Overview of MMP Biology and Gene Associations in Human Diseases

Interactions of cell with the extracellular matrix (ECM) are crucial for normal development and functioning of the human organism. By regulating ECM integrity and composition matrix metalloproteinases (MMPs) play the main role in ECM molecules signaling and influence processes such as proliferation, migration, differentiation and apoptosis. ECM remodeling is a highly regulated process. When imbalanced it could contribute to pathophysiology of many diseases. The MMPs actions and activity are regulated through different mechanisms such as regulation of transcription, activation of latent MMPs, inhibition of MMP function by tissue inhibitors of metalloproteinases. MMPs are a family of calcium- and zinc-dependent endoproteinase, which share similar structural domains, but differs in substrate specificity, cell localizations and inducibility. Genetic variations in MMPs have been associated with a number of diseases, still not all findings are reproducible. Nine of 23 human genes encoding MMPs are located in a cluster on chromosome 11, which implicate their haplotype-driven effects. They could be important mediators of disease severity and could trigger acute events. In this chapter, we will review the basics of MMP biology and the most significant associations of MMPs variations with cardiovascular and neurological diseases in humans and MMPs therapeutic potential through synthetic inhibitors

Involvement of the Renin‐Angiotensin System in Atherosclerosis

The renin-angiotensin system (RAS) is a well known for its role in the regulation of the blood pressure (BP). Angiotensin II (Ang II), the main mediator of the RAS, may act either, as a systemic molecule or a locally produced factor. Within the vessel wall it has significant proinflammatory role by inducing the oxidative stress, secretion of inflammatory cytokines and adhesion molecules. Ang II could trigger proliferation of vascular smooth muscle cells (VSMC) and its migration to the outer layer of the vessel wall. It could induce the release of matrix metalloproteinase (MMPs), from human VSMC and thus increase susceptibility to rupture of atherosclerotic lesions. Binding of Ang II to AT1R/AT2R could have opposing actions in vascular injury. The ACE2/Ang (1-7)/Mas axis of the RAS also opposes the unfavourable actions of ACE/Ang II/ATR1 axis. Inhibition of RAS could reduce inflammation-associated processes in vasculature, independently of lowering BP. RAS is significantly modulated by the genes coding for this system. Certain genetic variants (SNPs) in the RAS genes have been denoted as the functional ones and have been associated with hypertension, cardiovascular phenotypes and atherosclerosis. Also, the genetic components of the RAS interfere with the regulators of gene expression by microRNAs (miRs)

Genetic Factors Underlying Susceptibility to Acute Pyelonephritis and Post-infectious Renal Damage

Chapter of the book "Recent Advances in the Field of Urinary Tract Infections" [https://doi.org/10.5772/46044

The blues of Romuliana

The paper presents a set of glass fragments excavated at several different locations within and outside the late Roman fortified imperial residence Felix Romuliana (Gamzigrad, Serbia). This small group of eighteen fragments and mosaic glass tesserae are distinguished by their cobalt blue colour. The majority of the finds are mosaic tesserae (six pcs) and sheets of glass (five pcs), which could be related to architectural decoration (sectilia panels). Others are pieces left behind from secondary glass working (four pcs). There are also two fragments tentatively identified as window pane pieces, and only one find is a vessel sherd. The materials are dated to the 4th century. Significantly, some of the production debris and the two “window pane” fragments were found inside the destruction of a glass furnace. The analyses of the chemical glass composition of the finds confirmed that the blue colourant in all samples is cobalt, and antimony is also present at notable levels (except for one sample), likely to produce opacification of the glass. Regarding the origin of the raw glass, the data on almost all pieces suggests a Syro-Palestinian provenance, and a single sample could be related to Egyptian primary glass production. Importantly, the concentrations of the oxides added to the base glasses in order to modify the colour are positively correlated in certain samples, hinting at the makeup of the cobalt bearing ingredient and at a likely existence of particular production practices of the late Roman period

HALLUCINATORY EXPERIENCES IN VISUALLY IMPAIRED INDIVIDUALS: CHARLES BONNET SYNDROME – IMPLICATIONS FOR RESEARCH AND CLINICAL PRACTICE

