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1
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Lu W, Wen J. Role and Relationship Between Homocysteine and H 2S in Ischemic Stroke. Mol Neurobiol 2025:10.1007/s12035-025-04968-5. [PMID: 40327309 DOI: 10.1007/s12035-025-04968-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 04/14/2025] [Indexed: 05/07/2025]
Abstract
Homocysteine (Hcy), a sulfur-containing amino acid, is an important intermediate product of methionine metabolism. Hcy can be either metabolized to cysteine, a precursor for glutathione synthesis and hydrogen sulfide (H2S) production, or regenerated back to methionine. Besides, the Hcy metabolism is central to supply methyl groups, which are essential for DNA methylation. In the transsulfuration pathway of Hcy metabolism, Hcy is metabolized to form cysteine and H2S by catalytic enzymes, containing cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). Hcy metabolism-related enzymes and coenzymes, such as vitamin B6, vitamin B12, and folic acid, are closely related to hyperhomocysteinemia (HHcy), which is frequently accompanied by reduced H2S content. An accumulating study has revealed that HHcy is a risk factor for ischemic stroke, while H2S, served as a gaseous mediator at the physiological level, has protective effects against ischemic stroke. This review outlined the literature data from recent research related to Hcy metabolism and H2S production and described the roles and relationship among Hcy metabolism and H2S in ischemic stroke.
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Affiliation(s)
- Weizhuo Lu
- Department of Pharmacology, School of Pharmaceutical Sciences, Anhui Medical University, Hefei, China
- Medical Branch, Hefei Technology College, Hefei, China
| | - Jiyue Wen
- Department of Pharmacology, School of Pharmaceutical Sciences, Anhui Medical University, Hefei, China.
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
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2
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Jiménez MDCFF. Plant-Based Diet and Erectile Dysfunction: A Narrative Review. J Nutr 2025:S0022-3166(25)00229-9. [PMID: 40274235 DOI: 10.1016/j.tjnut.2025.04.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Accepted: 04/08/2025] [Indexed: 04/26/2025] Open
Abstract
Evidence shows that the consumption of plant foods, particularly those in their whole form (fruits, vegetables, whole grains, nuts, seeds, and legumes from which no edible part has been removed), improves cardiometabolic risk factors and is associated with reduced risk of cardiovascular diseases (CVDs), diabetes, cancer, chronic kidney disease and mortality compared with animal (meat, fish, eggs and dairy) and nonwhole plant foods (sugar-sweetened beverages, refined grains, etc.). Erectile dysfunction (ED) is considered a strong predictor of CVD. The underlying defect in arteriogenic ED is endothelial dysfunction. A plant-based diet focused on whole plant foods could enhance penile erection as it improves endothelial function through various mechanisms. First, it provides nitrates, L-arginine, and L-citrulline, substrates for nitric oxide production. In addition, this diet lowers low-density lipoprotein cholesterol, trimethylamine N-oxide, postprandial triglycerides, advanced glycation end product, inflammation, and vasoconstrictors levels, contributing to higher nitric oxide concentrations, increased endothelial progenitor cells preservation and decreased arterial stiffness. This review explores the epidemiological evidence of a plant-based diet emphasizing whole plant foods on ED and the potential biological pathways involved.
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Ortiz-Salguero C, Romero-Bernal M, González-Díaz Á, Doush ES, del Río C, Echevarría M, Montaner J. Hyperhomocysteinemia: Underlying Links to Stroke and Hydrocephalus, with a Focus on Polyphenol-Based Therapeutic Approaches. Nutrients 2024; 17:40. [PMID: 39796474 PMCID: PMC11722995 DOI: 10.3390/nu17010040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Hyperhomocysteinemia (HHcy), characterized by elevated homocysteine (HCys) levels, is associated with increased risks of neurovascular diseases such as stroke or hydrocephalus. HHcy promotes oxidative stress, neuroinflammation, and endothelial dysfunction, disrupting the blood-brain barrier and accelerating neurodegeneration. These processes highlight HCys as both a biomarker and a potential therapeutic target in vascular-related neurological disorders. Current research suggests that polyphenols, known for their antioxidant and anti-inflammatory properties, may reduce HCys levels and offer neuroprotection. Polyphenols have demonstrated effectiveness in modulating oxidative stress and inflammatory pathways triggered by HHcy. These compounds may also upregulate enzymatic functions involved in HCys metabolism, thus reducing neurotoxicity. Furthermore, polyphenol-rich diets, like the Mediterranean diet, have been linked to lower HCys levels and a reduced incidence of neurovascular disorders. This review provides an overview of HHcy's role in neurovascular pathologies and examines the therapeutic potential of polyphenols in managing HCys levels and preventing HCys-induced neurovascular damage.
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Affiliation(s)
- Carmen Ortiz-Salguero
- Instituto de Biomedicina de Sevilla, IBiS, Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, 41013 Sevilla, Spain; (C.O.-S.); (M.R.-B.); (E.S.D.)
| | - Marina Romero-Bernal
- Instituto de Biomedicina de Sevilla, IBiS, Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, 41013 Sevilla, Spain; (C.O.-S.); (M.R.-B.); (E.S.D.)
| | - Ángela González-Díaz
- Instituto de Biomedicina de Sevilla, IBiS, Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, 41013 Sevilla, Spain; (C.O.-S.); (M.R.-B.); (E.S.D.)
| | - Elaheh Sobh Doush
- Instituto de Biomedicina de Sevilla, IBiS, Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, 41013 Sevilla, Spain; (C.O.-S.); (M.R.-B.); (E.S.D.)
| | - Carmen del Río
- Instituto de Biomedicina de Sevilla, IBiS, Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, 41013 Sevilla, Spain; (C.O.-S.); (M.R.-B.); (E.S.D.)
| | - Miriam Echevarría
- Instituto de Biomedicina de Sevilla, IBiS, Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, 41013 Sevilla, Spain; (C.O.-S.); (M.R.-B.); (E.S.D.)
| | - Joan Montaner
- Instituto de Biomedicina de Sevilla, IBiS, Hospital Universitario Virgen Macarena, CSIC, Universidad de Sevilla, 41004 Sevilla, Spain
- Department of Neurology, Hospital Universitario Virgen Macarena, 41004 Sevilla, Spain
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Kaihara JNS, de Moraes FR, Nunes PR, Alves MG, Cavalli RC, Tasic L, Sandrim VC. Plasma metabolic profile reveals signatures of maternal health during gestational hypertension and preeclampsia without and with severe features. PLoS One 2024; 19:e0314053. [PMID: 39591465 PMCID: PMC11594399 DOI: 10.1371/journal.pone.0314053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 11/04/2024] [Indexed: 11/28/2024] Open
Abstract
Preeclampsia, a pregnancy-specific syndrome, poses substantial risks to maternal and neonatal health, particularly in cases with severe features. Our study focuses on evaluating the impact of low molecular weight metabolites on the intricate mechanisms and pathways involved in the pathophysiology of preeclampsia when severe features are present. We aim to pinpoint the distinct metabolomic profile in maternal plasma during pregnancies affected by hypertensive disorders and to correlate the metabolite levels with the clinical characteristics of the study cohort. A total of 173 plasma samples were collected, comprising 36 healthy pregnant women (HP), 52 patients with gestational hypertension (GH), 43 with preeclampsia without (PE-), and 42 with severe features (PE+). Nuclear magnetic resonance spectroscopy and metabolite identification were conducted to establish the metabolomic profiles. Univariate and chemometric analyses were conducted using MetaboAnalyst, and correlations were performed using GraphPad Prism. Our study unveils distinct metabolomic profiles differentiating HP women, patients featuring GH, and patients with PE-and PE+. Our analysis highlights an increase in acetate, N,N-dimethylglycine, glutamine, alanine, valine, and creatine levels in the PE+ group compared to the HP and GH groups. The PE+ group exhibited higher concentrations of N,N-dimethylglycine, glutamine, alanine, and valine compared to the PE-group. Moreover, elevated levels of specific metabolites, including N,N-dimethylglycine, alanine, and valine, were associated with increased blood pressure, worse obstetric outcomes, and poorer end-organ function, particularly renal and hepatic damage. Metabolomic analysis of PE+ individuals indicates heightened disturbances in nitrogen metabolism, methionine, and urea cycles. Additionally, the exacerbated metabolic disturbance may have disclosed renal impairment and hepatic dysfunction, evidenced by elevated levels of creatine and alanine. These findings not only contribute novel insights but also provide a more comprehensive understanding of the pathophysiological mechanisms at play in cases of PE+.
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Affiliation(s)
- Julyane N. S. Kaihara
- Department of Biophysics and Pharmacology, Institute of Biosciences of Botucatu, Sao Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Fabio Rogerio de Moraes
- Multiuser Center for Biomolecular Innovation, Department of Physics, Institute of Biosciences, Languages and Exact Sciences, Sao Paulo State University (UNESP), Sao Jose do Rio Preto, SP, Brazil
| | - Priscila Rezeck Nunes
- Department of Biophysics and Pharmacology, Institute of Biosciences of Botucatu, Sao Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Marco G. Alves
- Institute of Biomedicine and Department of Medical Science (iBiMED), University of Aveiro, Aveiro, Portugal
| | - Ricardo C. Cavalli
- Department of Gynecology and Obstetrics, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo (USP), Ribeirao Preto, SP, Brazil
| | - Ljubica Tasic
- Department of Organic Chemistry, Institute of Chemistry, State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Valeria Cristina Sandrim
- Department of Biophysics and Pharmacology, Institute of Biosciences of Botucatu, Sao Paulo State University (UNESP), Botucatu, SP, Brazil
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Cueto R, Shen W, Liu L, Wang X, Wu S, Mohsin S, Yang L, Khan M, Hu W, Snyder N, Wu Q, Ji Y, Yang XF, Wang H. SAH is a major metabolic sensor mediating worsening metabolic crosstalk in metabolic syndrome. Redox Biol 2024; 73:103139. [PMID: 38696898 PMCID: PMC11070633 DOI: 10.1016/j.redox.2024.103139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 03/26/2024] [Indexed: 05/04/2024] Open
Abstract
In this study, we observed worsening metabolic crosstalk in mouse models with concomitant metabolic disorders such as hyperhomocysteinemia (HHcy), hyperlipidemia, and hyperglycemia and in human coronary artery disease by analyzing metabolic profiles. We found that HHcy worsening is most sensitive to other metabolic disorders. To identify metabolic genes and metabolites responsible for the worsening metabolic crosstalk, we examined mRNA levels of 324 metabolic genes in Hcy, glucose-related and lipid metabolic systems. We examined Hcy-metabolites (Hcy, SAH and SAM) by LS-ESI-MS/MS in 6 organs (heart, liver, brain, lung, spleen, and kidney) from C57BL/6J mice. Through linear regression analysis of Hcy-metabolites and metabolic gene mRNA levels, we discovered that SAH-responsive genes were responsible for most metabolic changes and all metabolic crosstalk mediated by Serine, Taurine, and G3P. SAH-responsive genes worsen glucose metabolism and cause upper glycolysis activation and lower glycolysis suppression, indicative of the accumulation of glucose/glycogen and G3P, Serine synthesis inhibition, and ATP depletion. Insufficient Serine due to negative correlation of PHGDH with SAH concentration may inhibit the folate cycle and transsulfurarion pathway and consequential reduced antioxidant power, including glutathione, taurine, NADPH, and NAD+. Additionally, we identified SAH-activated pathological TG loop as the consequence of increased fatty acid (FA) uptake, FA β-oxidation and Ac-CoA production along with lysosomal damage. We concluded that HHcy is most responsive to other metabolic changes in concomitant metabolic disorders and mediates worsening metabolic crosstalk mainly via SAH-responsive genes, that organ-specific Hcy metabolism determines organ-specific worsening metabolic reprogramming, and that SAH, acetyl-CoA, Serine and Taurine are critical metabolites mediating worsening metabolic crosstalk, redox disturbance, hypomethylation and hyperacetylation linking worsening metabolic reprogramming in metabolic syndrome.
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Affiliation(s)
- Ramon Cueto
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Wen Shen
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA; Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, China
| | - Lu Liu
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Xianwei Wang
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Sheng Wu
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Sadia Mohsin
- Cardiovascular Research Center, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Ling Yang
- Medical Genetics & Molecular Biochemistry, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Mohsin Khan
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Wenhui Hu
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Nathaniel Snyder
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Qinghua Wu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, China
| | - Yong Ji
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China
| | - Xiao-Feng Yang
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA; Cardiovascular Research Center, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
| | - Hong Wang
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA.
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Marrone G, Cornali K, Di Lauro M, Ceravolo MJ, Di Marco L, Manca di Villahermosa S, Mitterhofer AP, Noce A. Innovative Treatments to Counteract Endothelial Dysfunction in Chronic Kidney Disease Patients. Biomedicines 2024; 12:1085. [PMID: 38791047 PMCID: PMC11117580 DOI: 10.3390/biomedicines12051085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 05/02/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
In chronic kidney disease (CKD) patients, several risk factors contribute to the development of endothelial dysfunction (ED), which can be described as an alteration in the cell structure or in the function of the endothelium. Among the well-known CKD-related risk factors capable of altering the production of endothelium-derived relaxing factors, we include asymmetric dimethylarginine increase, reduced dimethylarginine dimethylamine hydrolase enzyme activity, low-grade chronic systemic inflammation, hyperhomocysteinemia, oxidative stress, insulin resistance, alteration of calcium phosphorus metabolism, and early aging. In this review, we also examined the most important techniques useful for studying ED in humans, which are divided into indirect and direct methods. The direct study of coronary endothelial function is considered the gold standard technique to evaluate if ED is present. In addition to the discussion of the main pharmacological treatments useful to counteract ED in CKD patients (namely sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonist), we elucidate innovative non-pharmacological treatments that are successful in accompanying the pharmacological ones. Among them, the most important are the consumption of extra virgin olive oil with high intake of minor polar compounds, adherence to a plant-dominant, low-protein diet (LPD), an adaptive physical activity program and, finally, ketoanalogue administration in combination with the LPD or the very low-protein diet.
