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Cystathionine beta-synthase (EC 4.2.1.22) (Beta-thionase) (Serine sulfhydrase)

Publications[править]

H S Donors Reverse Age-Related Gastric Malfunction Impaired Due to Fructose-Induced Injury [i]via[/i] CBS, CSE, and TST Expression.

Excess of fructose consumption is related to life-treating conditions that affected more than a third of the global population. Therefore, to identify a newer therapeutic strategy for the impact prevention of high fructose injury in age-related malfunctions of the gastric mucosa (GM) in the animal model is important. Adult and aged male rats were divided into control groups (standard diet, SD) and high fructose diet (HFD) groups; acute water immersion restraint stress (WIRS) was induced for evaluation of GM adaptive response and effects of testing the therapeutic potential of H S-releasing compounds (H S donors). Histological examination of gastric damage was done on hematoxylin-eosin stained slides. Cystathionine beta-synthase (CBS), Cystathionine gamma-lyase (CSE), and Thiosulfate-dithiol sulfurtransferase (TST) activities and oxidative index were assessed during exogenous administration of H S donors: sodium hydrosulfide (NaHS) and the novel hybrid H S-releasing aspirin (ATB-340). The results showed that HFD increased gastric damage in adult and aged rats. HFD-associated malfunction characterized by low activities of H S key enzymes, inducing increased oxidation. Pretreatment with NaHS, ATB-340 of aged rats in the models of HFD, and WIRS attenuated gastric damage in contrast to vehicle-treated group (p < 0.05). The effect of ATB-340 was characterized by reverse oxidative index and increased CBS, CSE, and TST activities. In conclusion, H S donors prevent GM age-related malfunctions by enhancement of CBS, CSE, and TST expression against fructose excess injury though reduction of oxidative damage.


Keywords

  • aging
  • donor
  • fructose
  • gastric mucosa
  • hydrogen sulfide
  • oxidative stress


Permanent cystathionine-β-Synthase gene knockdown promotes inflammation and oxidative stress in immortalized human adipose-derived mesenchymal stem cells, enhancing their adipogenic capacity.

In the present study, we aimed to investigate the impact of permanent cystathionine-β-Synthase (CBS) gene knockdown in human telomerase reverse transcriptase (hTERT) immortalized human adipose-derived mesenchymal stem cells (ASC52telo) and in their capacity to differentiate into adipocytes. CBS gene KD in ASC52telo cells led to increased cellular inflammation (IL6, CXCL8, TNF) and oxidative stress markers (increased intracellular reactive oxygen species and decreased reduced glutathione levels) in parallel to decreased H S production and rejuvenation (LC3 and SIRT1)-related gene expression. In addition, CBS gene KD in ASC52telo cells resulted in altered mitochondrial respiratory function, characterised by decreased basal respiration (specifically proton leak) and spare respiratory capacity, without significant effects on cell viability and proliferation. In this context, shCBS-ASC52telo cells displayed enhanced adipogenic (FABP4, ADIPOQ, SLC2A4, CEBPA, PPARG)-, lipogenic (FASN, DGAT1)- and adipocyte (LEP, LBP)-related gene expression markers, decreased expression of proinflammatory cytokines, and increased intracellular lipid accumulation during adipocyte differentiation compared to control ASC52telo cells. Otherwise, the increased adipogenic potential of shCBS-ASC52telo cells was detrimental to the ability to differentiate into osteogenic linage. In conclusion, this study demonstrated that permanent CBS gene KD in ASC52telo cells promotes a cellular senescence phenotype with a very increased adipogenic potential, promoting a non-physiological enhanced adipocyte differentiation with excessive lipid storage.


Keywords

  • Cellular senescence
  • Cystathionine β-synthase
  • Human adipose-derived mesenchymal stem cells
  • Inflammation
  • Oxidative stress and adipogenesis


Cardiovascular phenotype of mice lacking 3-mercaptopyruvate sulfurtransferase.

Hydrogen sulfide (H S) is a physiological mediator that regulates cardiovascular homeostasis. Three major enzymes contribute to the generation of endogenously produced H S, namely cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). Although the biological roles of CSE and CBS have been extensively investigated in the cardiovascular system, very little is known about that of 3-MST. In the present study we determined the importance of 3-MST in the heart and blood vessels, using a genetic model with a global 3-MST deletion. 3-MST is the most abundant transcript in the mouse heart, compared to CSE and CBS. 3-MST was mainly localized in smooth muscle cells and cardiomyocytes, where it was present in both the mitochondria and the cytosol. Levels of serum and cardiac H S species were not altered in adult young (2-3 months old) 3-MST mice compared to WT animals. No significant changes in the expression of CSE and CBS were observed. Additionally, 3-MST mice had normal left ventricular structure and function, blood pressure and vascular reactivity. Interestingly, genetic ablation of 3-MST protected mice against myocardial ischemia reperfusion injury, and abolished the protection offered by ischemic pre- and post-conditioning. 3-MST mice showed lower expression levels of thiosulfate sulfurtransferase, lower levels of cellular antioxidants and elevated basal levels of cardiac reactive oxygen species. In parallel, 3-MST mice showed no significant alterations in endothelial NO synthase or downstream targets. Finally, in a separate cohort of older 3-MST mice (18 months old), a hypertensive phenotype associated with cardiac hypertrophy and NO insufficiency was observed. Overall, genetic ablation of 3-MST impacts on the mouse cardiovascular system in an age-dependent manner. Loss of 3-MST exerts a cardioprotective role in young adult mice, while with aging it predisposes them to hypertension and cardiac hypertrophy.

MeSH Terms

  • Animals
  • Antioxidants
  • Cardiovascular System
  • Cystathionine beta-Synthase
  • Cystathionine gamma-Lyase
  • Gene Expression Regulation, Enzymologic
  • Hydrogen Sulfide
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Reperfusion Injury
  • Myocytes, Cardiac
  • Nitric Oxide
  • Phenotype
  • Reactive Oxygen Species
  • Sulfurtransferases
  • Vasodilation

Keywords

  • 3-mercaptopyruvate transferase (3-MST)
  • Aging
  • Blood pressure
  • Myocardial infarction
  • Nitric Oxide (NO)
  • Reactive Oxygen Species (ROS)


Methionine restriction leads to hyperhomocysteinemia and alters hepatic H S production capacity in Fischer-344 rats.

