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1.
Mol Cell Biochem ; 476(2): 663-673, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33074445

RESUMEN

Epigenetic memory plays crucial roles in gene regulation. It not only modulates the expression of specific genes but also has ripple effects on transcription as well as translation of other genes. Very often an alteration in expression occurs either via methylation or demethylation. In this context, "1-carbon metabolism" assumes a special significance since its dysregulation by higher levels of homocysteine; Hcy (known as hyperhomocysteinemia; HHcy), a byproduct of "1-Carbon Metabolism" during methionine biosynthesis leads to serious implications in cardiovascular, renal, cerebrovascular systems, and a host of other conditions. Currently, the circular RNAs (circRNAs) generated via non-canonical back-splicing events from the pre-mRNA molecules are at the center stage for their essential roles in diseases via their epigenetic manifestations. We recently identified a circular RNA transcript (circGRM4) that is significantly upregulated in the eye of cystathionine ß-synthase-deficient mice. We also discovered a concurrent over-expression of the mGLUR4 receptor in the eyes of these mice. In brief, circGRM4 is selectively transcribed from its parental mGLUR4 receptor gene (GRM4) functions as a "molecular-sponge" for the miRNAs and results into excessive turnover of the mGLUR4 receptor in the eye in response to extremely high circulating glutamate concentration. We opine that this epigenetic manifestation potentially predisposes HHcy people to retinovascular malfunctioning.


Asunto(s)
Cistationina betasintasa/genética , Ojo/irrigación sanguínea , Ojo/metabolismo , Ácido Glutámico/metabolismo , MicroARNs/metabolismo , ARN Circular/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Cistationina betasintasa/metabolismo , Células Endoteliales/metabolismo , Epigénesis Genética , Oftalmopatías/inducido químicamente , Oftalmopatías/genética , Oftalmopatías/metabolismo , Oftalmopatías/patología , Homocisteína/metabolismo , Humanos , Hiperhomocisteinemia/genética , MicroARNs/genética , ARN Circular/genética , Receptores de Glutamato Metabotrópico/genética , Enfermedades Vasculares/inducido químicamente , Enfermedades Vasculares/genética , Enfermedades Vasculares/metabolismo , Enfermedades Vasculares/patología
2.
Can J Physiol Pharmacol ; 99(1): 56-63, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32799662

RESUMEN

Epigenetic DNA methylation (1-carbon metabolism) is crucial for gene imprinting/off-printing that ensures epigenetic memory but also generates a copious amount of homocysteine (Hcy), unequivocally. That is why during pregnancy, expectant mothers are recommended "folic acid" preemptively to avoid birth defects in the young ones because of elevated Hcy levels (i.e., hyperhomocysteinemia (HHcy)). As we know, children born with HHcy have several musculoskeletal abnormalities, including growth retardation. Here, we focus on the gut-dysbiotic microbiome implication(s) that we believe instigates the "1-carbon metabolism" and HHcy causing growth retardation along with skeletal muscle abnormalities. We test our hypothesis whether high-methionine diet (HMD) (an amino acid that is high in red meat), a substrate for Hcy, can cause skeletal muscle and growth retardation, and treatment with probiotics (PB) to mitigate skeletal muscle dysfunction. To test this, we employed cystathionine ß-synthase, CBS deficient mouse (CBS+/-) fed with/without HMD and with/without a probiotic (Lactobacillus rhamnosus) in drinking water for 16 weeks. Matrix metalloproteinase (MMP) activity, a hallmark of remodeling, was measured by zymography. Muscle functions were scored via electric stimulation. Our results suggest that compared to the wild-type, CBS+/- mice exhibited reduced growth phenotype. MMP-2 activity was robust in CBS+/- and HMD effects were successfully attenuated by PB intervention. Electrical stimulation magnitude was decreased in CBS+/- and CBS+/- treated with HMD. Interestingly; PB mitigated skeletal muscle growth retardation and atrophy. Collectively, results imply that individuals with mild/moderate HHcy seem more prone to skeletal muscle injury and its dysfunction.


Asunto(s)
Disbiosis/complicaciones , Trastornos del Crecimiento/prevención & control , Hiperhomocisteinemia/complicaciones , Músculo Esquelético/patología , Probióticos/administración & dosificación , Animales , Cistationina betasintasa/deficiencia , Cistationina betasintasa/genética , Metilación de ADN , Modelos Animales de Enfermedad , Disbiosis/metabolismo , Disbiosis/microbiología , Disbiosis/terapia , Epigénesis Genética , Femenino , Microbioma Gastrointestinal/fisiología , Trastornos del Crecimiento/sangre , Trastornos del Crecimiento/metabolismo , Trastornos del Crecimiento/patología , Homocisteína/sangre , Homocisteína/metabolismo , Humanos , Hiperhomocisteinemia/sangre , Hiperhomocisteinemia/genética , Hiperhomocisteinemia/metabolismo , Lacticaseibacillus rhamnosus , Masculino , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metionina/administración & dosificación , Metionina/metabolismo , Ratones , Ratones Transgénicos , Músculo Esquelético/metabolismo
3.
Can J Physiol Pharmacol ; 98(2): 51-60, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31369712

