Molecular Biomarkers and Their Implications for the Early Diagnosis of Selected Neurodegenerative Diseases.

The degeneration and dysfunction of neurons are key features of neurodegenerative diseases (NDs). Currently, one of the main challenges facing researchers and clinicians is the ability to obtain reliable diagnostic tools that will allow for the diagnosis of NDs as early as possible and the detection of neuronal dysfunction, preferably in the presymptomatic stage. Additionally, better tools for assessing disease progression in this group of disorders are also being sought. The ideal biomarker must have high sensitivity and specificity, be easy to measure, give reproducible results, and reflect the disease progression. Molecular biomarkers include miRNAs and extracellular microvesicles known as exosomes. They may be measured in two extracellular fluids of the highest importance in NDs, i.e., cerebrospinal fluid (CSF) and blood. The aim of the current review is to summarize the pathophysiology of the four most frequent NDs-i.e., Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)-as well as current progress in the research into miRNAs as biomarkers in these major neurodegenerative diseases. In addition, we discuss the possibility of using miRNA-based therapies in the treatment of neurodegenerative diseases, and present the limitations of this type of therapy.

Sensitisation and allergic reactions to alpha-1,3-galactose in Podlasie, Poland, an area endemic for tick-borne infections.

PURPOSE: Ticks transmit several pathogens and seem implicated in the production of specific IgE antibodies to alpha-1,3-galactose (α-gal sIgE). They cause delayed and immediate allergy to mammalian meat and medication including antivenoms, vaccines and monoclonal antibodies. METHODS: We assessed the prevalence of α-gal sIgE in forest workers and healthy controls in the Podlasie voivodeship, north-eastern Poland; the relationship between α-gal sIgE and allergy to α-gal-containing products; the correlation between α-gal sIgE and anti-Borrelia burgdorferi and anti-tick-borne encephalitis virus (TBEV) antibodies; the relationship between α-gal sIgE and markers of infection with lesser-known pathogens transmitted by ticks such as Anaplasma phagocytophilum. RESULTS: Production of α-gal sIgE was closely related to tick bites. The odds ratio for detectable α-gal sIgE was 9.31 times higher among people with a history of tick bites (OR 9.3; p < .05). There was no correlation with the history of TBE, Lyme disease or human granulocytic anaplasmosis. However, serum α-gal sIgE correlated with anti-TBEV IgM antibodies in CSF. There was a strong correlation between α-gal sIgE and total IgE and sIgE to pork and beef. CONCLUSIONS: Our data support the link between I.ricinus ticks and the production of α-gal sIgE and confirm that the pathogens carried by ticks we examined for do not seem implicated in this immune response.

The Role of Gut Microbiota and Gut-Brain Interplay in Selected Diseases of the Central Nervous System.

The gut microbiome has attracted increasing attention from researchers in recent years. The microbiota can have a specific and complex cross-talk with the host, particularly with the central nervous system (CNS), creating the so-called "gut-brain axis". Communication between the gut, intestinal microbiota, and the brain involves the secretion of various metabolites such as short-chain fatty acids (SCFAs), structural components of bacteria, and signaling molecules. Moreover, an imbalance in the gut microbiota composition modulates the immune system and function of tissue barriers such as the blood-brain barrier (BBB). Therefore, the aim of this literature review is to describe how the gut-brain interplay may contribute to the development of various neurological disorders, combining the fields of gastroenterology and neuroscience. We present recent findings concerning the effect of the altered microbiota on neurodegeneration and neuroinflammation, including Alzheimer's and Parkinson's diseases, as well as multiple sclerosis. Moreover, the impact of the pathological shift in the microbiome on selected neuropsychological disorders, i.e., major depressive disorders (MDD) and autism spectrum disorder (ASD), is also discussed. Future research on the effect of balanced gut microbiota composition on the gut-brain axis would help to identify new potential opportunities for therapeutic interventions in the presented diseases.

Pro- and Antiangiogenic Factors in Gliomas: Implications for Novel Therapeutic Possibilities.