Dietary methionine restriction (MR) increases lifespan in several animal models. Despite low dietary intake of sulphur amino acids, rodents on MR develop hyperhomocysteinemia. On the contrary, MR has been reported to increase H S production in mice. Enzymes involved in homocysteine metabolism also take part in H S production and hence, in this study, the impact of MR on hyperhomocysteinemia and H S production capacity were investigated using Fischer-344 rats assigned either a control or a MR diet for 8 weeks. The MR animals showed elevated plasma homocysteine accompanied with a reduction in liver cysteine content and methylation potential. It was further found that MR decreased cystathionine-β-synthase (CBS) activity in the liver, however, MR increased hepatic cystathionine-γ-lyase (CGL) activity which is the second enzyme in the transsulfuration pathway and also participates in regulating H S production. The relative contribution of CGL in H S production increased concomitantly with the increased CGL activity. Additionally, hepatic mercaptopyruvate-sulphur-transferase (MPST) activity also increased in response to MR. Taken together, our results suggest that reduced CBS activity and S-Adenosylmethionine availability contributes to hyperhomocysteinimia in MR animals. Elevated CGL and MPST activities may provide a compensatory mechanism for maintaining hepatic H S production capacity in response to the decreased CBS activity.

MeSH Terms

  • Animals
  • Food, Formulated
  • Hydrogen Sulfide
  • Hypercholesterolemia
  • Liver
  • Male
  • Methionine
  • Rats
  • Rats, Inbred F344

Keywords

  • H(2)S
  • Longevity
  • Methionine restriction
  • Methylation potential
  • Transsulfuration
  • sulfur amino acids


Human Cord Blood Serum-Derived APP α-Secretase Cleavage Activity is Mediated by C1 Complement.

Alzheimer's Disease (AD) is the leading cause of dementia in the elderly. In healthy individuals, amyloid precursor protein (APP) is cleaved by α-secretase, generating soluble α-amyloid precursor protein (sAPPα), which contributes neuroprotective functions in the neuronal environment. In contrast, in the neurodegenerative environment of AD patients, amyloid-β-peptide (Aβ) of either 40 or 42 residues are generated by increased activity of β- and γ-secretase. These proteins amalgamate in specific regions of the brain, which disrupts neuronal functions and leads to cognitive impairment. Human umbilical cord blood cells (HUCBC) have proven useful as potential immunomodulatory therapies in various models of neurodegenerative diseases, including AD. Our most recent work studied the impact of umbilical cord blood serum (CBS) on modulation of sAPPα production. Heat-sensitive CBS significantly promoted sAPPα production, indicating that heat-sensitive factor(s) play(s) a role in this process. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis was used to determine the molecular source of α-secretase in purified CBS and aged blood serum (AgBS) fraction. Of the proteins identified, the subunits of C1 complex (C1q, C1r, and C1s) and alpha-2-macroglobulin showed significantly greater levels in purified α-CBS fraction (α-CBSF) compared with the AgBS fraction (AgBSF). Specifically, C1 markedly increased sAPPα and alpha-carboxyl-terminal fragment (α-CTF) production in a dose-dependent fashion, whereas C1q alone only minimally increased and C3 did not increase sAPPα production in the absence of sera. Furthermore, C1q markedly increased sAPPα and α-CTF, while decreasing Aβ, in CHO/APPwt cells cultured in the presence of whole sera. These results confirm our initial assumption that APP α-secretase activity in human blood serum is mediated by complement C1, opening a potential therapeutic modality for the future of AD.

MeSH Terms

  • Aged
  • Aging
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides
  • Animals
  • CHO Cells
  • Complement C1
  • Complement C3b
  • Cricetinae
  • Cricetulus
  • Fetal Blood
  • Hot Temperature
  • Humans
  • Mice
  • Proteomics

Keywords

  • Alzheimer’s Disease
  • amyloid precursor protein
  • complement C1 complex
  • complement system
  • cord blood serum
  • human umbilical cord blood cell
  • soluble α-amyloid precursor protein


Dietary and Endocrine Regulation of Endogenous Hydrogen Sulfide Production: Implications for Longevity.

Hydrogen sulfide (H S) at the right concentration is associated with numerous health benefits in experimental organisms, ranging from protection from ischemia/reperfusion injury to life span extension. Given the considerable translation potential, two major strategies have emerged: supplementation of exogenous H S and modulation of endogenous H S metabolism. Recent Advances: Recently, it was reported that hepatic H S production capacity is increased in two of the best-characterized mammalian models of life span extension, dietary restriction, and hypopituitary dwarfism, leading to new insights into dietary and hormonal regulation of endogenous H S production together with broader changes in sulfur amino acid (SAA) metabolism with implications for DNA methylation and redox status. Here, we discuss the role of dietary SAAs and growth hormone (GH)/thyroid hormone (TH) signaling in regulation of endogenous H S production largely via repression of H S generating enzymes cystathionine γ-lyase (CGL) and cystathionine β-synthase (CBS) on the level of gene transcription, as well as reciprocal regulation of GH and TH signaling by H S itself. We also discuss plasticity of CGL and CBS gene expression in response to environmental stimuli and the potential of the microbiome to impact overall H S levels. The relative contribution of increased H S to health span or lifespan benefits in models of extended longevity remains to be determined, as does the mechanism by which such benefits occur. Nonetheless, our ability to control H S levels using exogenous H S donors or by modifying the endogenous H S production/consumption equilibrium has the potential to improve health and increase "shelf-life" across evolutionary boundaries, including our own. Antioxid. Redox Signal. 28, 1483-1502.

MeSH Terms

  • Animals
  • Diet
  • Endocrine Glands
  • Humans
  • Hydrogen Sulfide
  • Longevity

Keywords

  • aging
  • cystathionine γ-lyase
  • dietary restriction
  • growth hormone
  • hydrogen sulfide
  • thyroid hormone


Nitration-mediated deficiency of cystathionine β-synthase activity accelerates the progression of hyperhomocysteinemia.

