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1.  Pretreatment with Ginseng Fruit Saponins Affects Serotonin Expression in an Experimental Comorbidity Model of Myocardial Infarction and Depression 
Aging and Disease  2016;7(6):680-686.
We previously demonstrated that serotonin (5-HT) and 5-HT2A receptor (5-HT2AR) levels in platelets were up- or down-regulated after myocardial infarction (MI) associated with depression. In this study, we further evaluated the effects of pretreatment with ginseng fruit saponins (GFS) on the expression of 5-HT and 5-HT2AR in MI with or without depression. Eighty Sprague-Dawley (SD) rats were treated with saline and GFS (n=40 per group). The animals were then randomly divided into four subgroups: sham, MI, depression, and MI + depression (n=10 per subgroup). Protein levels of 5-HT and 5-HT2AR in the serum, platelets and brain tissues were determined with ELISA. The results demonstrated that serum 5-HT levels was significantly increased by GFS pretreatment in all subgroups (except the sham subgroup) when compared with saline-treated counterparts (p<0.01). In platelets, GFS pretreatment significantly increased 5-HT levels in all subgroups when compared with their respective saline-treated counterparts (p<0.01). Brain 5-HT levels also declined with GFS pretreatment in the MI-only and depression-only subgroups (p<0.05 vs. saline pretreatment). With respect to 5-HT2AR levels, platelet 5-HT2AR was decreased in GFS pretreated MI, depression and MI + depression subgroups (p<0.01 vs. saline pretreatment). Similarly, brain 5-HT2AR levels decreased in all four subgroups pretreated with GFS (p<0.01 vs. saline pretreatment). We conclude that GFS plays a clear role in modulating 5-HT and 5-HT2AR expressions after MI and depression. Although the effects of GFS on brain 5-HT remain to be elucidated, its therapeutic potential for comorbidities of acute cardiovascular events and depression appears to hold much promise.
doi:10.14336/AD.2016.0729
PMCID: PMC5198858  PMID: 28053817
serotonin; ginseng; myocardial infarction; depression; brain
2.  Association between Serum Magnesium Levels and Depression in Stroke Patients 
Aging and Disease  2016;7(6):687-690.
Post-stroke depression (PSD) is a common psychiatric complication of stroke that is associated with a poor outcome in stroke patients. Our aim was to assess the association between the serum magnesium levels and the presence of PSD in Chinese patients. Two hundred nine stroke patients were included in the study. Depressive symptoms were measured by the 17-Hamilton Rating Scale for Depression at 3 months after stroke. Based on the depressive symptoms, diagnoses of depression were made in line with the DSM-IV criteria for PSD. Serum magnesium levels were evaluated using the dimethyl aniline blue colorimetric method at admission. Multivariate analyses were conducted using logistic regression models. Further, 120 normal subjects were recruited, and their serum magnesium levels were also measured as control. At 3 months, fifty-nine patients (28.2%) were diagnosed as PSD. The serum magnesium levels were significantly lower in both PSD patients and non-PSD patients than in normal subjects (p < 0.001). Indeed, patients with PSD showed lower serum magnesium levels (p < 0.001) than did non-PSD patients at admission. In the multivariate analyses, after adjusting for potential variables, we found that an increased risk of PSD was associated with serum magnesium levels ≤ 0.84mmol/L (OR 2.614, 95% CI 1.178-5.798, p=0.018). Low serum magnesium levels at admission were found to be associated with the presence of PSD at 3 months after stroke.
doi:10.14336/AD.2016.0402
PMCID: PMC5198859  PMID: 28053818
magnesium; depression; stroke; biochemical marker
3.  Thalamic Atrophy Contributes to Low Slow Wave Sleep in Neuromyelitis Optica Spectrum Disorder 
Aging and Disease  2016;7(6):691-696.
Slow wave sleep abnormality has been reported in neuromyelitis optica spectrum disorder (NMOSD), but mechanism for such abnormality is unknown. To determine the structural defects in the brain that account for the decrease of slow wave sleep in NMOSD patients. Thirty-three NMOSD patients and 18 matched healthy controls (HC) were enrolled. Polysomnography was used to monitor slow wave sleep and three-dimensional T1-weighted MRIs were obtained to assess the alterations of grey matter volume. The percentage of deep slow wave sleep decreased in 93% NMOSD patients. Compared to HC, a reduction of grey matter volume was found in the bilateral thalamus of patients with a lower percentage of slow wave sleep (FWE corrected at cluster-level, p < 0.05, cluster size > 400 voxels). Furthermore, the right thalamic fraction was positively correlated with the decrease in the percentage of slow wave sleep in NMOSD patients (p < 0.05, FDR corrected, cluster size > 200 voxels). Our study identified that thalamic atrophy is associated with the decrease of slow wave sleep in NMOSD patients. Further studies should evaluate whether neurotransmitters or hormones which stem from thalamus are involved in the decrease of slow wave sleep.
doi:10.14336/AD.2016.0419
PMCID: PMC5198860  PMID: 28053819
neuromyelitis optica spectrum disorder; slow wave sleep; brain structure; magnetic resonance imaging
4.  Effects of Different Concurrent Resistance and Aerobic Training Frequencies on Muscle Power and Muscle Quality in Trained Elderly Men: A Randomized Clinical Trial 
Aging and Disease  2016;7(6):697-704.
