Amyloid-ß42/Neurogranin Ratio as a Potential Index for Cognitive Impairment in Parkinson's Disease.

BACKGROUND: Synaptopathy is critical in pathophysiology of Parkinson's disease (PD). Cerebrospinal fluid (CSF) levels of neurogranin (NG) and amyloid-ß42 (Aß42) are considered markers of synaptic dysfunction in neurodegenerative diseases. OBJECTIVE: To evaluate the CSF synaptopathy-related biomarkers, especially the novel Aß42/NG ratio, in PD, establishing possible associations with cognitive level and other clinical parameters. METHODS: Levels of NG, Aß42, amyloid-ß40, total and phosphorylated tau, and Aß42/NG ratio were measured in 30 PD patients and 30 controls and correlated with cognitive and motor parameters. The accuracy in distinguishing the cognitive status was determined. RESULTS: NG and Aß42 were significantly reduced in PD, with higher NG levels in patients with worse cognition. The Aß42/NG ratio showed a direct correlation with Mini-Mental State Examination, independently from age and sex, and differentiated cognitively impaired patients with 92% sensitivity and 71.4% specificity, accuracy higher than NG alone. No correlations resulted with motor disturbances or therapy. CONCLUSIONS: The novel Aß42/NG ratio couples either presynaptic or postsynaptic markers of synaptic dysfunction, representing a potential global index of synaptopathy, useful to track cognitive functions in PD.

Proposed Tandem Effect of Physical Activity and Sirtuin 1 and 3 Activation in Regulating Glucose Homeostasis.

Sirtuins (SIRTs) are seven nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases enzymes (SIRT1-7) that play an important role in maintaining cellular homeostasis. Among those, the most studied are SIRT1 and SIRT3, a nuclear SIRT and a mitochondrial SIRT, respectively, which significantly impact with an increase in mammals' lifespan by modulating metabolic cellular processes. Particularly, when activated, both SIRT1 and 3 enhance pancreatic ß-cells' insulin release and reduce inflammation and oxidative stress pancreatic damage, maintaining then glucose homeostasis. Therefore, SIRT1 and 3 activators have been proposed to prevent and counteract metabolic age-related diseases, such as type 2 diabetes mellitus (T2DM). Physical activity (PA) has a well-established beneficial effect on phenotypes of aging like ß-cell dysfunction and diabetes mellitus. Recent experimental and clinical evidence reports that PA increases the expression levels of both SIRT1 and 3, suggesting that PA may exert its healthy contribute even by activating SIRTs. Therefore, in the present article, we discuss the role of SIRT1, SIRT3, and PA on ß-cell function and on diabetes. We also discuss the possible interaction between PA and activation of SIRTs as a possible therapeutic strategy to maintain glucose hemostasis and to prevent T2DM and its complications, especially in the elderly population.

The effect of postural deformities on back function and pain in patients with Parkinson's disease.

BACKGROUND: Postural deformities, such as Pisa syndrome (PS), and camptocormia and antecollis (C&A) are common in patient with Parkinson's disease (PwPD). These deformities can lead to back disability and pain with different mechanisms, including abnormal loading or stress on soft tissues as muscles, lumbar discs and ligaments. OBJECTIVES: To evaluate the effect of different postural deformities including PS and C&A on back function and pain in PwPD. METHODS: The function, disability and pain were assessed by Oswestry disability index (ODI) and brief pain inventory (BPI). All participants completed clinical assessments by the Unified Parkinson's Disease Rating Scale (UPDRS), Modified Hoenh & Yahr (mH&Y) staging and the Levodopa Equivalent Daily Dose (LEDD). RESULTS: PS and C&A groups significantly showed worse disability ODI and pain BPI, and higher LEDD and mH&Y stage compared with PD groups. However, no differences were found in PD duration and UPDRS in the same groups. Moreover, no differences were observed between PS and C&A groups in the mentioned scales. CONCLUSION: These results demonstrated that PS and C&A are associated with severe impairment of back functions and pain. Rehabilitation programs for PwPD and PS, and C&A should include spine alignment and postural training.

