Carotenoids from Marine Sources as a New Approach in Neuroplasticity Enhancement.

An increasing number of people experience disorders related to the central nervous system (CNS). Thus, new forms of therapy, which may be helpful in repairing processes' enhancement and restoring declined brain functions, are constantly being sought. One of the most relevant physiological processes occurring in the brain for its entire life is neuroplasticity. It has tremendous significance concerning CNS disorders since neurological recovery mainly depends on restoring its structural and functional organization. The main factors contributing to nerve tissue damage are oxidative stress and inflammation. Hence, marine carotenoids, abundantly occurring in the aquatic environment, being potent antioxidant compounds, may play a pivotal role in nerve cell protection. Furthermore, recent results revealed another valuable characteristic of these compounds in CNS therapy. By inhibiting oxidative stress and neuroinflammation, carotenoids promote synaptogenesis and neurogenesis, consequently presenting neuroprotective activity. Therefore, this paper focuses on the carotenoids obtained from marine sources and their impact on neuroplasticity enhancement.

Variations in Blood Platelet Proteome and Transcriptome Revealed Altered Expression of Transgelin-2 in Acute Coronary Syndrome Patients.

Proteomic analyses based on mass spectrometry provide a powerful tool for the simultaneous identification of proteins and their signatures. Disorders detection at the molecular level delivers an immense impact for a better understanding of the pathogenesis and etiology of various diseases. Acute coronary syndrome (ACS) refers to a group of heart diseases generally associated with rupture of an atherosclerotic plaque and partial or complete thrombotic obstruction of the blood flow in the infarct-related coronary artery. The essential role in the pathogenesis of ACS is related to the abnormal, pathological activation of blood platelets. The multifactorial and complex character of ACS indicates the need to explain the molecular mechanisms responsible for thrombosis. In our study, we performed screening and comparative analysis of platelet proteome from ACS patients and healthy donors. Two-dimensional fluorescence difference gel electrophoresis and nanoscale liquid chromatography coupled to tandem mass spectrometry showed altered expressions of six proteins (i.e., vinculin, transgelin-2, fibrinogen ß and γ chains, apolipoprotein a1, and tubulin ß), with the overlapping increased expression at the mRNA level for transgelin-2. Dysregulation in protein expression identified in our study may be associated with an increased risk of thrombotic events, correlated with a higher aggregability of blood platelets and induced shape change, thus explaining the phenomenon of the hyperreactivity of blood platelets in ACS.

Variations in the Gene Expression Profile in Atherosclerotic Patients with Non-Fatal ACS: A Preliminary Study.

The pathophysiology of atherosclerosis and acute coronary syndrome (ACS) is related to interactions between immune cells, endothelium, and blood platelets. An increasing number of reports confirm the link between excessive immune activation and cellular cross-talk with ACS incidence. Our genetic and proteomic analysis was performed on strictly selected atherosclerotic patients with non-fatal ACS without typical risk factors and healthy donors. Results showed changes in the gene expression levels of the various inflammatory factors derived from the peripheral blood cells that drive the over-activation of the immune system. The enhanced activation of the immune system may lead to the overexpression of the pro-inflammatory mediators, which causes self-perpetuating machinery of processes associated with thrombosis. In our preliminary study, we confirmed an altered expression of genes associated with the inflammation and overall interaction of the vascular microenvironment. Furthermore, 5 of 92 analyzed genes, CCL2, CCR2, CSF2, GZMB, and ICOS, were expressed only in patients with ACS. In conclusion, the augmented expression of the pro-inflammatory genes from the peripheral blood cells may be a crucial genetic factor leading to the occurrence of acute inflammation and thus be significant in ACS pathogenesis.

The Green Anti-Cancer Weapon. The Role of Natural Compounds in Bladder Cancer Treatment.