Angiogenesis, a complex, multistep process of forming new blood vessels, plays crucial role in normal development, embryogenesis, and wound healing. Malignant tumors characterized by increased proliferation also require new vasculature to provide an adequate supply of oxygen and nutrients for developing tumor. Gliomas are among the most frequent primary tumors of the central nervous system (CNS), characterized by increased new vessel formation. The processes of neoangiogenesis, necessary for glioma development, are mediated by numerous growth factors, cytokines, chemokines and other proteins. In contrast to other solid tumors, some biological conditions, such as the blood-brain barrier and the unique interplay between immune microenvironment and tumor, represent significant challenges in glioma therapy. Therefore, the objective of the study was to present the role of various proangiogenic factors in glioma angiogenesis as well as the differences between normal and tumoral angiogenesis. Another goal was to present novel therapeutic options in oncology approaches. We performed a thorough search via the PubMed database. In this paper we describe various proangiogenic factors in glioma vasculature development. The presented paper also reviews various antiangiogenic factors necessary in maintaining equilibrium between pro- and antiangiogenic processes. Furthermore, we present some novel possibilities of antiangiogenic therapy in this type of tumors.

Cerebrospinal Fluid and Blood CX3CL1 as a Potential Biomarker in Early Diagnosis and Prognosis of Dementia.

BACKGROUND: A growing body of evidence highlights the crucial role of neuroinflammation and chemokine involvement in cognitive impairment pathophysiology. Fractalkine (CX3CL1) appears to be a relevant causative factor in the development of dementia, particularly at the early stages of the disease. However, limited data are available on the levels of CX3CL1 in the cerebrospinal fluid (CSF) and blood. Additionally, to date, its utility as a biomarker for MCI or AD has not been studied. OBJECTIVE: The aim of the present study was to evaluate the clinical utility of CX3CL1 in the early diagnosis of cognitive impairment. We also compared the diagnostic usefulness of CX3CL1 with other biomarkers associated with neuroinflammation. METHODS: A total of 60 patients with cognitive impairment, including 42 patients with AD and 18 subjects with MCI, as well as 20 cognitively healthy controls were enrolled in the study. CSF and blood concentrations of CX3CL1, CCL-2, and YKL-40 were measured by ELISA. RESULTS: Significantly higher CSF and blood concentrations of CX3CL1 were observed in MCI and AD patients compared to older individuals without cognitive impairment. The increase in the levels of CX3CL1 and YKL-40 in non-demented subjects was associated with MCI. The area under the ROC curve for CX3CL1 in MCI subjects was larger in comparison to classical AD markers. CONCLUSION: Presented results indicate a crucial role of CX3CL1 in the pathology of cognitive impairment and the potential usefulness of this protein in the early diagnosis of MCI and AD.

The Role of Selected Chemokines and Their Receptors in the Development of Gliomas.

Among heterogeneous primary tumors of the central nervous system (CNS), gliomas are the most frequent type, with glioblastoma multiforme (GBM) characterized with the worst prognosis. In their development, certain chemokine/receptor axes play important roles and promote proliferation, survival, metastasis, and neoangiogenesis. However, little is known about the significance of atypical receptors for chemokines (ACKRs) in these tumors. The objective of the study was to present the role of chemokines and their conventional and atypical receptors in CNS tumors. Therefore, we performed a thorough search for literature concerning our investigation via the PubMed database. We describe biological functions of chemokines/chemokine receptors from various groups and their significance in carcinogenesis, cancer-related inflammation, neo-angiogenesis, tumor growth, and metastasis. Furthermore, we discuss the role of chemokines in glioma development, with particular regard to their function in the transition from low-grade to high-grade tumors and angiogenic switch. We also depict various chemokine/receptor axes, such as CXCL8-CXCR1/2, CXCL12-CXCR4, CXCL16-CXCR6, CX3CL1-CX3CR1, CCL2-CCR2, and CCL5-CCR5 of special importance in gliomas, as well as atypical chemokine receptors ACKR1-4, CCRL2, and PITPMN3. Additionally, the diagnostic significance and usefulness of the measurement of some chemokines and their receptors in the blood and cerebrospinal fluid (CSF) of glioma patients is also presented.

The Role of Protein Misfolding and Tau Oligomers (TauOs) in Alzheimer's Disease (AD).

Although the causative role of the accumulation of amyloid ß 1-42 (Aß42) deposits in the pathogenesis of Alzheimer's disease (AD) has been under debate for many years, it is supposed that the toxicity soluble oligomers of Tau protein (TauOs) might be also the pathogenic factor acting on the initial stages of this disease. Therefore, we performed a thorough search for literature pertaining to our investigation via the MEDLINE/PubMed database. It was shown that soluble TauOs, especially granular forms, may be the most toxic form of this protein. Hyperphosphorylated TauOs can reduce the number of synapses by missorting into axonal compartments of neurons other than axon. Furthermore, soluble TauOs may be also responsible for seeding Tau pathology within AD brains, with probable link to AßOs toxicity. Additionally, the concentrations of TauOs in the cerebrospinal fluid (CSF) and plasma of AD patients were higher than in non-demented controls, and revealed a negative correlation with mini-mental state examination (MMSE) scores. It was postulated that adding the measurements of TauOs to the panel of CSF biomarkers could improve the diagnosis of AD.