Muscle power is a strong predictor of functional status in the elderly population and is required to perform different daily activities. To compare the effects of different weekly training frequencies on muscle power and muscle quality induced by concurrent training (resistance + aerobic) in previously trained elderly men. Twenty-four trained elderly men (65 ± 4 years), previously engaged in a regular concurrent training program, three times per week, for the previous five months, were randomly allocated to concurrent training programs in which training was performed either twice a week (2·week-1, n = 12) or three times per week (3·week-1, n = 12). The groups trained with an identical exercise intensity and volume per session for 10 weeks. Before and after the exercise training, we examined muscle power, as estimated by countermovement jump height; knee extensor isokinetic peak torque at 60 and 180o.s-1; and muscle quality, a quotient between the one-repetition maximum of the knee extensors and the sum of quadriceps femoris muscle thickness determined by ultrasonography. Additionally, as secondary outcomes, blood pressure and reactive hyperemia were evaluated. Two-way ANOVA with repeated measures were used and statistical significance was set at α = 0.05. Muscular power (2·week-1: 7%, and 3·week-1: 10%) and muscle quality (2·week-1: 15%, and 3·week-1: 8%) improved with the concurrent exercise training (p < 0.001) but with no differences between groups. The isokinetic peak torque at 60 (2·week-1: 4%, and 3·week-1: 2%) and 180o.s-1 (2·week-1: 7%, and 3·week-1: 1%) increased in both groups (p = 0.036 and p=0.014, respectively). There were no changes in blood pressure or reactive hyperemia with the concurrent training. Concurrent training performed twice a week promotes similar adaptations in muscular power and muscle quality when compared with the same program performed three times per week in previously trained elderly men.
doi:10.14336/AD.2016.0504
PMCID: PMC5198861  PMID: 28053820
Exercise; combined training; resistance training; aerobic training; aging; functional outcomes
5.  MicroRNA-181c Exacerbates Brain Injury in Acute Ischemic Stroke 
Aging and Disease  2016;7(6):705-714.
MicroRNA-181 (miR-181) is highly expressed in the brain, and downregulated in miRNA expression profiles of acute ischemic stroke patients. However, the roles of miR-181c in stroke are not known. The clinical relevance of miR-181c in acute stroke patients was evaluated by real-time PCR and correlation analyses. Proliferation and apoptosis of BV2 microglial cells and Neuro-2a cells cultured separately or together under oxidative stress or inflammation were assessed with the Cell Counting Kit-8 and by flow cytometry, respectively. Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in C57/BL6 mice, and cerebral infarct volume, microglia activation, and expression of pro-apoptotic factors were evaluated by 2,3,5-triphenyl-2H-tetrazolium chloride staining, immunocytochemistry, and western blotting, respectively. Plasma levels of miR-181c were decreased in stroke patients relative to healthy individuals, and were positively correlated with neutrophil number and blood platelet count and negatively correlated with lymphocyte number. Lipopolysaccharide (LPS)/hydrogen peroxide (H2O2) treatment inhibited BV2 microglia proliferation without inducing apoptosis, while miR-181c reduced proliferation but increased the apoptosis of these cells with or without LPS/H2O2 treatment. LPS/H2O2 induced apoptosis in Neuro-2a cells co-cultured with BV2 cells, an effect that was potentiated by miR-181c. In the MCAO model, miR-181c agomir modestly increased infarct volume, markedly decreased microglia activation and B cell lymphoma-2 expression, and increased the levels of pro-apoptotic proteins in the ischemic brain. Our data indicate that miR-181c contributes to brain injury in acute ischemic stroke by promoting apoptosis of microglia and neurons via modulation of pro- and anti-apoptotic proteins.
doi:10.14336/AD.2016.0320
PMCID: PMC5198862  PMID: 28053821
microRNA-181; stroke; microglia; neuron; apoptosis
6.  Bulbocavernosus Reflex Test for Diagnosis of Pudendal Nerve Injury in Female Patients with Diabetic Neurogenic Bladder 
Aging and Disease  2016;7(6):715-720.
The study was designed to investigate the clinical application and significance of the bulbocavernosus reflex (BCR) test for diagnosing diabetic neurogenic bladder (DNB) in female subjects. In this study, 68 female patients with DNB and 40 female normal controls were subjected to a nerve conduction study (NCS) of all four limbs and the BCR test. The data were analyzed and compared, and the corresponding diagnostic sensitivities were discussed. Mean BCR latency for female DNB patients was significantly prolonged, compared to that of the control group, suggesting pudendal nerve injuries in female DNB patients. Moreover, DNB patients were categorized according to the diabetes course. Compared to that of Group A (diabetes course < 5 y), the mean BCR latency was significantly prolonged in Group B (diabetes course between 5 and 10 y) and then further prolonged in Group C (diabetes course > 10 y), which were all longer than the control group. Furthermore, compared with that of the controls, the mean BCR latency was prolonged in DNB patients with or without NCS abnormalities in limbs. Nevertheless, no significant difference was observed in BCR latency between DNB patients with and without NCS abnormalities. Significantly increasing trends were also observed in the NCS and BCR abnormality rates along with increased diabetes course. Most importantly, compared with the NCS of limbs, the BCR test was more sensitive in diagnosing DNB in the female subjects. Overall, our findings suggest that the BCR test would help to assess the pudendal nerve injury in female DNB patients, which might be a potential diagnostic tool in the clinic.
doi:10.14336/AD.2016.0309
PMCID: PMC5198863  PMID: 28053822
diabetic neurogenic bladder (DNB); bulbocavernosus reflex (BCR); nerve conduction study (NCS); female; diagnosis
7.  Global Metabolic Profiling of Plasma Shows that Three-Year Mild-Caloric Restriction Lessens an Age-Related Increase in Sphingomyelin and Reduces L-leucine and L-phenylalanine in Overweight and Obese Subjects 
Aging and Disease  2016;7(6):721-733.