Bladder cancer (BC) is the second most common genitourinary cancer. In 2018, 550,000 people in the world were diagnosed with BC, and the number of new cases continues to rise. BC is also characterized by high recurrence risk, despite therapies. Although in the last few years, the range of BC therapy has considerably widened, it is associated with severe side effects and the development of drug resistance, which is hampering treatment success. Thus, patients are increasingly choosing products of natural origin as an alternative or complementary therapeutic options. Therefore, in this article, we aim to elucidate, using the available literature, the role of natural substances such as curcumin, sulforaphane, resveratrol, quercetin, 6-gingerol, delphinidin, epigallocatechin-3-gallate and gossypol in the BC treatment. Numerous clinical and preclinical studies point to their role in the modulation of the signaling pathways, such as cell proliferation, cell survival, apoptosis and cell death.

The Molecular Aspects of Disturbed Platelet Activation through ADP/P2Y12 Pathway in Multiple Sclerosis.

Epidemiological studies confirm a high risk of ischemic events in secondary-progressive multiple sclerosis (SP MS) patients, directly associated with an increased level of pro-thrombotic activity of platelets. Our work aimed to verify potential molecular abnormalities of the platelet P2Y12 receptor expression and functionality as a cause of an increased risk of thromboembolism observed in the course of MS. We have demonstrated an enhanced platelet reactivity in response to adenosine diphosphate (ADP) in SP MS relative to controls. We have also shown an increased mRNA expression for the P2RY12 gene in both platelets and megakaryocytes, as well as enhanced density of these receptors on the platelet surface. We postulate that one of the reasons for the elevated risk of ischemic events observed in MS may be a genetically or phenotypically reinforced expression of the platelet P2Y12 receptor. In order to analyze the effect of the PAR1 (protease activated receptor type 1) signaling pathway on the expression level of P2Y12, we also analyzed the correlation parameters between P2Y12 expression and the markers of platelet activation in MS induced by selective PAR1 agonist (thrombin receptor activating peptide-6, TRAP-6). Identifying the molecular base responsible for the enlarged pro-thrombotic activity of platelets in SP MS could contribute to the implementation of prevention and targeted treatment, reducing the development of cardiovascular disorders in the course of the disease.

Circulating miRNAs as Potential Biomarkers Distinguishing Relapsing-Remitting from Secondary Progressive Multiple Sclerosis. A Review.

Multiple sclerosis (MS) is a debilitating neurodegenerative, highly heterogeneous disease with a variable course. The most common MS subtype is relapsing-remitting (RR), having interchanging periods of worsening and relative stabilization. After a decade, in most RR patients, it alters into the secondary progressive (SP) phase, the most debilitating one with no clear remissions, leading to progressive disability deterioration. Among the greatest challenges for clinicians is understanding disease progression molecular mechanisms, since RR is mainly characterized by inflammatory processes, while in SP, the neurodegeneration prevails. This is especially important because distinguishing RR from the SP subtype early will enable faster implementation of appropriate treatment. Currently, the MS course is not well-correlated with the biomarkers routinely used in clinical practice. Despite many studies, there are still no reliable indicators correlating with the disease stage and its activity degree. Circulating microRNAs (miRNAs) may be considered valuable molecules for the MS diagnosis and, presumably, helpful in predicting disease subtype. MiRNA expression dysregulation is commonly observed in the MS course. Moreover, knowledge of diverse miRNA panel expression between RRMS and SPMS may allow for deterring disability progression through successful treatment. Therefore, in this review, we address the current state of research on differences in miRNA panel expression between the phases.

The Interplay between Oxidative Stress, Inflammation and Angiogenesis in Bladder Cancer Development.

In 2018, 550,000 people were diagnosed with bladder cancer (BC), of which nearly 200,000 people died. Moreover, men are 4 times more likely than women to be diagnosed with BC. The risk factors include exposure to environmental and occupational chemicals, especially tobacco smoke, benzidine and genetic factors. Despite numerous studies, the molecular basis of BC development remains unclear. A growing body of evidence suggests that inflammation, oxidant-antioxidant imbalance and angiogenesis disorders may play a significant role in the development and progression of bladder cancer. The patients with bladder cancer were characterised by an increased level of reactive oxygen species (ROS), the products of lipid peroxidation, proinflammatory cytokines and proangiogenic factors as compared to controls. Furthermore, it was shown that polymorphisms localised in genes associated with these pathways may modulate the risk of BC. Interestingly, ROS overproduction may induce the production of proinflammatory cytokines, which finally activated angiogenesis. Moreover, the available literature shows that both inflammation and oxidative stress may lead to activation of angiogenesis and tumour progression in BC patients.

miR-155 as an Important Regulator of Multiple Sclerosis Pathogenesis. A Review.