Deficiency of cystathionine β-synthase (CBS) activity is the most common cause of increased homocysteine (Hcy). However, until now the underlying mechanisms why CBS activity decreased still remain unresolved. The goal of this study was to explore the contribution of nitrative stress to deficiency of CBS activity, and further identify the possible nitration sites of CBS protein. Results showed that in elderly people, there was an increased nitrative stress level, which was relative to elevated Hcy level. In natural aging rats and diet-induced hyperhomocysteinemia (HHcy) rats, the levels of Hcy and nitrative stress were both elevated, and interestingly, pretreatment with peroxynitrite (ONOO ) scavenger FeTMPyP ameliorated the elevation of Hcy as well as nitrative stress. Further experiments showed the reduction of CBS bioactivity and elevation of CBS nitration in two rats models were both reversed by FeTMPyP pretreatment. In vitro, replacement of tyrosine (Tyr, Y) residue (Tyr , Tyr , Tyr , Tyr ) in CBS with alanine (Ala, A) abolished the Hcy-mediated CBS inactivation. These results highlighted that deficiency of CBS activity was correlated with the nitration of CBS at Tyr , Tyr , Tyr and Tyr , which may play a mutual role in the progression of HHcy. This discovery may shed a novel light on the pathogenesis of HHcy and provide a possible gene therapy target to HHcy.

MeSH Terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Cystathionine beta-Synthase
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Free Radical Scavengers
  • Homocysteine
  • Humans
  • Hyperhomocysteinemia
  • Male
  • Metalloporphyrins
  • Middle Aged
  • Mutation
  • Nitro Compounds
  • Nitrosative Stress
  • Protein Processing, Post-Translational
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Tyrosine

Keywords

  • Aging
  • Cystathionine β-synthase
  • Homocysteine
  • Hyperhomocysteinemia
  • Nitration
  • Nitrative stress


Standing sagittal alignment of the whole axial skeleton with reference to the gravity line in humans.

Human beings stand upright with the chain of balance beginning at the feet, progressing to the lower limbs (ankles, knees, hip joints, pelvis), each of the spinal segments, and then ending at the cranium to achieve horizontal gaze and balance using minimum muscle activity. The details of the alignment and balance of the chain, however, are not clearly understood, due to the lack of information regarding the three-dimensional (3D) orientation of all bony elements in relation to the gravity line (GL). We performed a clinical study to clarify the standing sagittal alignment of whole axial skeletons in reference to the GL using the EOS slot-scanning 3D X-ray imaging system with simultaneous force plate measurement in a healthy human population. The GL was defined as a vertical line drawn through the centre of vertical pressure measured by the force plate. The present study yielded a complete set of physiological alignment measurements of the standing axial skeleton from the database of 136 healthy subjects (a mean age of 39.7 years, 20-69 years; men: 40, women: 96). The mean offset of centre of the acoustic meati from the GL was 0.0 cm. The offset of the cervical and thoracic vertebrae was posterior to the GL with the apex of thoracic kyphosis at T7, 5.0 cm posterior to the GL. The sagittal alignment changed to lordosis at the level of L2. The apex of the lumbar lordosis was L4, 0.6 cm anterior to the GL, and the centre of the base of the sacrum (CBS) was just posterior to the GL. The hip axis (HA) was 1.4 cm anterior to the GL. The knee joint was 2.4 cm posterior and the ankle joint was 4.8 cm posterior to the GL. L4-, L5- and the CBS-offset in subjects in the age decades of 40s, 50s and 60s were significantly posterior to those of subjects in their 20s. The L5- and CBS-offset in subjects in their 50s and 60s were also significantly posterior to those in subjects in their 30s. HA was never posterior to the GL. In the global alignment, there was a positive correlation between offset of C7 vertebra from the sagittal vertical axis (a vertical line drawn through the posterior superior corner of the sacrum in the sagittal plane) and age, but no correlation was detected between the centre of the acoustic meati-GL offset and age. Cervical lordosis (CL), pelvic tilt (PT), pelvic incidence, hip extension, knee flexion and ankle dorsiflexion increased significantly with age. Our results revealed that aging induces trunk stooping, but the global alignment is compensated for by an increase in the CL, PT and knee flexion, with the main function of CL and PT to maintain a horizontal gaze in a healthy population.

MeSH Terms

  • Adult
  • Aged
  • Female
  • Gravitation
  • Humans
  • Male
  • Middle Aged
  • Postural Balance
  • Posture
  • Radiography
  • Skeleton
  • Young Adult

Keywords

  • aging
  • force plate measurement
  • gravity line
  • sagittal whole body alignment
  • standing balance


Hydrogen sulfide mediates the protection of dietary restriction against renal senescence in aged F344 rats.

Renal aging is always accompanied by increased oxidative stress. Hydrogen sulfide (H2S) can be up-regulated by 50% dietary restriction (DR) for 7-day and can block mitochondrial oxidative stress. H2S production exerts a critical role in yeast, worm, and fruit fly models of DR-mediated longevity. In this study, we found that renal aging could be attenuated by 30% DR for 6-month (DR-6M) and life-long (DR-LL), but not for 6-week (DR-6W). The expressions of cystathionine-γ-lyase (CGL) and cystathionine-β- synthase (CBS) were improved by DR-6M and DR-LL. Endogenous H2S production shared the same trend with CBS and CGL, while glutathione (GSH) didn't. When comparing efficiencies of DR for different durations, more evident production of H2S was found in DR-6M and DR-LL than in DR-6W. Finally the level of oxidative stress was improved by DR-6M and DR-LL rather than by DR-6W. It concluded that aged rats had the ability to produce enough H2S on 30% DR interventions protecting against renal aging, and the effect of DR for long-term were more significant than that of DR for short-term.

