Disease, 2004

The E4 allele of apolipoprotein E (ApoE) is associated with neurodegeneration in part due to incr... more The E4 allele of apolipoprotein E (ApoE) is associated with neurodegeneration in part due to increased oxidative stress. Transgenic mice lacking ApoE (−/−) represent a model for the consequences of deficiencies in ApoE function. Dietary deficiency in folate and vitamin E has previously been shown to potentiate the impact of ApoE deficiency; ApoE−/− mice deprived of folate and vitamin E for 1 month demonstrated increased oxidative damage in brain tissue and impaired cognitive performance as compared to ApoE+/+ mice. Since individuals homozygous for E4 can demonstrate more increased risk for neurodegeneration and an earlier age of onset than individuals heterozygous for E4, we tested the impact of folate and vitamin E deprivation on ApoE+/− mice. Thiobarbituric acid-reactive substances in brain tissue of ApoE+/− were significantly increased compared to ApoE+/+ mice, but this increase was less than that observed in ApoE−/− mice.

17 β-Estradiol alleviates synergistic oxidative stress resulting from folate deprivation and amyloid-β treatment

Journal of Alzheimer's Disease, 2003

Oxidative stress is thought to be a pivotal factor in Alzheimer's disease (AD). Amyloid-β (Aβ) in... more Oxidative stress is thought to be a pivotal factor in Alzheimer's disease (AD). Amyloid-β (Aβ) induces oxidative damage, which is likely to be compounded by deficiencies in endogenous antioxidant capacity. Indeed, folate deprivation, which has been associated with AD, potentiates generation of reactive oxygen species (ROS) by Aβ. We examined whether the antioxidant 17-β-estradiol could attenuate ROS generation following Aβ treatment in the presence and absence of folate using differentiated SH-SY-5Y human neuroblastoma cells. Folate-deprivation and Aβ treatment each induced an increase in ROS, and treatment of folate-deprived cultures with Aβ induced a synergistic increase in ROS. 17-β-estradiol reduced ROS levels in Aβ-treated, folate-deprived cultures to ROS levels observed in cultures treated with Aβ in the presence of folate, suggesting that this antioxidant was able to prevent the synergistic impact of Aβ and folate deprivation on ROS generation. 17-β-estradiol also completely prevented neuronal death induced by both Aβ and folate deprivation individually, and reduced neuronal death following Aβ treatment along with folate deprivation. These findings suggest that therapeutic approaches utilizing antioxidants may be particularly important in conditions such as AD, where multiple factors, including compromises in endogenous antioxidants, promote oxidative stress.

Amyloid-β promotes calcium influx and neurodegeneration via stimulation of L voltage-sensitive calcium channels rather than NMDA channels in cultured neurons

Journal of Alzheimer's Disease, 2001

Communicated by Garth Hall Exposure of cultured neurons and neuronal cells to aggregated amyloid-... more Communicated by Garth Hall Exposure of cultured neurons and neuronal cells to aggregated amyloid-β (Aβ) induces multiple neurodegenerative events including accumulation of cytosolic calcium, generation of reactive oxygen species, abnormal levels of phosphorylation of the microtubule-associated protein tau, and apoptosis. Prevention of accumulation of calcium within the cytosol also prevents all other events, suggesting that calcium accumulation is an early and pivotal event in Aβ neurotoxicity. Calcium influx has been suggested to occur via L voltagesensitive calcium channels or NMDA channels. Calcium influx into differentiated human neuroblastoma cells has been previously attributed to the L voltage-sensitive calcium channel, but the contribution of the NMDA channel was not examined. In the present study, treatment of these cells with MK-801, an antagonist of NMDA channels, failed to attenuate Aβ-induced calcium influx or neurodegeneration, while nimopridine, an antagonist of the L voltage-sensitive calcium channel, blocked Aβ-induced calcium influx. Our findings suggest that NMDA channels do not contribute significantly to Aβ neurotoxicity in these acute cell culture analyses.

Apple juice prevents oxidative stress induced by amyloid-beta in culture

Journal of Alzheimer's Disease, 2004

Increased oxidative stress contributes to the decline in cognitive performance during normal agin... more Increased oxidative stress contributes to the decline in cognitive performance during normal aging and in neurodegerative conditions such as Alzheimer's disease. Dietary supplementation with fruits and vegetables that are high in antioxidant potential have in some cases compensated for oxidative stress. Herein, we examined whether apple juice could alleviate the neurotoxic consequences of exposure of cultured neuronal cells to amyloid-β (Aβ), since at least a portion of the neurotoxicity of Aβ is due to oxidative stress. Apple juice concentrate (AJC; 70 degree brix) was diluted into culture medium of SH-SY-5Y human neuroblastoma cells that had been differentiated for 7 days with 5 µM retinoic acid concurrent with the addition of 20 µM Aβ. AJC prevented the increased generation of reactive oxygen species (ROS) normally induced by Aβ treatment under these conditions. AJC also prevented Aβ-induced calcium influx and apoptosis, each of which results in part due to increased ROS. These findings suggest that the antioxidant potential of apple products can prevent Aβ-induced oxidative damage.

