The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

Kolb, Philipp; Ayaub, Ehab; Zhou, Wenjing; Yum, Victoria; Dickhout, Jeffrey G.; Ask, Kjetil

doi:10.1016/j.biocel.2015.01.015

Cited by 221 publications

(193 citation statements)

References 83 publications

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“…This small chemical chaperone inhibits endoplasmic reticulum stress and is effective against many of endoplasmic reticulum stress-mediated diseases, such as various types of cancers, as well as neurodegenerative disorders such as Parkinson's disease. Furthermore, it imparts its anti-inflammatory activity by reducing inflammatory cytokines [23] . Meanwhile, phenylacetic acid is the metabolite of 4-Phenylbutyric acid and is believed to partially exert the pharmacological actions of the parent drug.…”

Section: Discussionmentioning

confidence: 99%

In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures

Loron¹,

Sardari²,

Narenjkar³

et al. 2017

IBJ

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Background: Resistance to antiepileptic drugs and the intolerability in 20-30% of the patients raises demand for developing new drugs with improved efficacy and safety. Acceptable anticonvulsant activity, good tolerability, and inexpensiveness of docosahexaenoic acid (DHA) make it as a good candidate for designing and development of the new anticonvulsant medications. Methods: Ten DHA-based molecules were screened based on in silico screening of DHA-like molecules by root-mean-square deviation of atomic positions, the biological activity score of Professional Association for SQL Server, and structural requirements suggested by pharmacophore design. Anticonvulsant activity was tested against clonic seizures induced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) and tonic seizures induced by maximal electroshock (MES, 50 mA, 50 Hz, 1 ms duration) by intracerebroventricular (i.c.v.) injection of the screened compounds to mice. Results: Among screened compounds, 4-Phenylbutyric acid, 4-Biphenylacetic acid, phenylacetic acid, and 2-Phenylbutyric acid showed significant protective activity in pentylenetetrazole test with ED 50 values of 4, 5, 78, and 70 mM, respectively. In MES test, shikimic acid and 4-tertButylcyclo-hexanecarboxylic acid showed significant activity with ED 50 values 29 and 637 mM, respectively. Effective compounds had no mortality in mice up to the maximum i.c.v. injectable dose of 1 mM. Conclusion: Common electrochemical features and three-dimensional spatial structures of the effective compounds suggest the involvement of the anticonvulsant mechanisms similar to the parent compound DHA.

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Section: Discussionmentioning

confidence: 99%

In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures

Loron¹,

Sardari²,

Narenjkar³

et al. 2017

IBJ

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“…The chemical chaperone 4 phenylbutyrate (4PBA) was found to relieve ER stress by stabilizing proteins in their native conformation and refolding misfolded proteins 201 . Given that 4PBA is already on the market (as Ammonaps in Europe and Buphenyl in the USA) for the treatment of urea cycle disorders 202,203 and is currently in phase I and II clinical trials for various (misfolded protein) diseases including amyotrophic lateral sclerosis, Parkinson disease, and Huntington disease, this drug might be a good candidate to attenu ate the unfolded protein response and proteotoxicity in cardiomyocytes (TABLE 2).…”

Section: Pharmacological Modulation Of Pqcmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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“…Then we evaluated the effect of ER stress on neutrophil differentiation in HL-60 cells. HL-60 cells were treated with 4-PBA, a chemical chaperone, which reduces ER stress [12], and assessed ER stress level by BiP and differentiation by CD11b differentiation marker. 4-PBA treatment reduced ER stress marker expression dose-dependently, and concomitantly both up-regulation of CD11b expression and nuclear morphological changes were observed with 2mM of 4-PBA (Fig.…”

Section: Er Stress Levels During Hematopoietic Differentiation Of Hl-mentioning

confidence: 99%

Mitochondrial Activity and Unfolded Protein Response are Required for Neutrophil Differentiation

Tanimura

Miyoshi

Horiguchi

et al. 2018

Cell Physiol Biochem

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Background/Aims: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are involved in hematopoietic differentiation. However, the mechanistic linkage between ER stress/UPR and hematopoietic differentiation remains unclear. Methods: We used bipotent HL-60 cells as an in vitro hematopoietic differentiation system to investigate the role of ER stress and UPR activity in neutrophil and macrophage differentiation. Results: The in vitro differentiation analysis revealed that ER stress decreased during both neutrophil and macrophage differentiations, and the activities of PERK and ATF6 were decreased and that of IRE1α was increased during neutrophil differentiation in a stage-specific manner. By contrast, the activities of ATF6 and ATF4 decreased during macrophage differentiation. When the cells were treated with oligomycin, the expression of CD11b, a myelocytic differentiation marker, and morphological differentiation were suppressed, and XBP-1 activation was inhibited during neutrophil differentiation, whereas CD11b expression was maintained, and morphological differentiation was not obviously affected during macrophage differentiation. Conclusion: In this study, we demonstrated that neutrophil differentiation is regulated by ER stress/UPR that is supported by mitochondrial ATP supply, in which IRE1α-XBP1 activation is essential. Our findings provide the evidence that mitochondrial energy metabolism may play a critical role in neutrophil differentiation.

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The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

Cited by 221 publications

References 83 publications

In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures

In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures

Proteostasis in cardiac health and disease

Mitochondrial Activity and Unfolded Protein Response are Required for Neutrophil Differentiation

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