Dietary Vitamin E as a Protective Factor for Parkinson's Disease: Clinical and Experimental Evidence.

Effective disease-modifying treatments are an urgent need for Parkinson's disease (PD). A putative successful strategy is to counteract oxidative stress, not only with synthetic compounds, but also with natural agents or dietary choices. Vitamin E, in particular, is a powerful antioxidant, commonly found in vegetables and other components of the diet. In this work, we performed a questionnaire based case-control study on 100 PD patients and 100 healthy controls. The analysis showed that a higher dietary intake of Vitamin E was inversely associated with PD occurrence independently from age and gender (OR = 1.022; 95% CI = 0.999-1.045; p < 0.05), though unrelated to clinical severity. Then, in order to provide a mechanistic explanation for such observation, we tested the effects of Vitamin E and other alimentary antioxidants in vitro, by utilizing the homozygous PTEN-induced kinase 1 knockout (PINK1 -/-) mouse model of PD. PINK1 -/- mice exhibit peculiar alterations of synaptic plasticity at corticostriatal synapses, consisting in the loss of both long-term potentiation (LTP) and long-term depression (LTD), in the absence of overt neurodegeneration. Chronic administration of Vitamin E (alpha-tocopherol and the water-soluble analog trolox) fully restored corticostriatal synaptic plasticity in PINK1 -/- mice, suggestive of a specific protective action. Vitamin E might indeed compensate PINK1 haploinsufficiency and mitochondrial impairment, reverting some central steps of the pathogenic process. Altogether, both clinical and experimental findings suggest that Vitamin E could be a potential, useful agent for PD patients. These data, although preliminary, may encourage future confirmatory trials.

Association between physical activity and dementia's risk factors in patients with Parkinson's disease.

Evidence suggests that physical activity (PA) exerts beneficial effects on neurodegenerative processes, either as symptomatic relief or disease-modifying strategy. Actually, it may represent a viable neuroprotective intervention in Parkinson's disease dementia (PDD), a severe, frequent, and untreatable complication of Parkinson's disease (PD). According to such hypothesis, this cross-sectional study tested, in PD patients, the association between levels of PA and well-known risk factors for PDD, such as mood disorders and amyloid-ß42 CSF content. Amount of PA was measured by the International Physical Activity Questionnaires-Short Form (IPAQ-SF) in 128 cognitively intact PD patients and correlated with the Hamilton-Depression (HAM-D) and the Hamilton-Anxiety (HAM-A) scores; in a homogenous subgroup of 40 patients, it was further correlated with a panel of CSF biomarkers, including amyloid-ß42, total α-synuclein, total, and phosphorylated tau. The statistical model was corrected for the main potential confounding factors (motor impairment, dopaminergic treatment, disease duration, age, and sex). Both the HAM-A and HAM-D scores, as well as the Aß42 CSF content, improved in parallel with the increase of the total week amount of PA. Although with several limitations, we preliminarily demonstrated that a high level of PA is associated with a more favourable profile of PDD risk factors, in terms of both mood disturbances and CSF markers of neurodegeneration. However, confirmative studies are necessary to validate the efficacy of PA as protective intervention for PDD.

The influence of postural deformities on neck function and pain in patients with Parkinson's disease.