The Mul maize transposable element induces tissue-specific aberrant splicing and polyadenylation in two Adhl mutants

Molecular and Cellular Biology, 1990

Tissue of Apolipoprotein E-Deficient Mice

Amyloid- promotes calcium influx and

Journal of Alzheimer's disease: JAD

ABSTRACT

Bone Augmentation, Presurgical Expectations and Outcomes in Dental Implant Therapy

Objective: to assess expectations about implant therapy among women who required alveolar bone au... more Objective: to assess expectations about implant therapy among women who required alveolar bone augmentation and how expectations shape post-surgical outcomes. Methods: This is an observational study of postmenopausal women receiving implants with bone augmentation focused on the relationship between osteopenia/osteoporosis and augmentation outcomes. The augmentation procedures included: expansion, particulate graft, expansion+particulate graft or block graft. Inclusion criteria: age between 45 and 85; 12 teeth; edentulous area with a narrow alveolar ridge. Participants completed questionnaires prior to treatment, at one week, eight weeks and nine months. Data were collected on demographics, implant location and bone density. Expectations and perceived outcomes were measured using a 15-item scale on symptoms, oral and social function. Items were rated on a 7-point scale from 1 being no discomfort to 7 being much discomfort. Results: The mean age of participants (n=80) was 62 years (s...

Bone Health in Postmenopausal Women Undergoing Bone Augmentation and Implantation

Objective: No reports to date have evaluated specific measures of bone metabolism, bone health pa... more Objective: No reports to date have evaluated specific measures of bone metabolism, bone health parameters and success of alveolar bone augmentation procedures. This ongoing best practice descriptive study, in response to an NIDCR initiative, is designed to evaluate surgical bone augmentation and dental implant placement outcomes among postmenopausal women of varying bone health. This abstract reports preliminary descriptive bone health findings for the first 31 participants. Methods: Participants (mean=61.2 yrs) were recruited from the University of Connecticut Health Center clinics and the population at large. Bone mineral density (BMD) at lumbar spine, femoral neck and total hip as well as 25-hydroxyvitamin D was determined at baseline. Bone turnover markers, including C-telopeptide (sCTX) and procollagen peptide (P1NP), were measured at baseline, 1 week and 8 weeks post-procedure. Results: All participants had augmentation simultaneous with dental implant placement. Sixteen parti...

Expectations about dental implant treatment among postmenopausal women

Objectives: to assess expectations about treatment among postmenopausal women who received alveol... more Objectives: to assess expectations about treatment among postmenopausal women who received alveolar bone augmentation and dental implants Methods: This is an observational study of women receiving one of three bone augmentation procedures during implant placement: expansion, dehiscence repair, or block graft. Inclusion criteria: age between 55 and 80; twelve remaining teeth; one intra-oral edentulous area with a narrow alveolar ridge. Participants completed questionnaires prior to treatment; data were collected on demographic characteristics, medical/dental history and clinical assessment of the implant. Patient expectations were measured using a 15-item scale assessing expectations about oral function, aesthetics, general health, social function and well-being. Each item was rated on a 7-point scale from 1 being no discomfort, 4 being so-so and 7 being much discomfort. Results: Data are available on 54 women. Mean age of participants was 61.9 (sd=5.4), most were married (54%), had ...

Increased Alveolar Bone Width In Postmenopausal Women Following Implant Placement

Objective: To evaluate the fate of the buccal cortical plate and width of the alveolar bone resul... more Objective: To evaluate the fate of the buccal cortical plate and width of the alveolar bone resulting from surgical augmentation simultaneous with dental implant placement after 9 months using cone beam CT. Method: A subset of 14 patients, who were participants in a best-practice study of postmenopausal women receiving dental implants with horizontal ridge augmentation were analyzed. Cases with a single implant in the posterior mandible with a 6-inch field of view CBCT scan done preoperatively, immediately post-implant placement and at 9 month recalls were selected for this analysis. All implant study sites received a particulate graft or buccal plate expansion. Cross sectional images of the region of interest were created using CB works software version-3.0 with a pitch distance of 1.5mm and a slice thickness of 5mm. The width of the implant site was measured at the center of the implant at a standardized point on the cross sectional images generated at the aforementioned time poin...

