BAD
Bcl2-associated agonist of cell death (BAD) (Bcl-2-binding component 6) (Bcl-2-like protein 8) (Bcl2-L-8) (Bcl-xL/Bcl-2-associated death promoter) (Bcl2 antagonist of cell death) [BBC6] [BCL2L8]
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Brain aging and dementia are current problems that must be solved. The levels of imidazoline 2 receptors (I -IRs) are increased in the brain in Alzheimer's disease (AD) and other neurodegenerative diseases. We tested the action of the specific and selective I -IR ligand B06 in a mouse model of accelerated aging and AD, the senescence-accelerated mouse prone 8 (SAMP8) model. Oral administration of B06 for 4 weeks improved SAMP8 mouse behavior and cognition and reduced AD hallmarks, oxidative stress, and apoptotic and neuroinflammation markers. Likewise, B06 regulated glial excitatory amino acid transporter 2 and N-methyl-D aspartate 2A and 2B receptor subunit protein levels. Calcineurin (CaN) is a phosphatase that controls the phosphorylation levels of cAMP response element-binding (CREB), apoptotic mediator BCL-2-associated agonist of cell death (BAD) and GSK3β, among other molecules. Interestingly, B06 was able to reduce the levels of the CaN active form (CaN A). Likewise, CREB phosphorylation, BAD gene expression, and other factors were modified after B06 treatment. Moreover, phosphorylation of a target of CaN, nuclear factor of activated T-cells, cytoplasmic 1 (NFAT ), was increased in B06-treated mice, impeding the transcription of genes related to neuroinflammation and neural plasticity. In summary, this I imidazoline ligand can exert its beneficial effects on age-related conditions by modulating CaN pathway action and affecting several molecular pathways, playing a neuroprotective role in SAMP8 mice.
Keywords
- Aging
- Alzheimer’s disease
- Behavior
- I2 imidazoline receptors
- NFAT
- Neuroinflammation
- Neuroprotection
Aging is associated with a deregulation of biological systems that lead to an increase in oxidative stress, inflammation, and apoptosis, among other effects. Xanthohumol is the main preylated chalcone present in hops (Humulus lupulus L.) whose antioxidant, anti-inflammatory and chemopreventive properties have been shown in recent years. In the present study, the possible protective effects of xanthohumol on liver alterations associated with aging were evaluated. Male young and old senescence-accelerated prone mice (SAMP8), aged 2 and 10 months, respectively, were divided into four groups: non-treated young, non-treated old, old treated with 1 mg/kg/day xanthohumol, and old treated with 5 mg/kg/day xanthohumol. Male senescence-accelerated resistant mice (SAMR1) were used as controls. After 30 days of treatment, animals were sacrificed and livers were collected. mRNA (AIF, BAD, BAX, Bcl-2, eNOS, HO-1, IL-1β, NF-κB2, PCNA, sirtuin 1 and TNF-α) and protein expressions (BAD, BAX, AIF, caspase-3, Blc-2, eNOS, iNOS, TNF-α, IL1β, NF-κB2, and IL10) were measured by RT-PCR and Western blotting, respectively. Mean values were analyzed using ANOVA. A significant increase in mRNA and protein levels of oxidative stress, pro-inflammatory and proliferative markers, as well as pro-apoptotic parameters was shown in old non-treated SAMP8 mice compared to the young SAMP8 group and SAMR1 mice. In general, age-related oxidative stress, inflammation and apoptosis were significantly decreased (p < 0.05) after XN treatment. In most cases, this effect was dose-dependent. XN was shown to modulate inflammation, apoptosis, and oxidative stress in aged livers, exerting a protective effect in hepatic alterations.