BACKGROUND: Trunk alignment is thought to contribute to neck function. However, this common assumption is not clear in patients with Parkinson's disease (PwPD) suffering from different postural deformities such as: Pisa syndrome (PS), Camptocormia & Antecollis (C&A). OBJECTIVES: to investigate the effect of different postural deformities including PS and C&A on neck function and pain in patient (PwPD). METHODS: Forty-five participants belonging to three groups: 15 PD patients without postural disorders (PD), 15 with PS, and 15 with C&A. The function, disability and pain were assessed by Neck Disability Index (NDI), and Brief Pain Inventory (BPI) which used to assess the pain severity (BPI-PS) and Pain Interference (BPI-PI). All groups completed clinical assessments by the Unified Parkinson's Disease Rating Scale (UPDRS), Modified Hoenh & Yahr (mH&Y) staging and the Levodopa Equivalent Daily Dose (LEDD). RESULTS: PD group compared with PS and C&A groups showed differences in NDI, BPI-PS, BPI-PI, LEDD and mH&Y staging (P < 0.001), but no differences found in PD duration, UPDRS-II and III in the same groups. Moreover, no differences were observed between PS and C&A groups in the mentioned scales. DISCUSSION AND CONCLUSION: These results demonstrated that PS and C&A are associated with severe impairment of neck functions, and pain in PwPD.

Influence of FTO rs9939609 and Mediterranean diet on body composition and weight loss: a randomized clinical trial.

BACKGROUND: The Mediterranean diet (MeD) plays a key role in the prevention of obesity. Among the genes involved in obesity, the Fat mass and obesity-associated gene (FTO) is one of the most known, but its interaction with MeD remained uncertain so far. METHODS: We carried out a study on a sample of 188 Italian subjects, analyzing their FTO rs9939609 alleles, and the difference in body composition between the baseline and a 4-weeks nutritional intervention. The sample was divided into two groups: the control group of 49 subjects, and the MeD group of 139 subjects. RESULTS: We found significant relations between MeD and both variation of total body fat (ΔTBFat) (p = 0.00) and gynoid body fat (p = 0.04). ∆TBFat (kg) demonstrated to have a significant relation with the interaction diet-gene (p = 0.04), whereas FTO was associated with the variation of total body water (p = 0.02). CONCLUSIONS: MeD demonstrated to be a good nutritional treatment to reduce the body fat mass, whereas data about FTO remain uncertain. Confirming or rejecting the hypothesis of FTO and its influence on body tissues during nutritional treatments is fundamental to decide whether its effect has to be taken into consideration during both development of dietetic plans and patients monitoring. Trial Registration ClinicalTrials.gov Id: NCT01890070. Registered 01 July 2013, https://clinicaltrials.gov/ct2/show/NCT01890070.

Effectiveness of robot-assisted gait training on motor impairments in people with Parkinson's disease: a systematic review and meta-analysis.

The aim of this systematic review and meta-analysis was to evaluate the effectiveness of robot-assisted gait training (RAGT) on motor impairments in people with Parkinson's disease (PD). A computer-based systematic literature search was performed in six databases according to PRISMA guidelines. Randomized controlled trials (RCTs) that assessed the effects of RAGT on motor impairments in people with PD were included. GRADE approach and PEDro scale were used to determine the studies' quality of evidence. Meta-analyses were performed by calculating the weighted mean difference (WMD) at 95% confidence interval. Seven RCTs (PEDro: 5-8) met the inclusion criteria for systematic review and meta-analyses. The meta-analysis showed significant improvement on Unified Parkinson Disease Rating Scale Part III after intervention [WMD=3.292; 95% confidence interval (CI)=1.378-5.207; P=0.000], and after 1-month follow-up (WMD=5.512; 95% CI=2.396-8.629; P=0.001). Stride length (WMD=9.283; 95% CI=7.153-11.414; P=0.00) and gait speed (WMD=0.166; 95% CI=-0.090 to 0.243; P=0.000) showed significant improvements after RAGT. Balance as measured by Berg Balance Scale was improved significantly after intervention (WMD=3.87; 95% CI=0.374-6.735; P=0.029) and at 1-month follow-up (WMD=3.87; 95% CI=1.324-6.413; P=0.002). The pooled analysis did not detect any significant changes regarding stride time, cadence and functional balance scales. GRADE level of evidence ranged between high and low. The RAGT showed better outcomes than conventional interventions on some motor aspects in PD. However, RAGT did not seem superior to control interventions. Further RCTs that examine the effect of RAGT on more specific outcomes and at different medication statuses are required.