Multiple sclerosis (MS) is a chronic, immune-mediated disease and the leading cause of disability among young adults. MicroRNAs (miRNAs) are involved in the post-transcriptional regulation of gene expression. Of them, miR-155 is a crucial regulator of inflammation and plays a role in modulating the autoimmune response in MS. miR-155 is involved in blood-brain barrier (BBB) disruption via down-regulation of key junctional proteins under inflammatory conditions. It drives demyelination processes by contributing to, e.g., microglial activation, polarization of astrocytes, and down-regulation of CD47 protein and affecting crucial transcription factors. miR-155 has a huge impact on the development of neuropathic pain and indirectly influences a regulatory T (Treg) cell differentiation involved in the alleviation of pain hypersensitivity. This review also focused on neuropsychiatric symptoms appearing as a result of disease-associated stressors, brain atrophy, and pro-inflammatory factors. Recent studies revealed the role of miR-155 in regulating anxiety, stress, inflammation in the hippocampus, and treatment-resistant depression. Inhibition of miR-155 expression was demonstrated to be effective in preventing processes involved in the pathophysiology of MS. This review aimed to support the better understanding the great role of miR-155 dysregulation in various aspects of MS pathophysiology and highlight future perspectives for this molecule.

Existing Drugs Considered as Promising in COVID-19 Therapy.

COVID-19 is a respiratory disease caused by newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease at first was identified in the city of Wuhan, China in December 2019. Being a human infectious disease, it causes high fever, cough, breathing problems. In some cases it can be fatal, especially in people with comorbidities like heart or kidney problems and diabetes. The current COVID-19 treatment is based on symptomatic therapy, so finding an appropriate drug against COVID-19 remains an immediate and crucial target for the global scientific community. Two main processes are thought to be responsible for the COVID-19 pathogenesis. In the early stages of infection, disease is determined mainly by virus replication. In the later stages of infection, by an excessive immune/inflammatory response, leading to tissue damage. Therefore, the main treatment options are antiviral and immunomodulatory/anti-inflammatory agents. Many clinical trials have been conducted concerning the use of various drugs in COVID-19 therapy, and many are still ongoing. The majority of trials examine drug reposition (repurposing), which seems to be a good and effective option. Many drugs have been repurposed in COVID-19 therapy including remdesivir, favipiravir, tocilizumab and baricitinib. The aim of this review is to highlight (based on existing and accessible clinical evidence on ongoing trials) the current and available promising drugs for COVID-19 and outline their characteristics.

The Impact of SARS-CoV-2 Infection on the Development of Neurodegeneration in Multiple Sclerosis.

The novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global challenge. Currently, there is some information on the consequences of COVID-19 infection in multiple sclerosis (MS) patients, as it is a newly discovered coronavirus, but its far-reaching effects on participation in neurodegenerative diseases seem to be significant. Recent cases reports showed that SARS-CoV-2 may be responsible for initiating the demyelination process in people who previously had no symptoms associated with any nervous system disorders. It is presently known that infection of SARS-CoV-2 evokes cytokine storm syndrome, which may be one of the factors leading to the acute cerebrovascular disease. One of the substantial problems is the coexistence of cerebrovascular disease and MS in an individual's life span. Epidemiological studies showed an enhanced risk of death rate from vascular disabilities in MS patients of approximately 30%. It has been demonstrated that patients with severe SARS-CoV-2 infection usually show increased levels of D-dimer, fibrinogen, C-reactive protein (CRP), and overactivation of blood platelets, which are essential elements of prothrombotic events. In this review, the latest knowledge gathered during an ongoing pandemic of SARS-CoV-2 infection on the neurodegeneration processes in MS is discussed.