MeSH Terms
- Aging
- Animals
- Antioxidants
- Apoptosis
- Blotting, Western
- Disease Models, Animal
- Flavonoids
- Inflammation
- Liver
- Male
- Mice
- Oxidative Stress
- Polymerase Chain Reaction
- Propiophenones
Keywords
- Aging
- Inflammation
- Liver
- Senescence-accelerated mouse
- Xanthohumol
It has been recently shown that xanthohumol, a flavonoid present in hops, possesses antioxidant, anti-inflammatory and chemopreventive properties. However, its role in the aging brain has not been addressed so far. Therefore, this study aimed to investigate the possible neuroprotective activity of xanthohumol against age-related inflammatory and apoptotic brain damage in male senescence-accelerated prone mice (SAMP8). Animals were divided into 4 groups: Untreated young mice, untreated old mice and old mice treated either with 1 mg kg day or 5 mg kg day xanthohumol. Young and old senescence accelerated resistant mice (SAMR1) were used as controls. After 30 days of treatment, animals were sacrificed and their brains were collected and immediately frozen in liquid nitrogen. mRNA (GFAP, TNF-α, IL-1β, AIF, BAD, BAX, XIAP, NAIP and Bcl-2) and protein (GFAP, TNF-α, IL-1β, AIF, BAD, BAX, BDNF, synaptophysin and synapsin) expressions were measured by RT-PCR and Western blotting, respectively. Significant increased levels of pro-inflammatory (TNF-α, IL-1β) and pro-apoptotic (AIF, BAD, BAX) markers were observed in both SAMP8 and SAMR1 old mice compared to young animals (P<.05) and also in SAMP8 untreated old mice compared to SAMR1 (P<.05). These alterations were significantly less evident in animals treated with both doses of xanthohumol (P<.05). Also, a reduced expression of synaptic markers was observed in old mice compared to young ones (P<.05) but it significantly recovered with 5 mg kg day xanthohumol treatment (P<.05). In conclusion, xanthohumol treatment modulated the inflammation and apoptosis of aged brains, exerting a protective effect on damage induced by aging.
MeSH Terms
- Aging
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
- Apoptosis
- Apoptosis Regulatory Proteins
- Biomarkers
- Brain
- Cognitive Dysfunction
- Dietary Supplements
- Encephalitis
- Flavonoids
- Gene Expression Regulation, Developmental
- Glial Fibrillary Acidic Protein
- Inflammation Mediators
- Male
- Mice, Inbred Strains
- Nerve Tissue Proteins
- Neurons
- Neuroprotective Agents
- Propiophenones
- Synaptophysin
Keywords
- Aging
- Apoptosis
- Brain
- Inflammation
- Xanthohumol
Aging is associated with an increase in oxidative stress and inflammation. The aging lung is particularly affected since it is continuously exposed to environmental oxidants while antioxidant machinery weakens with age. Melatonin, a free radical scavenger, counteracts inflammation and apoptosis in healthy cells from several tissues. Its effects on the aging lung are, however, not yet fully understood. This study aimed to investigate the effect of chronic administration of melatonin on the expression of inflammation markers (TNF-α, IL-1β, NFκB2, HO-1) and apoptosis parameters (BAD, BAX, AIF) in the lung tissue of male senescence-accelerated prone mice (SAMP8). In addition, RNA oxidative damage, as the formation of 8-hydroxyguanosine (8-OHG), was also evaluated. Young and old animals, aged 2 and 10 months respectively, were divided into 4 groups: untreated young, untreated old, old mice treated with 1mg/kg/day melatonin, and old animals treated with 10mg/kg/day melatonin. Untreated young and old male senescence accelerated resistant mice (SAMR1) were used as controls. After 30 days of treatment, animals were sacrificed. Lungs were collected and immediately frozen in liquid nitrogen. mRNA and protein expressions were measured by RT-PCR and Western blotting, respectively. Levels of 8-OHG were quantified by ELISA. Mean values were analyzed using ANOVA. Old nontreated SAMP8 animals showed increased (p<0.05) mRNA and protein levels of TNF-α, IL-1β, NFκB2, and HO-1 compared to young mice and SAMR1 mice. Melatonin treatment with either dose reversed the aging-derived inflammation (p<0.05). BAD, BAX and AIF expressions also rose with aging, the effect being counteracted with melatonin (p<0.05). Aging also caused a significant elevation (p<0.05) in SAMP8 8-OHG values. This increase was not observed in animals treated with melatonin (p<0.05). In conclusion, melatonin treatment was able to modulate the inflammatory and apoptosis status of the aging lungs, exerting a protective effect on age-induced damage.