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Affiliation(s)
- Giulia Marrone
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
| | - Kevin Cornali
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
| | - Manuela Di Lauro
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
| | - Maria Josè Ceravolo
- Nephrology and Dialysis Unit, Department of Systems Medicine, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
| | - Luca Di Marco
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
| | - Simone Manca di Villahermosa
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
- Nephrology and Dialysis Unit, Department of Systems Medicine, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
| | - Anna Paola Mitterhofer
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
- Nephrology and Dialysis Unit, Department of Systems Medicine, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
| | - Annalisa Noce
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
- Nephrology and Dialysis Unit, Department of Systems Medicine, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
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7
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Chaichanabut C, Sritara P, Sirivarasai J. Genetic Polymorphisms of Endothelial Nitric Oxide Synthase Associated with Hypertension and Blood Homocysteine Levels. Int J Gen Med 2024; 17:1509-1519. [PMID: 38660143 PMCID: PMC11041984 DOI: 10.2147/ijgm.s456519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 04/09/2024] [Indexed: 04/26/2024] Open
Abstract
Purpose Endothelial dysfunction is a key mechanism in the development of hypertension and is closely linked to impairment of endothelial nitric oxide synthase (eNOS) and hyperhomocysteinemia. Genetic polymorphisms of eNOS (rs1799983 and rs2070744) are strongly associated with the risk of hypertension in individuals of Asian ethnicities. This study aimed to investigate the relationship between these polymorphisms and the risk of hypertension associated with homocysteine levels. Participants and Methods For this cross-sectional study, we enrolled 370 Thai men aged 40-60 years from the Electricity Generating Authority of Thailand cohort study for both variants genotyping by TaqMan allelic discrimination analysis. Clinical, anthropometric, and biochemical parameters were also analyzed. Results In the high blood pressure group (n = 267), systolic and diastolic blood pressure and triglyceride levels were higher in those with homocysteine levels ≥ 15 µmol/L than in those with homocysteine levels < 15 µmol/L (p < 0.05). Significant risk of hypertension was found in GG and GT of rs1799983 (G894T), and in TT and TC of rs2070744 (T-786C), with higher ORs in heterozygous genotypes (all p values < 0.05). Further evaluation of the interactions between SNPs and HCY revealed that individuals with the GT or TC genotype, together with hyperhomocysteinemia, had an increased risk of hypertension (all p<0.05). Conclusion eNOS variants rs1799983 and rs2070744 may be risk factors for hypertension linked to hyperhomocysteinemia. These findings provide potentially useful healthcare strategies for the management of hypertension.
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Affiliation(s)
- Charinya Chaichanabut
- Master of Science Program in Nutrition, Faculty of Medicine Ramathibodi Hospital and Institute of Nutrition, Mahidol University, Bangkok, Thailand
| | - Piyamitr Sritara
- Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Jintana Sirivarasai
- Nutrition Unit, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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8
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Suszyńska-Zajczyk J, Witucki Ł, Perła-Kaján J, Jakubowski H. Diet-induced hyperhomocysteinemia causes sex-dependent deficiencies in offspring musculature and brain function. Front Cell Dev Biol 2024; 12:1322844. [PMID: 38559811 PMCID: PMC10979824 DOI: 10.3389/fcell.2024.1322844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 02/26/2024] [Indexed: 04/04/2024] Open
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.
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Affiliation(s)
- Joanna Suszyńska-Zajczyk
- Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, Poznań, Poland
| | - Łukasz Witucki
- Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, Poznań, Poland
| | - Joanna Perła-Kaján
- Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, Poznań, Poland
| | - Hieronim Jakubowski
- Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, Poznań, Poland
- Department of Microbiology, Biochemistry & Molecular Genetics, Rutgers University, New Jersey Medical School, International Center for Public Health, Newark, NJ, United States
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9
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Narayanan SA, Jamison DA, Guarnieri JW, Zaksas V, Topper M, Koutnik AP, Park J, Clark KB, Enguita FJ, Leitão AL, Das S, Moraes-Vieira PM, Galeano D, Mason CE, Trovão NS, Schwartz RE, Schisler JC, Coelho-Dos-Reis JGA, Wurtele ES, Beheshti A. A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection. Eur J Hum Genet 2024; 32:10-20. [PMID: 37938797 PMCID: PMC10772081 DOI: 10.1038/s41431-023-01462-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 09/01/2023] [Accepted: 09/13/2023] [Indexed: 11/09/2023] Open
Abstract
COVID-19, the disease caused by SARS-CoV-2, has caused significant morbidity and mortality worldwide. The betacoronavirus continues to evolve with global health implications as we race to learn more to curb its transmission, evolution, and sequelae. The focus of this review, the second of a three-part series, is on the biological effects of the SARS-CoV-2 virus on post-acute disease in the context of tissue and organ adaptations and damage. We highlight the current knowledge and describe how virological, animal, and clinical studies have shed light on the mechanisms driving the varied clinical diagnoses and observations of COVID-19 patients. Moreover, we describe how investigations into SARS-CoV-2 effects have informed the understanding of viral pathogenesis and provide innovative pathways for future research on the mechanisms of viral diseases.
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Affiliation(s)
- S Anand Narayanan
- COVID-19 International Research Team, Medford, MA, 02155, USA.
- Department of Health, Nutrition and Food Sciences, Florida State University, Tallahassee, FL, 32301, USA.
| | - David A Jamison
- COVID-19 International Research Team, Medford, MA, 02155, USA
| | - Joseph W Guarnieri
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Victoria Zaksas
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Center for Translational Data Science, University of Chicago, Chicago, IL, 60637, USA
- Clever Research Lab, Springfield, IL, 62704, USA
| | - Michael Topper
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Departments of Oncology and Medicine and the Sidney Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Andrew P Koutnik
- Human Healthspan, Resilience, and Performance, Florida Institute for Human and Machine Cognition, Pensacola, FL, 32502, USA
- Sansum Diabetes Research Institute, Santa Barbara, CA, 93015, USA
| | - Jiwoon Park
- Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, 10065, USA
| | - Kevin B Clark
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Cures Within Reach, Chicago, IL, 60602, USA
- Campus and Domain Champions Program, Multi-Tier Assistance, Training, and Computational Help (MATCH) Track, National Science Foundation's Advanced Cyberinfrastructure Coordination Ecosystem: Services and Support (ACCESS), Philadelphia, PA, USA
- Expert Network, Penn Center for Innovation, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Biometrics and Nanotechnology Councils, Institute for Electrical and Electronics Engineers, New York, NY, 10016, USA
- Peace Innovation Institute, The Hague 2511, Netherlands and Stanford University, Palo Alto, 94305, CA, USA
| | - Francisco J Enguita
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal
| | - Ana Lúcia Leitão
- MEtRICs, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516, Caparica, Portugal
| | - Saswati Das
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Atal Bihari Vajpayee Institute of Medical Sciences and Dr Ram Mannohar Lohia Hospital, New Delhi, 110001, India
| | - Pedro M Moraes-Vieira
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
- Experimental Medicine Research Cluster (EMRC) and Obesity and Comorbidities Research Center (OCRC), University of Campinas, Campinas, Brazil
| | - Diego Galeano
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Facultad de Ingeniería, Universidad Nacional de Asunción, San Lorenzo, Paraguay
| | - Christopher E Mason
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA
- New York Genome Center, New York, NY, USA
- The Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Nídia S Trovão
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Fogarty International Center, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Robert E Schwartz
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Jonathan C Schisler
- COVID-19 International Research Team, Medford, MA, 02155, USA
- McAllister Heart Institute and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jordana G A Coelho-Dos-Reis
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Basic and Applied Virology Lab, Department of Microbiology, Institute for Biological Sciences (ICB), Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Eve Syrkin Wurtele
- COVID-19 International Research Team, Medford, MA, 02155, USA
- Genetics Program, Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, 90011, USA
- Bioinformatics and Computational Biology Program, Center for Metabolomics, Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, 90011, USA
| | - Afshin Beheshti
- COVID-19 International Research Team, Medford, MA, 02155, USA.
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
- Blue Marble Space Institute of Science, Space Biosciences Division, NASA Ames Research Center, Moffett Field, Santa Clara, CA, 94035, USA.
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10
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Feng X, Mei Y, Xie P, Xing Z, Wang X, Cui L, Xu R. Serum folic acid: an effective indicator for arteriogenic erectile dysfunction. Front Endocrinol (Lausanne) 2023; 14:1080188. [PMID: 37554765 PMCID: PMC10405823 DOI: 10.3389/fendo.2023.1080188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 06/30/2023] [Indexed: 08/10/2023] Open
Abstract
Background The present study is the first to explore the correlation between serum folic acid (FA) level and penile arterial peak systolic velocity (PSV) as measured via penile color Doppler ultrasonography (PDU), which directly reflects endothelial function in the penile artery. Materials and methods A total of 244 consecutive erectile dysfunction (ED) patients and 72 healthy controls, recruited from the Andrology department and the Healthy Physical Examination Center of our hospital, respectively, from June 2020 to April 2022, were included in the study. Serum FA was measured in ED patients and healthy controls, and PDU examinations were conducted for all eligible ED patients. The Pearson method was used to evaluate the correlation between FA levels and PDU parameters in ED patients. A receiver operating characteristic (ROC) curve analysis was also performed to calculate the sensitivity and specificity of these parameters for prediction of arteriogenic ED. Results After the PDU test, the average serum FA level among patients diagnosed with arteriogenic ED was 8.08 ± 2.64 ng/ml, lower than the average of 10.78 ± 2.87 ng/ml among healthy controls. There were no statistically significant inter-group differences on any basic parameters, including age, body mass index, fasting blood glucose, total cholesterol, and triglyceride. For further analysis, we divided the arteriogenic ED group into three subgroups by PSV range to compare serum FA levels among these subgroups. The mean FA levels in each of these groups were 5.97 ± 1.51ng/ml, and 8.21 ± 2.37ng/ml, and 10.55 ± 2.56ng/ml, while the corresponding PSV values were 15.75 ± 2.39cm/s, 23.53 ± 2.19cm/s, and 32.72 ± 1.64cm/s. Overall, a positive correlation between PSV and FA level was found among patients with arteriogenic ED (r=0.605, P<0.001). Furthermore, when FA level was used, with a cut-off value of 10.045 ng/ml, as a criterion to distinguish patients with arteriogenic ED from healthy controls, the area under the curve (AUC) was 0.772 (95% confidential interval: [0.696, 0.848]), for a sensitivity of 0.611 and specificity of 0.824. Conclusion Serum FA level is positively correlated with PSV in ED patients, and has the ability to distinguish patients with arteriogenic ED from healthy controls. Taking these findings together, FA deficiency should be regarded as an independent risk factor for arteriogenic ED.
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Affiliation(s)
- Xingliang Feng
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Department of Urology, The First People’s Hospital of Changzhou, Changzhou, Jiangsu, China
| | - Yangyang Mei
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Pinpeng Xie
- Department of Clinical Medicine, The Second School of Clinical Medicine, Anhui Medical University, Hefei, China
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Zhaoyu Xing
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Department of Urology, The First People’s Hospital of Changzhou, Changzhou, Jiangsu, China
| | - Xiaogang Wang
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Department of Urology, The First People’s Hospital of Changzhou, Changzhou, Jiangsu, China
| | - Li Cui
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Department of Urology, The First People’s Hospital of Changzhou, Changzhou, Jiangsu, China
| | - Renfang Xu
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Department of Urology, The First People’s Hospital of Changzhou, Changzhou, Jiangsu, China
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11
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Aboukhater D, Morad B, Nasrallah N, Nasser SA, Sahebkar A, Kobeissy F, Boudaka A, Eid AH. Inflammation and hypertension: Underlying mechanisms and emerging understandings. J Cell Physiol 2023; 238:1148-1159. [PMID: 37039489 DOI: 10.1002/jcp.31019] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 03/24/2023] [Indexed: 04/12/2023]
Abstract
Hypertension remains a major contributor to cardiovascular disease (CVD), a leading cause of global death. One of the major insults that drive increased blood pressure is inflammation. While it is the body's defensive response against some homeostatic imbalances, inflammation, when dysregulated, can be very deleterious. In this review, we highlight and discuss the causative relationship between inflammation and hypertension. We critically discuss how the interplay between inflammation and reactive oxygen species evokes endothelial damage and dysfunction, ultimately leading to narrowing and stiffness of blood vessels. This, along with phenotypic switching of the vascular smooth muscle cells and the abnormal increase in extracellular matrix deposition further exacerbates arterial stiffness and noncompliance. We also discuss how hyperhomocysteinemia and microRNA act as links between inflammation and hypertension. The premises we discuss suggest that the blue-sky scenarios for targeting the underlying mechanisms of hypertension necessitate further research.
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Affiliation(s)
- Diana Aboukhater
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Bassel Morad
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Nadim Nasrallah
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Firas Kobeissy
- Department of Neurobiology and Neuroscience, Morehouse School of Medicine, Atlanta, Georgia, USA
| | - Ammar Boudaka
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
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12
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Shcheblykin DV, Bolgov AA, Pokrovskii MV, Stepenko JV, Tsuverkalova JM, Shcheblykina OV, Golubinskaya PA, Korokina LV. Endothelial dysfunction: developmental mechanisms and therapeutic strategies. RESEARCH RESULTS IN PHARMACOLOGY 2022. [DOI: 10.3897/rrpharmacology.8.80376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Introduction: Every year the importance of the normal functioning of the endothelial layer of the vascular wall in maintaining the health of the body becomes more and more obvious.
The physiological role of the endothelium: The endothelium is a metabolically active organ actively involved in the regulation of hemostasis, modulation of inflammation, maintenance of hemovascular homeostasis, regulation of angiogenesis, vascular tone, and permeability.
Risk factors for the development of endothelial dysfunction: Currently, insufficient bioavailability of nitric oxide is considered the most significant risk factor for endothelial dysfunction.
Mechanisms of development of endothelial dysfunction: The genesis of endothelial dysfunction is a multifactorial process. Among various complex mechanisms, this review examines oxidative stress, inflammation, hyperglycemia, vitamin D deficiency, dyslipidemia, excess visceral fat, hyperhomocysteinemia, hyperuricemia, as well as primary genetic defect of endotheliocytes, as the most common causes in the population underlying the development of endothelial dysfunction.
Markers of endothelial dysfunction in various diseases: This article discusses the main biomarkers of endothelial dysfunction currently used, as well as promising biomarkers in the future for laboratory diagnosis of this pathology.