Expression and Concentration of Matrix Metalloproteinase 9 and Tissue Inhibitor of Matrix Metalloproteinases 1 in Laryngeal Squamous Cell Carcinoma.

The aim of this study was to assess the expression of MMP-9 and TIMP-1 in cancerous tissue as well as in the serum and plasma concentrations of these proteins in patients with laryngeal cancer and compare the results to the inflammatory reaction in healthy subjects. Twenty-seven patients who were diagnosed with laryngeal carcinoma and selected for total laryngectomy were included in the study group. MMP-9 and TIMP-1 expression in tissues was assessed using immunohistochemical assays. Immunoenzymatic ELISA methods were used to measure MMP-9 and TIMP-1 concentrations in serum and plasma. MMP-9 and TIMP-1 were identified in tumor cells and in the tumor stroma compartment, as well as in macroscopically healthy mucous membrane. MMP-9 expression was more significant in tumor stroma than in the perimatrix of the mucous membrane (p = 0.047). TIMP-1 expression was significantly higher in the matrix and perimatrix of the mucous membrane than in cancer tissue (p = 0.0093) and the tumor stroma compartment (p < 0.0001). Expression of TIMP-1 was observed more frequently in tumors without infiltrated lymph nodes (p = 0.009). Serum concentrations of MMP-9 and TIMP-1 as well as plasma TIMP-1 concentration were significantly higher in the study group than in the control group (p = 0.0004, p = 0.002, and p = 0.0001, respectively). A significantly higher TIMP-1 level in plasma was found in patients with poorly differentiated tumors compared to G1 and G2 (p = 0.046). MMP-9/TIMP-1 rate in serum was significantly higher in the study group than in the control group. The balance between the level of MMP-9 and TIMP-1 is disrupted in laryngeal cancer. The significant correlation between TIMP-1 expression and the presence of lymph node metastases, as well as that between TIMP-1 plasma concentration and stage of cancer histological differentiation, might indicate the importance of this molecule as a prognostic factor during carcinogenesis.

Cellular Receptors of Amyloid ß Oligomers (AßOs) in Alzheimer's Disease.

It is estimated that Alzheimer's disease (AD) affects tens of millions of people, comprising not only suffering patients, but also their relatives and caregivers. AD is one of age-related neurodegenerative diseases (NDs) characterized by progressive synaptic damage and neuronal loss, which result in gradual cognitive impairment leading to dementia. The cause of AD remains still unresolved, despite being studied for more than a century. The hallmark pathological features of this disease are senile plaques within patients' brain composed of amyloid beta (Aß) and neurofibrillary tangles (NFTs) of Tau protein. However, the roles of Aß and Tau in AD pathology are being questioned and other causes of AD are postulated. One of the most interesting theories proposed is the causative role of amyloid β oligomers (AßOs) aggregation in the pathogenesis of AD. Moreover, binding of AßOs to cell membranes is probably mediated by certain proteins on the neuronal cell surface acting as AßO receptors. The aim of our paper is to describe alternative hypotheses of AD etiology, including genetic alterations and the role of misfolded proteins, especially Aß oligomers, in Alzheimer’s disease. Furthermore, in this review we present various putative cellular AßO receptors related to toxic activity of oligomers.

Amyloid ß oligomers (AßOs) in Alzheimer's disease.

The causative role of amyloid ß 1-42 (Aß42) aggregation in the pathogenesis of Alzheimer's disease (AD) has been under debate for over 25 years. Primarily, scientific efforts have focused on the dyshomeostasis between production and clearance of Aß42. This imbalance may result from mutations either in genes for the substrate, i.e., amyloid precursor protein or in genes encoding presenilin, the enzyme of the reaction that generates Aß42. Currently, it is supposed that soluble oligomers of amyloid beta (AßOs) and not fibrillar Aß42 within neuritic plaques may be the toxic factors acting on a very early stage of AD, perhaps even initiating pathological cascade. For example, soluble AßOs isolated from AD patients' brains reduced number of synapses, inhibited long-term potentiation, and enhanced long-term synaptic depression in brain regions responsible for memory in animal models of AD. Concentrations of AßOs in the cerebrospinal fluid (CSF) of AD patients are often reported higher than in non-demented controls, and show a negative correlation with mini-mental state examination scores. Furthermore, increased Aß42/oligomer ratio in the CSF of AD/MCI patients indicated that the presence of soluble AßOs in CSF may be linked to lowering of natively measured monomeric Aß42 by epitopes masking, and hence, concentrations of AßOs in the CSF are postulated to as useful AD biomarkers.