MeSH Terms

  • Aging
  • Animals
  • Caloric Restriction
  • Cellular Senescence
  • Cystathionine beta-Synthase
  • Cystathionine gamma-Lyase
  • Glutathione
  • Hydrogen Sulfide
  • Kidney
  • Longevity
  • Mitochondria
  • Oxidative Stress
  • Rats


Hippocampal cystathionine beta synthase in young and aged mice.

Cystathionine beta synthase (CBS) is the main contributor to the production of hydrogen sulfide (H2S) in the brain. Exogenously administered H2S has been reported to protect neurons against hypoxic injury, ischemia and LPS-induced neuro-inflammation and in the facilitating of long term potentiation (LTP). Dysregulation of CBS leads to different diseases, which all have mental retardation in common. Although multiple studies have implicated a link between the CBS/H2S pathway and neurodegeneration, no studies have been performed examining the pathway in healthy aging animals. We hypothesize that CBS/H2S pathway plays an important role in the protection of learning and memory functions in the brain at the level of the hippocampus. Thus, we studied a set of 8 young (4 months) and 14 aged (24 months (n=6) and 28 months (n=8)) C57Bl6 mice. The 24-month-old mice displayed a significant decrease of CBS immunoreactivity in the MoDG only, compared to 4-month-old mice. In 28-month-old mice, we observed a significant increase of CBS immunoreactivity in the MoDG, compared to 4-month-old mice. When comparing 28-month-old mice to 24-month-old mice, all areas showed a significant increase of CBS immunoreactivity. Thus, throughout aging, CBS expression is maintained in the hippocampus, and many other forebrain regions as well. Mice at the unusual age of 28 months even have a higher hippocampal CBS expression than young mice. Maintenance (and increase) of CBS levels may sustain memory and learning by precluding neuronal loss in areas of the hippocampus.

MeSH Terms

  • Age Factors
  • Aging
  • Animals
  • Cystathionine beta-Synthase
  • Hippocampus
  • Male
  • Mice, Inbred C57BL
  • Prosencephalon

Keywords

  • Aging
  • Cystathionine beta synthase
  • Hippocampal subregions


Sulfur-based redox alterations in long-lived Snell dwarf mice.

Changes in sulfur-based redox metabolite profiles in multiple tissues of long-lived Snell dwarf mice were compared with age- and sex-matched controls. Plasma methionine and its oxidation products, hypotaurine and taurine, were increased in Snell dwarfs while cystine and glutathione levels were decreased, leading to an oxidative shift in the redox potential. Sexual dimorphism in renal cystathionine β-synthase (CBS) activity was observed in control mice but not in Snell dwarfs. Instead, female Snell mice exhibited ~2-fold higher CBS activity, comparable to levels seen in male Snell dwarf and in control mice. Taurine levels were significantly higher in kidney and brain of Snell dwarf versus control mice. Methionine adenosyltransferase (MAT) was higher in liver of Snell dwarfs, and the higher concentration of its product, S-adenosylmethionine, was correlated with elevated global DNA methylation status. Application of a mathematical model for methionine metabolism revealed that the metabolite perturbations in Snell dwarfs could be explained by decreased methionine transport, increased MAT and increased methyltransferase activity. Our study provides a comprehensive map of systemic differences in the sulfur network between Snell dwarfs and controls, providing the necessary foundation for assessment of nutrition-linked metabolic status in long-lived versus control animals.

MeSH Terms

  • Animals
  • Cystathionine beta-Synthase
  • Cystine
  • Female
  • Glutathione
  • Longevity
  • Male
  • Methionine
  • Mice
  • Models, Biological
  • Oxidation-Reduction
  • Sex Characteristics
  • Sulfur


Cystathionine beta synthase modulates senescence of human endothelial cells.

Availability of methionine is known to modulate the rate of aging in model organisms, best illustrated by the observation that dietary methionine restriction extends the lifespan of rodents. However, the underlying mechanisms are incompletely understood. In eukaryotic cells, methionine can be converted to cysteine through the reverse transsulfuration pathway thereby modulating intracellular methionine availability. Whereas previous results obtained in yeast and fruit flies suggest that alterations in the reverse transsulfuration pathway modulate the rate of aging, it is not known whether this function is conserved in evolution. Here we show that depletion of cystathionine beta synthase (CBS), a rate limiting enzyme in the reverse transsulfuration pathway, induces premature senescence in human endothelial cells. We found that CBS depletion induces mild mitochondrial dysfunction and increases the sensitivity of endothelial cells to homocysteine, a known inducer of endothelial cell senescence and an established risk factor for vascular disease. Our finding that CBS deficiency induces endothelial cell senescencein vitro, involving both mitochondrial dysfunction and increased susceptibility of the cells to homocysteine, suggests a new mechanism linking CBS deficiency to vascular aging and disease.

MeSH Terms

  • Aging
  • Cellular Senescence
  • Cystathionine beta-Synthase
  • Endothelial Cells
  • Gene Knockdown Techniques
  • Human Umbilical Vein Endothelial Cells
  • Humans


Correlated evolution of senescence and ephemeral substrate use in the Sordariomycetes.

Evolutionary theory predicts that senescence--a decline in reproduction and survival with increasing age--can evolve as a trade-off between investment in reproduction on one side and in somatic maintenance and repair on the other. The ecology of a species is crucial because it provides the external causes of death that determine the statistical limit to a species' lifespan. Filamentous fungi are generally believed to be nonsenescent, and there are indeed spectacular examples of very old fungal individuals in nature. However, some fungi utilize ephemeral resources, and therefore, senescence is expected to have evolved, like in the coprophilic Podospora anserina, the only well-studied filamentous fungus with intrinsic senescence. Here, we hypothesize that rapid senescence is more common in fungi than generally believed and that the phylogenetic distribution of senescence correlates with ecology. We collected lifespan data for a set of Sordariomycetes and constructed phylogenies based on several nuclear sequences. Several of the strains were from the CBS culture collection, originally isolated from various substrates, some of which ephemeral. In addition, we isolated new strains from short-lived substrates. Senescence was observed throughout the phylogeny. Correlation tests support the hypothesis that in the Sordariomycetes, senescence is a trait that has arisen in response to ephemeral substrates, and that it has evolved repeatedly and independently along the phylogeny.

