Friday, June 24, 2016

Role of Tyrosine Isomers in Acute and Chronic Diseases Leading to Oxidative Stress - A Review

Author(s):

Gergő A. Molnár, Szilárd Kun, Eszter Sélley, Melinda Kertész, Lívia Szélig, Csaba Csontos, Katalin Böddi, Lajos Bogár, Attila Miseta and István WittmannPages 667-685 (19)

Abstract:


Oxidative stress plays a major role in the pathogenesis of a variety of acute and chronic diseases. Measurement of the oxidative stress-related end products may be performed, e.g. that of structural isomers of the physiological para-tyrosine, namely meta- and ortho-tyrosine, that are oxidized derivatives of phenylalanine. Recent data suggest that in sepsis, serum level of meta-tyrosine increases, which peaks on the 2nd and 3rd days (p<0.05 vs. controls), and the kinetics follows the intensity of the systemic inflammation correlating with serum procalcitonin levels. In a similar study subset, urinary meta-tyrosine excretion correlated with both need of daily insulin dose and the insulin-glucose product in non-diabetic septic cases (p<0.01 for both). Using linear regression model, meta-tyrosine excretion, urinary meta-tyrosine/para-tyrosine, urinary ortho-tyrosine/para-tyrosine and urinary (meta- + orthotyrosine)/ para-tyrosine proved to be markers of carbohydrate homeostasis.
In a chronic rodent model, we tried to compensate the abnormal tyrosine isomers using para-tyrosine, the physiological amino acid. Rats were fed a standard high cholesterol-diet, and were given para-tyrosine or vehicle orally. High-cholesterol feeding lead to a significant increase in aortic wall meta-tyrosine content and a decreased vasorelaxation of the aorta to insulin and the glucagon-like peptide-1 analogue, liraglutide, that both could be prevented by administration of para-tyrosine.
Concluding, these data suggest that meta- and ortho-tyrosine are potential markers of oxidative stress in acute diseases related to oxidative stress, and may also interfere with insulin action in septic humans. Competition of meta- and ortho-tyrosine by supplementation of para-tyrosine may exert a protective role in oxidative stress-related diseases.

Keywords:

Meta-tyrosine, ortho-tyrosine, para-tyrosine, sepsis, inflammation, oxidative stress, hormone resistance, carbohydrate metabolism.

Affiliation:

2nd Department of Medicine and Nephrological Center, Medical School, University of Pécs, Pacsirta str. 1., H-7624 Pécs, Hungary


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Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson’s Disease

Author(s):

Ikuko Miyazaki and Masato AsanumaPages 686-700 (15)

Abstract:


Astrocytes are the most abundant neuron-supporting glial cells in the central nervous system. The neuroprotective role of astrocytes has been demonstrated in various neurological disorders such as amyotrophic lateral sclerosis, spinal cord injury, stroke and Parkinson’s disease (PD). Astrocyte dysfunction or loss-of-astrocytes increases the susceptibility of neurons to cell death, while astrocyte transplantation in animal studies has therapeutic advantage. We reported recently that stimulation of serotonin 1A (5-HT1A) receptors on astrocytes promoted astrocyte proliferation and upregulated antioxidative molecules to act as a neuroprotectant in parkinsonian mice. PD is a progressive neurodegenerative disease with motor symptoms such as tremor, bradykinesia, rigidity and postural instability, that are based on selective loss of nigrostriatal dopaminergic neurons, and with non-motor symptoms such as orthostatic hypotension and constipation based on peripheral neurodegeneration. Although dopaminergic therapy for managing the motor disability associated with PD is being assessed at present, the main challenge remains the development of neuroprotective or disease- modifying treatments. Therefore, it is desirable to find treatments that can reduce the progression of dopaminergic cell death. In this article, we summarize first the neuroprotective properties of astrocytes targeting certain molecules related to PD. Next, we review neuroprotective effects induced by stimulation of 5-HT1A receptors on astrocytes. The review discusses new promising therapeutic strategies based on neuroprotection against oxidative stress and prevention of dopaminergic neurodegeneration.

Keywords:

5-HT1A receptor, S100β, astrocyte, Parkinson’s disease, neuroprotection, dopaminergic neuron.

Affiliation:

Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan


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    Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases

    Author(s):

    Marisa Cabeza, Araceli Sánchez-Márquez, Mariana Garrido, Aylín Silva and Eugene BratoeffPages 792-815 (24)

    Abstract:


    This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT. This review also discusses the most recent studies reported in the literature that describe the therapeutic potential of novel compounds, as well as the new drugs, principally inhibitors of 5α-reductase.

    Keywords:

    Benign prostatic hyperplasia, prostate cancer, 5-alpha reductase, 17-beta hydroxysteroid dehydrogenase, protein kinase A, androgen receptor, dehydroepiandrosterone derivatives, non-permeable testosterone conjugates, G proteins, PKA.

    Affiliation:

    Departamento De Sistemas Biológicos, Universidad Autónoma Metropolitana- Xochimilco Calzada Del Hueso No. 1100, México, D.F., C.P. 04960, México.


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    Structure and Expression of Different Serum Amyloid A (SAA) Variants and their Concentration-Dependent Functions During Host Insults

    Author(s):

    Mieke De Buck, Mieke Gouwy, Ji Ming Wang, Jacques Van Snick, Ghislain Opdenakker, Sofie Struyf and Jo Van DammePages 1725-1755 (31)

    Abstract:


    Serum amyloid A (SAA) is, like C-reactive protein (CRP), an acute phase protein and can be used as a diagnostic, prognostic or therapy follow-up marker for many diseases. Increases in serum levels of SAA are triggered by physical insults to the host, including infection, trauma, inflammatory reactions and cancer. The order of magnitude of increase in SAA levels varies considerably, from a 10- to 100- fold during limited inflammatory events to a 1000-fold increase during severe bacterial infections and acute exacerbations of chronic inflammatory diseases. This broad response range is reflected by SAA gene duplications resulting in a cluster encoding several SAA variants and by multiple biological functions of SAA. SAA variants are single-domain proteins with simple structures and few post-translational modifications. SAA1 and SAA2 are inducible by inflammatory cytokines, whereas SAA4 is constitutively produced. We review here the regulated expression of SAA in normal and transformed cells and compare its serum levels in various disease states. At low concentrations (10-100 ng/ml), early in an inflammatory response, SAA induces chemokines or matrix degrading enzymes via Toll-like receptors and functions as an activator and chemoattractant through a G protein-coupled receptor. When an infectious or inflammatory stimulus persists, the liver continues to produce more SAA (≥ 1000 ng/ml) to become an antimicrobial agent by functioning as a direct opsonin of bacteria or by interference with virus infection of host cells. Thus, SAA regulates innate and adaptive immunity and this information may help to design better drugs to treat specific diseases.

    Keywords:

    SAA variants, FPR2, TLR2, leukocytes, chemotaxis, cytokines, inflammatory diseases, amyloidosis.

    Affiliation:

    University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, Minderbroedersstraat 10, 3000 Leuven, Belgium.


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