Background: Charles Bonnet syndrome (CBS) refers to visual hallucinations that occur in individuals with preserved cognitive functions associated with visual impairment. Methods: This article reviews occurence of visual hallucinations in subjects with CBS by journals published in English in the Pubmed database in the period 1992-2018. Criteria for selection of appropriate papers were sufficient information and perspicuous view on pathogenesis, epidemiology, clinical presentation and treatment possibilities of CBS. Results: Most commonly, visual hallucinations in patients with CBS are complex, repetitive and stereotyped. Such individuals have preserved insight that those percepts are not real, and there is an absence of secondary explanatory delusions and hallucinations within other modalities. Seeing as the aforementioned percepts do not share all the characteristics of hallucinations, it remains unresolved how they should be referred to. Terms as release hallucinations, one that is reflecting its underlying pathogenesis, or confabulatory hallucinatory experiences have been proposed. Moreover, CBS has also been referred to as phantom vision syndrome and may occur in any ophthalmological disease. It is not particularly connected with loss of function along any level of the visual pathway. Although this syndrome is mostly associated with age-related macular degeneration, glaucoma and cataract, it could be related to almost any other ophthalmological conditions. The incidence of CBS alongside with mostly other ocular pathology is rising as population is ageing. Conclusions: Nonetheless, CBS remains commonly underreported, under recognized and/or misrecognized. Albeit the treatment recommendations and guidelines are not yet fully established, it is important to raise awareness of this specific and distinct condition, which inevitably implicates many differential diagnostic deliberations

Acute effects of nandrolone decanoate on oxidative stress in isolated rat heart

Abuse of anabolic-androgenic steroids (AAS) produces side effects in different tissues, with oxidative stress linked to their pathophysiology, being involved in fibrosis, cellular proliferation, and tumorigenesis. The aim of this study was to examine the acute effects of nandrolone decanoate (ND) on oxidative stress in isolated rat heart. The hearts of male Wistar albino were excised and perfused according to the Langendorff technique at gradually increasing coronary perfusion pressures (40-120 cm H2O). The hearts were perfused with ND at doses of 1, 10 and 100 μM. Oxidative stress markers, including the index of lipid peroxidation (thiobarbituric acid reactive substances (TBARS)), nitric oxide (nitrites; NO2-), the superoxide anion radical (O2-) and hydrogen peroxide (H2O2) were measured in the coronary venous effluent. Our results showed that acute effects of ND do not promote the production of reactive oxygen species (ROS). Our finding pointed out that the highest concentration of ND may even possess some anti-oxidative potential, which should be examined further

LINE-1 DNA METHYLATION AND CONGENITAL HEART DEFECTS IN DOWN SYNDROME

DNA methylation is a key epigenetic mechanism that plays a significant role in regulating gene activity during cardiac development. Congenital heart defects (CHD) are one of the most common abnormalities occurring in 40% -60% of cases with Down syndrome (DS). The main aim of this study was to establish the association of long interspersed nucleotide element-1 (LINE-1) DNA methylation in children with DS and the presence of CHD. The LINE-1 DNA methylation was investigated in peripheral blood lymphocytes on a sample of 42 people with DS by quantification of LINE-1 methylation using the MethyLight method. No significant differences in global DNA methylation were found according to the presence of CHD (P=1.000), but values of LINE-1 DNA methylation were significantly influenced by gender (R2=19.1%; P=0.025). Significant probability of 19.1% was found in women with DS who had lower LINE-1 DNA methylation values than DS male. Gender was a statistically significant predictor of LINE-1 DNA methylation, although the difference was not statistically significant, female subjects had lower LINE-1 DNA methylation values (P=0.068). Further research will clarify the role of lower LINE-1 DNA methylation in the formation of CHD among DS females

ETHICAL APPROACH TO PREVENTION OF SCHIZOPHRENIA - CONCEPTS AND CHALLENGES

Patients with schizophrenia, nowadays chronic, frequently disabling mental disorder, get initial treatment after detection of a psychotic episode, seemingly late, potentially preventable stage of illness. As our knowledge about the nature of schizophrenia and other diseases of the spectrum is growing, so are the early interventions becoming more possible, and it is important to conceptualize the clinical, legal and moral issues emerging with new preventive treatments. Every intervention, especially in pre-clinical population, demands a careful risk-benefit assessment and having basic bioethical principles - primacy of patient\u27s welfare, beneficience/non-maleficience, autonomy and justice - in mind. We believe that pharmacological treatments, considering today\u27s drugs safety and effectiveness profiles, should stay reserved for cases with higly probable negative outcomes to patient\u27s wellbeing, and that all other low-risk interventions, like psychosocial treatments, should be considered for reducing the conversion to disorder, if possible, or relieving the distress in vulnerable persons, when such vulnerability gets detected. How to recognize persons at risk before the start of the disorder, without missing the majority of cases or burdening healthy persons with stigma, is another challenge and not only mental health professionals should be included in finding the solutions. The broadest public, and especially the experts that will build the safety-net for the at-risk individuals, should get best possible appropriate education about the schizophrenia in order to stigmatize less and help more