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Article: Diet-induced hyperhomocysteinemia causes sex-dependent deficiencies in offspring musculature and brain function.

Suszyńska-Zajczyk, Joanna / Witucki, Łukasz / Perła-Kaján, Joanna / Jakubowski, Hieronim

Frontiers in cell and developmental biology

2024 Volume 12, Page(s) 1322844

Abstract: Hyperhomocysteinemia (HHcy), characterized by elevated homocysteine (Hcy) levels, is a known risk factor for cardiovascular, renal, and neurological diseases, as well as pregnancy complications. Our study aimed to investigate whether HHcy induced by a ... ...

Abstract	Hyperhomocysteinemia (HHcy), characterized by elevated homocysteine (Hcy) levels, is a known risk factor for cardiovascular, renal, and neurological diseases, as well as pregnancy complications. Our study aimed to investigate whether HHcy induced by a high-methionine (high-Met) diet exacerbates cognitive and behavioral deficits in offspring and leads to other breeding problems. Dietary HHcy was induced four weeks before mating and continued throughout gestation and post-delivery. A battery of behavioral tests was conducted on offspring between postnatal days (PNDs) 5 and 30 to assess motor function/activity and cognition. The results were correlated with brain morphometric measurements and quantitative analysis of mammalian target of rapamycin (mTOR)/autophagy markers. The high-Met diet significantly increased parental and offspring urinary tHcy levels and influenced offspring behavior in a sex-dependent manner. Female offspring exhibited impaired cognition, potentially related to morphometric changes observed exclusively in HHcy females. Male HHcy pups demonstrated muscle weakness, evidenced by slower surface righting, reduced hind limb suspension (HLS) hanging time, weaker grip strength, and decreased activity in the beaker test. Western blot analyses indicated the downregulation of autophagy and the upregulation of mTOR activity in HHcy cortexes. HHcy also led to breeding impairments, including reduced breeding rate, in-utero fetal death, lower pups' body weight, and increased mortality, likely attributed to placental dysfunction associated with HHcy. In conclusion, a high-Met diet impairs memory and cognition in female juveniles and weakens muscle strength in male pups. These effects may stem from abnormal placental function affecting early neurogenesis, the dysregulation of autophagy-related pathways in the cortex, or epigenetic mechanisms of gene regulation triggered by HHcy during embryonic development.
Language	English
Publishing date	2024-03-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2024.1322844
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: COVID-19 and One-Carbon Metabolism.

Perła-Kaján, Joanna / Jakubowski, Hieronim

International journal of molecular sciences

2022 Volume 23, Issue 8

Abstract: Dysregulation of one-carbon metabolism affects a wide range of biological processes and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Accumulating evidence suggests that one-carbon ... ...

Abstract	Dysregulation of one-carbon metabolism affects a wide range of biological processes and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Accumulating evidence suggests that one-carbon metabolism plays an important role in COVID-19. The symptoms of long COVID-19 are similar to those presented by subjects suffering from vitamin B
MeSH term(s)	COVID-19/complications ; Carbon/metabolism ; Folic Acid/metabolism ; Homocysteine ; Humans ; Methionine/metabolism ; SARS-CoV-2 ; Vitamin B 12/metabolism
Chemical Substances	Homocysteine (0LVT1QZ0BA) ; Carbon (7440-44-0) ; Folic Acid (935E97BOY8) ; Methionine (AE28F7PNPL) ; Vitamin B 12 (P6YC3EG204)
Language	English
Publishing date	2022-04-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23084181
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Article ; Online: Dysregulation of Epigenetic Mechanisms of Gene Expression in the Pathologies of Hyperhomocysteinemia.

Perła-Kaján, Joanna / Jakubowski, Hieronim

International journal of molecular sciences

2019 Volume 20, Issue 13

Abstract: Hyperhomocysteinemia (HHcy) exerts a wide range of biological effects and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Although mechanisms of HHcy toxicity are not fully uncovered, ... ...

Abstract	Hyperhomocysteinemia (HHcy) exerts a wide range of biological effects and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Although mechanisms of HHcy toxicity are not fully uncovered, there has been a significant progress in their understanding. The picture emerging from the studies of homocysteine (Hcy) metabolism and pathophysiology is a complex one, as Hcy and its metabolites affect biomolecules and processes in a tissue- and sex-specific manner. Because of their connection to one carbon metabolism and editing mechanisms in protein biosynthesis, Hcy and its metabolites impair epigenetic control of gene expression mediated by DNA methylation, histone modifications, and non-coding RNA, which underlies the pathology of human disease. In this review we summarize the recent evidence showing that epigenetic dysregulation of gene expression, mediated by changes in DNA methylation and histone
MeSH term(s)	Animals ; DNA Methylation ; Epigenesis, Genetic ; Histone Code ; Homocysteine/metabolism ; Humans ; Hyperhomocysteinemia/genetics ; Hyperhomocysteinemia/metabolism ; RNA, Untranslated/genetics
Chemical Substances	RNA, Untranslated ; Homocysteine (0LVT1QZ0BA)
Language	English
Publishing date	2019-06-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20133140
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Article ; Online: Homocysteine thiolactone contributes to the prognostic value of fibrin clot structure/function in coronary artery disease.

