scholarly journals Cystathionine-β-synthase: Molecular Regulation and Pharmacological Inhibition

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 697 ◽  
Author(s):  
Karim Zuhra ◽  
Fiona Augsburger ◽  
Tomas Majtan ◽  
Csaba Szabo
Keyword(s):  
Molecular Regulation ◽  
Aminooxyacetic Acid ◽  
Comprehensive Overview ◽  
Physiological Conditions ◽  
Beneficial Effects ◽  
Transsulfuration Pathway ◽  
Health And Disease ◽  
Cytotoxic Molecule ◽  
Mammalian Enzyme ◽  
Rate Limiting

Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H2S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used “CBS inhibitors” (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models.

scholarly journals Maturation of the Na,K-ATPase in the Endoplasmic Reticulum in Health and Disease

2021 ◽  
Author(s):  
Vitalii Kryvenko ◽  
Olga Vagin ◽  
Laura A. Dada ◽  
Jacob I. Sznajder ◽  
István Vadász
Keyword(s):  
Endoplasmic Reticulum ◽  
Intracellular Signaling ◽  
Loss Of Function ◽  
Α Subunit ◽  
Rate Limiting Step ◽  
Atpase Subunits ◽  
A Cell ◽  
Health And Disease ◽  
And Function ◽  
Rate Limiting

Abstract The Na,K-ATPase establishes the electrochemical gradient of cells by driving an active exchange of Na+ and K+ ions while consuming ATP. The minimal functional transporter consists of a catalytic α-subunit and a β-subunit with chaperon activity. The Na,K-ATPase also functions as a cell adhesion molecule and participates in various intracellular signaling pathways. The maturation and trafficking of the Na,K-ATPase include co- and post-translational processing of the enzyme in the endoplasmic reticulum (ER) and the Golgi apparatus and subsequent delivery to the plasma membrane (PM). The ER folding of the enzyme is considered as the rate-limiting step in the membrane delivery of the protein. It has been demonstrated that only assembled Na,K-ATPase α:β-complexes may exit the organelle, whereas unassembled, misfolded or unfolded subunits are retained in the ER and are subsequently degraded. Loss of function of the Na,K-ATPase has been associated with lung, heart, kidney and neurological disorders. Recently, it has been shown that ER dysfunction, in particular, alterations in the homeostasis of the organelle, as well as impaired ER-resident chaperone activity may impede folding of Na,K-ATPase subunits, thus decreasing the abundance and function of the enzyme at the PM. Here, we summarize our current understanding on maturation and subsequent processing of the Na,K-ATPase in the ER under physiological and pathophysiological conditions. Graphic Abstract

scholarly journals Impact of Dietary Flavanols on Microbiota, Immunity and Inflammation in Metabolic Diseases

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 850
Author(s):  
María Ángeles Martín ◽  
Sonia Ramos
Keyword(s):  
Immune System ◽  
Fruits And Vegetables ◽  
Metabolic Diseases ◽  
Nuclear Factor Κb ◽  
Low Grade ◽  
Beneficial Effects ◽  
Health And Disease ◽  
Immunological Reactions ◽  
And Function ◽  
Positive Properties

Flavanols are natural occurring polyphenols abundant in fruits and vegetables to which have been attributed to beneficial effects on health, and also against metabolic diseases, such as diabetes, obesity and metabolic syndrome. These positive properties have been associated to the modulation of different molecular pathways, and importantly, to the regulation of immunological reactions (pro-inflammatory cytokines, chemokines, adhesion molecules, nuclear factor-κB [NF-κB], inducible enzymes), and the activity of cells of the immune system. In addition, flavanols can modulate the composition and function of gut microbiome in a prebiotic-like manner, resulting in the positive regulation of metabolic pathways and immune responses, and reduction of low-grade chronic inflammation. Moreover, the biotransformation of flavanols by gut bacteria increases their bioavailability generating a number of metabolites with potential to affect human metabolism, including during metabolic diseases. However, the exact mechanisms by which flavanols act on the microbiota and immune system to influence health and disease remain unclear, especially in humans where these connections have been scarcely explored. This review seeks to summarize recent advances on the complex interaction of flavanols with gut microbiota, immunity and inflammation focus on metabolic diseases.

scholarly journals Aromatase: Contributions to Physiology and Disease in Women and Men

Physiology ◽  
2016 ◽  
Vol 31 (4) ◽  
pp. 258-269 ◽  
Author(s):  
Jennifer Blakemore ◽  
Fredrick Naftolin
Keyword(s):  
Human Physiology ◽  
Estrogen Receptor ◽  
Aromatase Inhibitors ◽  
Reproductive System ◽  
Short Review ◽  
Estrogen Response Element ◽  
Comprehensive Overview ◽  
Response Element ◽  
Estrogen Response ◽  
Health And Disease

Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known for its roles in reproduction and reproductive system diseases, and as a target for inhibitor therapy in estrogen-sensitive diseases including cancer, endometriosis, and leiomyoma (141, 143). However, all tissues contain estrogen receptor-expressing cells, the majority of genes have a complete or partial estrogen response element that regulates their expression (61), and there are plentiful nonreceptor effects of estrogens (79); therefore, the effect of aromatase through the provision of estrogen is almost universal in terms of health and disease. This review will provide a brief but comprehensive overview of the enzyme, its role in steroidogenesis, the problems that arise with its functional mutations and mishaps, the roles in human physiology of aromatase and its product estrogens, its current clinical roles, and the effects of aromatase inhibitors. While much of the story is that of the consequences of the formation of its product estrogens, we also will address alternative enzymatic roles of aromatase as a demethylase or nonenzymatic actions of this versatile molecule. Although this short review is meant to be thorough, it is by no means exhaustive; rather, it is meant to reflect the cutting-edge, exciting properties and possibilities of this ancient enzyme and its products.

scholarly journals MicroRNA-214 in Health and Disease

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3274
Author(s):  
Meer M. J. Amin ◽  
Christopher J. Trevelyan ◽  
Neil A. Turner
Keyword(s):  
Transcriptional Repression ◽  
Lung Cancers ◽  
Rna Molecules ◽  
Beneficial Effects ◽  
Non Coding Rna ◽  
Extensive Range ◽  
Health And Disease ◽  
Artery Disease ◽  
Future Direction ◽  
Improve Health

MicroRNAs (miRNAs) are endogenously expressed, non-coding RNA molecules that mediate the post-transcriptional repression and degradation of mRNAs by targeting their 3′ untranslated region (3′-UTR). Thousands of miRNAs have been identified since their first discovery in 1993, and miR-214 was first reported to promote apoptosis in HeLa cells. Presently, miR-214 is implicated in an extensive range of conditions such as cardiovascular diseases, cancers, bone formation and cell differentiation. MiR-214 has shown pleiotropic roles in contributing to the progression of diseases such as gastric and lung cancers but may also confer cardioprotection against excessive fibrosis and oxidative damage. These contrasting functions are achieved through the diverse cast of miR-214 targets. Through silencing or overexpressing miR-214, the detrimental effects can be attenuated, and the beneficial effects promoted in order to improve health outcomes. Therefore, discovering novel miR-214 targets and understanding how miR-214 is dysregulated in human diseases may eventually lead to miRNA-based therapies. MiR-214 has also shown promise as a diagnostic biomarker in identifying breast cancer and coronary artery disease. This review provides an up-to-date discussion of miR-214 literature by describing relevant roles in health and disease, areas of disagreement, and the future direction of the field.

scholarly journals Polyunsaturated Fatty Acids: Impact on Health and Disease Status

2021 ◽  
Vol 2 (2) ◽  
pp. 12
Author(s):  
Samina Akbar ◽  
Muhammad Zeeshan Bhatti ◽  
Rida Fatima Saeed ◽  
Asma Saleem Qazi
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Disease Status ◽  
Epidemiological Studies ◽  
Lipid Lowering ◽  
Therapeutic Effects ◽  
Omega 3 ◽  
Beneficial Effects ◽  
Omega 6 ◽  
Health And Disease

Over the last decades, the polyunsaturated fatty acids (PUFAs) have been largely explored not only for their nutritional value but also for the numerous biological functions and therapeutic effects. The serum and erythrocyte levels of PUFAs depend on the genetic control of metabolism as well as the dietary intake and are considered to reflect the health and disease status of an individual. Two families of PUFAs, omega-3 (n-3) and omega-6 (n-6), have gained much attention because of their involvement in the production of bioactive lipid mediators and therefore, a balanced omega-6/omega-3 ratio is crucial in maintaining the overall health of an individual. Omega-3 PUFAs, notably eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) have been shown to exert beneficial effects, possibly due to their lipid-lowering, anti-inflammatory, anti-hypertensive and cardioprotective effects, whereas omega-6 fatty acids such as arachidonic acid (ARA, 20:4n-6) exhibit the opposite properties. Even though, numerous epidemiological studies and clinical interventions have clearly established the effectiveness of omega-3 PUFAs in various pathological conditions including dyslipidemia, obesity, diabetes, cancer, cardiovascular and neurodegenerative diseases, some controversies do exist about the beneficial effects of omega-3 PUFAs and need to be clarified. Larger clinical trials with extended follow-up periods are required along with a careful dose selection, in order to confirm the clinical significance and efficacy of omega-3 PUFAs as therapeutic agents.