MeSH Terms
- Aging
- Aging, Premature
- Animals
- Apoptosis
- Biomarkers
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Drug Evaluation, Preclinical
- Gene Expression Regulation
- Inflammation Mediators
- Lung
- Male
- Melatonin
- Mice, Mutant Strains
- Oxidative Stress
Keywords
- Aging
- Apoptosis
- Inflammation
- Lung
- Melatonin
- Oxidative stress
Aging increases oxidative stress and inflammation. Melatonin counteracts inflammation and apoptosis. This study investigated the possible protective effect of melatonin on the inflammatory and apoptotic response secondary to ischemia induced by blockade of the right middle cerebral artery (MCA) in aging male Wistar rats. Animals were subjected to MCA obstruction. After 24 h or 7 days of procedure, 14-month-old nontreated and treated rats with a daily dose of 10 mg/kg melatonin were sacrificed and right and left hippocampus and cortex were collected. Rats aged 2 and 6 months, respectively, were subjected to the same brain injury protocol, but they were not treated with melatonin. mRNA expression of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), Bcl-2-associated death promoter (BAD), Bcl-2-associated X protein (BAX), glial fibrillary acidic protein (GFAP), B-cell lymphoma 2 (Bcl-2), and sirtuin 1 was measured by reverse transcription-polymerase chain reaction. In nontreated animals, a significant time-dependent increase in IL-1β, TNF-α, BAD, and BAX was observed in the ischemic area of both hippocampus and cortex, and to a lesser extent in the contralateral hemisphere. Hippocampal GFAP was also significantly elevated, while Bcl-2 and sirtuin 1 decreased significantly in response to ischemia. Aging aggravated these changes. Melatonin administration was able to reverse significantly these alterations. In conclusion, melatonin may ameliorate the age-dependent inflammatory and apoptotic response secondary to ischemic cerebral injury.
Keywords
- aging
- brain
- ischemia
- melatonin
- middle cerebral artery blockade
Vegetarianism is associated with a lower risk of cardiovascular disease. However, studies of arterial function in vegetarians are limited. This study investigated arterial function in vegetarianism by comparing 49 healthy postmenopausal vegetarians with 41 age-matched omnivores. The arterial function of the common carotid artery was assessed by carotid duplex, while the pulse dynamics method was used to measure brachial artery distensibility (BAD), compliance (BAC), and resistance (BAR). Fasting blood levels of glucose, lipids, lipoprotein (a), high-sensitivity C-reactive protein, homocysteine, and vitamin B12 were also measured. Vegetarians had significantly lower serum cholesterol, high-density and low-density lipoprotein, and glucose compared with omnivores. They also had lower vitamin B12 but higher homocysteine levels. Serum levels of lipoprotein (a) and high-sensitivity C-reactive protein were no different between the two groups. There were no significant differences in carotid beta stiffness index, BAC, and BAD between the two groups even after adjustment for associated covariates. However, BAR was significantly lower in vegetarians than in omnivores. Multiple linear regression analysis revealed that age and pulse pressure were two important determinants of carotid beta stiffness index and BAD. Vegetarianism is not associated with better arterial elasticity. Apparently healthy postmenopausal vegetarians are not significantly better in terms of carotid beta stiffness index, BAC, and BAD, but have significantly decreased BAR than omnivores. Prevention of vitamin B12 deficiency might be beneficial for cardiovascular health in vegetarians.
MeSH Terms
- Age Factors
- Aging
- Biomarkers
- Blood Glucose
- Brachial Artery
- C-Reactive Protein
- Carotid Artery, Common
- Chi-Square Distribution
- Compliance
- Cross-Sectional Studies
- Diet, Vegetarian
- Female
- Homocysteine
- Humans
- Linear Models
- Lipids
- Lipoprotein(a)
- Middle Aged
- Postmenopause
- Pulsatile Flow
- Taiwan
- Ultrasonography, Doppler, Pulsed
- Vascular Resistance
- Vitamin B 12
Keywords
- brachial arterial distensibility
- carotid stiffness
- postmenopausal women
- vegetarians
The effect of a chronic combined treatment with growth hormone (GH) plus melatonin (Mel) on different age-related processes in cytosolic and nuclear fractions of hearts from SAMP8 mice (2 and 10 months) has been investigated. The parameters studied have been messenger RNA expressions of IL-1, IL-10, NFkBp50, NFkBp52, TNFα, eNOS, iNOS, HO-1, HO-2, BAD, BAX, and Bcl2 and protein expressions of iNOS, eNOS, TNFα, IL-1, IL-10, NFkBp50, NFKbp52, and caspase activity (3 and 9). Our results supported the existence of a proapoptotic and oxidative status together with inflammatory processes in the heart of old mice, with increases of inflammatory cytokines, caspase activity, HO-1, BAX, NFkBp50, and NFkBp52 and decreases of eNOS and Bcl2. Also, we were able to observe the translocation of NFkB to nuclei. The combined treatment was able to partially reduce the incidence of these deleterious changes, showing differences with the separated treatments with GH and Mel as were investigated in previous articles from our group.