Sikora, Marta / Skrzydlewski, Paweł / Perła-Kaján, Joanna / Jakubowski, Hieronim

PloS one

2022 Volume 17, Issue 10, Page(s) e0275956

Abstract: Fibrin clot structure/function contributes to cardiovascular disease. We examined sulfur-containing metabolites as determinants of fibrin clot lysis time (CLT) and maximum absorbance (Absmax) in relation to outcomes in coronary artery disease (CAD) ... ...

Abstract	Fibrin clot structure/function contributes to cardiovascular disease. We examined sulfur-containing metabolites as determinants of fibrin clot lysis time (CLT) and maximum absorbance (Absmax) in relation to outcomes in coronary artery disease (CAD) patients. Effects of B-vitamin/folate therapy on CLT and Absmax were studied. Plasma samples were collected from 1,952 CAD patients randomized in a 2 x 2 factorial design to (i) folic acid, vitamins B12, B6; (ii) folic acid, vitamin B12; (iii) vitamin B6; (iv) placebo for 3.8 years in the Western Norway B-Vitamin Intervention Trial. Clot lysis time (CLT) and maximum absorbance (Absmax) were determined using a validated turbidimetric assay. Acute myocardial infarction (AMI) and mortality were assessed during a 7-year follow-up. Data were analyzed using bivariate and multiple regression. Survival free of events was studied using Kaplan Mayer plots. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Baseline urinary homocysteine (uHcy)-thiolactone and plasma cysteine (Cys) were significantly associated with CLT while plasma total Hcy was significantly associated with Absmax, independently of fibrinogen, triglycerides, vitamin E, glomerular filtration rate, body mass index, age, sex plasma creatinine, CRP, HDL-C, ApoA1, and previous diseases. B-vitamins/folate did not affect CLT and Absmax. Kaplan-Meier analysis showed associations of increased baseline CLT and Absmax with worse outcomes. In Cox regression analysis, baseline CLT and Absmax (>cutoff) predicted AMI (CLT: HR 1.58, 95% CI 1.10-2.28; P = 0.013. Absmax: HR 3.22, CI 1.19-8.69; P = 0.021) and mortality (CLT: HR 2.54, 95% CI 1.40-4.63; P = 0.002. Absmax: 2.39, 95% CI 1.17-4.92; P = 0.017). After adjustments for other prognostic biomarkers these associations remained significant. Cys and uHcy-thiolactone, but not tHcy, were significant predictors of AMI in Cox regression models that included CLT. Conclusions uHcy-thiolactone and plasma Cys are novel determinants of CLT, an important predictor of adverse CAD outcomes. CLT and Absmax were not affected by B-vitamin/folate therapy, which could account for the lack of efficacy of such therapy in CAD. Trial registration: URL: http://clinicaltrials.gov. Identifier: NCT00354081.
MeSH term(s)	Humans ; Coronary Artery Disease ; Fibrin/metabolism ; Prognosis ; Vitamin B Complex ; Vitamin B 12 ; Folic Acid ; Homocysteine ; Myocardial Infarction/drug therapy ; Thrombosis/drug therapy ; Risk Factors
Chemical Substances	Fibrin (9001-31-4) ; homocysteine thiolactone (D5H88XF24X) ; Vitamin B Complex (12001-76-2) ; Vitamin B 12 (P6YC3EG204) ; Folic Acid (935E97BOY8) ; Homocysteine (0LVT1QZ0BA)
Language	English
Publishing date	2022-10-27
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0275956
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Article ; Online: The Cbs Locus Affects the Expression of Senescence Markers and mtDNA Copy Number, but not Telomere Dynamics in Mice.

Utyro, Olga / Perła-Kaján, Joanna / Jakubowski, Hieronim

International journal of molecular sciences

2020 Volume 21, Issue 7

Abstract: Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step of the homocysteine to cysteine transsulfuration pathway. Homozygous deletion of ... ...