Alcoholic Beverage and Meal Choices for the Prevention of Noncommunicable Diseases: A Randomized Nutrigenomic Trial.

BACKGROUND: Noncommunicable diseases (NCDs) are the first cause of death worldwide. Mediterranean diet may play a crucial role in the prevention of NCDs, and the presence of wine in this diet could play a positive role on health. METHODS: 54 healthy volunteers consumed one of the following beverages: red (RW) or white wine (WW), vodka (VDK), and/or Mediterranean meal (MeDM) and high-fat meal (HFM). RESULTS: OxLDL-C changed significantly between baseline versus HFM, MeDM versus HFM, and HFM versus HFM + RW (p < 0.05). Significant upregulation of catalase (CAT) was observed only after RW. Conversely, WW, VDK, RW + MeDM, HF + WW, and HF + VDK determined a significant downregulation of CAT gene. Superoxide dismutase 2 (SOD2) gene expression was upregulated in WW, MeDM + VDK, and RW. Contrariwise, HFM + VDK determined a downregulation of its expression. RW, RW + MeDM, and RW + HFM caused the upregulation of glutathione peroxidase-1 (GPX1). CONCLUSIONS: Our results suggest that the association of low/moderate intake of alcohol beverages, with nutraceutical-proven effectiveness, and ethanol, in association with a Mediterranean diet, could determine a reduction of atherosclerosis risk onset through a positive modulation of antioxidant gene expression helping in the prevention of inflammatory and oxidative damages.

Association between hypertension and metabolic disorders among elderly patients in North Jordan.

BACKGROUND: Hypertension (HTN), dyslipidemia and hyperglycemia are major risk factors for cardiovascular disease, accounting for the highest morbidity and mortality among the elderly Jordanian population. This study aimed to evaluate serum lipid and glucose profiles of hypertensive patients and normotensive controls, and determine the risk factors for HTN among elderly population in Jordan. METHODS: A cross-sectional study was carried out among 200 participants, including 111 hypertensive patients and 89 normotensive controls from June to October 2017 in North Jordan. Data were collected on sociodemographic factors, anthropometric measurements, blood pressure, and lipid profile including total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL) and fasting blood sugar (FBS). RESULTS: Serum levels of TC, TG, LDL and FBS were higher while HDL levels were lower in hypertensive subjects compared to normotensives (p < 0.01). There were no differences between hypertensive and normotensives patients regarding their age, waist circumference (WC), waist-to-height ratio (WHtR) and body mass index (BMI). Anthropometric and biochemical parameters were significantly correlated only in normotensive group. Significant associations between blood pressure and biochemical parameters were seen only in the HTN group. Overweight/obesity, abdominal obesity (WHtR), hyperglycemia, hypertriglyceridemia and low HDL were found as the risk factors for HTN. CONCLUSION: from our results, future strategies for preventing dyslipidemia, hyperglycemia and, consequently, HTN through modification of risk factors such as lifestyle changes and medical management. It's recommended for patients with HTN to measure the BP, lipid and glucose profiles regularly throughout their primary health care to prevent non-communicable diseases.

Effects of long-term stimulation of textured insoles on postural control in health elderly.