Therapeutic strategies: Therapeutic approaches to the endothelium in order to prevent or reduce a degree of damage to the vascular wall are briefly described.
Conclusion: Endothelial dysfunction is a typical pathological process involved in the pathogenesis of many diseases. Thus, pharmacological agents with endothelioprotective properties can provide more therapeutic benefits than a drug without such an effect.
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13
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Jung S, Choi BH, Joo NS. Serum Homocysteine and Vascular Calcification: Advances in Mechanisms, Related Diseases, and Nutrition. Korean J Fam Med 2022; 43:277-289. [PMID: 36168899 PMCID: PMC9532189 DOI: 10.4082/kjfm.21.0227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 04/08/2022] [Indexed: 11/08/2022] Open
Abstract
Identifying and preventing modifiable risk factors for cardiovascular disease is very important. Vascular calcification has been studied clinically as an asymptomatic preclinical marker of atherosclerosis and a risk factor for cardio-cerebrovascular disease. It is known that higher homocysteine levels are associated with calcified plaques and the higher the homocysteine level, the higher the prevalence and progression of vascular calcification. Homocysteine is a byproduct of methionine metabolism and is generally maintained at a physiological level. Moreover, it may increase if the patient has a genetic deficiency of metabolic enzymes, nutritional deficiencies of related cofactors (vitamins), chronic diseases, or a poor lifestyle. Homocysteine is an oxidative stress factor that can lead to calcified plaques and trigger vascular inflammation. Hyperhomocysteinemia causes endothelial dysfunction, transdifferentiation of vascular smooth muscle cells, and the induction of apoptosis. As a result of transdifferentiation and cell apoptosis, hydroxyapatite accumulates in the walls of blood vessels. Several studies have reported on the mechanisms of multiple cellular signaling pathways that cause inflammation and calcification in blood vessels. Therefore, in this review, we take a closer look at understanding the clinical consequences of hyperhomocysteinemia and apply clinical approaches to reduce its prevalence.
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Affiliation(s)
- Susie Jung
- Department of Family Practice and Community Health, Ajou University School of Medicine, Suwon, Korea
| | | | - Nam-Seok Joo
- Department of Family Practice and Community Health, Ajou University School of Medicine, Suwon, Korea
- Corresponding Author: Nam-Seok Joo Tel: +82-31-219-5324, Fax: +82-31-219-5218, E-mail:
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14
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Marino M, Martini D, Ciappellano S, Brusamolino A, Gardana C, Battezzati A, Riso P, Porrini M, Bo CD. Cobalamin status is negatively correlated with vascular endothelial (VE)-cadherin in vegetarian and vegan women with a vitamin B12 deficiency. Nutr Res 2022; 105:126-137. [DOI: 10.1016/j.nutres.2022.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 06/28/2022] [Accepted: 07/11/2022] [Indexed: 10/17/2022]
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15
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Liu Z, Jiang H, Townsend JH, Wang J. Improved Retinal Microcirculation in Mild Diabetic Retinopathy Patients Carrying MTHFR Polymorphisms Who Received the Medical Food, Ocufolin ®. Clin Ophthalmol 2022; 16:1497-1504. [PMID: 35607436 PMCID: PMC9123245 DOI: 10.2147/opth.s358753] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 05/11/2022] [Indexed: 02/03/2023] Open
Abstract
Purpose To evaluate the effects of Ocufolin® on retinal microcirculation in patients with mild diabetic retinopathy carrying MTHFR polymorphisms. Methods In a prospective, case-controlled study, eight patients with mild diabetic retinopathy and MTHFR polymorphisms and 15 normal controls (NC) were recruited. MTHFR polymorphisms were subtyped as normal, C677T, or A1298C. Best-corrected visual acuity (BCVA) was evaluated. Retinal blood flow velocity (BFV) was measured using Retinal Function Imager. Retinal tissue perfusion (RTP, blood flow rate per inner retinal volume) was calculated within a 2.5 mm diameter circle centered on the fovea. The eight retinopathy patients received Ocufolin® for 6 months, and their imaging was performed at baseline, 4 months, and 6 months. The NC group was imaged once. Results BCVA and vascular indices of DR + PM patients at baseline were below those of NC and improved after Ocufolin® administration. Compared to baseline, DR + PM patients had significantly improved BCVA during the follow-up period (P < 0.05). RTP and arteriolar BFV were significantly increased at 6 months (P < 0.05), approaching NC. Conclusion Ocufolin® may be effective in improving both visual acuity and retinal microcirculation in patients with DR + PM. Further studies with increasing sample size, and longer duration, including cases with severe DR, are needed.
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Affiliation(s)
- Zhiping Liu
- Ophthalmic Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Hong Jiang
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Justin H Townsend
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jianhua Wang
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
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16
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Al-Shabrawey M, Elmarakby A, Samra Y, Moustafa M, Looney SW, Maddipati KR, Tawfik A. Hyperhomocysteinemia dysregulates plasma levels of polyunsaturated fatty acids-derived eicosanoids. LIFE RESEARCH 2022; 5:14. [PMID: 36341141 PMCID: PMC9632953 DOI: 10.53388/2022-0106-103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Hyperhomocysteinemia (HHcy) contributes to the incidence of many cardiovascular diseases (CVD). Our group have previously established crucial roles of eicosanoids and homocysteine in the incidence of vascular injury in diabetic retinopathy and renal injury. Using cystathionine-β-synthase heterozygous mice (cβs+/-) as a model of HHcy, the current study was designed to determine the impact of homocysteine on circulating levels of lipid mediators derived from polyunsaturated fatty acids (PUFA). Plasma samples were isolated from wild-type (WT) and cβs+/- mice for the assessment of eicosanoids levels using LC/MS. Plasma 12/15-lipoxygenase (12/15-LOX) activity significantly decreased in cβs+/- vs. WT control mice. LOX-derived metabolites from both omega-3 and omega-6 PUFA were also reduced in cβs+/- mice compared to WT control (P < 0.05). Contrary to LOX metabolites, cytochrome P450 (CYP) metabolites from omega-3 and omega-6 PUFA were significantly elevated in cβs+/- mice compared to WT control. Epoxyeicosatrienoic acids (EETs) are epoxides derived from arachidonic acid (AA) metabolism by CYP with anti-inflammatory properties and are known to limit vascular injury, however their physiological role is limited by their rapid degradation by soluble epoxide hydrolase (sEH) to their corresponding diols (DiHETrEs). In cβs+/- mice, a significant decrease in the plasma EETs bioavailability was obvious as evident by the decrease in EETs/ DiHETrEs ratio relative to WT control mice. Cyclooxygenase (COX) metabolites were also significantly decreased in cβs+/- vs. WT control mice. These data suggest that HHcy impacts eicosanoids metabolism through decreasing LOX and COX metabolic activities while increasing CYP metabolic activity. The increase in AA metabolism by CYP was also associated with increase in sEH activity and decrease in EETs bioavailability. Dysregulation of eicosanoids metabolism could be a contributing factor to the incidence and progression of HHcy-induced CVD.
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Affiliation(s)
- Mohamed Al-Shabrawey
- Department of Foundational Medical Studies and Eye Research Center, Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA
- Eye Research Institute, Oakland University, Rochester, Michigan, USA
| | - Ahmed Elmarakby
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia, USA
- Departments of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Yara Samra
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia, USA
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Egypt
| | - Mohamed Moustafa
- Department of Foundational Medical Studies and Eye Research Center, Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA
- Eye Research Institute, Oakland University, Rochester, Michigan, USA
| | - Stephen W. Looney
- Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Krishna Rao Maddipati
- Bioactive Lipids Research Program, Department of Pathology, Wayne State University, Michigan, USA
| | - Amany Tawfik
- Department of Foundational Medical Studies and Eye Research Center, Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA
- Eye Research Institute, Oakland University, Rochester, Michigan, USA
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17
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Mojtahedi S, Hooshmand-Moghadam B, Rosenkranz S, Shourideh Z, Amirshaghaghi F, Shabkhiz F. Improvement of inflammatory status following saffron (Crocus sativus L.) and resistance training in elderly hypertensive men: A randomized controlled trial. Exp Gerontol 2022; 162:111756. [DOI: 10.1016/j.exger.2022.111756] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/20/2022] [Accepted: 02/24/2022] [Indexed: 11/04/2022]
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18
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Pavão ML, Ferin R, Lima A, Baptista J. Cysteine and related aminothiols in cardiovascular disease, obesity and insulin resistance. Adv Clin Chem 2022; 109:75-127. [DOI: 10.1016/bs.acc.2022.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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19
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Hayden MR, Tyagi SC. Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer's Disease and Long COVID. MEDICINA (KAUNAS, LITHUANIA) 2021; 58:16. [PMID: 35056324 PMCID: PMC8779539 DOI: 10.3390/medicina58010016] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 12/25/2022]
Abstract
Impaired folate-mediated one-carbon metabolism (FOCM) is associated with many pathologies and developmental abnormalities. FOCM is a metabolic network of interdependent biosynthetic pathways that is known to be compartmentalized in the cytoplasm, mitochondria and nucleus. Currently, the biochemical mechanisms and causal metabolic pathways responsible for the initiation and/or progression of folate-associated pathologies have yet to be fully established. This review specifically examines the role of impaired FOCM in type 2 diabetes mellitus, Alzheimer's disease and the emerging Long COVID/post-acute sequelae of SARS-CoV-2 (PASC). Importantly, elevated homocysteine may be considered a biomarker for impaired FOCM, which is known to result in increased oxidative-redox stress. Therefore, the incorporation of hyperhomocysteinemia will be discussed in relation to impaired FOCM in each of the previously listed clinical diseases. This review is intended to fill gaps in knowledge associated with these clinical diseases and impaired FOCM. Additionally, some of the therapeutics will be discussed at this early time point in studying impaired FOCM in each of the above clinical disease states. It is hoped that this review will allow the reader to better understand the role of FOCM in the development and treatment of clinical disease states that may be associated with impaired FOCM and how to restore a more normal functional role for FOCM through improved nutrition and/or restoring the essential water-soluble B vitamins through oral supplementation.
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Affiliation(s)
- Melvin R. Hayden
- Departments of Internal Medicine, Endocrinology Diabetes and Metabolism Diabetes and Cardiovascular Disease Center, University of Missouri School of Medicine, Columbia, MO 65212, USA
| | - Suresh C. Tyagi
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
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20
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The significance of homocysteine in patients with hypertension. POSTEP HIG MED DOSW 2021. [DOI: 10.2478/ahem-2021-0002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Cardiovascular disease is the most common cause of death in developed countries. Important factors leading to ischemic heart disease and strokes are hypertension and high levels of homocysteine in blood serum. The coexistence of these two factors significantly increases the risk of these diseases and premature deaths. Many studies indicate that patients with hypertension are significantly more likely to demonstrate increased blood serum homocysteine levels than those with normal blood pressure. This may be caused by a higher incidence of overweight, high intake of salt and increased uric acid levels. It has been shown that both these factors increase the prevalence of hypertension and lead to higher homocysteine levels. However, the results of some studies indicate that arterial hypertension and homocysteinemia are causally related. It was shown, among other things, that high homocysteine levels damage the endothelium and reduce nitric oxide synthesis, which may directly lead to hypertension. Serum homocysteine levels are slightly higher in patients with white coat hypertension than they are in healthy individuals and may therefore also increase the risk of cardiovascular diseases. Several authors have also shown that the levels of homocysteine in blood serum are higher in so-called non-dippers, i.e., patients with no night-time pressure drop. The lack of a 10%–20% decrease in blood pressure at night is associated with increased cardiovascular complications. Strokes occur especially frequently in older people with arterial hypertension and hyperhomocysteinemia. The administration of B vitamins and folic acid significantly reduces serum homocysteine levels. The administration of this acid also slightly, but statistically significantly, increases the effectiveness of hypotensive drugs. Large meta-analyses meta-analysis indicate that the increased supply of folic acid in patients with hypertension significantly reduces the risk of stroke. Such management is particularly effective in patients with hypertension and hyperhomocysteinemia.
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21
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Cheng CK, Luo JY, Lau CW, Cho WCS, Ng CF, Ma RCW, Tian XY, Huang Y. A GLP-1 analog lowers ER stress and enhances protein folding to ameliorate homocysteine-induced endothelial dysfunction. Acta Pharmacol Sin 2021; 42:1598-1609. [PMID: 33495519 PMCID: PMC8463564 DOI: 10.1038/s41401-020-00589-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/15/2020] [Indexed: 02/02/2023]
Abstract
Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases and increases mortality in type 2 diabetic patients. HHcy induces endoplasmic reticulum (ER) stress and oxidative stress to impair endothelial function. The glucagon-like peptide 1 (GLP-1) analog exendin-4 attenuates endothelial ER stress, but the detailed vasoprotective mechanism remains elusive. The present study investigated the beneficial effects of exendin-4 against HHcy-induced endothelial dysfunction. Exendin-4 pretreatment reversed homocysteine-induced impairment of endothelium-dependent relaxations in C57BL/6 mouse aortae ex vivo. Four weeks subcutaneous injection of exendin-4 restored the impaired endothelial function in both aortae and mesenteric arteries isolated from mice with diet-induced HHcy. Exendin-4 treatment lowered superoxide anion accumulation in the mouse aortae both ex vivo and in vivo. Exendin-4 decreased the expression of ER stress markers (e.g., ATF4, spliced XBP1, and phosphorylated eIF2α) in human umbilical vein endothelial cells (HUVECs), and this change was reversed by cotreatment with compound C (CC) (AMPK inhibitor). Exendin-4 induced phosphorylation of AMPK and endothelial nitric oxide synthase in HUVECs and arteries. Exendin-4 increased the expression of endoplasmic reticulum oxidoreductase (ERO1α), an important ER chaperone in endothelial cells, and this effect was mediated by AMPK activation. Experiments using siRNA-mediated knockdown or adenoviral overexpression revealed that ERO1α mediated the inhibitory effects of exendin-4 on ER stress and superoxide anion production, thus ameliorating HHcy-induced endothelial dysfunction. The present results demonstrate that exendin-4 reduces HHcy-induced ER stress and improves endothelial function through AMPK-dependent ERO1α upregulation in endothelial cells and arteries. AMPK activation promotes the protein folding machinery in endothelial cells to suppress ER stress.