Biomarkers of Angiogenesis and Neuroplasticity as Promising Clinical Tools for Stroke Recovery Evaluation.

Several key issues impact the clinical practice of stroke rehabilitation including a patient's medical history, stroke experience, the potential for recovery, and the selection of the most effective type of therapy. Until clinicians have answers to these concerns, the treatment and rehabilitation are rather intuitive, with standard procedures carried out based on subjective estimations using clinical scales. Therefore, there is a need to find biomarkers that could predict brain recovery potential in stroke patients. This review aims to present the current state-of-the-art stroke recovery biomarkers that could be used in clinical practice. The revision of biochemical biomarkers has been developed based on stroke recovery processes: angiogenesis and neuroplasticity. This paper provides an overview of the biomarkers that are considered to be ready-to-use in clinical practice and others, considered as future tools. Furthermore, this review shows the utility of biomarkers in the development of the concept of personalized medicine. Enhancing brain neuroplasticity and rehabilitation facilitation are crucial concerns not only after stroke, but in all central nervous system diseases.

Unusual Bioactive Compounds with Antioxidant Properties in Adjuvant Therapy Supporting Cognition Impairment in Age-Related Neurodegenerative Disorders.

Cognitive function decline is strictly related to age, resulting in the loss of the ability to perform daily behaviors and is a fundamental clinical neurodegeneration symptom. It has been proven that an adequate diet, comprehensive nutrition, and a healthy lifestyle may significantly inhibit neurodegenerative processes, improving cognitive functions. Therefore, intensive research has been conducted on cognitive-enhancing treatment for many years, especially with substances of natural origin. There are several intervention programs aimed at improving cognitive functions in elderly adults. Cognitive functions depend on body weight, food consumed daily, the quality of the intestinal microflora, and the supplements used. The effectiveness in the prevention of dementia is particularly high before the onset of the first symptoms. The impact of diet and nutrition on age-associated cognitive decline is becoming a growing field as a vital factor that may be easily modified, and the effects may be observed on an ongoing basis. The paper presents a review of the latest preclinical and clinical studies on the influence of natural antioxidants on cognitive functions, with particular emphasis on neurodegenerative diseases. Nevertheless, despite the promising research results in animal models, the clinical application of natural compounds will only be possible after solving a few challenges.

The Role of Supplementation with Natural Compounds in Post-Stroke Patients.

Malnutrition is a serious problem in post-stroke patients. Importantly, it intensifies with hospitalization, and is related to both somatic and psychological reasons, as well as is associated with the insufficient knowledge of people who accompany the patient. Malnutrition is a negative prognostic factor, leading to a reduction in the quality of life. Moreover, this condition significantly extends hospitalization time, increases the frequency of treatment in intensive care units, and negatively affects the effectiveness of rehabilitation. Obtaining growing data on the therapeutic effectiveness of new compounds of natural origin is possible through the use of pharmacodynamic and analytical methods to assess their therapeutic properties. The proper supply of nutrients, as well as compounds of natural origin, is an important element of post-stroke therapy, due to their strong antioxidant, anti-inflammatory, neuroprotective and neuroplasticity enhancing properties. Taking the above into account, in this review we present the current state of knowledge on the benefits of using selected substances of natural origin in patients after cerebral stroke.

Th17-Related Cytokines as Potential Discriminatory Markers between Neuromyelitis Optica (Devic's Disease) and Multiple Sclerosis-A Review.

Multiple sclerosis (MS) and Devic's disease (NMO; neuromyelitis optica) are autoimmune, inflammatory diseases of the central nervous system (CNS), the etiology of which remains unclear. It is a serious limitation in the treatment of these diseases. The resemblance of the clinical pictures of these two conditions generates a partial possibility of introducing similar treatment, but on the other hand, a high risk of misdiagnosis. Therefore, a better understanding and comparative characterization of the immunopathogenic mechanisms of each of these diseases are essential to improve their discriminatory diagnosis and more effective treatment. In this review, special attention is given to Th17 cells and Th17-related cytokines in the context of their potential usefulness as discriminatory markers for MS and NMO. The discussed results emphasize the role of Th17 immune response in both MS and NMO pathogenesis, which, however, cannot be considered without taking into account the broader perspective of immune response mechanisms.