BACKGROUND: The aim of this study was to confirm the effects of long term (chronic) stimulating surface (textured insole) on body balance of elderly people. METHODS: Twenty-four healthy elderly individuals were randomly distributed in two groups: control and experimental (67.75±6.04 years, 74.55±12.14 kg, 163.7±8.55 cm, 27.75±3.04 kg/m2). Over one month, control group (CG) used smooth insoles and the experimental group (ExG) used textured insoles every day. Velocity net (Vnet), anteroposterior (VA/P), mediolateral (VM/L) and sway path of CoP were assessed in different eye conditions before and after the experimental procedure. RESULTS: A mixed between-within subject ANOVA was conducted to assess the impact of soft and textured insoles and two visual conditions (vision vs. no vision) across two time periods (α≤0.05). The results showed any statistical difference between groups in each parameter assessed in this study. CoP, Vnet and VM/L in the experimental group showed a statistically significant effect of textured insoles only without vision (CoP: P=0.002; η2=0.35), Vnet P=0.02; η2=0.24, VM/L P=0.04; η2=0.177) whereas VA/P showed no statistically significant effect in the same group and condition. There was no significant effect in Vnet, VA/P, VM/L and COP in control group that used smooth insole for both eye conditions. CONCLUSIONS: The results confirm that postural stability improved in healthy elderly individuals, increasing somatosensory information's from feet plantar mechanoreceptors. Long term stimulation with textured insoles decreased CoP, Vnet and VM/L with eyes closed.

Evidences of a New Psychobiotic Formulation on Body Composition and Anxiety.

BACKGROUND: Gut microbiota is implied in obesity, because of its ability to harvest energy from diet, and in the regulation of behavior. Given the link between gut microbiota, body composition, obesity, and anxiety, the aim of this study was to evaluate the effects of a new psychobiotic formulation. METHODS: Eligible patients were randomly divided into three groups: psychobiotics oral suspension group (POSG); dietary treatment group (DTG); combined treatment group (CTG). All subjects underwent body composition and psychological profile evaluation. RESULTS: Significant changes in body composition parameters in each group were relieved after all treatments. Hamilton anxiety rating scale (HAM-A) highlighted a significant reduction of the total score for all study population after treatments in POSG (p = 0.01) and CTG (p = 0.04). A reduction of HAM-A total score in anxious subjects in POSG or CTG and a significant reduction of positive subjects for HAM-A in POSG (p = 0.03) and in CDG (p = 0.01) were shown. DISCUSSION: Three-week intake of selected POS represents a good approach to solve problems related to obesity and behavior disorders. However, new clinical trials need to be performed on a larger population and for a longer period of treatment before definitive conclusions can be made. This trial is registered with NCT01890070.

Antioxidant Effects of a Hydroxytyrosol-Based Pharmaceutical Formulation on Body Composition, Metabolic State, and Gene Expression: A Randomized Double-Blinded, Placebo-Controlled Crossover Trial.

Hydroxytyrosol (HT) plays a significant role in cardiovascular disease (CVD) protection, and its metabolites are able to protect from the endothelial dysfunction commonly present in atherosclerosis. This randomized double-blinded, placebo-controlled crossover trial determined the effect in healthy volunteers of two gastroresistant capsules containing 15 mg/day of HT, for a 3-week period (HTT). Evaluation of nutritional status, serum metabolites, oxidative stress biomarkers, and gene expression of 9 genes related to oxidative stress, inflammation, and CVDs was performed. Oxidation biomarkers like thiol group (p = 0.001), total antioxidant status (TAS) (p = 0.001), superoxide dismutase 1 (SOD1) (2-ΔΔCt = 3.7), and plasma concentration of HT (2.83 µg·mL-1) were significantly increased, while nitrite (p = 0.001), nitrate (p = 0.001), and malondialdehyde (MDA) (p = 0.02) were drastically reduced after HTT. A significant reduction of body fat mass percentage (p = 0.01), suprailiac skinfold (p = 0.01), and weight (p = 0.04; Δ% = -0.46%) was observed after HTT. This study shows that regular intake of 15 mg/day of HT changed body composition parameters and modulated the antioxidant profile and the expression of inflammation and oxidative stress-related genes. However, it is advisable to personalize HT doses in order to exert its health benefits in CVD prevention and protection of LDL-C particles from oxidative damage. This trial is registered with ClinicalTrials.gov NCT01890070.

Training-Load Distribution in Endurance Runners: Objective Versus Subjective Assessment.