MeSH Terms

  • Aging
  • Animals
  • Ascomycota
  • Biological Evolution
  • Feces
  • Molecular Sequence Data
  • Phylogeny
  • Podospora
  • Rabbits


[Caring friends and neighbors as informal caregivers of older adults: A comparison with offspring].

This study compared informal care to older, non-coresiding adults provided by friends and neighbours and informal care by children or their partners. Using data from a Dutch representative survey among informal caregivers conducted by CBS and SCP, caregivers of friends (n=133), neighbours (n=108) and parents (n=1,008) were compared with one another to investigate care that friends and neighbours provide to the elderly non-coresiding adults (age 55 and over). Nine percent of those providing care to someone outside the household were friends and nine percent were neighbours. Friends, like children, usually provide long-lasting care, up to four or five years. Friends are similar to neighbours in the number of hours that they provide care. Friends and neighbours experience a lower caregiver burden than children. However, when fulfilling multiple caring tasks, both friends and children, have a greater chance of experiencing higher levels of burden. When there were other caregivers to help, friends experienced a small reduction in burden. Friends and neighbours deserve to be recognized as informal caregivers by policy makers and they deserve attention and support along with family caregivers.

MeSH Terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Caregivers
  • Family
  • Female
  • Friends
  • Geriatrics
  • Humans
  • Male
  • Middle Aged
  • Social Support
  • Stress, Psychological
  • Young Adult


Yi-gan san for treatment of charles bonnet syndrome (visual hallucination due to vision loss): an open-label study.

Recent studies indicate that the traditional Japanese herbal medicine yi-gan san (YGS, yokukan-san in Japanese) may be safe and useful for treating behavioral and psychological symptoms in dementia, borderline personality disorder, neuroleptic-induced tardive dyskinesia, and treatment-resistant schizophrenia. Visual hallucinations are common and often distressing consequences of vision loss, particularly in age-related macular degeneration. Charles Bonnet syndrome (CBS) is defined by the triad of complex visual hallucinations, ocular pathology causing visual deterioration, and preserved cognitive status. We aimed at evaluating both the efficacy and safety of YGS in patients with CBS. Twenty patients diagnosed with CBS were investigated, according to the diagnostic criteria established by Gold and Rabins and Teunisse. Participants were treated in a 4-week open-label study with YGS at an average daily dose of 5.8 ± 2.6 g (2.5-7.5 g). Psychometric instruments used to assess efficacy included the Neuropsychiatric Inventory, hallucination subscale of the Positive and Negative Syndrome Scale, and Clinical Global Impression. No cases of serious adverse events were attributed to the study's drug therapy. A significant decrease in visual hallucination was observed at 2 and 4 weeks in the Neuropsychiatric Inventory, hallucination subscale of the Positive and Negative Syndrome Scale, and Clinical Global Impression scores. Yi-gan san may be an effective and safe therapy to control visual hallucination in patients with CBS and should be further tested in double-blind, placebo-controlled trials. Given the design characteristics of this trial, the present findings should be taken cautiously.

MeSH Terms

  • Aged
  • Aged, 80 and over
  • Aging
  • Drugs, Chinese Herbal
  • Female
  • Hallucinations
  • Humans
  • Macular Degeneration
  • Male
  • Middle Aged
  • Psychiatric Status Rating Scales
  • Psychometrics
  • Vision, Low


The hydrogen sulfide signaling system: changes during aging and the benefits of caloric restriction.

Hydrogen sulfide gas (H(2)S) is a putative signaling molecule that causes diverse effects in mammalian tissues including relaxation of blood vessels and regulation of perfusion in the liver, but the effects of aging on H(2)S signaling are unknown. Aging has negative impacts on the cardiovascular system. However, the liver is more resilient with age. Caloric restriction (CR) attenuates affects of age in many tissues. We hypothesized that the H(2)S signaling system is negatively affected by age in the vasculature but not in the liver, which is typically more resilient to age, and that a CR diet minimizes the age affect in the vasculature. To investigate this, we determined protein and mRNA expression of the H(2)S-producing enzymes cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), H(2)S production rates in the aorta and liver, and the contractile response of aortic rings to exogenous H(2)S. Tissue was collected from Fisher 344 × Brown Norway rats from 8-38 months of age, which had been maintained on an ad libitum (AL) or CR diet. The results demonstrate that age and diet have differential effects on the H(2)S signaling system in aorta and liver. The aorta showed a sizeable effect of both age and diet, whereas the liver only showed a sizeable effect of diet. Aortic rings showed increased contractile sensitivity to H(2)S and increased protein expression of CSE and CBS with age, consistent with a decrease in H(2)S concentration with age. CR appears to benefit CSE and CBS protein in both aorta and liver, potentially by reducing oxidative stress and ameliorating the negative effect of age on H(2)S concentration. Therefore, CR may help maintain the H(2)S signaling system during aging.

MeSH Terms

  • Aging
  • Animals
  • Aorta
  • Caloric Restriction
  • Cystathionine beta-Synthase
  • Cystathionine gamma-Lyase
  • Hydrogen Sulfide
  • In Vitro Techniques
  • Liver
  • Oxidative Stress
  • RNA, Messenger
  • Rats
  • Rats, Inbred BN
  • Rats, Inbred F344
  • Signal Transduction


Perceived color of hallucinations in the Charles Bonnet Syndrome is related to residual color contrast sensitivity.