Increased Pro-Thrombotic Platelet Activity Associated with Thrombin/PAR1-Dependent Pathway Disorder in Patients with Secondary Progressive Multiple Sclerosis.

Epidemiological studies confirm the high risk of ischemic events in multiple sclerosis (MS) that are associated with increased pro-thrombotic activity of blood platelets. The most potent physiological platelet agonist is thrombin, which activates platelets via cleavage of specific protease-activated receptors (PARs). Our current study is aimed to determine the potential genetics and proteomic abnormalities of PAR1 in both platelets and megakaryocytes, which may have thromboembolic consequences in the course of MS. The obtained results were correlated with the expression level of platelet and megakaryocyte transcripts for APOA1 and A2M genes encoding atherosclerosis biomarkers: apolipoprotein A1 (ApoA1) and α-2-macroglobulin (α2M), respectively. Moreover, PAR1 functionality in MS platelets was assessed by flow cytometry, determining the level of platelet-platelet and platelet-leukocyte aggregates, platelet microparticles and surface expression of P-selectin. As a PAR1 agonist, the synthetic TRAP-6 peptide was used, which made it possible to achieve platelet activation in whole blood without triggering clotting. Comparative analyses showed an elevated level of platelet activation markers in the blood of MS patients compared to controls. The mRNA expression of gene coding α2M was upregulated, whilst ApoA1 was down-regulated, both in platelets and megakaryocytes from MS patients. Furthermore, we observed an increase in both mRNA expression and surface density of PAR1 in platelets and megakaryocytes in MS compared to controls. Both the level of platelet activation markers and PAR1 expression showed a high correlation with the expression of transcripts for APOA1 and A2M genes.

Metformin as a Potential Agent in the Treatment of Multiple Sclerosis.

Metformin, a synthetic derivative of guanidine, is commonly used as an oral antidiabetic agent and is considered a multi-vector application agent in the treatment of other inflammatory diseases. Recent studies have confirmed the beneficial effect of metformin on immune cells, with special emphasis on immunological mechanisms. Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by various clinical courses. Although the pathophysiology of MS remains unknown, it is most likely a combination of disturbances of the immune system and biochemical pathways with a disruption of blood-brain barrier (BBB), and it is strictly related to injury of intracerebral blood vessels. Metformin has properties which are greatly desirable for MS therapy, including antioxidant, anti-inflammatory or antiplatelet functions. The latest reports relating to the cardiovascular disease confirm an increased risk of ischemic events in MS patients, which are directly associated with a coagulation cascade and an elevated pro-thrombotic platelet function. Hence, this review examines the potential favourable effects of metformin in the course of MS, its role in preventing inflammation and endothelial dysfunction, as well as its potential antiplatelet role.

The GPR17 Receptor-A Promising Goal for Therapy and a Potential Marker of the Neurodegenerative Process in Multiple Sclerosis.

One of the most important goals in the treatment of demyelinating diseases such as multiple sclerosis (MS) is, in addition to immunomodulation, reconstruction of the lost myelin sheath. The modulator of the central nervous system myelination is the metabotropic receptor coupled to the G-protein: GPR17. GPR17 receptors are considered to be sensors of local damage to the myelin sheath, and play a role in the reconstruction and repair of demyelinating plaques caused by ongoing inflammatory processes. GPR17 receptors are present on nerve cells and precursor oligodendrocyte cells. Under physiological conditions, they are responsible for the differentiation and subsequent maturation of oligodendrocytes, while under pathological conditions (during damage to nerve cells), their expression increases to become mediators in the demyelinating processes. Moreover, they are essential not only in both the processes of inducing damage and the death of neurons, but also in the local repair of the damaged myelin sheath. Therefore, GPR17 receptors may be recognized as the potential goal in creating innovative therapies for the treatment of the neurodegenerative process in MS, based on the acceleration of the remyelination processes. This review examines the role of GRP17 in pathomechanisms of MS development.