PURPOSE: To assess the distribution of exercise intensity in long-distance recreational athletes (LDRs) preparing for a marathon and to test the hypothesis that individual perception of effort could provide training responses similar to those provided by standardized training methodologies. METHODS: Seven LDRs (age 36.5 ± 3.8 y) were followed during a 5-mo training period culminating with a city marathon. Heart rate at 2.0 and 4.0 mmol/L and maximal heart rate were used to establish 3 intensity training zones. Internal training load (TL) was assessed by training zones and TRIMPi methods. These were compared with the session-rating-of-perceived-exertion (RPE) method. RESULTS: Total time spent in zone 1 was higher than in zones 2 and 3 (76.3% ± 6.4%, 17.3% ± 5.8%, and 6.3% ± 0.9%, respectively; P = .000 for both, ES = 0.98, ES = 0.99). TL quantified by session-RPE provided the same result. The comparison between session-RPE and training-zones-based methods showed no significant difference at the lowest intensity (P = .07, ES = 0.25). A significant correlation was observed between TL RPE and TL TRIMPi at both individual and group levels (r = .79, P < .001). There was a significant correlation between total time spent in zone 1 and the improvement at the running speed of 2 mmol/L (r = .88, P < .001). A negative correlation was found between running speed at 2 mmol/L and the time needed to complete the marathon (r = -.83, P < .001). CONCLUSIONS: These findings suggest that in recreational LDRs most of the training time is spent at low intensity and that this is associated with improved performances. Session-RPE is an easy-to-use training method that provides responses similar to those obtained with standardized training methodologies.

Sphingosine kinase 1 overexpression is regulated by signaling through PI3K, AKT2, and mTOR in imatinib-resistant chronic myeloid leukemia cells.

OBJECTIVE: As a better understanding of the molecular basis of carcinogenesis has emerged, oncogene-specific cell-signaling pathways have been successfully targeted to treat human malignances. Despite impressive advances in oncogene-directed therapeutics, genetic instability in cancer cells often manifest acquired resistance. This is particularly noted in the use of tyrosine kinase inhibitors therapies and not more evident than for chronic myeloid leukemia. Therefore, it is of great importance to understand the molecular mechanisms affecting cancer cell sensitivity and resistance to tyrosine kinase inhibitors. MATERIALS AND METHODS: In this study, we used continuous exposure to stepwise increasing concentrations of imatinib (0.6-1 µM) to select imatinib-resistant K562 cells. RESULTS: Expression of BCR-ABL increased both at RNA and protein levels in imatinib-resistant cell lines. Furthermore, expression levels of sphingosine kinase 1 (SphK1) were increased significantly in resistant cells, channeling sphingoid bases to the SphK1 pathway and activating sphingosine-1-phosphate-dependent tyrosine phosphorylation pathways that include the adaptor protein Crk. The partial inhibition of SphK1 activity by N,N-dimethylsphingosine or expression by small interfering RNA increased sensitivity to imatinib-induced apoptosis in resistant cells and returned BCR-ABL to baseline levels. To determine the resistance mechanism-induced SphK1 upregulation, we used pharmacological inhibitors of the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathway and observed robust downmodulation of SphK1 expression and activity when AKT2, but not AKT1 or AKT3, was suppressed. CONCLUSIONS: These results demonstrate that SphK1 is upregulated in imatinib-resistant K562 cells by a pathway contingent on a phosphoinositide 3-kinase/AKT2/mammalian target of rapamycin signaling pathway. We propose that SphK1 plays an important role in development of acquired resistance to imatinib in chronic myeloid leukemia cell lines.

Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) exert their anti-proliferative activity by interfering with Akt-mTOR signaling and bax:bcl-2 ratio modulation in cells from chronic myeloid leukemic patients.