We sought to determine whether the change in cortical excitability secondary to deafferentation in patients with Charles Bonnet Syndrome (CBS) who hallucinate in a predominant color or combination of colors is related to an alteration in color contrast thresholds and whether the change is specific to the color of the hallucination. We prospectively categorized each patient's hallucinations using the Institute of Psychiatry Visual Hallucinations Interview. We measured color contrast thresholds with a computerized test designed to assess red-green and blue-yellow color confusion axes against a background of luminance noise. We calculated the ratio of red-green threshold to blue-yellow threshold (R-G/B-Y ratio) for each patient. Because central vision was impaired in all patients, we used a sectoral annular stimulus that projected to the retina at 12.5 degrees eccentricity. There were 10 patients with age-related macular degeneration and CBS who were hallucinating in a predominant color or combination of colors at the time of recruitment. Patients hallucinating in red, green, or a combination of red and green had R-G/B-Y ratios of less than 1.0 (n = 5). Patients hallucinating in blue, yellow, or a combination of blue and yellow had R-G/B-Y ratios of greater than 1.0 (n = 2). Patients hallucinating in purple had ratios between the red-green and blue-yellow hallucinators (n = 2). The 1 patient hallucinating in white had the lowest thresholds for red-green and blue-yellow confusion axes. Comparing the R-G/B-Y ratios for the "red/green hallucinators" and "blue/yellow hallucinators" returned a significant result with Fisher's exact test (P = 0.047, n = 7). Deafferentation and secondary cortical hyperexcitability in CBS have a correlate in psychophysical threshold. This change in sensitivity relates specifically to the hallucinated color axis rather than across all colors. This is the first published evidence for cerebral hyperexcitability leading to a decrease in color contrast thresholds.

MeSH Terms

  • Age Factors
  • Aged
  • Aged, 80 and over
  • Aging
  • Color Vision
  • Color Vision Defects
  • Contrast Sensitivity
  • Diagnostic Techniques, Ophthalmological
  • Female
  • Hallucinations
  • Humans
  • Macular Degeneration
  • Male
  • Prospective Studies
  • Psychophysics
  • Syndrome
  • Visual Cortex


Genetic variation in homocysteine metabolism, cognition, and white matter lesions.

Several studies have shown an association between homocysteine concentration and cognitive performance or cerebral white matter lesions. However, variations in genes encoding for enzymes and other proteins that play a role in homocysteine metabolism have hardly been evaluated in relation to these outcome measures. In the population-based Rotterdam Scan Study, we examined the association of seven polymorphisms of genes involved in homocysteine metabolism (MTHFR 677C>T, MTHFR 1298A>C, RFC 80G>A, TC 776C>G, MTR 2756A>G, MTRR 66A>G, and CBS 844ins68) with plasma total homocysteine, cognitive performance, and cerebral white matter lesions among 1011 non-demented elderly participants. Of all the studied polymorphisms, only MTHFR 677C>T was associated with homocysteine concentration. No significant relationship was observed for any of the polymorphisms with cognitive performance or severity of cerebral white matter lesions.

MeSH Terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Aged
  • Aged, 80 and over
  • Aging
  • Brain
  • Cognition
  • Cross-Sectional Studies
  • Cystathionine beta-Synthase
  • Ferredoxin-NADP Reductase
  • Homocysteine
  • Humans
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Middle Aged
  • Nerve Fibers, Myelinated
  • Reduced Folate Carrier Protein
  • Transcobalamins


Mouse models of cystathionine beta-synthase deficiency reveal significant threshold effects of hyperhomocysteinemia.

Untreated cystathionine beta-synthase (CBS) deficiency in humans is characterized by extremely elevated plasma total homocysteine (tHcy>200 microM), with thrombosis as the major cause of morbidity. Treatment with vitamins and diet leads to a dramatic reduction in thrombotic events, even though patients often still have severe elevations in tHcy (>80 microM). To understand the difference between extreme and severe hyperhomocysteinemia, we have examined two mouse models of CBS deficiency: Tg-hCBS Cbs(-/-) mice, with a mean serum tHcy of 169 microM, and Tg-I278T Cbs(-/-) mice, with a mean tHcy of 296 microM. Only Tg-I278T Cbs(-/-) animals exhibited strong biological phenotypes, including facial alopecia, osteoporosis, endoplasmic reticulum (ER) stress in the liver and kidney, and a 20% reduction in mean survival time. Metabolic profiling of serum and liver reveals that Tg-I278T Cbs(-/-) mice have significantly elevated levels of free oxidized homocysteine but not protein-bound homocysteine in serum and elevation of all forms of homocysteine and S-adenosylhomocysteine in the liver compared to Tg-hCBS Cbs(-/-) mice. RNA profiling of livers indicate that Tg-I278T Cbs(-/-) and Tg-hCBS Cbs(-/-) mice have unique gene signatures, with minimal overlap. Our results indicate that there is a clear pathogenic threshold effect for tHcy and bring into question the idea that mild elevations in tHcy are directly pathogenic.

MeSH Terms

  • Animals
  • Aorta
  • Cystathionine beta-Synthase
  • Disease Models, Animal
  • Endoplasmic Reticulum
  • Gene Expression Profiling
  • Gene Expression Regulation, Enzymologic
  • Genetic Predisposition to Disease
  • Hyperhomocysteinemia
  • Liver
  • Longevity
  • Mice
  • Myocardium
  • Oligonucleotide Array Sequence Analysis
  • Osteoporosis
  • Protein Folding


The distribution of cystathionine beta-synthase (CBS) in the eye: implication of the presence of a trans-sulfuration pathway for oxidative stress defense.

Clinical abnormalities in cystathionine-beta-synthase (CBS) deficiency, a key enzyme in the trans-sulfuration pathway, associate with many eye disorders. However, little is known about this enzyme in the eye. The goal of this study is to examine the distribution of CBS in the various regions of the eye, including conjunctiva, cornea, iris, lens, vitreous, retina and optic nerve using fresh eyes from both pigs (6 months) and humans (4-82 years). We have found that pig eye showed the highest CBS protein presence in cornea, conjunctiva and iris, followed by retina and optic nerve. The whole lens had a relatively lower amount and vitreous body had none. CBS protein distribution in the human eyes showed a similar pattern, with high level in the anterior segments but much lower amount in retina and optic nerve. CBS in anterior segments remained high throughout the lifespan, but retinal CBS showed a trend of age-dependent increase. The presence of CBS in human and pig eye tissues was further confirmed by RT-PCR, CBS activity assay, both showed similar distribution profiles as the Western blot analysis. This is the first evidence of the presence of CBS enzyme in the eye outside of the lens, which indicates that a functional trans-sulfuration pathway may be present in various eye tissues.