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Affiliation(s)
- Chak Kwong Cheng
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jiang-Yun Luo
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chi Wai Lau
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - William Chi-Shing Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong SAR, China
| | - Chi Fai Ng
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ronald Ching Wan Ma
- Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, and The Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xiao Yu Tian
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Yu Huang
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
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22
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Curcumin Alleviates Palmitic Acid-Induced LOX-1 Upregulation by Suppressing Endoplasmic Reticulum Stress in HUVECs. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9983725. [PMID: 34471643 PMCID: PMC8405307 DOI: 10.1155/2021/9983725] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 07/24/2021] [Indexed: 01/06/2023]
Abstract
Excessive free fatty acid- (FFA-) induced endothelial lipotoxicity is involved in the pathogenesis of atherosclerosis. Endoplasmic reticulum (ER) stress is mechanistically related to endothelial lipotoxicity. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major oxidatively modified low-density lipoprotein (OxLDL) receptor in endothelial cells and is highly abundant in atherosclerotic lesions. Curcumin reduces the LOX-1 expression; however, the mechanism underlying this effect remains unknown. In the current study, we explored whether curcumin ameliorates palmitic acid- (PA-) induced endothelial lipotoxicity and LOX-1 upregulation by reducing ER stress in human umbilical vein endothelial cells (HUVECs). We built endothelial lipotoxicity in vitro and found that LOX-1 was upregulated after PA stimulation, during which ER stress played an important role. Next, we observed that curcumin substantially alleviated PA-induced lipotoxicity by restoring cell viability, increasing angiogenesis, and decreasing lipid deposition. Furthermore, LOX-1 upregulation in HUVECs was blocked by curcumin, possibly via ER stress suppression. Overall, our findings demonstrated that curcumin alleviates endothelial lipotoxicity and LOX-1 upregulation, and ER stress inhibition may play a critical role in this effect.
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Avagimyan A. Hyperhomocysteinemia as a Link of Chemotherapy-Related Endothelium Impairment. Curr Probl Cardiol 2021; 47:100932. [PMID: 34313228 DOI: 10.1016/j.cpcardiol.2021.100932] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 06/30/2021] [Accepted: 07/09/2021] [Indexed: 02/05/2023]
Abstract
Atherosclerosis is a well-known risk factor of cardiovascular disease development. This research presents the AC mode of chemotherapy-related homocysteine level changes, with the simultaneous trimetazidine administration as a possible therapeutic inhibitor of chemotherapy-associated disturbances of morphofunctional homeostasis, for assessing the possible normalization effects. In order to the implementation of this experimental research, 80 Wistar rats were used. The chemotherapy was administered in AC mode. Trimetazidine was used as a stabilizer of homocysteine concentration. Analysis of homocysteine concentration was carried out by quantitative enzyme immunoassay. Given results state that AC-mode of chemotherapy modulates homocysteine production, a known risk factor for endothelial dysfunction development. At the same time, trimetazidine showed an unexpected limitation of homocysteine concentration. The obtained data indicate that hyperhomocysteinemia also plays a particular role in implementing the chemotherapy-induced cardiovascular disturbances continuum. While homocysteine's stabilizing properties of trimetazidine appear to be quite promising, withal further research is needed.
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Affiliation(s)
- Ashot Avagimyan
- Yerevan State Medical University After M. Heratsi, Yerevan, Republic of Armenia.
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Gou Y, Ye Q, Liang X, Zhang Q, Luo S, Liu H, Wang X, Sai N, Zhang X. Homocysteine restrains hippocampal neurogenesis in focal ischemic rat brain by inhibiting DNA methylation. Neurochem Int 2021; 147:105065. [PMID: 33940063 DOI: 10.1016/j.neuint.2021.105065] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 04/07/2021] [Accepted: 04/27/2021] [Indexed: 11/29/2022]
Abstract
Ischemic stroke represents a major cause of mortality worldwide. An elevated level of homocysteine (Hcy) is recognized as a powerful risk factor of ischemic stroke. We previously reported that Hcy induces cytotoxicity and proliferation inhibition in neural stem cells (NSCs) derived from the neonatal rat hippocampus in vitro. However, the toxic potential of Hcy on NSCs and its underlying mechanisms are not entirely clear in ischemic brain. Since DNA methylation is critical for establishing the diverse cell fates in the central nervous system, we hypothesized that negative effect of Hcy (an intermediate in the one-carbon metabolism) on neurogenesis might be link to DNA methylation in ischemic stroke. In our study, the rats in Hcy intervention group were intraperitoneally injected with 2% Hcy solution (5 mL/kg/d) for 7 consecutive days before MCAO surgery until they were sacrificed. Our study indicated that Hcy inhibited NSCs self-renewal capacity, which was exhibited by lowering the number of DCX+/BrdU+ and NeuN+/BrdU+ in ischemic brain hippocampus. A reduction in the activity of the DNA methyltransferases (DNMTs), total methylation level and the number of 5mC+/NeuN+ and DCX+/5mC+ cells was observed in Hcy-treated ischemic brains. Additionally, Hcy also induced an increase in S-adenosylhomocysteine (SAH), and a decrease in the ratio of S-adenosylmethionine (SAM) to SAH. These results suggest that the alterations in DNA methylation may be an important mechanism by which Hcy inhibits neurogenesis after stroke. Hcy-induced DNA hypomethylation may be mainly caused by a reduction in the DNMT activity which is regulated by the concentrations of SAM and SAH. Maintaining normal DNA methylation by lowering Hcy level may possess therapeutic potential for promoting neurological recovery and reconstruction after stroke.
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Affiliation(s)
- Yun Gou
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, 300070, China; Department of Nutriology, Tianjin Children's Hospital, Tianjin, 300074, China
| | - Qi Ye
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Xiaoshan Liang
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Qiang Zhang
- Tianjin Key Laboratory of Environment, Nutrition and Public Health, Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin Medical University, Tianjin, 300070, China; Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Suhui Luo
- Tianjin Key Laboratory of Environment, Nutrition and Public Health, Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Huan Liu
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Xuan Wang
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Na Sai
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Xumei Zhang
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin Medical University, Tianjin, 300070, China.
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Tawfik A, Elsherbiny NM, Zaidi Y, Rajpurohit P. Homocysteine and Age-Related Central Nervous System Diseases: Role of Inflammation. Int J Mol Sci 2021; 22:ijms22126259. [PMID: 34200792 PMCID: PMC8230490 DOI: 10.3390/ijms22126259] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/02/2021] [Accepted: 06/07/2021] [Indexed: 02/07/2023] Open
Abstract
Hyperhomocysteinemia (HHcy) is remarkably common among the aging population. The relation between HHcy and the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and eye diseases, and age-related macular degeneration (AMD) and diabetic retinopathy (DR) in elderly people, has been established. Disruption of the blood barrier function of the brain and retina is one of the most important underlying mechanisms associated with HHcy-induced neurodegenerative and retinal disorders. Impairment of the barrier function triggers inflammatory events that worsen disease pathology. Studies have shown that AD patients also suffer from visual impairments. As an extension of the central nervous system, the retina has been suggested as a prominent site of AD pathology. This review highlights inflammation as a possible underlying mechanism of HHcy-induced barrier dysfunction and neurovascular injury in aging diseases accompanied by HHcy, focusing on AD.
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Affiliation(s)
- Amany Tawfik
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA; (N.M.E.); (Y.Z.); (P.R.)
- James and Jean Culver Vision Discovery Institute, MCG, Augusta University, Augusta, GA 30912, USA
- Department of Cellular Biology and Anatomy, Medical College of Georgia (MCG), Augusta University, Augusta, GA 30912, USA
- Department of Ophthalmology, MCG, Augusta University, Augusta, GA 30912, USA
- Eye Research Institue, Oakland University, Rochester, MI 48309, USA
- Correspondence: ; Tel.: +1-706-721-2582; Fax: +1-706-721-9415
| | - Nehal M. Elsherbiny
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA; (N.M.E.); (Y.Z.); (P.R.)
- James and Jean Culver Vision Discovery Institute, MCG, Augusta University, Augusta, GA 30912, USA
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Yusra Zaidi
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA; (N.M.E.); (Y.Z.); (P.R.)
- James and Jean Culver Vision Discovery Institute, MCG, Augusta University, Augusta, GA 30912, USA
| | - Pragya Rajpurohit
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA; (N.M.E.); (Y.Z.); (P.R.)
- James and Jean Culver Vision Discovery Institute, MCG, Augusta University, Augusta, GA 30912, USA
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Li Z, Kosgei VJ, Bison A, Alberto JM, Umoret R, Maskali F, Brunaud L, Guéant JL, Guéant-Rodriguez RM. Programming by Methyl Donor Deficiency during Pregnancy and Lactation Produces Cardiomyopathy in Adult Rats Subjected to High Fat Diet. Mol Nutr Food Res 2021; 65:e2100065. [PMID: 33991387 DOI: 10.1002/mnfr.202100065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 04/12/2021] [Indexed: 12/15/2022]
Abstract
SCOPE Vitamin B12 and folate (methyl donors) deficiency is frequent during pregnancy. Experimental rat models with methyl donor deficit during pregnancy and lactation (Initial methyl donor deficit (iMDD)) produce impaired myocardium fatty acid oxidation and mitochondrial energy metabolism at weaning. METHODS AND RESULTS The consequences of iMDD on heart of rat pups under normal diet after weaning and high fat diet (HF) between day (D) 50 and D185 are investigated. iMDD/HF induces increased histological fibrosis and increased B-type natriuretic peptide blood level. Inflammation is evidenced by increased protein expression of NFkB, Caspase1, and IL1β and fibrosis by increased expression of αSMA, col1a1, and col1a2 in females, but not in males. Fibrosis is related to increased angiotensin at D50 and D185 and increased protein expression of TGFB1 and AT1 angiotensin receptors at D185. The limited fibrosis in males is consistent with increased expression of AT2, the antagonist receptor of AT1. The increased expression of GLUT4 and decreased expression of PGC1α and PPARα reflect a shift from fatty acid oxidation to glycolysis. CONCLUSION Developmental programming by iMDD produces cardiomyopathy in female offspring exposed to HF. The cardiomyopathy is linked to inflammation and fibrosis through angiotensin-AT2 and TGFB1 pathways and alteration of energy metabolism.
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Affiliation(s)
- Zhen Li
- UMR Inserm 1256 N-GERE (Nutrition, Génetique et Exposition aux Risques Environmentaux), Université de Lorraine, Vandoeuvre-lès-Nancy, 54500, France
| | - Viola J Kosgei
- UMR Inserm 1256 N-GERE (Nutrition, Génetique et Exposition aux Risques Environmentaux), Université de Lorraine, Vandoeuvre-lès-Nancy, 54500, France
| | - Anais Bison
- UMR Inserm 1256 N-GERE (Nutrition, Génetique et Exposition aux Risques Environmentaux), Université de Lorraine, Vandoeuvre-lès-Nancy, 54500, France
| | - Jean-Marc Alberto
- UMR Inserm 1256 N-GERE (Nutrition, Génetique et Exposition aux Risques Environmentaux), Université de Lorraine, Vandoeuvre-lès-Nancy, 54500, France
| | - Remi Umoret
- UMR Inserm 1256 N-GERE (Nutrition, Génetique et Exposition aux Risques Environmentaux), Université de Lorraine, Vandoeuvre-lès-Nancy, 54500, France
| | - Fatiha Maskali
- Nancyclotep-GIE, CHRU of Nancy, Rue du Morvan, Vandoeuve-Lès-Nancy, 54500, France
| | - Laurent Brunaud
- UMR Inserm 1256 N-GERE (Nutrition, Génetique et Exposition aux Risques Environmentaux), Université de Lorraine, Vandoeuvre-lès-Nancy, 54500, France
| | - Jean-Louis Guéant
- UMR Inserm 1256 N-GERE (Nutrition, Génetique et Exposition aux Risques Environmentaux), Université de Lorraine, Vandoeuvre-lès-Nancy, 54500, France.,Departments of Digestive Diseases, Nutrition and Endocrinology and Molecular Medicine and National Center of Inborn Errors of Metabolism, University Hospital Center, Université de Lorraine, Vandoeuvre-lès-Nancy, 54500, France
| | - Rosa-Maria Guéant-Rodriguez
- UMR Inserm 1256 N-GERE (Nutrition, Génetique et Exposition aux Risques Environmentaux), Université de Lorraine, Vandoeuvre-lès-Nancy, 54500, France.,Departments of Digestive Diseases, Nutrition and Endocrinology and Molecular Medicine and National Center of Inborn Errors of Metabolism, University Hospital Center, Université de Lorraine, Vandoeuvre-lès-Nancy, 54500, France
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Zhang Y, Zhang W, Dai Y, Jiang H, Zhang X. Serum Folic Acid and Erectile Dysfunction: A Systematic Review and Meta-Analysis. Sex Med 2021; 9:100356. [PMID: 34051538 PMCID: PMC8240352 DOI: 10.1016/j.esxm.2021.100356] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 03/10/2021] [Accepted: 03/13/2021] [Indexed: 11/18/2022] Open
Abstract
Introduction The association between folic acid (FA) and erectile dysfunction (ED) was contradictory in the published original articles, and no meta-analysis was conducted to pool these data. Aim To verify the role of FA in the pathology of ED and explore the treatment efficacy of FA for ED patients. Methods An extensive search was performed on PubMed, Cochrane Library, and Web of Science to obtain all relevant studies published up to October 31, 2020. Studies comparing the serum FA level between ED patients and healthy controls, or comparing the score of the IIEF-5, or IIEF before and after folic acid therapy alone or combination in ED patient were eligible for our meta-analysis. The Newcastle-Ottawa Scales (NOS) was used to qualify included studies. Main Outcome Measures The standardized mean differences (SMD) and their corresponding 95% confidence intervals (95% CIs) were calculated to pool our data. Results Nine studies were eligible for our meta-analysis to verify the association between FA and ED, and to explore the treatment efficacy of FA for ED patients. The pooled SMD of the FA level difference between ED patients and healthy subjects was -0.94 (95% CI: -1.59, -0.30, P = .004). Moreover, the level of folic acid in healthy subjects, Mild ED patients, Moderate ED patients and Severe ED patients was 11.847 (95%CI = 9.671, 14.022), 9.496 (95%CI = 8.425, 10.567), 6.597 (95%CI = 5.187, 8.007) and 5.623 (95%CI = 3.535, 7.711) respectively. The SMD of changes in score of IIEF-5 was 1.89 with 95%CI (1.60, 2.17) after FA administration in ED patients. Our analysis also showed that combination therapy of FA plus tadalafil changed the score of IIEF with 0.90 (95%CI = 0.44, 1.36) comparing to combination of placebo plus tadalafil. Conclusion This novel meta-analysis demonstrated that FA was an independent risk factor for ED and FA supplement may have potentially positive effects in the treatment of ED patients. Zhang Y, Zhang W, Dai Y, et al. Serum Folic Acid and Erectile Dysfunction: A Systematic Review and Meta-Analysis. Sex Med 2021;9:100356.