Various Aspects of a Gene Editing System-CRISPR-Cas9.

The discovery of clustered, regularly interspaced short palindromic repeats (CRISPR) and their cooperation with CRISPR-associated (Cas) genes is one of the greatest advances of the century and has marked their application as a powerful genome engineering tool. The CRISPR-Cas system was discovered as a part of the adaptive immune system in bacteria and archaea to defend from plasmids and phages. CRISPR has been found to be an advanced alternative to zinc-finger nucleases (ZFN) and transcription activator-like effector nucleases (TALEN) for gene editing and regulation, as the CRISPR-Cas9 protein remains the same for various gene targets and just a short guide RNA sequence needs to be altered to redirect the site-specific cleavage. Due to its high efficiency and precision, the Cas9 protein derived from the type II CRISPR system has been found to have applications in many fields of science. Although CRISPR-Cas9 allows easy genome editing and has a number of benefits, we should not ignore the important ethical and biosafety issues. Moreover, any tool that has great potential and offers significant capabilities carries a level of risk of being used for non-legal purposes. In this review, we present a brief history and mechanism of the CRISPR-Cas9 system. We also describe on the applications of this technology in gene regulation and genome editing; the treatment of cancer and other diseases; and limitations and concerns of the use of CRISPR-Cas9.

Molecular Aspects of Mycotoxins-A Serious Problem for Human Health.

Mycotoxins are toxic fungal secondary metabolities formed by a variety of fungi (moulds) species. Hundreds of potentially toxic mycotoxins have been already identified and are considered a serious problem in agriculture, animal husbandry, and public health. A large number of food-related products and beverages are yearly contaminated by mycotoxins, resulting in economic welfare losses. Mycotoxin indoor environment contamination is a global problem especially in less technologically developed countries. There is an ongoing effort in prevention of mould growth in the field and decontamination of contaminated food and feed in order to protect human and animal health. It should be emphasized that the mycotoxins production by fungi (moulds) species is unavoidable and that they are more toxic than pesticides. Human and animals are exposed to mycotoxin via food, inhalation, or contact which can result in many building-related illnesses including kidney and neurological diseases and cancer. In this review, we described in detail the molecular aspects of main representatives of mycotoxins, which are serious problems for global health, such as aflatoxins, ochratoxin A, T-2 toxin, deoxynivalenol, patulin, and zearalenone.

Increased level of fibrinogen chains in the proteome of blood platelets in secondary progressive multiple sclerosis patients.

Epidemiological studies indicate a high risk of stroke, heart failure and myocardial infarction in patients with multiple sclerosis, especially in its secondary progressive (SPMS) phase. Some ischaemic events are directly associated with abnormal platelet functions and their prothrombotic activity. Recent reports, including this study, confirm the increased activation of circulating platelets in SPMS, and also show increased platelet reactivity, among other responses, as well as strong aggregation. In this current study, we conducted a comparative analysis of the platelet proteome in SPMS patients and in healthy controls, to demonstrate the quantitative and qualitative differences likely to affect functional changes observed in SPMS. During densitometry evaluation of 2-D fluorescence difference gel electrophoresis, we observed differences between the electrophoretic patterns of SPMS platelets and the control samples. To determine a detailed characterisation of the proteome changes in the SPMS patients' blood platelets, in the next stage, we performed mass spectrometry of selected spots and indicated the increased presence of four proteins (fibrinogen, α-2 macroglobulin, septin-14 and tubulin ß-1 chain). The most important of these is the increased amount of prothrombotic protein, fibrinogen, which seems to confirm the accuracy of the imaging and potentially explains the increased risk of platelet-origin thrombotic events. This study provides new knowledge of the potential existence of the molecular mechanisms responsible for the acceleration of the platelet pro-coagulant function in SPMS. This can help to identify new targets for therapy, which can then be used not only in the second stage of the disease.