The effect of weight loss from long-term, mild-calorie diets (MCD) on plasma metabolites is unknown. This study was to examine whether MCD-induced weight reduction caused changes in the extended plasma metabolites. Overweight and obese subjects aged 40-59 years consumed a MCD (approximately 100 kcal/day deficit, n=47) or a weight-maintenance diet (control, n=47) in a randomized, controlled design with a three-year clinical intervention period and plasma samples were analyzed by using UPLC-LTQ-Orbitrap mass spectrometry. The three-year MCD intervention resulted in weight loss (-8.87%) and significant decreases in HOMA-IR and TG. The three-year follow-up of the MCD group showed reductions in the following 13 metabolites: L-leucine; L-phenylalanine; 9 lysoPCs; PC (18:0/20:4); and SM (d18:0/16:1). The three-year MCD group follow-up identified increases in palmitic amide, oleamide, and PC (18:2/18:2). Considering the age-related alterations in the identified metabolites, the MCD group showed a greater decrease in L-leucine, L-phenylalanine, and SM (d18:0/16:1) compared with those of the control group. Overall, the change (Δ) in BMI positively correlated with the ΔTG, ΔHOMA-IR, ΔL-leucine, and ΔSM (d18:0/16:1). The ΔHOMA-IR positively correlated with ΔTG, ΔL-leucine, ΔL-phenylalanine, and ΔSM (d18:0/16:1). The weight loss resulting from three-year mild-caloric restriction lessens the age-related increase in SM and reduces L-leucine and L-phenylalanine in overweight and obese subjects. These changes were coupled with improved insulin resistance (ClinicalTrials.gov: NCT02081898).
doi:10.14336/AD.2016.0330
PMCID: PMC5198864  PMID: 28053823
mild-calorie diet; BMI; sphingomyelin; L-leucine; L-phenylalanine
8.  Low Normal TSH levels are Associated with Impaired BMD and Hip Geometry in the Elderly 
Aging and Disease  2016;7(6):734-743.
Subclinical hyperthyroidism is known to be associated with the risk of fractures in elderly people. However, there are few studies assessing whether low normal thyroid-stimulating hormone (TSH) levels affect bone density and geometry. Here, we aimed to assess the influence of the TSH level on bone mineral density (BMD) and geometry in elderly euthyroid subjects. This was a cross-sectional cohort study. A total of 343 men and 674 women with euthyroidism were included and analyzed separately. The subjects were divided into tertiles based on the serum TSH level. The BMD and geometry were measured using dual-energy X-ray absorptiometry and a hip structural analysis program. Multiple regression analysis was used to compute the odds ratios of osteoporosis in the lower TSH tertile group and the association between geometry parameters and the TSH level. We found that the femoral neck and total hip BMDs were lower in the lower TSH tertile group. In women, the cross-sectional area and cortical thickness of the femur were negatively associated with the TSH level in all three regions (the narrow neck, intertrochanter, and femoral shaft); however, in men, these geometry parameters were significantly associated with the TSH level only in the intertrochanter region. The buckling ratio, a bone geometry parameter representing cortical instability, was significantly higher in the lower TSH tertile group in all three regions in women, but not in men. Our results indicated that lower TSH levels in the euthyroid range are related to lower BMD and weaker femoral structure in elderly women.
doi:10.14336/AD.2016.0325
PMCID: PMC5198865  PMID: 28053824
TSH; euthyroidism; elderly people; bone density; bone geometry
9.  Sensorineural Organs Dysfunction and Cognitive Decline: A Review Article 
Aging and Disease  2016;7(6):763-769.
Vision, hearing, olfaction, and cognitive function are essential components of healthy and successful aging. Multiple studies demonstrate relationship between these conditions with cognitive function. The present article focuses on hearing loss, visual impairment, olfactory loss, and dual sensory impairments in relation to cognitive declination and neurodegenerative disorders. Sensorineural organ impairment is a predictive factor for mild cognitive impairment and neurodegenerative disorders in the elderly. We recommend early detection of sensorineural dysfunction by history, physical examination, and screening tests. Assisted device and early cognitive rehabilitation may be beneficial. Future research is warranted in order to explore advanced treatment options and method to slow progression for cognitive declination and sensorineural organ impairment.
doi:10.14336/AD.2016.0515
PMCID: PMC5198866  PMID: 28053826
cognitive decline; olfaction loss; vision loss; hearing loss; aging
10.  Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson’s Disease 
Aging and Disease  2016;7(6):745-762.
