The DOI matches its Crossref record; 226 of the 227 references it cites were found in a registry or an index.
The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: It's time for reconciliation
Open accessAbstract
Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. These clinical features are due in part to the increase of reactive oxygen and nitrogen species that mediate neurotoxic effects. The up-regulation of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system is one of the earlier events in the adaptive response to stress. HO-1/BVR-A reduces the intracellular levels of pro-oxidant heme and generates equimolar amounts of the free radical scavengers biliverdin-IX alpha (BV)/bilirubin-IX alpha (BR) as well as the pleiotropic gaseous neuromodulator carbon monoxide (CO) and ferrous iron. Two main and opposite hypotheses for a role of the HO-1/BVR-A system in AD propose that this system mediates neurotoxic and neuroprotective effects, respectively. This apparent controversy was mainly due to the fact that for over about 20years HO-1 was the only player on which all the analyses were focused, excluding the other important and essential component of the entire system, BVR. Following studies from the Butterfield laboratory that reported alterations in BVR activity along with decreased phosphorylation and increased oxidative/nitrosative post-translational modifications in the brain of subjects with AD and amnestic mild cognitive impairment (MCI) subjects, a debate was opened on the real pathophysiological and clinical significance of BVR-A. In this paper we provide a review of the main discoveries about the HO/BVR system in AD and MCI, and propose a mechanism that reconciles these two hypotheses noted above of neurotoxic and the neuroprotective aspects of this important stress responsive system.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It also suggests that atorvastatin, although not a direct antioxidant and not able to cross the BBB, leads to antioxidant-like effects in brain100.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [100]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“BVR-A, in addition to being a reductase, is a kinase that can phosphorylate insulin receptor substrate-1100.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [100]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Both HO-1 and BVR-A are oxidatively damaged in aMCI and AD brain100.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [100]
The cited source says what the claim attributes to it.
In the citing paper
“BVR-A is nitrosatively modified and dysfunctional in AD and MCI brain100, and its impairment promotes insulin resistance101.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [100]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Recently, intranasal treatment of a 3 X Tg mice model of AD with insulin showed a significant reduction of brain nitrosative stress, tau phosphorylation, and Aβ oligomers coupled to improved cognition, and these effects were dependent on the activity of biliverdin reductase-A (BVR-A)99,100.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [100]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Items 201–226 of 226
CO modulates pulmonary vascular response to acute hypoxia: relation to endothelin
Zhang, F., Kaide, J.-I., Yang, L., Jiang, H., Quan, S., Kemp, R., Gong, W., Balazy, M., Abraham, N. G., & Nasjletti, A. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00678.2002 · Cited by 38
Torp, R., Head, E., & Cotman, C. W. (2000) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(00)00107-x · Cited by 37
Gibbs, P., Tudor, C., & Maines, M. D. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00031 · Cited by 36
Gibbs, P., Miralem, T., Lerner‐Marmarosh, N., Tudor, C., & Maines, M. D. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.279612 · Cited by 36
Heme Catabolism and Heme Oxygenase in Neurodegenerative Disease
Takeda, A., Itoyama, Y., Kimpara, T., Zhu, X., Ávila, J., Dwyer, B. E., Perry, G. L., & Smith, M. A. (2004) · Antioxidants and Redox Signaling · doi:10.1089/ars.2004.6.888 · Cited by 35
Regulation of CO production in cerebral microvessels of newborn pigs
Leffler, C. W., Balabanova, L., Sullivan, C. D., Wang, X., Fedinec, A. L., & Parfenova, H. (2003) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01059.2002 · Cited by 35
Palozza, P., Serini, S., Currò, D., Calviello, G., Igarashi, K., & Mancuso, C. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.1069 · Cited by 34
Self-citationMcCoubrey, W. K., Cooklis, M., & Maines, M. D. (1995) · Gene · doi:10.1016/0378-1119(95)00112-j · Cited by 33
Serum Nitrosative Stress Levels Are Increased in Alzheimer Disease but Not in Vascular Dementia
Konukoğlu, D., Fırtına, S., Erkol, G., Yağız, O., & Günaydın, F. M. (2010) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e3181c53d0d · Cited by 26
Role of the locus coeruleus carbon monoxide pathway in endotoxin fever in rats
Ravanelli, M. I. B., Almeida, M. C., & Branco, L. G. S. (2006) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-006-0136-8 · Cited by 25