scholarly journals N-Acetyl-Cysteine supplementation lowers high homocysteine plasma levels and increases Glutathione synthesis in the trans-sulfuration pathway

2019 ◽  
Vol 13 (4) ◽  
pp. 234-240
Author(s):  
Federico Cacciapuoti
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disorders ◽  
Active Form ◽  
The Body ◽  
Glutamate Cysteine Ligase ◽  
Pathological Conditions ◽  
Transsulfuration Pathway ◽  
Antioxidant Function ◽  
Acetyl Cysteine ◽  
Rate Limiting

Glutathione (GSH), a compound derived of a combination of three amino acids – cysteine, glycine and glutamine – is the final product of homocysteine (Hcy) metabolism  in the transsulfuration pathway. The major determinants of GSH synthesis are the availability of cysteine and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL). A deficiency in  transsulfuration pathway leads to excessive Hcy production (HHcy) and reduced GSH synthesis. This tripeptide, that exists in the reduced or active  form (GSH) and oxidized variant (GSH), is the main antioxidant of the  body.  Independently of its antioxidant function, the compound  has an anti-inflammatory role too, reducing the production of interleukines and the expression of TNF-alfa and iNOS synthase. A dysregulation of GSH synthesis is recognized as contributing factor to the pathogenesis of many pathological conditions. But, the insufficiency of the transsulfuration pathway is also responsible of HHcy. Besides, this condition  decreases the activity of cellular “gluthatione peroxidase”, an intracellular antioxidant enzyme that reduces hydrogen peroxide to water with the prevalence of GSSH on GSH. The consequent GSH/GSSH impaired ratio also causes some common cardiovascular and neurodegenerative disorders. In both occurrences, N-Acetyl-Cysteine (NAC) supplementation supplies the cysteine necessary for GSH synthesis and contemporarily reduces HHcy, improving  the GPx1 activity and further reducing oxidative stress.

Effects of methionine on endogenous antioxidants in the heart

1999 ◽  
Vol 277 (6) ◽  
pp. H2124-H2128 ◽  
Author(s):  
Charita K. Seneviratne ◽  
Timao Li ◽  
Neelam Khaper ◽  
Pawan K. Singal
Keyword(s):  
Antioxidant Enzyme Activities ◽  
Mrna Levels ◽  
Sod Activity ◽  
Time Points ◽  
Physiological Conditions ◽  
Control Value ◽  
Beneficial Effects ◽  
Different Types ◽  
Endogenous Antioxidants ◽  
Gshpx Activity

The deficiency of methionine, an essential amino acid, is associated with cardiovascular lesions. Because different types of cardiac pathologies are caused by a decrease in antioxidants, we examined the effects of methionine on myocardial antioxidant enzymes in hemodynamically assessed rats that were treated with methionine (10 mg/ml) in drinking water for 12, 24, and 48 h. Glutathione peroxidase (GSHPx) activity was significantly increased to 150.5 ± 12.2 and 191.7 ± 13.7% of the control value at 12 and 24 h, respectively, followed by a decline to 120 ± 24.6% at 48 h. The mRNA levels of GSHPx at these time points were 151.2 ± 12.0, 218.7 ± 35.3, and 173.5 ± 25.2%, respectively. Superoxide dismutase (SOD) activity was 144.3 ± 3.7, 114.3 ± 10.1, and 143.1 ± 11.2% at 12, 24, and 48 h, respectively. Catalase (Cat) activity was 272.4 ± 5.4, 237.8 ± 16.6, and 224.1 ± 17.3% of the control value. The expression of Cat and SOD mRNA was unchanged at 12, 24, and 48 h. The lipid peroxidation was decreased by 24.4 ± 11.2, 54.9 ± 0.1, and 6.4 ± 2.1% at 12, 24, and 48 h, respectively. Methionine had no effect on the ventricular or aortic pressures, heart rate, and myocardial glutathione levels at any of the time points. The study shows that methionine has a significant effect on the myocardial antioxidant enzyme activities, and only changes in GSHPx enzyme activity correlated with the mRNA changes. These antioxidant changes may have a role in the beneficial effects of methionine in pathological rather than physiological conditions.

scholarly journals Uremic Toxin Lanthionine Interferes with the Transsulfuration Pathway, Angiogenetic Signaling and Increases Intracellular Calcium

2019 ◽  
Vol 20 (9) ◽  
pp. 2269 ◽  
Author(s):  
Carmela Vigorito ◽  
Evgeniya Anishchenko ◽  
Luigi Mele ◽  
Giovanna Capolongo ◽  
Francesco Trepiccione ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Content ◽  
Cell Cultures ◽  
Uremic Toxin ◽  
Vascular Endothelial ◽  
Beneficial Effects ◽  
Transsulfuration Pathway ◽  
Strip Test ◽  
Endothelial Growth Factor

(1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel uremic toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release; reduces protein content and glutathionylation of transsulfuration enzyme cystathionine-β-synthase; modifies the expression of miR-200c and miR-423; lowers expression of vascular endothelial growth factor VEGF; increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with uremic dysfunctional characteristics and further support the uremic toxin role of this amino acid.