Flavonoids are known to trigger the intrinsic genetic adaptive programs to hypoxic or oxidative stress via estrogen receptor engagement or upstream kinase activation. To reveal specific structural requirements for direct stabilization of the transcription factors responsible for triggering the antihypoxic and antioxidant programs, we studied flavones, isoflavones and catechols including dihydroxybenzoate, didox, levodopa, and nordihydroguaiaretic acid (NDGA), using novel luciferase-based reporters specific for the first step in HIF1 or Nrf2 protein stabilization. Distinct structural requirements for either transcription factor stabilization have been found: as expected, these requirements for activation of HIF ODD-luc reporter correlate with in silico binding to HIF prolyl hydroxylase. By contrast, stabilization of Nrf2 requires the presence of 3,4-dihydroxy- (catechol) groups. Thus, only some but not all flavonoids are direct activators of the hypoxic and antioxidant genetic programs. NDGA from the Creosote bush resembles the best flavonoids in their ability to directly stabilize HIF1 and Nrf2 and is superior with respect to LOX inhibition thus favoring this compound over others. Given much higher bioavailability and stability of NDGA than any flavonoid, NDGA has been tested in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-animal model of Parkinson’s Disease and demonstrated neuroprotective effects.
doi:10.14336/AD.2016.0505
PMCID: PMC5201116  PMID: 28053825
Parkinson’s disease model; glutathione depletion model; HIF prolyl hydroxylase; lipoxygenase; fisetin; luteolin; Keap1
11.  Oxidative Stress-induced Telomere Length Shortening of Circulating Leukocyte in Patients with Obstructive Sleep Apnea 
Aging and Disease  2016;7(5):604-613.
The main mechanism of pathogenesis which causes systemic complications in obstructive sleep apnea (OSA) patients is believed to be intermittent hypoxia-induced intermediary effect and it depends on the burden of oxidative stress during sleep. We aimed to search the predictive markers which reflect the burden of systemic oxidative stress in patients with OSA and whether excessive telomere length shortening is a characteristic feature that can assess oxidative stress levels. We used quantitative PCR to measure telomere length using peripheral blood genomic DNA. Telomere lengths were compared in an age- and body mass index (BMI)-dependent manner in 34 healthy volunteers and 43 OSA subjects. We also performed reactive oxygen species assay to measure the concentration of hydrogen peroxide in the peripheral blood of healthy volunteers and OSA subjects. We found that the serum concentration of hydrogen peroxide was considerably higher in OSA patients, and that this was closely related with the severity of OSA. Significantly shortened telomere length was observed in the circulating leukocytes of the peripheral blood of OSA patients, and telomere length shortening was aggravated more acutely in an age- and BMI-dependent manner. An inverse correlation was observed between the concentration of hydrogen peroxide and the telomere length of OSA patients and excessive telomere length shortening was also linked to severity of OSA. The results provided evidence that telomere length shortening or excessive cellular aging might be distinctive in circulating leukocyte of OSA patients and may be an predictive biomarker for reflect the burden of oxidative stress in the peripheral blood of OSA patients.
doi:10.14336/AD.2016.0215
PMCID: PMC5036955  PMID: 27699083
obstructive sleep apnea; telomere length; oxidative stress; peripheral blood; leukocyte
12.  Brain Formaldehyde is Related to Water Intake behavior 
Aging and Disease  2016;7(5):561-584.
A promising strategy for the prevention of Alzheimer’s disease (AD) is the identification of age-related changes that place the brain at risk for the disease. Additionally, AD is associated with chronic dehydration, and one of the significant changes that are known to result in metabolic dysfunction is an increase in the endogenous formaldehyde (FA) level. Here, we demonstrate that the levels of uric formaldehyde in AD patients were markedly increased compared with normal controls. The brain formaldehyde levels of wild-type C57 BL/6 mice increased with age, and these increases were followed by decreases in their drinking frequency and water intake. The serum arginine vasopressin (AVP) concentrations were also maintained at a high level in the 10-month-old mice. An intravenous injection of AVP into the tail induced decreases in the drinking frequency and water intake in the mice, and these decreases were associated with increases in brain formaldehyde levels. An ELISA assay revealed that the AVP injection increased both the protein level and the enzymatic activity of semicarbazide-sensitive amine oxidase (SSAO), which is an enzyme that produces formaldehyde. In contrast, the intraperitoneal injection of formaldehyde increased the serum AVP level by increasing the angiotensin II (ANG II) level, and this change was associated with a marked decrease in water intake behavior. These data suggest that the interaction between formaldehyde and AVP affects the water intake behaviors of mice. Furthermore, the highest concentration of formaldehyde in vivo was observed in the morning. Regular water intake is conducive to eliminating endogenous formaldehyde from the human body, particularly when water is consumed in the morning. Establishing good water intake habits not only effectively eliminates excess formaldehyde and other metabolic products but is also expected to yield valuable approaches to reducing the risk of AD prior to the onset of the disease.
doi:10.14336/AD.2016.0323
PMCID: PMC5036952  PMID: 27699080
formaldehyde; water intake; semicarbazide-sensitive amine oxidase; arginine vasopressin; behavior
13.  Fear of Falling Correlates with Subtle Neuromuscular Balance and Strength Deficits of Fragility Fracture Patients 
Aging and Disease  2016;7(5):585-592.