Abstract	Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step of the homocysteine to cysteine transsulfuration pathway. Homozygous deletion of the
MeSH term(s)	Animals ; Brain/growth & development ; Brain/metabolism ; Cystathionine beta-Synthase/genetics ; DNA, Mitochondrial/genetics ; Female ; Gene Dosage ; Genetic Loci ; Kidney/growth & development ; Kidney/metabolism ; Liver/growth & development ; Liver/metabolism ; Longevity/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Telomerase/genetics ; Telomerase/metabolism ; Telomere Homeostasis
Chemical Substances	DNA, Mitochondrial ; Telomerase (EC 2.7.7.49) ; Tert protein, mouse (EC 2.7.7.49) ; Cystathionine beta-Synthase (EC 4.2.1.22)
Language	English
Publishing date	2020-04-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21072520
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Article ; Online: Homocysteine thiolactone contributes to the prognostic value of fibrin clot structure/function in coronary artery disease.

Marta Sikora / Paweł Skrzydlewski / Joanna Perła-Kaján / Hieronim Jakubowski

PLoS ONE, Vol 17, Iss 10, p e

2022 Volume 0275956

Abstract	Fibrin clot structure/function contributes to cardiovascular disease. We examined sulfur-containing metabolites as determinants of fibrin clot lysis time (CLT) and maximum absorbance (Absmax) in relation to outcomes in coronary artery disease (CAD) patients. Effects of B-vitamin/folate therapy on CLT and Absmax were studied. Plasma samples were collected from 1,952 CAD patients randomized in a 2 x 2 factorial design to (i) folic acid, vitamins B12, B6; (ii) folic acid, vitamin B12; (iii) vitamin B6; (iv) placebo for 3.8 years in the Western Norway B-Vitamin Intervention Trial. Clot lysis time (CLT) and maximum absorbance (Absmax) were determined using a validated turbidimetric assay. Acute myocardial infarction (AMI) and mortality were assessed during a 7-year follow-up. Data were analyzed using bivariate and multiple regression. Survival free of events was studied using Kaplan Mayer plots. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Baseline urinary homocysteine (uHcy)-thiolactone and plasma cysteine (Cys) were significantly associated with CLT while plasma total Hcy was significantly associated with Absmax, independently of fibrinogen, triglycerides, vitamin E, glomerular filtration rate, body mass index, age, sex plasma creatinine, CRP, HDL-C, ApoA1, and previous diseases. B-vitamins/folate did not affect CLT and Absmax. Kaplan-Meier analysis showed associations of increased baseline CLT and Absmax with worse outcomes. In Cox regression analysis, baseline CLT and Absmax (>cutoff) predicted AMI (CLT: HR 1.58, 95% CI 1.10-2.28; P = 0.013. Absmax: HR 3.22, CI 1.19-8.69; P = 0.021) and mortality (CLT: HR 2.54, 95% CI 1.40-4.63; P = 0.002. Absmax: 2.39, 95% CI 1.17-4.92; P = 0.017). After adjustments for other prognostic biomarkers these associations remained significant. Cys and uHcy-thiolactone, but not tHcy, were significant predictors of AMI in Cox regression models that included CLT. Conclusions uHcy-thiolactone and plasma Cys are novel ...
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Dysregulation of Epigenetic Mechanisms of Gene Expression in the Pathologies of Hyperhomocysteinemia

Joanna Perła-Kaján / Hieronim Jakubowski

International Journal of Molecular Sciences, Vol 20, Iss 13, p

2019 Volume 3140

Abstract	Hyperhomocysteinemia (HHcy) exerts a wide range of biological effects and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Although mechanisms of HHcy toxicity are not fully uncovered, there has been a significant progress in their understanding. The picture emerging from the studies of homocysteine (Hcy) metabolism and pathophysiology is a complex one, as Hcy and its metabolites affect biomolecules and processes in a tissue- and sex-specific manner. Because of their connection to one carbon metabolism and editing mechanisms in protein biosynthesis, Hcy and its metabolites impair epigenetic control of gene expression mediated by DNA methylation, histone modifications, and non-coding RNA, which underlies the pathology of human disease. In this review we summarize the recent evidence showing that epigenetic dysregulation of gene expression, mediated by changes in DNA methylation and histone N -homocysteinylation, is a pathogenic consequence of HHcy in many human diseases. These findings provide new insights into the mechanisms of human disease induced by Hcy and its metabolites, and suggest therapeutic targets for the prevention and/or treatment.
Keywords	hyperhomocysteinemia ; DNA methylation ; histone ; homocysteine thiolactone ; N -homocysteinylation ; miRNA ; epigenetic ; atherosclerosis ; Alzheimer’s disease ; gene expression ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	612
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Cbs Locus Affects the Expression of Senescence Markers and mtDNA Copy Number, but not Telomere Dynamics in Mice

Olga Utyro / Joanna Perła-Kaján / Hieronim Jakubowski

International Journal of Molecular Sciences, Vol 21, Iss 2520, p

2020 Volume 2520

Abstract: Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step of the homocysteine to cysteine transsulfuration pathway. Homozygous deletion of the Cbs gene in mice causes severe hyperhomocysteinemia and reduces life span. Here, we ...

