Plasma levels of soluble RAGE, AGEs and AOPPs at the early stage of amyotrophic lateral sclerosis: A preliminary study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with largely unknown pathogenesis and no effective cure. It is believed that several, not mutually exclusive mechanisms contribute to the pathogenesis and progression of this disease, including, among others, elevated oxidative stress, excitotoxicity, increased neuroinflammation, and protein aggregation. Receptor for advanced glycation end products (RAGE) is a part of immunoglobulin superfamily; it is believed to participate in ALS pathogenesis. OBJECTIVES: Our previous studies on ALS demonstrated that RAGE is likely one of the key players in ALS, acting on its own and in tandem with its oxidative stress and pro-inflammatory ligands, such as advanced glycation end products (AGEs) or advanced oxidation protein products (AOPPs). In this study, based on our previous results, we aimed to establish blood levels of soluble RAGE, AGE and AOPP in ALS patients. MATERIAL AND METHODS: Forty-six coded and anonymized surplus plasma samples from ALS patients and non-neurological control were used in the study. The plasma levels of RAGE, AGE and AOPP were measured using enzyme-linked immunosorbent assay (ELISA) commercially available kits. Statistical evaluation of data was performed using one-way non-parametric analysis of variance (ANOVA) with Kruskal-Wallis post hoc test. RESULTS: Our results revealed a decline in soluble RAGE level, concurrent with an increase in the levels of AGEs and AOPPs in blood samples from ALS patients, signifying a loss of neuroprotective form of RAGE and a simultaneous increase in AGE and AOPP production and uptake at the early stage of the disease. CONCLUSIONS: The results obtained from our study indicate that further longitudinal study of RAGE, AGE and AOPP levels would be beneficial, outlining the dynamics between RAGE and its ligand levels as the disease progresses, and making them valuable diagnostic tools and potential therapeutic targets.

The Genetic Background of Abnormalities in Metabolic Pathways of Phosphoinositides and Their Linkage with the Myotubular Myopathies, Neurodegenerative Disorders, and Carcinogenesis.

Myo-inositol belongs to one of the sugar alcohol groups known as cyclitols. Phosphatidylinositols are one of the derivatives of Myo-inositol, and constitute important mediators in many intracellular processes such as cell growth, cell differentiation, receptor recycling, cytoskeletal organization, and membrane fusion. They also have even more functions that are essential for cell survival. Mutations in genes encoding phosphatidylinositols and their derivatives can lead to many disorders. This review aims to perform an in-depth analysis of these connections. Many authors emphasize the significant influence of phosphatidylinositols and phosphatidylinositols' phosphates in the pathogenesis of myotubular myopathies, neurodegenerative disorders, carcinogenesis, and other less frequently observed diseases. In our review, we have focused on three of the most often mentioned groups of disorders. Inositols are the topic of many studies, and yet, there are no clear results of successful clinical trials. Analysis of the available literature gives promising results and shows that further research is still needed.

Lead Exposure Assessment and Its Impact on the Structural Organization and Morphological Peculiarities of Rat Ovaries.

Lead is known to be highly toxic to humans, causing various disorders infetal development. An experiment was conducted to examine the effects of lead acetate on the structural organization of female rat ovaries. The study involved 40 non-linear female rats divided into four groups: a control group, a low-dose group, a moderate-dose group, and a high-dose group. The rats were given lead acetate solutions in varying doses for 30 days, and their ovarian tissue was examined using light microscopy.The results showed that increasing doses of lead acetate led to morphological changes in the cortex and medulla of the rat ovaries. The changes were characterized by a decrease in ovarian mass, alterations in the thickness of the tunica albuginea (protein envelope), and a reduction in the number of follicles. Light microscopy revealed that exposure to lead acetate resulted in a significant decrease in the number of follicles in all experimental groups, with the high-dose group experiencing the most significant decrease.These findings suggest that lead acetate has a dose-dependent negative impact on the morphology and function of female rat ovaries. Further studies are needed to investigate the potential impact of lead on human ovarian tissue.

The Role of Lyophilized Xenodermotransplants in Repairing the Atria's Structure and the Peculiarities of Regenerative Processes after Thermal Trauma in an Experiment.

The effects of severe burn injuries on the cardiovascular system, specifically the atria and auricles of the heart, were investigated. The potential benefits of using lyophilized xenodermotransplants as a treatment option were also evaluated. The experiments were conducted on adult guinea pigs divided into three groups: intact animals, animals with burns, and animals with burns who underwent early necrectomy followed by wound closure with lyophilized xenodermotransplants. Third-degree burns caused significant ultrastructural changes in atrial cardiomyocytes, leading to long-term destructive changes in the structural components of the atria. However, the use of lyophilized xenodermotransplants had a positive effect on the atrial ultrastructure over time. This study highlights the complex and varied effects of burn injuries on the body and the potential benefits of lyophilized xenodermotransplants in treating severe burn injuries. By preventing destructive changes in the heart and activating regenerative processes, lyophilized xenodermotransplants can improve the condition of the heart after thermal injury. Further research and development in this area are necessary for understanding the potential of lyophilized xenodermotransplants in tissue repair and regeneration.