Fragility fractures, or fractures occurring from a low-trauma event, are extremely prevalent among the elderly population worldwide and associated with significant mortality and morbidity. This study evaluated the relationship between FES-I Fear of Falling Survey results, self-reported activity restrictions via the SF-36 survey, and scores recorded by portable, inexpensive clinical assessment tools (CATs) during dynamic functional tasks. Low scores during these tasks may indicate functional deficits that put patients at risk for falls and subsequent fragility fractures. Forty-one subjects (20 fragility fracture patients, 21 controls without history of fragility fractures) over the age of 50 were recruited from three outpatient orthopaedic clinics. All subjects were administered a FES-I Fear of Falling Survey, a portion of an SF-36 survey, and tested using three different portable CATs: the Wii Balance Board, iPod Level Belt and Saehan Squeeze Hand Grip Dynamometer. There were several measured variables that showed a moderate correlation with Fear of Falling scores. Of note, correlations between FES-I scores and maximum hand grip strength for both the dominant hand (R= -0.302, p=0.069) and non-dominant hand (R= -0.309, p=0.059), as well as maximum anterior-posterior sway measured by the iPod Level Belt (R=0.320, p=0.056) were found to be marginally significant. In addition, the correlation between FES-I and average anterior-posterior sway was found to be significant (R=0.416, p=0.012). The Nintendo Wii and iPod Level Belt are relatively inexpensive, portable tools that can assess patients for subtle deficits during dynamic functional tasks. The results indicate that these tools can provide a more objective measure of a patient’s limitations during daily activities such as walking by assigning them a numerical value and correlating this value to physical deficits that impact balance and coordination. In the future, CATs may also have a role in predicting outcomes and in individualizing care, therapy, and at-home preventive measures.
doi:10.14336/AD.2016.0302
PMCID: PMC5036953  PMID: 27699081
clinical assessment tool; Nintendo® Wii Balance Board; Level Belt; advanced practice provider; fragility fracture
14.  Relevance Study on Cerebral Infarction and Resistin Gene Polymorphism in Chinese Han Population 
Aging and Disease  2016;7(5):593-603.
Recent research on genome-wide associations has implicated that the serum resistin level and its gene polymorphism are associated with cerebral infarction (CI) morbidity and prognosis, and could thereby regulate CI. This study aimed to investigate the association between the resistin single nucleotide polymorphism (SNP) and the susceptibility to CI in the Chinese Han population. A total of 550 CI patients and 313 healthy controls were genotyped. Nine SNPs of the resistin gene previously shown were sequenced and assessed for an association with CI. The numbers of GG genotype carriers of rs3219175 and rs3486119 in the CI group were significantly higher than those in the control group among the middle-aged group (aged 45-65), at 76% vs 67.9% (P=0.025) and 75.5% vs 67.9% (P=0.031). rs3219175 and rs34861192 were associated with CI in the dominant and superdominant models according to the genetic model analysis (P<0.05). Meanwhile, there was strong linkage disequilibrium among the rs34124816, rs3219175, rs34861192, rs1862513, rs3745367, 180C/G and rs3745369 sites. In a haplotype analysis, the occurrence rate of the haplotype AGGCAGC was 1.97 times (P<0.05) higher in the patient group than in the control group. In addition, the numbers of GG genotype carriers of rs3219175 and rs3486119 in the middle-aged male CI patients and the middle-aged small artery occlusion (SAO) CI patients were higher than those in the control group (P<0.05). In the Chinese Han middle-aged population, the GG gene type carriers of the resistin gene sites rs3219175 and rs34861192 had a high risk for CI onset, especially in middle-aged male patients and SAO CI in all middle-aged patients.
doi:10.14336/AD.2016.0201
PMCID: PMC5036954  PMID: 27699082
Cerebral infarction; Resistin; Single nucleotide polymorphism; Male; Small artery occlusion type
15.  Serum IL-33 Is a Novel Diagnostic and Prognostic Biomarker in Acute Ischemic Stroke 
Aging and Disease  2016;7(5):614-622.
Interleukin-33 (IL-33), a newly recognized IL-1 family member, is expressed in various tissues and cells, and involved in pathogenesis of many human diseases. For example, IL-33 plays a protective role in cardiovascular diseases. However, the role of IL-33 in acute ischemic stroke (AIS) remains unclear. This study aims to investigate whether IL-33 level in AIS patient serum can be used as a potential diagnostic and prognostic marker. The study included two hundred and six patients with first-ever ischemic stroke, who were admitted within 72 hours after stroke onset. The serum level of IL-33 was measured with ELISA and the severity of AIS patients on admission was evaluated based on the National Institutes of Health Stroke Scale (NIHSS) score. The functional outcome at 3 months was determined using the Barthel index (BI). We found that serum IL-33 was significantly higher (P < 0.001) in patients with AIS [57.68 ng/L (IQR, 44.95-76.73)] compared with healthy controls [47.48 ng/L (IQR, 38.67-53.78)]. IL-33 was an independent diagnostic biomarker for AIS with an OR of 1.051 (95%Cl, 1.018-1.085; P=0.002). Serum IL-33 was higher (P < 0.05) in the stroke patients with small cerebral infarction volume compared to AIS patients with large cerebral infarction. In addition, serum IL-33 was also significantly higher (P = 0.001) in the patients with mild stroke, compared to the patients with severe stroke. Furthermore, serum IL-33 level in AIS patients with a worse outcome was higher (P < 0.001) compared to AIS patients with a better outcome. IL-33 was also an independent predictor for the functional outcome with an adjusted OR of 0.932 (95% CI, 0.882-0.986). Our results suggest that the lower level of serum IL-33 is associated with large infarction volume and greater stroke severity in AIS patients. Thus, IL-33 can be used as a novel and independent diagnostic and predicting prognostic marker in AIS.
doi:10.14336/AD.2016.0207
PMCID: PMC5036956  PMID: 27699084
interleukin-33; acute ischemic stroke; outcome; biomarker; diagnosis
16.  Proteomic Analysis of the Peri-Infarct Area after Human Umbilical Cord Mesenchymal Stem Cell Transplantation in Experimental Stroke 
Aging and Disease  2016;7(5):623-634.