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Affiliation(s)
- Yuyang Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Province, China; Institute of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Province, China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Anhui Province, China
| | - Wei Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Province, China; Institute of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Province, China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Anhui Province, China
| | - Yutian Dai
- Department of Andrology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Hui Jiang
- The Department of Urology, Peking University Third Hospital, Beijing, China
| | - Xiansheng Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Province, China; Institute of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Province, China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Anhui Province, China.
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Jan M, Cueto R, Jiang X, Lu L, Sardy J, Xiong X, Yu JE, Pham H, Khan M, Qin X, Ji Y, Yang XF, Wang H. Molecular processes mediating hyperhomocysteinemia-induced metabolic reprogramming, redox regulation and growth inhibition in endothelial cells. Redox Biol 2021; 45:102018. [PMID: 34140262 PMCID: PMC8282538 DOI: 10.1016/j.redox.2021.102018] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/13/2021] [Accepted: 05/19/2021] [Indexed: 01/04/2023] Open
Abstract
Hyperhomocysteinemia (HHcy) is an established and potent independent risk factor for degenerative diseases, including cardiovascular disease (CVD), Alzheimer disease, type II diabetes mellitus, and chronic kidney disease. HHcy has been shown to inhibit proliferation and promote inflammatory responses in endothelial cells (EC), and impair endothelial function, a hallmark for vascular injury. However, metabolic processes and molecular mechanisms mediating HHcy-induced endothelial injury remains to be elucidated. This study examined the effects of HHcy on the expression of microRNA (miRNA) and mRNA in human aortic EC treated with a pathophysiologically relevant concentration of homocysteine (Hcy 500 μM). We performed a set of extensive bioinformatics analyses to identify HHcy-altered metabolic and molecular processes. The global functional implications and molecular network were determined by Gene Set Enrichment Analysis (GSEA) followed by Cytoscape analysis. We identified 244 significantly differentially expressed (SDE) mRNA, their relevant functional pathways, and 45 SDE miRNA. HHcy-altered SDE inversely correlated miRNA-mRNA pairs (45 induced/14 reduced mRNA) were discovered and applied to network construction using an experimentally verified database. We established a hypothetical model to describe the biochemical and molecular network with these specified miRNA/mRNA axes, finding: 1) HHcy causes metabolic reprogramming by increasing glucose uptake and oxidation, by glycogen debranching and NAD+/CoA synthesis, and by stimulating mitochondrial reactive oxygen species production via NNT/IDH2 suppression-induced NAD+/NADP-NADPH/NADP+ metabolism disruption; 2) HHcy activates inflammatory responses by activating inflammasome-pyroptosis mainly through ↓miR193b→↑CASP-9 signaling and by inducing IL-1β and adhesion molecules through the ↓miR29c→↑NEDD9 and the ↓miR1256→↑ICAM-1 axes, as well as GPCR and interferon α/β signaling; 3) HHcy promotes cell degradation by the activation of lysosome autophagy and ubiquitin proteasome systems; 4) HHcy causes cell cycle arrest at G1/S and S/G2 transitions, suppresses spindle checkpoint complex and cytokinetic abscission, and suppresses proliferation through ↓miRNA335/↑VASH1 and other axes. These findings are in accordance with our previous studies and add a wealth of heretofore-unexplored molecular and metabolic mechanisms underlying HHcy-induced endothelial injury. This is the first study to consider the effects of HHcy on both global mRNA and miRNA expression changes for mechanism identification. Molecular axes and biochemical processes identified in this study are useful not only for the understanding of mechanisms underlying HHcy-induced endothelial injury, but also for discovering therapeutic targets for CVD in general.
Identified multiple HHcy-altered metabolic and molecular processes potentially responsible for HHcy-induced endothelial injury via examining global mRNA/miRNA expression changes in Hcy-treated EC and performing comprehensive bioinformatic studies. HHcy may activate glucose uptake signaling via the ↓miR148b→↑SLC2A axis. HHcy may induce glucose oxidation signaling by switching pyruvate metabolism from lactate synthesis to mitochondrial oxidation via expression changes of ↑MPC1 & ↓LDHB. HHcy may disrupt redox homeostasis mostly by suppressing NNT/IDH2-related mt-NADPH/mt-NAD+ signaling. HHcy may increase FA β-oxidation, glutamine, TCA cycle and OXPHOS signaling. HHcy may activate inflammatory signaling via the ↓miR29c→↑NEDD9 and the ↓miR1256→↑ICAM-1 axes. HHcy may activate inflammasome/pyroptosis-related signaling by the ↓miR137→↑TLR3, the ↓miR574→↑TRAF5, and the ↓miR193b→↑CASP-9 axes, and induce IL1α/β and CASP-10/7. HHcy may induce inflammation signaling via GPCR activation through the ↓miRNA335→↑CXCR4/↑GNA14 axes. HHcy may activate molecular degradation process signaling through the ↓miRNA335→↑ASAH1/↑ABCB9 axes. HHcy may suppress cell cycle and proliferation through the miR491→↓HMGA2→↓CCNA2/CCNB2, the ↓miR335→↑VASH1, the ↓miR181a→↑PHLDA1, the miR6045→↓CENPH, the miR22→↓PRR11/↓BRCA2, and the miR605/miR497/miR514a→CEP55 axes
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Affiliation(s)
- Michael Jan
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States; Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, United States
| | - Ramon Cueto
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States
| | - Xiaohua Jiang
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States
| | - Liu Lu
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States
| | - Jason Sardy
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States
| | - Xinyu Xiong
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States
| | - Justine E Yu
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States
| | - Hung Pham
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States
| | - Mohsin Khan
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States
| | - Xuebing Qin
- Tulane National Primate Research Center, School of Medicine, Tulane University, Covington, LA, United States
| | - Yong Ji
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China
| | - Xiao-Feng Yang
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, United States
| | - Hong Wang
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, United States.
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Cacciapuoti F. What Could be the Most Advantageous Therapeutic Approach to Avoid both Arterial and Venous Thrombosis in Hyperhomocysteinemia? Curr Cardiol Rev 2021; 17:171-172. [PMID: 32392117 PMCID: PMC8226209 DOI: 10.2174/1573403x16666200511085701] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 03/27/2020] [Accepted: 04/09/2020] [Indexed: 12/27/2022] Open
Affiliation(s)
- Federico Cacciapuoti
- Department of Internal Medicine, "L. Vanvitelli" Campania University-Naples, Italy
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30
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Li S, Ma F, Yokota T, Garcia G, Palermo A, Wang Y, Farrell C, Wang YC, Wu R, Zhou Z, Pan C, Morselli M, Teitell MA, Ryazantsev S, Fishbein GA, Hoeve JT, Arboleda VA, Bloom J, Dillon B, Pellegrini M, Lusis AJ, Graeber TG, Arumugaswami V, Deb A. Metabolic reprogramming and epigenetic changes of vital organs in SARS-CoV-2-induced systemic toxicity. JCI Insight 2021; 6:145027. [PMID: 33284134 PMCID: PMC7934846 DOI: 10.1172/jci.insight.145027] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/03/2020] [Indexed: 01/08/2023] Open
Abstract
Extrapulmonary manifestations of COVID-19 are associated with a much higher mortality rate than pulmonary manifestations. However, little is known about the pathogenesis of systemic complications of COVID-19. Here, we create a murine model of SARS-CoV-2-induced severe systemic toxicity and multiorgan involvement by expressing the human ACE2 transgene in multiple tissues via viral delivery, followed by systemic administration of SARS-CoV-2. The animals develop a profound phenotype within 7 days with severe weight loss, morbidity, and failure to thrive. We demonstrate that there is metabolic suppression of oxidative phosphorylation and the tricarboxylic acid (TCA) cycle in multiple organs with neutrophilia, lymphopenia, and splenic atrophy, mirroring human COVID-19 phenotypes. Animals had a significantly lower heart rate, and electron microscopy demonstrated myofibrillar disarray and myocardial edema, a common pathogenic cardiac phenotype in human COVID-19. We performed metabolomic profiling of peripheral blood and identified a panel of TCA cycle metabolites that served as biomarkers of depressed oxidative phosphorylation. Finally, we observed that SARS-CoV-2 induces epigenetic changes of DNA methylation, which affects expression of immune response genes and could, in part, contribute to COVID-19 pathogenesis. Our model suggests that SARS-CoV-2-induced metabolic reprogramming and epigenetic changes in internal organs could contribute to systemic toxicity and lethality in COVID-19.
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Affiliation(s)
- Shen Li
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine
- UCLA Cardiovascular Research Theme, David Geffen School of Medicine
- Department of Molecular, Cell and Developmental Biology, Division of Life Sciences
- Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Molecular Biology Institute
- California Nanosystems Institute
| | - Feiyang Ma
- UCLA Cardiovascular Research Theme, David Geffen School of Medicine
- Department of Molecular, Cell and Developmental Biology, Division of Life Sciences
- Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research
| | - Tomohiro Yokota
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine
- UCLA Cardiovascular Research Theme, David Geffen School of Medicine
- Department of Molecular, Cell and Developmental Biology, Division of Life Sciences
- Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Molecular Biology Institute
- California Nanosystems Institute
| | - Gustavo Garcia
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine
| | - Amelia Palermo
- California Nanosystems Institute
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine
- UCLA Metabolomics Center
- Crump Institute for Molecular Imaging
| | - Yijie Wang
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine
- UCLA Cardiovascular Research Theme, David Geffen School of Medicine
- Department of Molecular, Cell and Developmental Biology, Division of Life Sciences
- Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Molecular Biology Institute
- California Nanosystems Institute
| | - Colin Farrell
- Department of Human Genetics, David Geffen School of Medicine
| | - Yu-Chen Wang
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine
- UCLA Cardiovascular Research Theme, David Geffen School of Medicine
- Department of Human Genetics, David Geffen School of Medicine
| | - Rimao Wu
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine
- UCLA Cardiovascular Research Theme, David Geffen School of Medicine
- Department of Molecular, Cell and Developmental Biology, Division of Life Sciences
- Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Molecular Biology Institute
- California Nanosystems Institute
| | - Zhiqiang Zhou
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine
- UCLA Cardiovascular Research Theme, David Geffen School of Medicine
- Department of Human Genetics, David Geffen School of Medicine
| | - Calvin Pan
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine
- UCLA Cardiovascular Research Theme, David Geffen School of Medicine
- Department of Human Genetics, David Geffen School of Medicine
| | - Marco Morselli
- Department of Molecular, Cell and Developmental Biology, Division of Life Sciences
- Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Molecular Biology Institute
| | - Michael A. Teitell
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine
| | | | - Gregory A. Fishbein
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine
| | - Johanna ten Hoeve
- California Nanosystems Institute
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine
- UCLA Metabolomics Center
- Crump Institute for Molecular Imaging
| | - Valerie A. Arboleda
- Department of Human Genetics, David Geffen School of Medicine
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine
| | - Joshua Bloom
- Department of Human Genetics, David Geffen School of Medicine
- Department of Biological Chemistry, David Geffen School of Medicine
- Howard Hughes Medical Institute, and
| | - Barbara Dillon
- Department of Environment, Health and Safety, UCLA, Los Angeles, California, USA
| | - Matteo Pellegrini
- Department of Molecular, Cell and Developmental Biology, Division of Life Sciences
- Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Molecular Biology Institute
| | - Aldons J. Lusis
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine
- UCLA Cardiovascular Research Theme, David Geffen School of Medicine
- Department of Human Genetics, David Geffen School of Medicine
| | - Thomas G. Graeber
- Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- California Nanosystems Institute
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine
- UCLA Metabolomics Center
- Crump Institute for Molecular Imaging
| | - Vaithilingaraja Arumugaswami
- Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine
| | - Arjun Deb
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine
- UCLA Cardiovascular Research Theme, David Geffen School of Medicine
- Department of Molecular, Cell and Developmental Biology, Division of Life Sciences
- Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Molecular Biology Institute
- California Nanosystems Institute
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Tawfik A, Mohamed R, Kira D, Alhusban S, Al-Shabrawey M. N-Methyl-D-aspartate receptor activation, novel mechanism of homocysteine-induced blood-retinal barrier dysfunction. J Mol Med (Berl) 2021; 99:119-130. [PMID: 33159240 PMCID: PMC7785674 DOI: 10.1007/s00109-020-02000-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 10/18/2020] [Accepted: 10/27/2020] [Indexed: 12/14/2022]
Abstract
Elevated levels of amino acid homocysteine (Hcy) recognized as hyperhomocysteinemia (HHcy) was reported in several human visual disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Breakdown of blood-retinal barrier (BRB) is concomitant with vision loss in DR and AMD. We previously reported that HHcy alters BRB. Here, we tested the hypothesis that HHcy alters BRB via activation of N-methyl-D-aspartate receptor (NMDAR). Human retinal endothelial cells subjected to high level of Hcy and mouse model of HHcy were used. We injected Hcy intravitreal and used a mouse model of HHcy that lacks cystathionine-β-synthase (CBS). RT-PCR, western blot, and immunofluorescence showed that retinal endothelial cells (RECs) express NMDAR at the gene and protein levels both in vitro and in vivo and this was increased by HHcy. We assessed BRB function and retinal morphology using fluorescein angiogram and optical coherence tomography (OCT) under HHcy with and without pharmacological inhibition of NMDAR by (MK801) or in mice lacking endothelial NMDAR (NMDARE-/- mouse). Additionally, retinal albumin leakage and tight junction proteins ZO-1 and occludin were assessed by western blotting analysis. Inhibition or elimination of NMDAR was able to improve the altered retinal hyperpermeability and morphology under HHcy as indicated by significant decrease in retinal albumin leakage and restoration of tight junction proteins ZO-1 and occludin. Our findings underscore a potential role for endothelial NMDAR in mediating Hcy-induced breakdown of BRB and subsequently as a potential therapeutic target in retinal diseases associated with HHcy such as DR and AMD. KEY MESSAGES: • Elevated levels of homocysteine (Hcy) are defined as hyperhomocysteinemia (HHcy). • HHcy is implicated in diabetic retinopathy and age-related macular degeneration. • HHcy alters BRB via activation of N-methyl-D-aspartate receptor.