MeSH Terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aging
  • Animals
  • Child
  • Child, Preschool
  • Cystathionine beta-Synthase
  • Eye
  • Gene Expression
  • Humans
  • Middle Aged
  • Oxidative Stress
  • RNA, Messenger
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Species Specificity
  • Swine
  • Tissue Distribution


Cystathionine beta-synthase is enriched in the brains of Down's patients.

Down's syndrome (DS) or trisomy 21 is the most common genetic cause of mental retardation, and adults with DS develop Alzheimer type of disease (AD). Cystathionine beta-synthase (CBS) is encoded on chromosome 21 and deficiency in its activity causes homocystinuria, the most common inborn error of sulfur amino acid metabolism and characterized by mental retardation and vascular disease. Here, we show that the levels of CBS in DS brains are approximately three times greater than those in the normal individuals. CBS is localized to astrocytes and those surrounding senile plaques in the brains of DS patients with AD. The over-expression of CBS may cause the developmental abnormality in cognition in DS children and that may lead to AD in DS adults.

MeSH Terms

  • Adolescent
  • Adult
  • Aging
  • Autopsy
  • Brain
  • Child
  • Child, Preschool
  • Cystathionine beta-Synthase
  • Down Syndrome
  • Humans
  • Infant
  • Infant, Newborn
  • Middle Aged


The presence of a transsulfuration pathway in the lens: a new oxidative stress defense system.

The finding that a lens under oxidative stress accumulated free and protein-bound cysteine (protein-S-S-cysteine) in the fiber cells prompted us to examine if there is an alternative source for cysteine pools besides the active cysteine transport system in the lens, namely, the transsulfuration pathway of homocysteine-cystathionine-cysteine, which utilises methionine through transmethylation. We examined the presence of the gene for cystathionine-beta-synthase (CBS), the rate limiting enzyme that converts homocysteine to cystathionine in the transsulfuration pathway, in human lens epithelial (HLE) B3 cells using PCR with primers designed based on the sequence of human liver CBS (Forward 5'-CCA CAC TGC CCC GGC AAA AT-3'; Reverse 5'-CTG GCA ATG CCC GTG ATG GT-3'). The purified DNA fragment (586 bp) from PCR analysis was sequenced and confirmed the homology with CBS gene from other human tissues. The CBS protein band (67 kDa) was present in the HLE cells, which reacted positively with the human liver anti-CBS antibody. The enzyme protein was detected in the pig and human lenses with the highest intensity in the epithelial layer, lower but equal quantities of CBS was present in the cortical and nuclear regions. Human nuclear CBS increased while epithelial CBS decreased with aging. Oxidative stress transiently upregulated the gene expression of CBS both in HLE cells (0.1 mMH2O2) and in pig lens cultured in TC 199 medium (0.5 mMH2O2). The catalytic activity for CBS, which was assayed by measuring the production of C14-cystathionine from C14-serine in the presence of homocysteine, S-adenosyl-methionine and pyridoxal phosphate, was detectable in the HLE cells and transiently activated with H2O2. Free cystathionine accumulated when HLE B3 cells were treated with propargylglycine (PGG), an inhibitor of cystathionase, the downstream enzyme that converts cystathionine to cysteine. More cystathionine accumulation occurred when the cells were simultaneously exposed to PGG and 0.1 mMH2O2. We have shown that oxidative stress of H2O2 could increase the flux of this transsulfuration pathway by committing more homocysteine to cysteine and glutathione production as H2O2 (0.1 mM) inhibited the remethylation enzyme of methionine synthase while concurrently activating the CBS enzyme. This is the first evidence that a transsulfuration pathway is present in the lens, and that it can be upregulated under oxidative stress to provide additional redox potential for the cells.

MeSH Terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Adolescent
  • Adult
  • Aged
  • Aging
  • Animals
  • Chromatography, High Pressure Liquid
  • Cystathionine beta-Synthase
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme Inhibitors
  • Epithelial Cells
  • Gene Expression Regulation, Enzymologic
  • Glutathione
  • Humans
  • Hydrogen Peroxide
  • Lens Capsule, Crystalline
  • Lens, Crystalline
  • Lyases
  • Middle Aged
  • Organ Culture Techniques
  • Oxidative Stress
  • Sulfur
  • Swine


The production of hydrogen sulfide is regulated by testosterone and S-adenosyl-L-methionine in mouse brain.

Hydrogen sulfide (H2S) is endogenously produced in the brain from L-cysteine by the enzyme cystathionine beta-synthase (CBS) and functions as a neuromodulator in the brain. H2S selectively enhances NMDA receptor-mediated responses and alters hippocampal long-term potentiation (LTP). The production of H2S is regulated by Ca2 /calmodulin-mediated pathways and is enhanced in response to neuronal excitation. In addition to this fast regulation, we describe here a slower form of the regulation of H2S production by testosterone and S-adenosyl-L-methionine (SAM), a CBS activator. Endogenous H2S in the mouse brain increases after birth, reaches a maximum level at 8 weeks and then decreases. Female brain contains less H2S than male brain at each age. A single administration of testosterone to female mice increases the endogenous H2S and SAM, which reach levels similar to those of male mice. In contrast, castration of male mice decreases the levels of testosterone, SAM and H2S in the brain. Administration of SAM once a day for 3 days increases the brain H2S without significantly changing the testosterone level. These observations suggest that testosterone can regulate the brain H2S level via changing the level of SAM.

MeSH Terms

  • Age Factors
  • Aging
  • Animals
  • Brain
  • Chromatography, High Pressure Liquid
  • Cystathionine beta-Synthase
  • Cysteine
  • Female
  • Hydrogen Sulfide
  • Male
  • Mice
  • Mice, Inbred BALB C
  • S-Adenosylmethionine
  • Sex Factors
  • Testosterone


[Charles Bonnet syndrome].