In our study we found that pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) mediated apoptosis in primary leukemia cells from 27 chronic myelogenous leukemia (CML) patients at onset through the activation of the caspase-9 and -3, and cleavage of poly (ADP-ribose) polymerase (PARP). The bax:bcl-2 ratio was increased as a consequence of down-regulation of bcl-2 and up-regulation of bax proteins in response to treatment with PBTDs. In addition, PBTDs were able to induce cell death in primary leukemia cells derived from 23 CML-chemoresistant patients. Furthermore, the effects of PBTDs on the Akt-mTOR (mammalian target of rapamycin) pathway were determined by Western blot. PBTDs possessed inhibitory activity against mTOR and also impeded hyper-phosphorylation of Akt as a feedback of inhibition of mTOR by rapamycin. The results presented in this study demonstrate that we have identified the PBTDs as restoring the apoptotic pathways both in primary leukemia cells derived from CML patients at onset and in primary leukemia cells derived from CML-chemoresistant patients, thus showing their ability to undergo apoptosis. These compounds constitute a promising therapeutic approach for patients with leukemia. They provide the basis for new strategies for an additional anticancer drug in leukemia therapies, especially when conventional ones fail.

The effect of marathon on mRNA expression of anti-apoptotic and pro-apoptotic proteins and sirtuins family in male recreational long-distance runners.

BACKGROUND: A large body of evidence shows that a single bout of strenuous exercise induces oxidative stress in circulating human lymphocytes leading to lipid peroxidation, DNA damage, mitochondrial perturbations, and protein oxidation.In our research, we investigated the effect of physical load on the extent of apoptosis in primary cells derived from blood samples of sixteen healthy amateur runners after marathon (a.m.). RESULTS: Blood samples were collected from ten healthy amateur runners peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and bcl-2, bax, heat shock protein (HSP)70, Cu-Zn superoxide dismutase (SOD), Mn-SOD, inducible nitric oxide synthase (i-NOS), SIRT1, SIRT3 and SIRT4 (Sirtuins) RNA levels were determined by Northern Blot analysis. Strenuous physical load significantly increased HSP70, HSP32, Mn-SOD, Cu-Zn SOD, iNOS, GADD45, bcl-2, forkhead box O (FOXO3A) and SIRT1 expression after the marathon, while decreasing bax, SIRT3 and SIRT4 expression (P < 0.0001). CONCLUSION: These data suggest that the physiological load imposed in amateur runners during marathon attenuates the extent of apoptosis and may interfere with sirtuin expression.

Kaempferol induces apoptosis in two different cell lines via Akt inactivation, Bax and SIRT3 activation, and mitochondrial dysfunction.

Kaempferol (3,4',5,7-tetrahydroxyflavone) is a flavonoid with anti- and pro-oxidant activity present in various natural sources. Kaempferol has been shown to posses anticancer properties through the induction of the apoptotic program. Here we report that treatment of the chronic myelogenous leukemia cell line K562 and promyelocitic human leukemia U937 with 50 microM kaempferol resulted in an increase of the antioxidant enzymes Mn and Cu/Zn superoxide dismutase (SOD). Kaempferol treatment induced apoptosis by decreasing the expression of Bcl-2 and increasing the expressions of Bax. There were also induction of mitochondrial release of cytochrome c into cytosol and significant activation of caspase-3, and -9 with PARP cleavage. Kaempferol treatment increased the expression and the mitochondria localization of the NAD-dependent deacetylase SIRT3. K562 cells stably overexpressing SIRT3 were more sensitive to kaempferol, whereas SIRT3 silencing did not increase the resistance of K562 cells to kaempferol. Inhibition of PI3K and de-phosphorylation of Akt at Ser473 and Thr308 was also observed after treating both K562 and U937 cells with kaempferol. In conclusion our study shows that the oxidative stress induced by kaempferol in K562 and U937 cell lines causes the inactivation of Akt and the activation of the mitochondrial phase of the apoptotic program with an increase of Bax and SIRT3, decrease of Bcl-2, release of cytochrome c, caspase-3 activation, and cell death.