Cyclitols: From Basic Understanding to Their Association with Neurodegeneration.

One of the most common cyclitols found in eukaryotic cells-Myo-inositol (MI) and its derivatives play a key role in many cellular processes such as ion channel physiology, signal transduction, phosphate storage, cell wall formation, membrane biogenesis and osmoregulation. The aim of this paper is to characterize the possibility of neurodegenerative disorders treatment using MI and the research of other therapeutic methods linked to MI's derivatives. Based on the reviewed literature the researchers focus on the most common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Spinocerebellar ataxias, but there are also works describing other seldom encountered diseases. The use of MI, d-pinitol and other methods altering MI's metabolism, although research on this topic has been conducted for years, still needs much closer examination. The dietary supplementation of MI shows a promising effect on the treatment of neurodegenerative disorders and can be of great help in alleviating the accompanying depressive symptoms.

Pharmacokinetics of Myo-Inositol in a Wistar Rat Animal Model.

Myo-inositol is the most popular inositol in living organisms, where it is present as a sugar alcohol, in a free form, and can also be described as a lipid. The aim of this study was to check the concentration change of a myo-inositol solution from the time of oral administration and over a 48 h period in Wistar-type rats. All rats received 2 g/kg of inositol as a solution in distilled water by oral gavage. Estimated parameters were based on the serum concentration of myo-inositol observed in nine individual rats with regard to time. Observations were described as a one-compartment pharmacokinetic model with first-order absorption and zero-order endogenous input of checked inositol. The highest myo-inositol concentration was observed in the first hour after oral administration in the serum of all tested rats. Then, the concentration began decreasing immediately after the maximal peak. The inositol concentration continued to decrease, but after 24 h its level was still higher than before the administration. The plasma profile of the myo-inositol concentration showed a rapid decline over time, possibly due to the metabolism of this compound.

Study of the Potential Hepatoprotective Effect of Myo-Inositol and Its Influence on Zebrafish Development.

Inositol is a natural substance found widely in plants. It is used in therapies for many medical cases. The aim of this study was to determine the toxicity of myo-inositol (MI) and to investigate its potential hepatoprotective character. In the first part of the study, zebrafish embryos were incubated with 5, 10, 20, 40, 60, 80, and 100 mg/mL MI. Endpoints such as survivability, hatching rate, malformation, and mobility were evaluated. Our results demonstrated that the high doses of MI lead to increased mortality and malformations and reduce the hatching rate in comparison to the control group. Moreover, low doses of this compound do not produce a negative effect on zebrafish and even have the ability to increase the hatching rate and mobility. In the second part of the study, the hepatoprotective effect of MI was tested. Zebrafish larvae from the line Tg (fabp10a:DsRed) were incubated for 24 h with 1% and 2% ethanol (EtOH), 5 mg/mL of MI with 1% EtOH, and 5 mg/mL of MI with 2% EtOH. No significant differences between the groups with EtOH and the group treated with EtOH with MI were observed. Our results suggest that MI has no positive benefits on hepatocytes of zebrafish larvae.

Differentiation of Human Mesenchymal Stem Cells from Wharton's Jelly Towards Neural Stem Cells Using A Feasible and Repeatable Protocol.

The transplantation of neural stem cells (NSCs) capable of regenerating to the cells of the central nervous system (CNS) is a promising strategy in the treatment of CNS diseases and injury. As previous studies have highlighted mesenchymal stem cells (MSCs) as a source of NSCs, this study aimed to develop a feasible, efficient, and reproducible method for the neural induction of MSCs isolated from Wharton's jelly (hWJ-MSCs). We induced neural differentiation in a monolayer culture using epidermal growth factor, basic fibroblast growth factor, N2, and B27 supplements. This resulted in a homogenous population of proliferating cells that expressed certain neural markers at both the protein and mRNA levels. Flow cytometry and immunocytochemistry confirmed the expression of neural markers: nestin, sex-determining region Y (SRY) box 1 and 2 (SOX1 and SOX2), microtubule-associated protein 2 (MAP2), and glial fibrillary acidic protein (GFAP). The qRT-PCR analysis revealed significantly enhanced expression of nestin and MAP2 in differentiated cells. This study confirms that it is possible to generate NSCs-like cells from hWJ-MSCs in a 2D culture using a practical method. However, the therapeutic effectiveness of such differentiated cells should be extended to confirm the terminal differentiation ability and electrophysiological properties of neurons derived from them.