Among various therapeutic approaches for stroke, treatment with human umbilical cord mesenchymal stem cells (hUC-MSCs) has acquired some promising results. However, the underlying mechanisms remain unclear. We analyzed the protein expression spectrum of the cortical peri-infarction region after ischemic stroke followed by treatment with hUC-MSCs, and found 16 proteins expressed differentially between groups treated with or without hUC-MSCs. These proteins were further determined by Gene Ontology term analysis and network with CD200-CD200R1, CCL21-CXCR3 and transcription factors. Three of them: Abca13, Grb2 and Ptgds were verified by qPCR and ELISA. We found the protein level of Abca13 and the mRNA level of Grb2 consistent with results from the proteomic analysis. Finally, the function of these proteins was described and the potential proteins that deserve to be further studied was also highlighted. Our data may provide possible underlying mechanisms for the treatment of stroke using hUC-MSCs.
doi:10.14336/AD.2016.0121
PMCID: PMC5036957  PMID: 27699085
stroke; hUC-MSCs; proteomics; iTRAQ; transplantation; human
17.  Atrial Fibrillation: The Science behind Its Defiance 
Aging and Disease  2016;7(5):635-656.
Atrial fibrillation (AF) is the most prevalent arrhythmia in the world, due both to its tenacious treatment resistance, and to the tremendous number of risk factors that set the stage for the atria to fibrillate. Cardiopulmonary, behavioral, and psychological risk factors generate electrical and structural alterations of the atria that promote reentry and wavebreak. These culminate in fibrillation once atrial ectopic beats set the arrhythmia process in motion. There is growing evidence that chronic stress can physically alter the emotion centers of the limbic system, changing their input to the hypothalamic-limbic-autonomic network that regulates autonomic outflow. This leads to imbalance of the parasympathetic and sympathetic nervous systems, most often in favor of sympathetic overactivation. Autonomic imbalance acts as a driving force behind the atrial ectopy and reentry that promote AF. Careful study of AF pathophysiology can illuminate the means that enable AF to elude both pharmacological control and surgical cure, by revealing ways in which antiarrhythmic drugs and surgical and ablation procedures may paradoxically promote fibrillation. Understanding AF pathophysiology can also help clarify the mechanisms by which emerging modalities aiming to correct autonomic imbalance, such as renal sympathetic denervation, may offer potential to better control this arrhythmia. Finally, growing evidence supports lifestyle modification approaches as adjuncts to improve AF control.
doi:10.14336/AD.2016.0211
PMCID: PMC5036958  PMID: 27699086
atrial fibrillation; pathophysiology; catheter ablation; surgical maze procedure; antiarrhythmic drugs; autonomic imbalance
18.  Guanosine: a Neuromodulator with Therapeutic Potential in Brain Disorders 
Aging and Disease  2016;7(5):657-679.
Guanosine is a purine nucleoside with important functions in cell metabolism and a protective role in response to degenerative diseases or injury. The past decade has seen major advances in identifying the modulatory role of extracellular action of guanosine in the central nervous system (CNS). Evidence from rodent and cell models show a number of neurotrophic and neuroprotective effects of guanosine preventing deleterious consequences of seizures, spinal cord injury, pain, mood disorders and aging-related diseases, such as ischemia, Parkinson’s and Alzheimer’s diseases. The present review describes the findings of in vivo and in vitro studies and offers an update of guanosine effects in the CNS. We address the protein targets for guanosine action and its interaction with glutamatergic and adenosinergic systems and with calcium-activated potassium channels. We also discuss the intracellular mechanisms modulated by guanosine preventing oxidative damage, mitochondrial dysfunction, inflammatory burden and modulation of glutamate transport. New and exciting avenues for future investigation into the protective effects of guanosine include characterization of a selective guanosine receptor. A better understanding of the neuromodulatory action of guanosine will allow the development of therapeutic approach to brain diseases.
doi:10.14336/AD.2016.0208
PMCID: PMC5036959  PMID: 27699087
guanosine; purines; neuromodulator; neuroprotection; neurotrophic effects; glutamate; adenosine
19.  Exposure to Persistent Organic Pollutants Predicts Telomere Length in Older Age: Results from the Helsinki Birth Cohort Study 
Aging and Disease  2016;7(5):540-552.