Anion transport as related to hemoglobin A1c in erythrocytes of diabetic children.

1988 ◽  
Vol 34 (7) ◽  
pp. 1414-1416
Author(s):  
J Brahm ◽  
H B Mortensen
Keyword(s):  
Erythrocyte Membrane ◽  
Hemoglobin A1c ◽  
Bicarbonate Transport ◽  
Physiological Conditions ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Diabetic Children ◽  
Tightly Coupled ◽  
Integral Transport ◽  
Rate Limiting

Abstract We determined chloride and bicarbonate transport [Jcl and Jbic, nmol/(cm2.s)] under physiological conditions (Cl- 110 and HCO3- 25 mmol per liter, respectively, pH 7.4, 38 degrees C) across the erythrocyte membrane in blood samples from 12 diabetic (Jcl 26.1, SD +/- 3.7, n = 24; Jbic 7.6, SD +/- 0.9, n = 19) and 10 non-diabetic children (Jcl 30.6, SD +/- 4.6, n = 16; Jbic 7.3, SD +/- 1.0, n = 20) with mean hemoglobin A1c values of 11.08% (SD +/- 2.45%) and 5.36% (SD +/- 0.25%), respectively. The concentration of HbA1c, which also reflects the degree of glycation of the membrane proteins, differed significantly (P greater than 0.001) between the two groups, whereas there was no significant variation (P greater than 0.1) in Jcl and Jbic. We conclude that glycation of the integral transport protein in the erythrocyte membrane, capnophorin (also called "band 3"), which mediates a tightly coupled anion exchange, does not change the capacity of the transport system under physiological conditions. Thus the rate-limiting step of the exploitation of the CO2 transport capacity of the blood is not impaired in diabetics and consequently does not endanger the compensatory hyperventilation after ketoacidosis.

scholarly journals Beneficial Effects of Dietary Polyphenols on Gut Microbiota and Strategies to Improve Delivery Efficiency

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2216 ◽  
Author(s):  
Amit Kumar Singh ◽  
Célia Cabral ◽  
Ramesh Kumar ◽  
Risha Ganguly ◽  
Harvesh Kumar Rana ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Clinical Data ◽  
Antimicrobial Activities ◽  
Dietary Polyphenols ◽  
Beneficial Effects ◽  
Obesity And Diabetes ◽  
Bacterial Quorum Sensing ◽  
Health And Disease ◽  
Bacterial Quorum ◽  
And Function

The human intestine contains an intricate ecological community of dwelling bacteria, referred as gut microbiota (GM), which plays a pivotal role in host homeostasis. Multiple factors could interfere with this delicate balance, including genetics, age, antibiotics, as well as environmental factors, particularly diet, thus causing a disruption of microbiota equilibrium (dysbiosis). Growing evidences support the involvement of GM dysbiosis in gastrointestinal (GI) and extra-intestinal cardiometabolic diseases, namely obesity and diabetes. This review firstly overviews the role of GM in health and disease, then critically reviews the evidences regarding the influence of dietary polyphenols in GM based on preclinical and clinical data, ending with strategies under development to improve efficiency of delivery. Although the precise mechanisms deserve further clarification, preclinical and clinical data suggest that dietary polyphenols present prebiotic properties and exert antimicrobial activities against pathogenic GM, having benefits in distinct disorders. Specifically, dietary polyphenols have been shown ability to modulate GM composition and function, interfering with bacterial quorum sensing, membrane permeability, as well as sensitizing bacteria to xenobiotics. In addition, can impact on gut metabolism and immunity and exert anti-inflammatory properties. In order to overcome the low bioavailability, several different approaches have been developed, aiming to improve solubility and transport of dietary polyphenols throughout the GI tract and deliver in the targeted intestinal regions. Although more research is still needed, particularly translational and clinical studies, the biotechnological progresses achieved during the last years open up good perspectives to, in a near future, be able to improve the use of dietary polyphenols modulating GM in a broad range of disorders characterized by a dysbiotic phenotype.

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