Inositols' Importance in the Improvement of the Endocrine-Metabolic Profile in PCOS.

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility and metabolic problems among women of reproductive age. The mechanism of PCOS is associated with concurrent alterations at the hormonal level. The diagnosis assumes the occurrence of three interrelated symptoms of varying severity, namely ovulation disorders, androgen excess, or polycystic ovarian morphology (PCOM), which all require a proper therapeutic approach. The main symptom seems to be an increased androgen concentration, which in turn may contribute to different metabolic disorders. A number of papers have demonstrated the significant role of inositol therapy in PCOS. However, there is a lack of detailed discussion about the importance of myo-inositol (MI) and d-chiro-inositol (DCI) in reference to particular symptoms. Thus, the aim of this review is to present the effectiveness of MI and DCI treatment for PCOS symptoms. Moreover, the review is focused on analyzing the use of inositols, taking into account their physiological properties, together with the mechanism of individual PCOS symptom formation.

Health-Promoting Properties of Selected Cyclitols for Metabolic Syndrome and Diabetes.

Cyclitols play a particularly important role in cell functioning because they are involved in ion channel physiology, phosphate storage, signal transduction, cell wall formation, membrane biogenesis, osmoregulation and they have antioxidant activity. They are involved in the cell membranes as a phosphatidyl myo-inositol, an inositol triphosphate precursor, which acts as a transmitter that regulates the activity of several hormones, such as follicle-stimulating hormone, thyrotropin, and insulin. The aim of this paper is to characterize the selected cyclitols: myo-inositol, D-chiro-inositol, and D-pinitol in type-2 metabolic syndrome and diabetes treatment. Results and discussion: Cyclitols have certain clinical applications in the treatment of metabolic syndromes and are considered to be an option as a dietary supplement for the treatment or prevention of gestational diabetes mellitus and type-2 diabetes. Improved metabolic parameters observed after using cyclitols, like myo-inositol, in the treatment of polycystic ovary syndrome and type-2 diabetes suggest that they may have a protective effect on the cardiovascular system. Pinitol, together with myo-inositol,maybe responsible for improving lipid profiles by reducing serum triglyceride and total cholesterol. Pinitol is also well-researched and documented for insulin-like effects. Myo-inositol, D-chiro-inositol, and D-pinitol indicate a number of therapeutic and health-promoting properties.

Cocaine- and amphetamine-regulated transcript (CART) peptide in the enteric nervous system of the porcine esophagus.

Cocaine- and amphetamine-regulated transcript peptide (CART) is widely distributed within the central and peripheral nervous system. In the brain, CART is considered as the main anorectic peptide involved in the regulation of food intake. Contrary to the central nervous system, a lot of aspects connected with the distribution and functions of CART within the enteric nervous system (ENS) still remain unknown. The aim of the present study was to investigate, for the first time, the population of CART-like immunoreactive (CART-LI) neurons within the porcine esophagus and the denotation of their neurochemical coding. During this experiment, the distribution of CART-LI neurons and the colocalization of CART with other neuronal active substances were examined using standard double- and triple-immunofluorescence techniques in enteric plexuses of cervical, thoracic, and abdominal esophagus fragments. The obtained results showed that CART is present in a relatively high percentage of esophageal neurons (values fluctuated from 45.2±0.9% in the submucous plexus of the thoracic esophagus to 58.1±5.0% in the myenteric plexus of the same fragment of the esophagus). Moreover, CART colocalized with a wide range of other active neuronal substances, mainly with the vesicular acetylcholine transporter (VAChT, a marker of cholinergic neurons), neuronal isoform of nitric oxide synthase (nNOS, a marker of nitrergic neurons), vasoactive intestinal polypeptide (VIP) and galanin (GAL). The number of CART-positive neuronal cells and their neurochemical coding clearly depended on the fragment of esophagus studied and the type of enteric plexus. The obtained results suggest that CART may play important and multidirectional roles in the neuronal regulation of esophageal functions.

Articular Cartilage Aging-Potential Regenerative Capacities of Cell Manipulation and Stem Cell Therapy.

Changes in articular cartilage during the aging process are a stage of natural changes in the human body. Old age is the major risk factor for osteoarthritis but the disease does not have to be an inevitable consequence of aging. Chondrocytes are particularly prone to developing age-related changes. Changes in articular cartilage that take place in the course of aging include the acquisition of the senescence-associated secretory phenotype by chondrocytes, a decrease in the sensitivity of chondrocytes to growth factors, a destructive effect of chronic production of reactive oxygen species and the accumulation of the glycation end products. All of these factors affect the mechanical properties of articular cartilage. A better understanding of the underlying mechanisms in the process of articular cartilage aging may help to create new therapies aimed at slowing or inhibiting age-related modifications of articular cartilage. This paper presents the causes and consequences of cellular aging of chondrocytes and the biological therapeutic outlook for the regeneration of age-related changes of articular cartilage.