RESUMEN

Homocysteine (Hcy), a sulfur-containing nonproteinogenic amino acid, is generated as a metabolic intermediate. Hcy constitutes an important part of the "1-carbon metabolism" during methionine turnover. Elevated levels of Hcy known as hyperhomocysteinemia (HHcy) results from vitamin B deficiency, lack of exercise, smoking, excessive alcohol intake, high-fat and methionine-rich diet, and the underlying genetic defects. These factors directly affect the "1-carbon metabolism (methionine-Hcy-folate)" of a given cell. In fact, the Hcy levels are determined primarily by dietary intake, vitamin status, and the genetic blueprint of the susceptible individual. Although Hcy performs an important role in cellular functions, genetic alterations in any of the key enzymes responsible for the "1-carbon metabolism" could potentially upset the metabolic cycle, thus causing HHcy environment in susceptible people. As such, HHcy relates to several clinical conditions like atherosclerosis, myocardial infarction, stroke, cognitive impairment, dementia, Parkinson's disease, multiple sclerosis, epilepsy, and ocular disorders, among others. This article summarizes the findings from our laboratory and public database regarding genetics of HHcy and its effects on ocular disorders, their respective management during dysregulation of the 1-carbon metabolism.


Asunto(s)
Carbono/metabolismo , Hiperhomocisteinemia/genética , Hiperhomocisteinemia/metabolismo , Retina/patología , Retina/fisiopatología , Animales , Humanos , Hiperhomocisteinemia/patología , Hiperhomocisteinemia/fisiopatología
4.
Front Physiol ; 11: 617953, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33708132

RESUMEN

Although a high-fat diet (HFD) induces gut dysbiosis and cardiovascular system remodeling, the precise mechanism is unclear. We hypothesize that HFD instigates dysbiosis and cardiac muscle remodeling by inducing matrix metalloproteinases (MMPs), which leads to an increase in white adipose tissue, and treatment with lactobacillus (a ketone body donor from lactate; the substrate for the mitochondria) reverses dysbiosis-induced cardiac injury, in part, by increasing lipolysis (PGC-1α, and UCP1) and adipose tissue browning and decreasing lipogenesis. To test this hypothesis, we used wild type (WT) mice fed with HFD for 16 weeks with/without a probiotic (PB) in water. Cardiac injury was measured by CKMB activity which was found to be robust in HFD-fed mice. Interestingly, CKMB activity was normalized post PB treatment. Levels of free fatty acids (FFAs) and methylation were increased but butyrate was decreased in HFD mice, suggesting an epigenetically governed 1-carbon metabolism along with dysbiosis. Levels of PGC-1α and UCP1 were measured by Western blot analysis, and MMP activity was scored via zymography. Collagen histology was also performed. Contraction of the isolated myocytes was measured employing the ion-optic system, and functions of the heart were estimated by echocardiography. Our results suggest that mice on HFD gained weight and exhibited an increase in blood pressure. These effects were normalized by PB. Levels of fibrosis and MMP-2 activity were robust in HFD mice, and treatment with PB mitigated the fibrosis. Myocyte calcium-dependent contraction was disrupted by HFD, and treatment with PB could restore its function. We conclude that HFD induces dysbiosis, and treatment with PB creates eubiosis and browning of the adipose tissue.

5.
Rev Cardiovasc Med ; 20(3): 121-128, 2019 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-31601086

RESUMEN

Recent studies have shown that the integrity of the gastrointestinal tract and its microbiome impact the functioning of various body systems by regulating immunological responses, extracting energy, remodeling intestinal epithelia, and strengthening the gut itself. The gastrointestinal tract microbiota includes bacteria, fungi, protozoa, viruses, and archaea which collectively comprise a dynamic community prone to alterations via influences such as the environment, illness, and metabolic processes. The idea that the host's diet possesses characteristics that could potentially alter microbiota composition is a novel notion. We hypothesize that a high fat diet leads to the alteration of the gastrointestinal microbiota composition and that metabolic transformation of the compound trimethylamine into trimethylamine-N-oxide promotes vasculopathy such as atherosclerosis and affects cardiovascular functionality. Furthermore, we hypothesize that treatment with probiotics will restore the homeostatic environment (eubiosis) of the gastrointestinal tract.


Asunto(s)
Aterosclerosis/metabolismo , Bacterias/metabolismo , Dieta Alta en Grasa/efectos adversos , Endotelio Vascular/metabolismo , Microbioma Gastrointestinal , Metilaminas/metabolismo , Animales , Aterosclerosis/microbiología , Aterosclerosis/fisiopatología , Aterosclerosis/terapia , Bacterias/crecimiento & desarrollo , Disbiosis , Endotelio Vascular/fisiopatología , Interacciones Huésped-Patógeno , Humanos , Lípidos/sangre , Placa Aterosclerótica , Probióticos/uso terapéutico , Factores de Riesgo
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