Abstract	Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step of the homocysteine to cysteine transsulfuration pathway. Homozygous deletion of the Cbs gene in mice causes severe hyperhomocysteinemia and reduces life span. Here, we examined a possible involvement of senescence, mitochondrial DNA, and telomeres in the reduced life span of Cbs −/− mice. We found that senescence-related p21 , Pai-1 , Mcp1 , and Il-6 mRNAs were significantly upregulated (2–10-fold) in liver, while p21 was upregulated in the brain of Cbs −/− mice ( n = 20) compared with control Cbs +/− siblings ( n = 20) in a sex- and age-dependent manner. Telomere length in blood ( n = 80), liver ( n = 40), and brain ( n = 40) was not affected by the Cbs −/− genotype, but varied with sex and/or age. Levels of mitochondrial DNA tended to be reduced in livers, but not brains and blood, of Cbs −/− females ( n = 20–40). The Cbs −/− genotype significantly reduced Tert mRNA expression in brain, but not liver, in a sex- and age-dependent manner. Multiple regression analysis showed that the senescence-related liver (but not brain) mRNAs and liver (but not brain or blood) mitochondrial DNA were associated with the Cbs genotype. In contrast, telomere length in blood, brain, and liver was not associated with the Cbs genotype or hyperhomocysteinemia, but was associated with sex (in brain and liver) and age (in brain and blood). Taken together, these findings suggest that the changes in senescence marker expression and mtDNA levels, but not telomere shortening, could account for the reduced life span of Cbs −/− mice.
Keywords	cystathionine β-synthase deficiency ; homocysteine ; life span ; mtDNA ; senescence markers ; telomere dynamics ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	333
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Genetic Attenuation of Paraoxonase 1 Activity Induces Proatherogenic Changes in Plasma Proteomes of Mice and Humans.

Sikora, Marta / Bretes, Ewa / Perła-Kaján, Joanna / Lewandowska, Izabela / Marczak, Łukasz / Jakubowski, Hieronim

Antioxidants (Basel, Switzerland)

2020 Volume 9, Issue 12

Abstract: High-density lipoprotein (HDL), in addition to promoting reverse cholesterol transport, possesses anti-inflammatory, antioxidative, and antithrombotic activities. Paraoxonase 1 (PON1), carried on HDL in the blood, can contribute to these antiatherogenic ... ...

Abstract	High-density lipoprotein (HDL), in addition to promoting reverse cholesterol transport, possesses anti-inflammatory, antioxidative, and antithrombotic activities. Paraoxonase 1 (PON1), carried on HDL in the blood, can contribute to these antiatherogenic activities. The
Language	English
Publishing date	2020-11-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox9121198
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Article ; Online: Telomere length and mtDNA copy number in human cystathionine β-synthase deficiency.

Utyro, Olga / Perła-Kaján, Joanna / Kubalska, Jolanta / Graban, Ałła / Jakubowski, Hieronim

Free radical biology & medicine

2020 Volume 160, Page(s) 219–226

Abstract: Telomere shortening and mitochondrial DNA (mtDNA) copy number are associated with human disease and a reduced life span. Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step in metabolic conversion of homocysteine (Hcy) ... ...

Abstract	Telomere shortening and mitochondrial DNA (mtDNA) copy number are associated with human disease and a reduced life span. Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step in metabolic conversion of homocysteine (Hcy) to cysteine. Mutations in the CBS gene cause CBS deficiency, a rare recessive metabolic disease, manifested by severe hyperhomocysteinemia (HHcy) and thromboembolism, which ultimately reduces the life span. However, it was not known whether telomere shortening or mtDNA is involved in the pathology of human CBS deficiency. We quantified leukocyte telomere length (TL), mtDNA copy number, and plasma Hcy levels in CBS
MeSH term(s)	Adolescent ; Adult ; Child ; Child, Preschool ; Cystathionine beta-Synthase/deficiency ; Cystathionine beta-Synthase/genetics ; DNA Copy Number Variations ; DNA, Mitochondrial/genetics ; Female ; Homocysteine ; Homocystinuria ; Humans ; Hyperhomocysteinemia ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Telomere/genetics ; Telomere Shortening ; Young Adult
Chemical Substances	DNA, Mitochondrial ; Homocysteine (0LVT1QZ0BA) ; Cystathionine beta-Synthase (EC 4.2.1.22)
Language	English
Publishing date	2020-08-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2020.07.036
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