As the population ages, the occurrence of chronic pathologies becomes more common. Leukocyte telomere shortening associates to ageing and age-related diseases. Recent studies suggest that environmental chemicals can affect telomere length. Persistent organic pollutants (POPs) are most relevant, since they are ingested with foods, and accumulate in the body for a long time. This longitudinal study was undertaken to test if circulating POPs predict telomere length and shortening in elderly people. We studied 1082 subjects belonging to the Helsinki Birth Cohort Study (born 1934-1944), undergoing two visits (2001-2004 and 2011-2014). POPs (oxychlordane, trans-nonachlor, p, p’-DDE, PCB 153, BDE 47, BDE 153) were analysed at baseline. Relative telomere length was measured twice, ’10 years apart, by quantitative real-time PCR. Oxychlordane, trans-nonachlor and PCB-153 levels were significant predictors of telomere length and shortening. In men, we did not find a linear relationship between POPs exposure and telomere shortening. In women, a significant reduction across quartiles categories of oxychlordane and trans-nonachlor exposure was observed. Baseline characteristics of subjects in the highest POPs categories included higher levels of C-reactive protein and fasting glucose, and lower body fat percentage. This is one of few studies combining POPs and telomere length. Our results indicate that exposure to oxychlordane, trans-nonachlor and PCB 153 predicts telomere attrition. This finding is important because concentrations of POPs observed here occur in contemporary younger people, and may contribute to an accelerated ageing.
doi:10.14336/AD.2016.0209
PMCID: PMC5036950  PMID: 27699078
telomere length; pops; aging; environmental chemicals
20.  Education and Genetic Risk Modulate Hippocampal Structure in Alzheimer’s Disease 
Aging and Disease  2016;7(5):553-560.
Genetic and environmental protective factors and risks modulate brain structure and function in neurodegenerative diseases and their preclinical stages. We wanted to investigate whether the years of formal education, a proxy measure for cognitive reserve, would influence hippocampal structure in Alzheimer’s disease patients, and whether apolipoprotein Eε4 (APOE4) carrier status and a first-degree family history of the disease would change a possible association. Fifty-eight Alzheimer’s disease patients underwent 3T magnetic resonance imaging. We applied a cortical unfolding approach to investigate individual subregions of the medial temporal lobe. Among patients homozygous for the APOE4 genotype or carrying both APOE4 and family history risks, lower education was associated with a thinner cortex in multiple medial temporal regions, including the hippocampus. Our data suggest that the years of formal education and genetic risks interact in their influence on hippocampal structure in Alzheimer’s disease patients.
doi:10.14336/AD.2016.0305
PMCID: PMC5036951  PMID: 27699079
hippocampus; apolipoprotein E; cognitive reserve; education
21.  Brain Atrophy, Anti-Smooth Muscle Antibody and Cognitive Impairment: An Association Study 
Aging and Disease  2015;7(4):318-325.
Cortical atrophy, neuronal loss, beta-amyloid deposition, neuritic plaques, and neurofibrillary tangles are neuropathological key features in the Alzheimer’s disease (AD). Antibodies against beta-amyloid, neurotransmitters, microvascular endothelium components and microglial cells have been detected in AD serum suggesting that AD could be another autoimmune disease and provides a link between vascular pathology, endothelium dysfunction and neuronal cells death. Aim of the present study was to evaluate the association between autoantibody profile and cognitive impairment in geriatric patients, accounting for ApoE genotype as a potential confounding factor. Three hundred and forty-four geriatric patients, attending the clinic for the cognitive decline, underwent a biochemical and immunological profile, chest X-ray, cerebral computed tomography scan and complete cognitive evaluation. All patients were also screened for the ApoE genotype. A significantly higher prevalence of Anti-Smooth Muscle Antibody (ASMA) positivity was found in 89/204 (43.63%) patients with diagnosed neuroradiological signs of cerebral atrophy compared with 15/140 (10.71%) patients without the condition (p<0.001). Multivariable logistic model evidenced that such association was independent of patient’s age, gender and Mini-Mental State Examination (OR=8.25, 95%CI: 4.26-15.99) and achieved a good discriminatory power (c-statistic=0.783). Results were also independent of ApoE genotype, which resulted not associated both with the presence of brain atrophy and with the presence of ASMA positivity. Our results shows a strong association between brain atrophy and ASMA positivity and are consistent with several studies that focused attention on the mechanisms of endothelial immune response in the development of dementia.
doi:10.14336/AD.2015.1124
PMCID: PMC4963186  PMID: 27493830
brain atrophy; anti-smooth muscle antibody; cognitive impairment
22.  Ischemia-induced Angiogenesis is Attenuated in Aged Rats 
Aging and Disease  2015;7(4):326-335.
To study whether focal angiogenesis is induced in aged rodents after permanent distal middle cerebral artery occlusion (MCAO), young adult (3-month-old) and aged (24-month-old) Fisher 344 rats underwent MCAO and sacrificed up to two months after MCAO. Immunohistochemistry and synchrotron radiation microangiography were performed to examine the number of newly formed blood vessels in both young adult and aged rats post-ischemia. We found that the number of capillaries and small arteries in aged brain was the same as young adult brain. In addition, we found that after MCAO, the number of blood vessels in the peri-infarct region of ipsilateral hemisphere in aged ischemic rats was significantly increased compared to the aged sham rats (p<0.05). We also confirmed that ischemia-induced focal angiogenesis occurred in young adult rat brain while the blood vessel density in young adult ischemic brain was significantly higher than that in the aged ischemic brain (p<0.05). Our data suggests that focal angiogenesis in aged rat brain can be induced in response to ischemic brain injury, and that aging impedes brain repairing and remodeling after ischemic stroke, possible due to the limited response of angiogenesis.
doi:10.14336/AD.2015.1125
PMCID: PMC4963187  PMID: 27493831
aging; angiogenesis; focal cerebral ischemia; rat; brain
23.  Inhibition of Endoplasmic Reticulum Stress is Involved in the Neuroprotective Effect of bFGF in the 6-OHDA-Induced Parkinson’s Disease Model 
Aging and Disease  2016;7(4):336-449.