The article reviews the current literature on Charles Bonnet syndrome (CBS), offers specific criteria to define this syndrome, evaluates its prevalence, analyses the possible associated ophthalmic and sociodemographic factors, suggests future work in this area. Despite the recent interest in CBS in contemporary medical literature, a universal definition of this entity has not been fully established yet. The syndrome is usually characterised by presence of vivid and complex visual hallucinations, which are recognised as unreal and occur in the absence of any other psychiatric symptoms. Therefore there are suggestions that the phenomena should be best described by the term 'pseudohallucinations' or 'parahallucinations'. Some researchers suggest that isolated visual hallucinations in older adults may be an indication of early stages of dementia. Contrary to what was considered for a long time, the syndrome seems to occur rather frequently. Recent findings support association of CBS with sensory deprivation and advanced age. CBS should be considered as a diagnosis in patients who complain of hallucinations and who meet the defined diagnostic criteria. There is no proven treatment, but many patients will benefit from reassurance that their hallucinations do not imply mental illness.

MeSH Terms

  • Aged
  • Aged, 80 and over
  • Aging
  • Antipsychotic Agents
  • Dementia
  • Female
  • Hallucinations
  • Haloperidol
  • Humans
  • Syndrome


Age and cystathionine beta-synthase activity in cultured fibroblasts from patients with arterial and venous vascular disease.

In order to determine if cystathionine beta-synthase (CBS) could separate groups of patients with various vascular disease, CBS activity was studied in cultured human skin fibroblasts from 30 subjects being either controls, atherosclerotic patients or patients having suffered a deep venous thrombosis. We found a tendency to a negative correlation between age and CBS activity in the control group only (r = -0.58, P = 0.08), with a tendency to lower CBS activities in the young patients with atherosclerotic (4.9) or venous disease (5.3) compared to the young control group (10.2). This could implicate higher levels of p-homocysteine with increased age as well as in young patients with atherosclerotic or thrombotic disease causing vascular damage. The results are important for the further discussion of the role of homocysteine as a risk factor for developing atherosclerotic and thrombogenic vascular disease and for finding a suitable screening method as prevention is by vitamin supplement only.

MeSH Terms

  • Adult
  • Aged
  • Aging
  • Arteriosclerosis
  • Cells, Cultured
  • Cystathionine beta-Synthase
  • Fibroblasts
  • Humans
  • Middle Aged
  • Reference Values
  • Skin
  • Venous Thrombosis


AVLT memory scores as a function of age among general medical, neurologic and alcoholic patients.

Analyzed data from the administration of the Rey AVLT to 232 general hospital patients according to age and type of diagnosis and influences of these variables on learning, recall and recognition. Aging has a different effect on these three test scores, depending on the classification of the patient. Non-organically impaired Ss had difficulties with recognition the older they were; Ss with ABS showed learning deficits; in CBS (alcoholic) Ss, aging was associated with poor recall performance, but not significantly. Younger, higher educated and more intelligent Ss have better recognition, whereas better learning is associated with only education as a factor. Analysis of these results was made in the context of storage system theory with further implications.

MeSH Terms

  • Acute Disease
  • Aging
  • Brain Diseases
  • Humans
  • Learning
  • Memory
  • Mental Recall
  • Middle Aged
  • Neuropsychological Tests
  • Psychoses, Alcoholic


Age dependency of cystathionine beta-synthase activity in human fibroblasts in homocyst(e)inemia and atherosclerotic vascular disease.

In order to clarify whether cystathionine beta-synthase (CBS) could differentiate groups of patients with various vascular diagnosis, CBS was studied in cultured human skin fibroblasts from 99 human subjects diagnosed as homozygotes or heterozygotes for CBS deficiency or suffering from atherosclerotic vascular disease or Down's syndrome (prone to less atherosclerosis). In addition, embryonic human skin fibroblasts and controls were analysed for CBS. We found significant group differences but the overlap in the hetero- and homozygotes for CBS deficiency was too extensive to allow any individual diagnosis based on cell culture studies. CBS activity was significantly lower in the atherosclerotic patients as compared to control subjects. The difference was mostly due to much higher CBS activity in the younger controls. Age dependency was markedly emphasized by very high values from embryonic cells. A strong negative correlation was noted for age and CBS activity in control subjects but not in the atherosclerotic patients. The results are important for the discussion of homocysteine in atherosclerosis and point to the importance of donor age on CBS activity in cultured cells. In addition, diagnosis of hetero-homozygosity for CBS activity is not possible on an individual basis by this method. Further studies in cell culture systems are needed to investigate if young patients (less than 45 years old) with atherosclerotic disease could be identified by low CBS activity in fibroblast cultures as indicated by this study.

MeSH Terms

  • Adult
  • Aged
  • Aging
  • Arteriosclerosis
  • Cells, Cultured
  • Cystathionine beta-Synthase
  • Down Syndrome
  • Female
  • Fibroblasts
  • Homocysteine
  • Homocystinuria
  • Humans
  • Male
  • Middle Aged
  • Skin


Mortality of the aged with chronic brain syndrome: further observations in a five-year study.

In order to pursue the question of excess mortality due to chronic brain syndrome (CBS), 330 residents of a home for the aged were independently evaluated prior to admission by psychiatrists and by general physicians. Five years later, their medical records were searched to determine: 1) age on admission, 2) diagnosis of CBS on admission, 3) physical status on admission, and 4) if death had occurred, the age at death and the cause of death. Women outnumbered men by 3:1. Subjects with CBS outnumbered those without CBS by 2:1. A previous mortality study on 145 aged subjects at the same institution provided an excellent frame of reference for this investigation. Among the men there was no difference between the mortality rates for those with CBS and those without. Among the women a statistically significant difference in mortality was found between those with CBS and those without. Women with CBS and a "poor" physical status had the highest mortality rate. Those who initially had CBS died significantly sooner even if their admission physical status had been "good." Their mortality rate exceeded that for women with a "poor" physical status who did not have CBS. Bronchopneumonia caused death twice as often in subjects with CBS as in those without CBS, both among men and women. It is concluded that CBS per se is a significant factor in increasing mortality in the aged.

MeSH Terms

  • Aged
  • Bronchopneumonia
  • Chronic Disease
  • Dementia
  • Female
  • Homes for the Aged
  • Humans
  • Long-Term Care
  • Longevity
  • Male
  • Sex Factors
  • Syndrome