MeSH Terms
- Administration, Oral
- Aging
- Animals
- Apoptosis
- Biomarkers
- Cell Nucleus
- Cytosol
- Drug Administration Schedule
- Drug Synergism
- Heme Oxygenase (Decyclizing)
- Human Growth Hormone
- Injections, Subcutaneous
- Interleukin-1
- Interleukin-10
- Isoenzymes
- Male
- Melatonin
- Mice
- Muscle Proteins
- Myocarditis
- Myocardium
- NF-kappa B
- Nitric Oxide Synthase
- Oxidative Stress
- RNA, Messenger
- Time Factors
- Tumor Necrosis Factor-alpha
This study investigates characteristics of aging in the central nervous system of the senescence accelerated prone mice (SAMP8). We examined 3 and 10-months old senescence-accelerated-prone mice (SAMP8) for functional and molecular changes in their brains, specifically in the hippocampus and somatosensory cortex. There was no statistically significant increase in the apoptosis indicators as revealed by Western Blotting for BAD and TUNEL experiments. However, the functional magnetic resonance imaging showed an increase in the area of BOLD images from the 3-month old to the 10-months old SAMP mice upon the application of tail stimulus. These results demonstrated a lack of neuronal deaths but an increase in the activated brain area with age.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Blotting, Western
- Brain Mapping
- Cellular Senescence
- Hippocampus
- In Situ Nick-End Labeling
- Magnetic Resonance Imaging
- Mice
- Mice, Inbred AKR
- Models, Animal
- Somatosensory Cortex
- bcl-Associated Death Protein
Chronic kidney disease (CKD) is associated with decreased arterial compliance (AC). The stage of development of impaired arterial function in CKD in relation to loss of glomerular filtration rate (GFR) is not known. This study's aim was to evaluate the relationship between GFR and AC in patients with CKD. We recruited 91 men aged > or =60 years with GFR 15-89 ml/min (mean 47 /- 21) to evaluate the relationship between GFR and AC in a cross-sectional study. We measured AC at the brachial artery with an oscillometric device (brachial artery distensibility; BAD). There was no correlation between GFR and BAD (r = 0.08, p = 0.44). When stratified according to CKD stages, all groups showed decreased BAD compared with reference values, and there were no differences among them (one-way ANOVA). Bivariate analyses showed statistically significant correlations between BAD and age (r = -0.23, p = 0.03), antihypertensive drug number (r = 0.27, p = 0.009) and serum hemoglobin (r = 0.24, p = 0.02), but only age and antihypertensive drug number remained significant markers of BAD in a multiple regression model. Older men with CKD have impaired arterial function, but GFR and CKD stage have no relationship to the degree of decrease in brachial artery distensibility.