Brain aging and late-onset Alzheimer's disease: many open questions
Behl, C. (2012) · International Psychogeriatrics · doi:10.1017/s104161021200052x · Cited by 25
Kooli, A., Kermorvant‐Duchemin, E., Sennlaub, F., Bossolasco, M., Hou, X., Honoré, J., Dennery, P. A., Sapieha, P. S., Varma, D. R., Lachapelle, P., et al. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.11.006 · Cited by 24
Torp, R., Ottersen, O. P., Cotman, C. W., & Head, E. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00320-8 · Cited by 23
Biomarker Potential of Heme Oxygenase-1 in Alzheimer‘s Disease and Mild Cognitive Impairment
Schipper, H. M. (2007) · Biomarkers in Medicine · doi:10.2217/17520363.1.3.375 · Cited by 23
Role of the brain heme oxygenase-carbon monoxide pathway in stress fever in rats
Steiner, A. A., Reste, G., & Branco, L. G. S. (2003) · Neuroscience Letters · doi:10.1016/s0304-3940(03)00197-6 · Cited by 22
Nuhn, P., Mitkus, T., Ceyhan, G. O., Künzli, B. M., Bergmann, F., Fischer, L., Giese, N. A., Friess, H., & Berberat, P. O. (2012) · Pancreas · doi:10.1097/mpa.0b013e318264cc8b · Cited by 22
Rukhsana Sultana, A., Robinson, R. A. S., Lange, M. L. B., Fiorini, A., Galván, V., Fombonne, J., Baker, A. S., Gorostiza, O. F., Zhang, J., Cai, J., et al. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4470 · Cited by 22
Self-citationIshizuka, K., KIMURA, T., Yoshitake, J., Akaike, T., Shono, M., TAKAMATSU, J., Katsuragi, S., Kitamura, T., & Miyakawa, T. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04814.x · Cited by 18
Miyazaki, T., Kirino, Y., Takeno, M., Hama, M., Ushihama, A., Watanabe, R., Takase, K., Tachibana, T., Matsumoto, K., Tanaka, M., et al. (2010) · International Journal of Hematology · doi:10.1007/s12185-010-0495-y · Cited by 18
A link between hyperbilirubinemia, oxidative stress and injury to neocortical synaptosomes
Brito, M. M., Brites, D. M. T. O., & Butterfield, D. A. (2003) · Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) · Cited by 18
Self-citationErrico, S., Shohreh, R., Barone, E., Pusateri, A., Mores, N., & Mancuso, C. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.01.036 · Cited by 17
Self-citationDomenico, F. D., Marzia Perluigi, A., & Barone, E. (2013) · PubMed Central · doi:10.3969/j.issn.1673-5374.2013.21.001 · Cited by 11
Self-citationYan, S., Krebs, S. J., Leister, K. J., & Wenner, C. E. (2000) · Journal of Cellular Physiology · doi:10.1002/1097-4652(200010)185:1 · Cited by 11
EFFECTS OF HEME OXYGENASE-1 EXPRESSION ON STEROL HOMEOSTASIS IN RAT ASTROGLIA
Vaya, J., Song, W., Khatib, S., Geng, G., & Schipper, H. (2008) · Atherosclerosis Supplements · doi:10.1016/s1567-5688(08)70133-8 · Cited by 8
Price (1999) · doi:10.1002/1531-8249(199903)45:3
Flagged first, then by citations
1 of the 227 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Di Domenico, 2013, Biliverdin reductase-A correlates with iNOS in atorvastatin treated aged canine brain, Neural. Reg. Res., 8, 1925
Cited by
Sorted by citations
Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease
Butterfield, D. A., & Halliwell, B. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0132-6 · Cited by 1,954
Self-citationProgrammed Cell-Death by Ferroptosis: Antioxidants as Mitigators
Kajarabille, N., & Latunde-Dada, G. O. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194968 · Cited by 687
Butterfield, D. A., Swomley, A. M., & Sultana, R. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.5027 · Cited by 526
Self-citationVerdile, G., Keane, K. N., Cruzat, V. F., Medic, S., Sabale, M., Rowles, J., Wijesekara, N., Martins, R. N., Fraser, P. E., & Newsholme, P. (2015) · Mediators of Inflammation · doi:10.1155/2015/105828 · Cited by 509
Butterfield, D. A., Di Domenico, F., & Barone, E. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.06.010 · Cited by 402
Self-citation
Metadata
- Authors
- Barone, E., Di Domenico, F., Mancuso, C., & Butterfield, D. A.
- Affiliations
- University of Kentucky (US)
- Università Cattolica del Sacro Cuore (IT)
- Corresponding author
- Butterfield, D. Allan
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 62
- Pages
- 144-159
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC3877707
- OpenAlex
- W2082990108
- Cited by
- 127
- References
- 227
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 10 · 2022: 8 · 2021: 12 · 2020: 15 · 2019: 12 · 2018: 10 · 2017: 8 · 2016: 8 · 2015: 18 · 2014: 11
- FWCI
- 1.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- NIH (AG-05119)
- Fondi Ateneo
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, heme oxygenase-1, biliverdin reductase A, biliverdin, bilirubin, carbon monoxide, ferrous iron, oxidative stress, nitrosative stress, neuroprotection, neurotoxicity, amnestic mild cognitive impairment, post-translational modification, stress response
- MeSH terms
- Alzheimer Disease, Animals, Brain, Heme Oxygenase (Decyclizing), Humans, Models, Neurological, Oxidative Stress, Oxidoreductases Acting on CH-CH Group Donors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