Parkinson's disease (PD) is a progressive neurodegenerative disorder with complicated pathophysiologic mechanisms. Endoplasmic reticulum (ER) stress appears to play a critical role in the progression of PD. We demonstrated that basic fibroblast growth factor (bFGF), as a neurotropic factor, inhibited ER stress-induced neuronal cell apoptosis and that 6-hydroxydopamine (6-OHDA)-induced ER stress was involved in the progression of PD in rats. bFGF administration improved motor function recovery, increased tyrosine hydroxylase (TH)-positive neuron survival, and upregulated the levels of neurotransmitters in PD rats. The 6-OHDA-induced ER stress response proteins were inhibited by bFGF treatment. Meanwhile, bFGF also increased expression of TH. The administration of bFGF activated the downstream signals PI3K/Akt and Erk1/2 in vivo and in vitro. Inhibition of the PI3K/Akt and Erk1/2 pathways by specific inhibitors partially reduced the protective effect of bFGF. This study provides new insight towards bFGF translational drug development for PD involving the regulation of ER stress.
doi:10.14336/AD.2016.0117
PMCID: PMC4963188  PMID: 27493838
Parkinson's disease; ER stress; bFGF; 6-OHDA
24.  Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage 
Aging and Disease  2015;7(4):450-465.
Transient forebrain ischemia induces delayed death of the hippocampal pyramidal neurons, particularly in the CA2 and medial CA1 area. Early pharmacological inhibition of inflammatory response can ameliorate neuronal death, but it also inhibits processes leading to tissue regeneration. Therefore, research efforts are now directed to modulation of post-ischemic inflammation, with the aim to promote beneficial effects of inflammation and limit adverse effects. Transcription factor NF-κB plays a key role in the inflammation and cell survival/apoptosis pathways. In the brain, NF-κB is predominantly found in the form of a heterodimer of p65 (RelA) and p50 subunit, where p65 has a transactivation domain while p50 is chiefly involved in DNA binding. In this study, we subjected middle-aged Nfkb1 knockout mice (lacking p50 subunit) and wild-type controls of both sexs to 17 min of transient forebrain ischemia and assessed mouse performance in a panel of behavioral tests after two weeks of post-operative recovery. We found that ischemia failed to induce clear memory and motor deficits, but affected spontaneous locomotion in genotype- and sex-specific way. We also show that both the lack of the NF-κB p50 subunit and female sex independently protected CA2 hippocampal neurons from ischemia-induced cell death. Additionally, the NF-κB p50 subunit deficiency significantly reduced ischemia-induced microgliosis, astrogliosis, and neurogenesis. Lower levels of hippocampal microgliosis significantly correlated with faster spatial learning. We conclude that NF-κB regulates the outcome of transient forebrain ischemia in middle-aged subjects in a sex-specific way, having an impact not only on neuronal death but also specific inflammatory responses and neurogenesis.
doi:10.14336/AD.2015.1123
PMCID: PMC4963189  PMID: 27493832
cerebrovascular disease; neuroinflammation; neurogenesis; memory; transgenic mice
25.  Mobility-Related Consequences of Reduced Lower-Extremity Peripheral Nerve Function with Age: A Systematic Review 
Aging and Disease  2015;7(4):466-478.
The objective of this study is to systematically review the relationship between lower-extremity peripheral nerve function and mobility in older adults. The National Library of Medicine (PubMed) was searched on March 23, 2015 with no limits on publication dates. One reviewer selected original research studies of older adults (≥65 years) that assessed the relationship between lower-extremity peripheral nerve function and mobility-related outcomes. Participants, study design and methods of assessing peripheral nerve impairment were evaluated and results were reported and synthesized. Eight articles were identified, including 6 cross-sectional and 2 longitudinal studies. These articles investigated 6 elderly cohorts (4 from the U.S. and 2 from Italy): 3 community-dwelling (including 1 with only disabled women and 1 without mobility limitations at baseline), 1 with both community-dwelling and institutionalized residents, 1 from a range of residential locations, and 1 of patients with peripheral arterial disease. Mean ages ranged from 71-82 years. Nerve function was assessed by vibration threshold (n=2); sensory measures and clinical signs and symptoms of neuropathy (n=2); motor nerve conduction (n=1); and a combination of both sensory measures and motor nerve conduction (n=3). Each study found that worse peripheral nerve function was related to poor mobility, although relationships varied based on the nerve function measure and mobility domain assessed. Six studies found that the association between nerve function and mobility persisted despite adjustment for diabetes. Evidence suggests that peripheral nerve function impairment at various levels of severity is related to poor mobility independent of diabetes. Relationships varied depending on peripheral nerve measure, which may be particularly important when investigating specific biological mechanisms. Future research needs to identify risk factors for peripheral nerve decline beyond diabetes, especially those common in late-life and modifiable. Interventions to preserve nerve function should be investigated with regard to their effect on postponing or preventing disability in older adults.
doi:10.14336/AD.2015.1127
PMCID: PMC4963190  PMID: 27493833
peripheral nerve function; mobility limitation; disability; sensory function; older adults; aging

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