MeSH Terms
- Aging
- Antihypertensive Agents
- Brachial Artery
- Chronic Disease
- Compliance
- Cross-Sectional Studies
- Drug Therapy, Combination
- Glomerular Filtration Rate
- Humans
- Hypertension
- Kidney Diseases
- Male
- Middle Aged
- Oscillometry
- Regression Analysis
The physiological mechanisms underlying the compensatory growth of beta-cell mass in insulin-resistant states are poorly understood. Using the insulin-resistant Zucker fatty (fa/fa) (ZF) rat and the corresponding Zucker lean control (ZLC) rat, we investigated the factors contributing to the age-/obesity-related enhancement of beta-cell mass. A 3.8-fold beta-cell mass increase was observed in ZF rats as early as 5 weeks of age, an age that precedes severe insulin resistance by several weeks. Closer investigation showed that ZF rat pups were not born with heightened beta-cell mass but developed a modest increase over ZLC rats by 20 days that preceded weight gain or hyperinsulinemia that first developed at 24 days of age. In these ZF pups, an augmented survival potential of beta-cells of ZF pups was observed by enhanced activated (phospho-) Akt, phospho-BAD, and Bcl-2 immunoreactivity in the postweaning period. However, increased beta-cell proliferation in the ZF rats was only detected at 31 days of age, a period preceding massive beta-cell growth. During this phase, we also detected an increase in the numbers of small beta-cell clusters among ducts and acini, increased duct pancreatic/duodenal homeobox-1 (PDX-1) immunoreactivity, and an increase in islet number in the ZF rats suggesting duct- and acini-mediated heightened beta-cell neogenesis. Interestingly, in young ZF rats, specific cells associated with ducts, acini, and islets exhibited an increased frequency of PDX-1 /phospho-Akt staining, indicating a potential role for Akt in beta-cell differentiation. Thus, several adaptive mechanisms account for the compensatory growth of beta-cells in ZF rats, a combination of enhanced survival and neogenesis with a transient rise in proliferation before 5 weeks of age, with Akt serving as a potential mediator in these processes.
MeSH Terms
- Aging
- Animals
- Cell Differentiation
- Cell Division
- Cell Survival
- Homeodomain Proteins
- In Situ Nick-End Labeling
- Insulin Resistance
- Islets of Langerhans
- Male
- Obesity
- Protein-Serine-Threonine Kinases
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-akt
- Rats
- Rats, Zucker
- Signal Transduction
- Trans-Activators
The damaging effects of superoxide in mitochondria leading to pathological disorders and aging are well documented and usually ascribed to superoxide's role as a precursor of reactive free radical species. However, the latest findings point out the importance of the nucleophilic properties of superoxide and its ability to regulate heterolytic enzymatic processes. Hypothetical mechanisms of superoxide mediation of phosphorylation and dephosphorylation reactions with participation of protein kinases and the apoptotic protein BAD are considered.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Carrier Proteins
- Free Radicals
- Humans
- Hydrolysis
- Mice
- Mitochondria
- Models, Biological
- Models, Chemical
- Phosphorylation
- Rats
- Rats, Inbred SHR
- Reactive Oxygen Species
- Signal Transduction
- Superoxides
- bcl-Associated Death Protein
Systemic pharmacokinetics of high dose (500 mg/m2), orally administered Elobromol (dibromodulcitol, DBD) were studied in 16 chemotherapeutic courses administered to five patients. Cerebrospinal fluid (CSF) DBD levels were also analyzed in two patients. Bromoepoxydulcitol (BED), dianhydrodulcitol (DAD) are cytotoxic, whereas bromoanhydrodulcitol (BAD) and anhydroepoxydulcitol (AED) are inactive metabolites detectable during the biotransformation of DBD. The HPLC method, developed by our team, is suitable for the determination of both DBD and its main metabolites (DAD and BAD). Our publication is the first in the literature to describe the pharmacokinetic properties of these three hexitol derivatives in pediatric patients. With the exception of one patient, concentration time curves were analyzed by the one-compartment model. From 30 min following administration, DBD was detectable in all plasma samples for at least 12 h; its concentration, however, was usually undetectable by 24 h. Though highly variable in value, DAD concentrations were detectable during all but one of the therapeutic courses. The following peak concentrations were observed: DBD = 3.46-30.63 microM, DAD = 1.70-6.17 microM and BAD = 0-5.63 microM. The correlation of AUCBAD and AUCDBD values were exponential up to 200 microM h with no additional increase detectable above this limit: the distribution of AUCBAD and AUCDBD was described by a maximum curve. The possibility of enterohepatic recirculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives was detectable in CSF even if the concentration of the individual metabolite remained undetectable in plasma. DBD CSF concentrations were almost constant in the period from 2.5 to 8 h following administration.(ABSTRACT TRUNCATED AT 250 WORDS)
MeSH Terms
- Aging
- Biotransformation
- Brain Neoplasms
- Child
- Child, Preschool
- Chromatography, High Pressure Liquid
- Enterohepatic Circulation
- Female
- Half-Life
- Humans
- Medulloblastoma
- Mitolactol