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Affiliation(s)
- Amany Tawfik
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1120 15th Street, CB 1114, Augusta, GA, 30912-2000, USA.
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA.
- Department of Cellular Biology and Anatomy, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA.
- Department of Ophthalmology, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA.
| | - Riyaz Mohamed
- Department of Physiology Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA
| | - Dina Kira
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1120 15th Street, CB 1114, Augusta, GA, 30912-2000, USA
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA
| | - Suhib Alhusban
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1120 15th Street, CB 1114, Augusta, GA, 30912-2000, USA
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA
| | - Mohamed Al-Shabrawey
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1120 15th Street, CB 1114, Augusta, GA, 30912-2000, USA
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA
- Department of Cellular Biology and Anatomy, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA
- Department of Ophthalmology, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA
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Luo R, Li L, Liu X, Yuan Y, Zhu W, Li L, Liu J, Lu Y, Cheng J, Chen Y. Mesenchymal stem cells alleviate palmitic acid-induced endothelial-to-mesenchymal transition by suppressing endoplasmic reticulum stress. Am J Physiol Endocrinol Metab 2020; 319:E961-E980. [PMID: 33044844 DOI: 10.1152/ajpendo.00155.2020] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
High levels of plasma free fatty acids (FFAs) lead to endothelial dysfunction (ED), which is involved in the pathogenesis of metabolic syndrome, diabetes, and atherosclerosis. Endoplasmic reticulum (ER) stress and endothelial-to-mesenchymal transition (EndMT) are demonstrated to be mechanistically related to endothelial dysfunction. Mesenchymal stem cells (MSCs) have exhibited an extraordinary cytoprotective effect on cellular lipotoxicity and vasculopathy. However, the underlying mechanisms have not been clearly defined. In the present study, we investigated whether MSCs could ameliorate palmitic acid (PA)-induced endothelial lipotoxicity by reducing ER stress and EndMT. We observed that MSC cocultures substantially alleviated PA-induced lipotoxicity in human umbilical vein endothelial cells (HUVECs). MSCs were able to restore the cell viability, increase tubule formation and migration ability, and decrease inflammation response and lipid deposition. Furthermore, PA caused endothelial-to-mesenchymal transition in HUVECs, which was abrogated by MSCs possibly through inhibiting ER stress. In addition, PA stimulated MSCs to secrete more stanniocalcin-1 (STC-1). Knocking down of STC-1 in MSCs attenuated their effects on PA-induced lipotoxicity in HUVECs. In vivo, MSC transplantation alleviated dyslipidemia and endothelial dysfunction in high-fat diet-fed Sprague-Dawley rats. MSC-treated rats showed reduced expressions of ER stress-related genes in aortas and suppressed expressions of EndMT-related proteins in rat aortic endothelial cells. Overall, our findings indicated that MSCs were able to attenuate endothelial lipotoxicity through inhibiting ER stress and EndMT, in which STC-1 secreted from MSCs may play a critical role.
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Affiliation(s)
- Ruixi Luo
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
- Department of Immunology and Microbiology, Stem Cell Therapy Research Center, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Linzhao Li
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaohong Liu
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yujia Yuan
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wuzheng Zhu
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Lan Li
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jingping Liu
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yanrong Lu
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jingqiu Cheng
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Younan Chen
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
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Gupta A, Priyadarshi S, Vyas N, Sharma G, Swain PK. Novel predictive risk factor for Erectile Dysfunction: Serum folic acid. Andrologia 2020; 53:e13890. [PMID: 33141950 DOI: 10.1111/and.13890] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 10/04/2020] [Indexed: 12/26/2022] Open
Abstract
The purpose of this study was to compare the serum Folic Acid (FA) levels in patients with Erectile Dysfunction (ED) and healthy controls and whether levels vary with its severity. The study was carried out on 77 sexually active individuals, out of which 41 complained of ED and 36 were apparently normal. Patients were excluded if they had any diseases known to cause ED. The severity was further categorised based on IIEF-5 scores. Blood serum levels of testosterone, lipid profile, random blood sugar, liver function test, renal function test and FA levels were obtained in each patient. Independent-samples t test of significance was used when comparing between two means. Pearson's correlation coefficient (r) test was used for correlating data. All clinical and biochemical parameters except FA were comparable in both the groups. FA levels were significantly decreased in ED group (5.29 vs. 10.8; p value = .004). Smoking habits were comparable between the groups, and FA levels did not vary among smokers and nonsmokers (p value = .46). Serum FA levels significantly declined with increasing severity of ED (8.28 vs. 5.56 vs. 4.37 vs. 3.5; p value < .001). Thus, decreased FA might possibly be one of the novel risk factors for ED.
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Affiliation(s)
- Abhimanyu Gupta
- Department of Urology and Renal Transplant, SMS Medical College and Hospital, Jaipur, India
| | - Shivam Priyadarshi
- Department of Urology and Renal Transplant, SMS Medical College and Hospital, Jaipur, India
| | - Nachiket Vyas
- Department of Urology and Renal Transplant, SMS Medical College and Hospital, Jaipur, India
| | - Govind Sharma
- Department of Urology and Renal Transplant, SMS Medical College and Hospital, Jaipur, India
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Silva GM, França-Falcão MS, Calzerra NTM, Luz MS, Gadelha DDA, Balarini CM, Queiroz TM. Role of Renin-Angiotensin System Components in Atherosclerosis: Focus on Ang-II, ACE2, and Ang-1-7. Front Physiol 2020; 11:1067. [PMID: 33013457 PMCID: PMC7494970 DOI: 10.3389/fphys.2020.01067] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/04/2020] [Indexed: 12/24/2022] Open
Abstract
Atherosclerosis is the leading cause of vascular disease worldwide and contributes significantly to deaths from cardiovascular complications. There is a remarkably close relationship between atherosclerotic plaque formation and the activation of renin-angiotensin system (RAS). However, depending on which RAS pathway is activated, pro- or anti-atherogenic outcomes may be observed. This brief review focuses on the role of three of the most important pieces of RAS axis, angiotensin II (Ang-II), angiotensin converting enzyme type 2 (ACE2), and angiotensin 1-7 (Ang-1-7) and their involvement in atherosclerosis. We focused on the effects of these molecules on vascular function and inflammation, which are important determinants of atherogenesis. Furthermore, we highlighted potential pharmacological approaches to treat this disorder.
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Affiliation(s)
- Gabriela M Silva
- Laboratory of Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, Vitória de Santo Antão, Brazil
| | | | | | - Mickael S Luz
- Center of Biotechnology, Federal University of Paraiba, João Pessoa, Brazil
| | | | - Camille M Balarini
- Health Sciences Center, Federal University of Paraiba, João Pessoa, Brazil
| | - Thyago M Queiroz
- Laboratory of Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, Vitória de Santo Antão, Brazil
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Potential role of hydrogen sulfide in diabetes-impaired angiogenesis and ischemic tissue repair. Redox Biol 2020; 37:101704. [PMID: 32942144 PMCID: PMC7498944 DOI: 10.1016/j.redox.2020.101704] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/12/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes is one of the most prevalent metabolic disorders and is estimated to affect 400 million of 4.4% of population worldwide in the next 20 year. In diabetes, risk to develop vascular diseases is two-to four-fold increased. Ischemic tissue injury, such as refractory wounds and critical ischemic limb (CLI) are major ischemic vascular complications in diabetic patients where oxygen supplement is insufficient due to impaired angiogenesis/neovascularization. In spite of intensive studies, the underlying mechanisms of diabetes-impaired ischemic tissue injury remain incompletely understood. Hydrogen sulfide (H2S) has been considered as a third gasotransmitter regulating angiogenesis under physiological and ischemic conditions. Here, the underlying mechanisms of insufficient H2S-impaired angiogenesis and ischemic tissue repair in diabetes are discussed. We will primarily focuses on the signaling pathways of H2S in controlling endothelial function/biology, angiogenesis and ischemic tissue repair in diabetic animal models. We summarized that H2S plays an important role in maintaining endothelial function/biology and angiogenic property in diabetes. We demonstrated that exogenous H2S may be a theraputic agent for endothelial dysfunction and impaired ischemic tissue repair in diabetes.
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Hyperhomocysteinemia and Low Folate and Vitamin B12 Are Associated with Vascular Dysfunction and Impaired Nitric Oxide Sensitivity in Morbidly Obese Patients. Nutrients 2020; 12:nu12072014. [PMID: 32645905 PMCID: PMC7400872 DOI: 10.3390/nu12072014] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 06/22/2020] [Accepted: 07/01/2020] [Indexed: 12/12/2022] Open
Abstract
There is a high prevalence of hyperhomocysteinemia that has been linked to high cardiovascular risk in obese individuals and could be attributed to poor nutritional status of folate and vitamin B12. We sought to examine the association between blood homocysteine (Hcy) folate, and vitamin B12 levels and vascular dysfunction in morbidly obese adults using novel ex vivo flow-induced dilation (FID) measurements of isolated adipose tissue arterioles. Brachial artery flow-mediated dilation (FMD) was also measured. Subcutaneous and visceral adipose tissue biopsies were obtained from morbidly obese individuals and non-obese controls. Resistance arterioles were isolated in which FID, acetylcholine-induced dilation (AChID), and nitric oxide (NO) production were measured in the absence or presence of the NO synthase inhibitor, L-NAME, Hcy, or the superoxide dismutase mimetic, TEMPOL. Our results demonstrated that plasma Hcy concentrations were significantly higher, while folate, vitamin B12, and NO were significantly lower in obese subjects compared to controls. Hcy concentrations correlated positively with BMI, fat %, and insulin levels but not with folate or vitamin B12. Brachial and arteriolar vasodilation were lower in obese subjects, positively correlated with folate and vitamin B12, and inversely correlated with Hcy. Arteriolar NO measurements and sensitivity to L-NAME were lower in obese subjects compared to controls. Finally, Hcy incubation reduced arteriolar FID and NO sensitivity, an effect that was abolished by TEMPOL. In conclusion, these data suggest that high concentrations of plasma Hcy and low concentrations of folate and vitamin B12 could be independent predictors of vascular dysfunction in morbidly obese individuals.
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The Multispecies Probiotic Effectively Reduces Homocysteine Concentration in Obese Women: A Randomized Double-Blind Placebo-Controlled Study. J Clin Med 2020; 9:jcm9040998. [PMID: 32252416 PMCID: PMC7230928 DOI: 10.3390/jcm9040998] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/20/2020] [Accepted: 03/30/2020] [Indexed: 12/15/2022] Open
Abstract
Dysregulated metabolism of homocysteine (Hcy) is associated with obesity. Supplementation with probiotics can potentially be a natural therapeutic method for metabolic disorders. The precise mechanism in which microbiota affect Hcy metabolism in obese individuals is still unknown. The aim of this study was to evaluate the effects of a 12-week supplementation with a multispecies probiotic on Hcy levels, oxidative stress, inflammation and lipid profile in obese patients. This randomized double-blind placebo-controlled trial was performed on 50 obese women (aged 45–70 years). Subjects were randomly assigned to take either a multispecies probiotic supplement (n = 25) or placebo (n = 25) for 12 weeks. The probiotic contained nine bacterial strains containing 2.5 × 109 CFU/g. Biochemical and anthropometric measurements were carried out at baseline and after 12 weeks of intervention. At the end of the study, a significant decrease in Hcy, tumor necrosis factor α (TNF-α), total cholesterol (TC), low-density lipoprotein cholesterol (LDL) and triglyceride (TG) levels were observed in the probiotic group. The amelioration of total antioxidant status (TAS) was also observed. The 12-week supplementation of the multispecies probiotic (Ecologic® BARIER) effectively reduced Hcy concentration, oxidative stress and inflammation, and improved the lipid profile. These multidirectional effects can potentially reduce cardiometabolic risks.
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Liu C, Luo D, Wang Q, Ma Y, Ping L, Wu T, Tang J, Peng D, PingZhao. Serum homocysteine and folate concentrations in early pregnancy and subsequent events of adverse pregnancy outcome: the Sichuan Homocysteine study. BMC Pregnancy Childbirth 2020; 20:176. [PMID: 32188414 PMCID: PMC7081627 DOI: 10.1186/s12884-020-02860-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Accepted: 03/06/2020] [Indexed: 02/08/2023] Open
Abstract
Background Hyperhomocysteinemia may be a risk factor for endothelial dysfunction. Folate and vitamin B12 regulate the homocysteine metabolic process. This study aimed to evaluate the associations between subsequent events of adverse pregnancy outcome and early variables of homocysteine, folate, and vitamin B12 in pregnant women. Methods This multicenter, retrospective, case–control study involved 563 pregnant women with adverse pregnancy outcome and 600 controls. Adverse pregnancy outcomes included one or more of the following events: preeclampsia, preterm birth, low birth weight, and stillbirth. The associations between subsequent events of adverse pregnancy outcome and early variables of homocysteine, folate, and vitamin B12; metabolic parameters; inflammatory markers; anthropometrics; and lifestyle habits at 11–12 weeks of gestation were analyzed using the logistic regression model. Results Compared to the lower quartile homocysteine concentrations, the upper quartile homocysteine concentrations were associated with preeclampsia, preterm birth and low birth weight. On the contrary, the lower quartile folate concentrations were associated with preeclampsia, preterm birth and low birth weight compared with the upper quartile folate concentrations. The incidence of adverse pregnancy outcome increased progressively from the first to fourth homocysteine quartiles but decreased progressively from the first to fourth folate quartiles. After adjusting for confounding factors, multivariate logistic regression analysis showed that besides systolic blood pressure, diastolic blood pressure, body mass index and age, homocysteine (IV vs I quartile, aOR 5.89, 95% CI 4.08–8.51, P < 0.001), folate (IV vs I quartile, aOR 0.35, 95% CI 0.25–0.50, P < 0.001), folate supplementation (yes vs no, aOR 0.55, 95% CI 0.35–0.86, P = 0.010) during early pregnancy were independently associated with subsequent events of adverse pregnancy outcome, and vitamin B12 was rejected. Of these, the homocysteine revealed the highest odds ratio in all risk variables, and folate showed the lowest odds ratio in all protective variables. Conclusions Higher homocysteine concentration and lower folate level during early pregnancy were associated with adverse pregnancy outcome. However, no association was found between vitamin B12 and adverse pregnancy outcome. Supplementation with folate in early pregnancy may reduce adverse pregnancy outcome.