Quality of life impacts of dental implant among postmenopausal women

Purpose: to assess quality of life impacts among postmenopausal women who receive alveolar bone a... more Purpose: to assess quality of life impacts among postmenopausal women who receive alveolar bone augmentation and dental implants Methods: This is an observational study of women receiving one of three bone augmentation procedures during implant placement: expansion, dehiscence repair, or block graft. Inclusion criteria: age between 55 and 80; twelve remaining teeth; one intra-oral edentulous area with a narrow alveolar ridge. Participants completed questionnaires prior to treatment, at 1 and 8 weeks and at 9 months post implant placement. Data were collected on demographic characteristics, medical/dental history, clinical assessment of the implant and quality of life impacts using the 14-item Oral Health Impact Profile (OHIP). Two scores were calculated: number of items checked occurring more than occasionally and total severity score. Results: Sixty-three women have enrolled in the study and 28 have been followed for 9 months post-implant placement. Mean age of participants was 61....

Relationship between bisphosphonate exposure, implant stability and serum CTX

Objectives: The effect of bone health and bisphosphonate (BSP) exposure on dental implant outcome... more Objectives: The effect of bone health and bisphosphonate (BSP) exposure on dental implant outcomes is an important issue. This analysis, part of an ongoing best practice investigation of bone health and bone augmentation techniques for implant surgery, assessed the relationship between BSP exposure, implant stability and serum (s)CTX, a biochemical marker of systemic bone resorption. Methods: One SLActive implant site was evaluated in each of 57 postmenopausal women. Each implant placement included a previous or simultaneous bone augmentation procedure. BSP exposure was assessed at time of enrollment and documented as either never or past/current exposure. Current users discontinued BSPs for three months prior to and up to three months after surgery. Implant stability was assessed by resonance frequency analysis at the time of surgery and eight weeks following implant placement (ISQ value). sCTX measurements were obtained by fasting blood collections at treatment planning, as well a...

Bone quality evaluation: Comparison of CBCT and subjective surgical assessment

Objectives: The assessment of local bone quantity and quality is crucial for implant treatment pl... more Objectives: The assessment of local bone quantity and quality is crucial for implant treatment planning. Bone quality depends on the thickness of cortical bone, the abundance of trabecular bone and the overall degree of mineralization. Cone beam computed tomography (CBCT) is an essential diagnostic tool for implant treatment planning. CBCT offers the opportunity to more quantitatively assess bone quality. However, whether these radiological assessments correlate with subjective assessments at surgery is unknown. In this study, we evaluated the relationship between CBCT gray scale values at the implant site and the subjective clinical bone quality assessed at surgery. Methods: Our sample comprised 37 female patients, representing the initial patients enrolled in a large clinical study to evaluate the outcome of bone augmentation procedures for implant placement. All patients were examined by CBCT for treatment planning and immediately after implant placement. The gray values of the c...

CBCT evaluation of buccal bone regeneration in postmenopausal women with and without osteopenia or osteoporosis undergoing dental implant therapy

The Journal of Prosthetic Dentistry, 2015

Because alveolar bone augmentation in osteopenic/osteoporotic women has an uncertain prognosis, o... more Because alveolar bone augmentation in osteopenic/osteoporotic women has an uncertain prognosis, objective and reliable methods should be used to study standard surgical approaches. The purpose of this study was to evaluate bone regeneration 9 months after bone augmentation and implant placement in postmenopausal women with different levels of systemic bone health by using cone beam computed tomography (CBCT) and to test proof of concept for this measurement approach. A subset of 14 participants was analyzed in a best practice study of postmenopausal women receiving dental implants and simultaneous horizontal ridge augmentation. Women were categorized as osteopenic/osteoporotic or normal based on the results of preoperative dual-energy x-ray absorptiometry. All implant study sites received a particulate graft and/or buccal plate expansion. The study sites were evaluated with CBCT preoperatively, immediately postoperatively, and 9 months postoperatively. Nonparametric statistics were used for all analyses. The related samples Wilcoxon signed rank test was used to assess the differences in bone width between time points (α=.05 for all tests). After 9 months, 13 out of 14 participants showed increased bone width compared to the preoperative baseline measurements. The increase was statistically significant for the osteopenic/osteoporotic participants (P=.007), but not for those with normal bone health (P=.066). The CBCT scans showed that mineralized tissue buccal to the implant surface had the radiographic appearance of mature bone. CBCT showed evidence of bone regeneration, with an increase in alveolar ridge width in postmenopausal osteopenic/osteoporotic women subsequent to surgical reconstruction.