Role of Stem Cells in Pathophysiology and Therapy of Spondyloarthropathies-New Therapeutic Possibilities?

Considerable progress has been made recently in understanding the complex pathogenesis and treatment of spondyloarthropathies (SpA). Currently, along with traditional disease modifying anti-rheumatic drugs (DMARDs), TNF-α, IL-12/23 and IL-17 are available for treatment of such diseases as ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Although they adequately control inflammatory symptoms, they do not affect the abnormal bone formation processes associated with SpA. However, the traditional therapeutic approach does not cover the regenerative treatment of damaged tissues. In this regards, stem cells may offer a promising, safe and effective therapeutic option. The aim of this paper is to present the role of mesenchymal stromal cells (MSC) in pathogenesis of SpA and to highlight the opportunities for using stem cells in regenerative processes and in the treatment of inflammatory changes in articular structures.

Evaluation of the characteristics of some plant polyphenols as molecules intercepting mitoxantrone.

This paper contains the results of a study on the interactions between mitoxantrone and some bioactive polyphenols. It has been demonstrated that polyphenols can intercept mitoxantrone. Quercetin shows the highest affinity for complexing with mitoxantrone, in contrast to resveratrol, which shows the lowest affinity. The main process underlying the association between cytostatic and polyphenols occurs in the ground state. The values of the constants of the association reactions between the analysed compounds and mitoxantrone are large enough to generate an evident intercepting effect in the three-component system (mitoxantrone-DNA-polyphenol). The affinity of the analysed plant-origin compounds is approximately 1000-fold weaker than the interaction of mitoxantrone with the DNA, which implies that the presence of these compounds in food should not adversely affect oncological therapy but rather could successfully aid oncological treatment by regulating the quantities of the drug in its active form.

Natural compounds in the human diet and their ability to bind mutagens prevents DNA-mutagen intercalation.

Human diet may contain many mutagenic or carcinogenic aromatic compounds as well as some beneficial physiologically active dietary components, especially plant food phytochemicals, which act as mutagenesis or carcinogenesis inhibitors. This study compared the binding properties of natural compounds in the human diet (caffeine, theophylline, theobromine, and resveratrol) with a water-soluble derivative of chlorophyll to bind to acridine orange, a known mutagen. An analysis was conducted to determine which substances were effective binding agents and may thus be useful in prevention of chemical-induced mutagenesis and carcinogenesis. Data indicated that in order to bind 50% of the mutagen in a complex, less than twice the concentration of chlorophyllin was needed, the resveratrol concentration was 20-fold higher, while a 1000-fold or even 10,000-fold excess of xanthines were required to bind acridine orange.

Determination of lead, cadmium, and persistent organic pollutants in wild and orchard-farm-grown fruit in northeastern Poland.

The concentrations of the heavy metals lead (Pb) and cadmium (Cd) were determined in berries (blackberry, raspberry, bilberry, wild strawberry), and hazelnuts picked from plants in the wild as well as in fruit (blackberry, raspberry, blueberry) and hazelnuts picked from orchard-farmed plants in northeastern Poland. The levels of seven congeners of polychlorinated biphenyls (PCB(7)), gamma isomer of hexachlorocyclohexane (gamma-HCH), and sum of dichlorodiphenyl trichloroethane and its metabolites (SigmaDDT) were also measured in plants and nuts. In addition, the concentrations of Pb, Cd, PCB(7,) gamma-HCH, and SigmaDDT were determined in the surface samples of soil from the sites of fruit picking. The highest acceptable concentrations based upon Polish standards for Pb and Cd were not exceeded in forest fruit. In wild berries, Pb occurred at a level below the detection limit, whereas the concentration of Cd ranged from 6 to 49 microg/kg fresh weight. The levels were Cd 72 microg/kg fresh weight and Pb 290 microg/kg fresh weight in raspberries from orchard plants and exceeded the maximal acceptable limit of 50 microg/kg for Cd and 200 microg/kg for Pb. The level of Pb at 210 microg/kg fresh weight in hazelnuts from orchard plants also exceeded maximal acceptable limits. Individual samples of fruit, regardless of their origin, were found to contain trace amounts of organic pollutants such as 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (p,p'-DDE) and PCB congeners 101 and 118. All soil samples contained from 3.2 to 14.9 mg/kg dry weight concentrations of Pb and most soil samples also contained Cd. Further, individual soil samples were found to contain high levels of SigmaDDT (145 microg/kg), including p,p'-DDT at a concentration of 67 microg/kg. The concentrations of persistent organic pollutants (POP) in wild and orchard-farm-grown fruit in northeastern Poland were generally below threshold permissible limits, and no correlation was found between levels of contaminants in soils and POP concentrations in fruit.