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Affiliation(s)
- Chenggui Liu
- Department of Clinical Laboratory, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China. .,, Chengdu, China.
| | - Dan Luo
- Department of Obstetrics, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Qin Wang
- Department of Clinical Laboratory, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Yan Ma
- Department of Pediatrics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Longyu Ping
- Department of Clinical Laboratory, Mianyang Hospital of Traditional Chinese Medicine, Mianyang, 621000, China
| | - Ting Wu
- Department of Nutrition, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Jian Tang
- Department of Clinical Laboratory, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Duanliang Peng
- Department of Clinical Laboratory, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - PingZhao
- Department of Obstetrics and Gynecology, Mianyang Hospital of Traditional Chinese Medicine, Mianyang, 621000, China
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Homocysteine is an independent predictor of long-term cardiac mortality in patients with stable coronary artery disease in the era of statins. Coron Artery Dis 2020; 31:152-156. [DOI: 10.1097/mca.0000000000000800] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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40
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Kikuno M, Ueno Y, Shimizu T, Kuriki A, Tateishi Y, Doijiri R, Shimada Y, Takekawa H, Yamaguchi E, Koga M, Kamiya Y, Ihara M, Tsujino A, Hirata K, Toyoda K, Hasegawa Y, Aizawa H, Hattori N, Urabe T. Underlying embolic and pathologic differentiation by cerebral microbleeds in cryptogenic stroke. J Neurol 2020; 267:1482-1490. [PMID: 32016623 DOI: 10.1007/s00415-020-09732-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/24/2020] [Accepted: 01/25/2020] [Indexed: 11/25/2022]
Abstract
BACKGROUND Cryptogenic stroke encompasses diverse emboligenic mechanisms and pathogeneses. Cerebral microbleeds (CMBs) occur differently among stroke subtypes. The association of CMBs with cryptogenic stroke is essentially unknown. METHODS CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for ESUS/CS) is a multicenter registry with comprehensive data including gradient-echo T2*-weighted magnetic resonance imaging of cryptogenic stroke patients who underwent transesophageal echocardiography. Patients' clinical characteristics were compared according to the presence and location of CMBs. RESULTS A total of 661 patients (68.7 ± 12.7 years; 445 males) were enrolled, and 209 (32%) had CMBs. Age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00-1.04, p = 0.020), male sex (OR 1.85, 95% CI 1.18-2.91, p = 0.007), hypertension (OR 1.71, 95% CI 1.03-2.86, p = 0.039), chronic kidney disease (OR 1.64, 95% CI 1.11-2.43, p = 0.013), deep and subcortical white matter hyperintensity (OR 1.82, 95% CI 1.16-2.85, p = 0.009), and periventricular hyperintensity (OR 2.18, 95% CI 1.37-3.46, p = 0.001) were independently associated with the presence of CMBs. Aortic complicated lesions (OR 1.78, 95% CI 1.12-2.84, p = 0.015) were associated with deep and diffuse CMBs, whereas prior anticoagulant therapy (OR 7.88, 95% CI, 1.83-33.9, p = 0.006) was related to lobar CMBs. CONCLUSIONS CMBs were common, and age, male sex, hypertension, chronic kidney disease, and cerebral white matter diseases were related to CMBs in cryptogenic stroke. Aortic complicated lesions were associated with deep and diffuse CMBs, while prior anticoagulant therapy was related to lobar CMBs.
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Affiliation(s)
- Muneaki Kikuno
- Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan
- Department of Neurology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Yuji Ueno
- Department of Neurology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Takahiro Shimizu
- Department of Neurology, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Ayako Kuriki
- Department of Neurology, Showa University Koto Toyosu Hospital, Tokyo, Japan
| | - Yohei Tateishi
- Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki, Japan
| | - Ryosuke Doijiri
- Department of Neurology, Iwate Prefectural Central Hospital, Iwate, Japan
| | - Yoshiaki Shimada
- Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan
| | | | - Eriko Yamaguchi
- Department of Neurology, Iwate Prefectural Central Hospital, Iwate, Japan
| | - Masatoshi Koga
- Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Yuki Kamiya
- Department of Neurology, Showa University Koto Toyosu Hospital, Tokyo, Japan
| | - Masafumi Ihara
- Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Akira Tsujino
- Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki, Japan
| | - Koichi Hirata
- Department of Neurology, Dokkyo Medical University, Tochigi, Japan
| | - Kazunori Toyoda
- Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Yasuhiro Hasegawa
- Department of Neurology, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Hitoshi Aizawa
- Department of Neurology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Nobutaka Hattori
- Department of Neurology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Takao Urabe
- Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan
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Abedimanesh S, Bathaie SZ, Ostadrahimi A, Asghari Jafarabadi M, Taban Sadeghi M. The effect of crocetin supplementation on markers of atherogenic risk in patients with coronary artery disease: a pilot, randomized, double-blind, placebo-controlled clinical trial. Food Funct 2019; 10:7461-7475. [PMID: 31667483 DOI: 10.1039/c9fo01166h] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND AND PURPOSE Molecular mechanisms of atherogenesis are considered to be emerging therapeutic targets for atherosclerosis prevention. Cell and animal studies have shown that crocetin can decelerate atherogenesis. However, the anti-atherogenic properties of crocetin in humans are still ambiguous. METHODS AND RESULTS Fifty clinically diagnosed CAD patients were randomly divided into two parallel groups, crocetin and placebo, who received one capsule of crocetin (10 mg) and placebo per day, respectively, for two months. Serum circulating homocysteine (Hcy) [-1.09 (-1.64 to -0.54) μM, P = 0.001], heart-type fatty acid binding protein (h-FABP) [-2.07 (-2.72 to -1.43) ng mL-1, P = 0.001], intercellular adhesion molecule 1 [-14.92 (-21.92 to -7.92) ng mL-1, P = 0.001], vascular cell adhesion molecule 1 [-18.61 (-29.73 to -7.49) ng mL-1, P = 0.002], and monocyte chemoattractant protein 1 [-4.67 (-6.50 to -2.83) pg mL-1, P = 0.001] decreased significantly after the trial in the crocetin group, while high-density lipoprotein (HDL) significantly increased [+4.21 (0.68 to 7.73) mg mL-1, P = 0.021]. Also, systolic [-0.21 (-0.32 to -0.10) mmHg, P = 0.001] and diastolic [-0.20 (-0.34 to -0.07) mmHg, P = 0.004] blood pressures decreased significantly in the crocetin group. Nevertheless, clinically significant percentage changes were only observed in Hcy (-15.25 ± 3.15, μM), HDL (-10.70 ± 5.06, mg dL-1), and h-FABP (-21.10 ± 3.09, ng mL-1) in the crocetin group. Furthermore, the relative increase in the gene expressions of sirtuin1 and AMP-activated protein kinase and a decrease in the lectin-type oxidized LDL receptor 1 and nuclear factor-kappa B expression in isolated peripheral blood mononuclear cells in the crocetin group were significant at the end of the trial in comparison with the placebo. CONCLUSION As the first human study, we showed the ability of crocetin to alter the expression of atherogenic genes and endothelial cell adhesion molecules in CAD patients. It appears that crocetin could be considered as a promising anti-atherogenic candidate for future studies.
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Affiliation(s)
- Saeed Abedimanesh
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - S Zahra Bathaie
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Alireza Ostadrahimi
- Nutritional Research Center, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Asghari Jafarabadi
- Department of Statistics and Epidemiology, Faculty of Health, Tabriz University of Medical Sciences, Tabriz, Iran
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Reddy VS, Trinath J, Reddy GB. Implication of homocysteine in protein quality control processes. Biochimie 2019; 165:19-31. [PMID: 31269461 DOI: 10.1016/j.biochi.2019.06.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 06/26/2019] [Indexed: 12/22/2022]
Abstract
Homocysteine (Hcy) is a key metabolite generated during methionine metabolism. The elevated levels of Hcy in the blood are reffered to as hyperhomocystenimeia (HHcy). The HHcy is caused by impaired metabolism/deficiency of either folate or B12 or defects in Hcy metabolism. Accumulating evidence suggests that HHcy is associated with cardiovascular and brain diseases including atherosclerosis, endothelial injury, and stroke etc. Vitamin B12 (cobalamin; B12) is a water-soluble vitamin essential for two metabolic reactions. It acts as a co-factor for methionine synthase and L-methylmalonyl-CoA mutase. Besides, it is also vital for DNA synthesis and maturation of RBC. Deficiency of B12 is associated with haematological and neurological disorders. Hyperhomocysteinemia (HHcy)-induced toxicity is thought to be mediated by the accumulation of Hcy and its metabolites, homocysteinylated proteins. Cellular protein quality control (PQC) is essential for the maintenance of proteome integrity, and cell viability and its failure contributes to the development of multiple diseases. Chaperones, unfolded protein response (UPR), ubiquitin-proteasome system (UPS), and autophagy are analogous strategies of PQC that maintain cellular proteome integrity. Recently, multiple studies reported that HHcy responsible for perturbation of PQC by reducing chaperone levels, activating UPR, and impairing autophagy. Besides, HHcy also induce cytotoxicity, inflammation, protein aggregation and apoptosis. It has been shown that some of the factors including altered SIRT1-HSF1 axis and irreversible homocysteinylation of proteins are responsible for folate and/or B12 deficiency or HHcy-induced impairment of PQC. Therefore, this review highlights the current understanding of HHcy in the context of cellular PQC and their pathophysiological and clinical consequences, epigenomic changes, therapeutic implications of B12, and chemical chaperones based on cell culture and experimental animal models.
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Affiliation(s)
- V Sudhakar Reddy
- Biochemistry Division, National Institute of Nutrition, Hyderabad, India.
| | - Jamma Trinath
- Department of Biological Sciences, BITS-Pilani, 500078, Hyderabad Campus, Hyderabad, Telangana, India
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Elshahid ARM, Shahein IM, Mohammed YF, Ismail NF, Zakarria HBAER, GamalEl Din SF. Folic acid supplementation improves erectile function in patients with idiopathic vasculogenic erectile dysfunction by lowering peripheral and penile homocysteine plasma levels: a case-control study. Andrology 2019; 8:148-153. [PMID: 31237081 DOI: 10.1111/andr.12672] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 05/19/2019] [Accepted: 05/29/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Erectile dysfunction (ED) has common risk factors with many cardiovascular (CV) impairments. In view of these facts, hyperhomocysteinemia (HHcys) has been postulated for involvement in endothelial dysfunction. OBJECTIVES We evaluated peripheral and penile homocysteine (Hcys) plasma levels before and after folic acid supplementation in idiopathic vasculogenic erectile dysfunction (ED) patients. MATERIALS AND METHODS This study included 50 consecutive patients and 50 consecutive healthy controls that were recruited from December 2017 to December 2018. The patients received folic acid (FA) daily for 3 months and were evaluated by the abridged 5-item International Index of Erectile Function (IIEF-5) and penile duplex before and after therapy, in addition to plasma Hcys levels. RESULTS Our study showed improvement in the severity of ED in our patients as all of them became mild to moderate ED after folic acid administration. Additionally, the median scores of IIEF-5 significantly increased from 6 to 14, respectively (p < 0.001). Furthermore, the median peripheral and penile Hcys plasma levels (μmol/l) significantly decreased after folic acid administration as 39 patients with moderate ED and 11 patients with severe ED were 0.62, 0.34, 5.37, 0.37, respectively, became mild to moderate ED with their median peripheral and penile Hcys plasma levels became 0.19, 0.15, p < 0.001, <0.001, respectively. Peripheral Hcys level correlates significantly with penile Hcys before and after folic acid administration (r: -0.06 p: 0.8, r: 0.9, p < 0.001, respectively). DISCUSSION AND CONCLUSION Recently, an emerging body of evidence suggests a role for Hcys and folate in erectile function. Interestingly, our interventional study is one of the first that evaluated the effect of folic acid supplementation on HHcys where it demonstrated a significant decrease in peripheral and penile Hcys plasma levels after folic acid administration. Thus, FA should be prescribed concomitantly with phosphodiesterase type 5 inhibitors in ED patients.
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Affiliation(s)
- A R M Elshahid
- Department of Dermatology and Venereolgy and Andrology, Al-Azhar University, Cairo, Egypt
| | - I M Shahein
- Department of Dermatology and Venereolgy and Andrology, Al-Azhar University, Cairo, Egypt
| | - Y F Mohammed
- Department of Dermatology and Venereolgy and Andrology, Al-Azhar University, Cairo, Egypt
| | - N F Ismail
- Clinical Pathology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | | | - S F GamalEl Din
- Andrology & STDs Department, Kasr Al-Ainy Faculty of Medicine, Giza, Egypt
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Homocysteine: A Potential Biomarker for Diabetic Retinopathy. J Clin Med 2019; 8:jcm8010121. [PMID: 30669482 PMCID: PMC6352029 DOI: 10.3390/jcm8010121] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 01/11/2019] [Accepted: 01/15/2019] [Indexed: 12/14/2022] Open
Abstract
Diabetic retinopathy (DR) is the most common cause of blindness in people under the age of 65. Unfortunately, the current screening process for DR restricts the population that can be evaluated and the disease goes undetected until irreversible damage occurs. Herein, we aimed to evaluate homocysteine (Hcy) as a biomarker for DR screening. Hcy levels were measured by enzyme-linked immuno sorbent assay (ELISA) and immunolocalization methods in the serum, vitreous and retina of diabetic patients as well as in serum and retina of different animal models of DM representing type 1 diabetes (streptozotocin (STZ) mice, Akita mice and STZ rats) and db/db mice which exhibit features of human type 2 diabetes. Our results revealed increased Hcy levels in the serum, vitreous and retina of diabetic patients and experimental animal models of diabetes. Moreover, optical coherence tomography (OCT) and fluorescein angiography (FA) were used to evaluate the retinal changes in mice eyes after Hcy-intravitreal injection into normal wild-type (WT) and diabetic (STZ) mice. Hcy induced changes in mice retina which were aggravated under diabetic conditions. In conclusion, our data reported Hcy as a strong candidate for use as a biomarker in DR screening. Targeting the clearance of Hcy could also be a future therapeutic target for DR.
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Ostrakhovitch EA, Tabibzadeh S. Homocysteine and age-associated disorders. Ageing Res Rev 2019; 49:144-164. [PMID: 30391754 DOI: 10.1016/j.arr.2018.10.010] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 09/30/2018] [Accepted: 10/25/2018] [Indexed: 12/26/2022]
Abstract
There are numerous theories of aging, a process which still seems inevitable. Aging leads to cancer and multi-systemic disorders as well as chronic diseases. Decline in age- associated cellular functions leads to neurodegeneration and cognitive decline that affect the quality of life. Accumulation of damage, mutations, metabolic changes, failure in cellular energy production and clearance of altered proteins over the lifetime, and hyperhomocysteinemia, ultimately result in tissue degeneration. The decline in renal functions, nutritional deficiencies, deregulation of methionine cycle and deficiencies of homocysteine remethylation and transsulfuration cofactors cause elevation of homocysteine with advancing age. Abnormal accumulation of homocysteine is a risk factor of cardiovascular, neurodegenerative and chronic kidney disease. Moreover, approximately 50% of people, aged 65 years and older develop hypertension and are at a high risk of developing cardiovascular insufficiency and incurable neurodegenerative disorders. Increasing evidence suggests inverse relation between cognitive impairment, cerebrovascular and cardiovascular events and renal function. Oxidative stress, inactivation of nitric oxide synthase pathway and mitochondria dysfunction associated with impaired homocysteine metabolism lead to aging tissue degeneration. In this review, we examine impact of high homocysteine levels on changes observed with aging that contribute to development and progression of age associated diseases.
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Affiliation(s)
- E A Ostrakhovitch
- Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine, CA, USA.
| | - S Tabibzadeh
- Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine, CA, USA.
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Zulfania, Khan A, Rehman S, Ghaffar T. Association of homocysteine with body mass index, blood pressure, HbA1c and duration of diabetes in type 2 diabetics. Pak J Med Sci 2018; 34:1483-1487. [PMID: 30559808 PMCID: PMC6290216 DOI: 10.12669/pjms.346.16032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Objective To determine the Homocysteine levels in type 2 diabetics and correlate homocysteine with HbA1c levels, BMI, blood pressure and duration of diabetes. Methods This cross-sectional study was conducted in Endocrinology Unit of Hayatabad Medical Complex (HMC) Peshawar and Rehman Medical Institute (RMI) Peshawar over a period of six months from July 2015 to December 2015. Data was recorded and analyzed in SPSS v 20. P value of less than 0.05 was taken as significant. Bivariate Pearson's correlation test was used to see the relationship between homocysteine and BMI, systolic BP and duration of diabetes. Results One hundred twenty five patients were included in our study in which female were 68% and 32% were male with mean age of 51.45 ±8.37 years. Mean BMI expressed in kg/m2 was 28.71±4.76, mean systolic blood pressure was 130±20.98 mmHg, mean diastolic blood pressure was 83.36±11.28 mmHg and mean duration of diabetes was 7.018± 6.18 years. Significant correlation was found between systolic blood pressure (r: 0.239, p: 0.007) and duration of diabetes with homocysteine (r: 0.302, p: 0.001). The correlation of homocysteine with HbA1c and BMI was not significant. Conclusion Systolic blood pressure and duration of diabetes showed a significant positive correlation with homocysteine. The correlation of homocysteine with HbA1c was not certain from researcher's point of view and further studies of larger sample size and longer duration must be conducted to ascertain the association between the two variables.
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Affiliation(s)
- Zulfania
- Dr. Zulfania, M.Phil. Department of Physiology, Rehman Medical College, Peshawar, Pakistan
| | - Adnan Khan
- Dr. Adnan Khan, MBBS. Postgraduate Resident (PGR 1) Paediatrics, Rehman Medical Institute, Peshawar, Pakistan
| | - Sohaib Rehman
- Dr. Sohaib Rehman, MPhil. Department of Biochemistry, Rehman Medical College, Peshawar, Pakistan
| | - Tahir Ghaffar
- Tahir Ghaffar, FCPS. Department of Endocrinology, Lady Reading Hospital, Peshawar, Pakistan
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Attia AAA, Amer MAEM, Hassan M, Din SFG. Low serum folic acid can be a potential independent risk factor for erectile dysfunction: a prospective case-control study. Int Urol Nephrol 2018; 51:223-229. [PMID: 30547361 DOI: 10.1007/s11255-018-2055-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 12/08/2018] [Indexed: 01/06/2023]
Abstract
PURPOSE The purpose of the study was to compare serum level of folic acid (FA) in patients with erectile dysfunction (ED) versus healthy controls and to assess its correlation with other well-known confounders for ED. METHODS Our prospective study compared FA in 60 patients with ED versus 30 healthy controls. Patients were excluded if they had any hormonal disorders, Peyronie's disease, or decompensated systemic illnesses. ED was evaluated by the validated Arabic version of the abbreviated five-item form of the International Index Of Erectile Function and confirmed by penile duplex. Serum FA level was assayed using ELIZA. Mann-Whitney, Kruskal-Wallis, and Chi-square tests and Spearman correlation were used as appropriate and confirmed by logistic regression model. RESULTS Our study revealed that the median FA of the cases and the controls were 7.1 ng/mL and 13.4 ng/mL, respectively, and this difference was of high statistical significance (p < 0.001). Moreover, our study demonstrated significant relations between serum FA with DM, HTN, smoking, age, and cholesterol (p 0.01, 0.03, 0.014, 0.001, and 0.015, respectively). Our study showed that the best cut-off point of serum FA to detect patients with ED was found to be ≤ 9.42 with sensitivity of 80.00%, specificity of 93.33% and area under curve (AUC) of 91.3%. CONCLUSION Serum FA level decreased as the severity of ED increased even after adjustment of age, serum testosterone, DM, HTN, and smoking. FA deficiency might be an independent risk factor of ED.
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Affiliation(s)
- Attia Abd Allah Attia
- Dermatology & Andrology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | | | - Mamdouh Hassan
- Dermatology & Andrology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Sameh Fayek GamalEl Din
- Andrology & STDs Department, Kasr Al-Ainy Faculty of Medicine, Cairo University, Giza, Egypt.
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Abdelhamid AA, Sherief MH, Nemr NA, Hassoba HM, El-Sakka AI. Homocysteine, insulin-like growth factor one and oestrogen levels in patients with erectile dysfunction-associated chronic hepatitis C virus infection. Andrologia 2018; 50:e13116. [PMID: 30063074 DOI: 10.1111/and.13116] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 06/05/2018] [Accepted: 06/19/2018] [Indexed: 12/13/2022] Open
Abstract
We assessed the change of homocysteine (Hcy), insulin-like growth factor one (IGF-Ι) and oestrogen (E2) levels in patients with erectile dysfunction (ED) associated with chronic hepatitis C virus (HCV) infection. Eighty-five male patients with chronic HCV and/or ED were enrolled in this study. Seventy-five men were assigned to three equal groups (n = 25/each); Group A: patients who had chronic HCV and ED. Group B: patients who had chronic HCV and had no ED complaint. Group C: patients who had ED with no chronic HCV. In addition to 10 control patients with no ED or chronic HCV (Group D). All patients were subjected to: detailed medical and sexual history, complete physical examination, laboratory assessment including measurement of serum Hcy, IGF-1 and E2. The means of international index of erectile function scores were 8 and 16 in groups A and C respectively. There were significant differences in Hcy, IGF-I and E2 among study groups (p < 0.05 for each). There were significant differences in Hcy between patients with Child B and Child C. A strong association between severity of ED and chronic HCV was demonstrated. There was statistically significant increase of Hcy and E2 levels and reduction in IGF-I level in patients with ED associated with chronic HCV infection.
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Affiliation(s)
| | | | - Nader A Nemr
- Department of Internal Medicine, Suez Canal University, Ismailia, Egypt
| | - Howayda M Hassoba
- Department of Clinical Pathology, Suez Canal University, Ismailia, Egypt
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Wang WM, Jin HZ. Homocysteine: A Potential Common Route for Cardiovascular Risk and DNA Methylation in Psoriasis. Chin Med J (Engl) 2018; 130:1980-1986. [PMID: 28776552 PMCID: PMC5555134 DOI: 10.4103/0366-6999.211895] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective: Homocysteine is a sulfur-containing amino acid with potential clinical significance. Abnormal homocysteine levels have been found in patients with psoriasis. This review summarizes the possible correlations among homocysteine, cardiovascular risk, and DNA methylation in psoriasis. Data Sources: We retrieved the articles published in English from the PubMed database up to January 2017, using the keywords including “psoriasis,” “homocysteine,” “cardiovascular risk,” “DNA methylation,” “methylenetetrahydrofolate reductase,” “MTHFR,” and “MTHFR C677T.” Study Selection: Articles about the roles of homocysteine in the cardiovascular risk and DNA methylation in psoriasis were obtained and reviewed. Results: Observational studies consistently reported that elevated homocysteine is an independent risk factor for cardiovascular diseases. Several studies also consistently reported an association between psoriasis and increased cardiovascular risk. A substantial body of evidence also suggested that an elevated homocysteine level is related to the demethylation of DNA. Data from clinical trials also demonstrated that MTHFR C677T polymorphisms as well as DNA methylation aberrations are associated with psoriasis. Conclusions: This review highlighted the relationships among homocysteine, cardiovascular risk, and DNA methylation, suggesting that homocysteine may be a biological link between cardiovascular risk and DNA methylation in psoriasis.
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Affiliation(s)
- Wen-Ming Wang
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Hong-Zhong Jin
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Cheng Z, Shen X, Jiang X, Shan H, Cimini M, Fang P, Ji Y, Park JY, Drosatos K, Yang X, Kevil CG, Kishore R, Wang H. Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide. Redox Biol 2018. [PMID: 29524844 PMCID: PMC5854893 DOI: 10.1016/j.redox.2018.02.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Insufficient hydrogen sulfide (H2S) has been implicated in Type 2 diabetic mellitus (T2DM) and hyperhomocysteinemia (HHcy)-related cardiovascular complications. We investigated the role of H2S in T2DM and HHcy-induced endothelial dysfunction in small mesenteric artery (SMA) of db/db mice fed a high methionine (HM) diet. HM diet (8 weeks) induced HHcy in both T2DM db/db mice and non-diabetic db/+ mice (total plasma Hcy: 48.4 and 31.3 µM, respectively), and aggravated the impaired endothelium-derived hyperpolarization factor (EDHF)-induced endothelium-dependent relaxation to acetylcholine (ACh), determined by the presence of eNOS inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) and prostacyclin (PGI2) inhibitor indomethacin (INDO), in SMA from db/db mice but not that from db/+ mice. A non-selective Ca2+-active potassium channel (KCa) opener NS309 rescued T2DM/HHcy-impaired EDHF-mediated vascular relaxation to ACh. EDHF-induced relaxation to ACh was inhibited by a non-selective KCa blocker TEA and intermediate-conductance KCa blocker (IKCa) Tram-34, but not by small-conductance KCa (SKCa) blocker Apamin. HHcy potentiated the reduction of free sulfide, H2S and cystathionine γ-lyase protein, which converts L-cysteine to H2S, in SMA of db/db mice. Importantly, a stable H2S donor DATS diminished the enhanced O2- production in SMAs and lung endothelial cells of T2DM/HHcy mice. Antioxidant PEG-SOD and DATS improved T2DM/HHcy impaired relaxation to ACh. Moreover, HHcy increased hyperglycemia-induced IKCa tyrosine nitration in human micro-vascular endothelial cells. EDHF-induced vascular relaxation to L-cysteine was not altered, whereas such relaxation to NaHS was potentiated by HHcy in SMA of db/db mice which was abolished by ATP-sensitive potassium channel blocker Glycolamide but not by KCa blockers. Conclusions Intermediate HHcy potentiated H2S reduction via CSE-downregulation in microvasculature of T2DM mice. H2S is justified as an EDHF. Insufficient H2S impaired EDHF-induced vascular relaxation via oxidative stress and IKCa inactivation in T2DM/HHcy mice. H2S therapy may be beneficial for prevention and treatment of micro-vascular complications in patients with T2DM and HHcy.
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Affiliation(s)
- Zhongjian Cheng
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA.
| | - Xinggui Shen
- Center for Cardiovascular Diseases and Sciences, Department of Pathology, Molecular and Cellular Physiology and Cell Biology and Anatomy Louisiana State University Health Sciences Center-Shreveport, New Orleans, LA 7110371103, USA
| | - Xiaohua Jiang
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA
| | - Huimin Shan
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA
| | - Maria Cimini
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA
| | - Pu Fang
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA
| | - Yong Ji
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing 210029, China
| | - Joon Young Park
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA
| | - Konstantinos Drosatos
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA; Department of Pharmacology, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA
| | - Xiaofeng Yang
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA; Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA; Department of Pharmacology, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA
| | - Christopher G Kevil
- Center for Cardiovascular Diseases and Sciences, Department of Pathology, Molecular and Cellular Physiology and Cell Biology and Anatomy Louisiana State University Health Sciences Center-Shreveport, New Orleans, LA 7110371103, USA
| | - Raj Kishore
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA; Department of Pharmacology, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA
| | - Hong Wang
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA; Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA; Department of Pharmacology, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA 19140, USA.
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