Soluble TREM-1 Serum Level can Early Predict Mortality of Patients with Sepsis, Severe Sepsis and Septic Shock.

Early prognostic prediction of sepsis is essential in adjusting therapeutic protocols to prevent deterioration and reduce mortality. We compared the predictive value of the serum concentration of the soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) for 28-day mortality and for the development of severe sepsis or septic shock on the third day with the levels of interleukin (IL)-6, C-reactive protein (CRP) and procalcitonin (PCT). The study was conducted on 85 patients with sepsis. sTREM-1, CRP, PCT and IL-6 concentrations were measured upon study inclusion (day 0) and on days 1, 2, 3 and 5. APACHE II, SAPS II and SOFA scores were analyzed. The sTREM-1 levels (pg/ml) were higher in non-survivors than in survivors at admission (773 vs. 391, p < 0.001) and on days 1, 2, 3 and 5. In predicting the development of severe sepsis, the highest AUCs were found for PCT (0.744, 95% CI 0.638-0.85) and sTREM-1 (0.664, 95% CI 0.55-0.778); and in septic shock prediction, for PCT (0.766, 95% CI 0.665-0.867) and IL-6 (0.707, 95% CI 0.595-0.819). sTREM-1 positively correlated with APACHE II, SAPS II and SOFA scores. At inclusion, significant AUC for predicting 28-day mortality was 0.772 for the sTREM-1 (95% CI 0.672-0.871), 0.858 for APACHE II (95% CI 0.768-0.948), 0.847 for SAPS II (95% CI 0.733-0.96), 0.806 for SOFA score (95% CI 0.698-0.915). sTREM-1 can early predict the 28-day sepsis mortality, although its effectiveness is lower in comparison with clinical severity scores.

YKL-40 as a Potential Biomarker and a Possible Target in Therapeutic Strategies of Alzheimer's Disease.

BACKGROUND: Growing body of evidence suggests that the pathogenesis of Alzheimer's disease (AD), a progressing neurodegenerative condition, is not limited to the neuronal compartment, but also involves various immunological mechanisms. Insoluble Aß aggregates in the brain can induce the activation of microglia, resulting in the synthesis of proinflammatory mediators, which further can stimulate astrocytic expression of YKL-40. Therefore, the aim of the current review is to present up-to-date data about the role of YKL-40 as a biomarker of AD as well as the possibility of therapeutic strategies targeting neuroinflammation. OBJECTIVE/METHODS: We searched PubMed articles for the terms "YKL-40", "neurodegeneration", "neuroinflammation" and "Alzheimer's disease", and included papers focusing on this review's scope. RESULTS: Recent studies indicate that CSF concentrations of YKL-40 were significantly higher in AD patients than in cognitively normal individuals and correlated with dementia biomarkers, such as tau proteins and amyloid beta. Determination of YKL-40 CSF concentration may be also helpful in differentiation between types of dementia and in the distinction of patients in the stable phase of MCI from those who progressed to dementia. Moreover, significantly increased levels of YKL-40 mRNA were found in AD brains in comparison with non-demented controls. Additionally, it was suggested that anti-inflammatory treatment might relief the symptoms of AD and slow its progression. CONCLUSION: Based on the recent knowledge, YKL-40 might be useful as a possible biomarker in the diagnosis and prognosis of AD. Modulation of risk factors and targeting of immune mechanisms, including systemic inflammation could lead to future preventive or therapeutic strategies for AD.

Neurobiochemical markers of brain ischemia in patients subjected to endoscopic skull base surgery under controlled hypotension.

BACKGROUND: Previous studies showed that moderate hypotension used to control bleeding during extensive endoscopic skull base procedures may cause a decrease in blood flow velocity (BFV) in the middle cerebral artery (MCA). We assessed possible metabolic consequences of reduction of arterial pressure applied in endoscopic skull base operations. METHODS: The serum concentrations of neuron specific enolase (NSE) and S-100 protein were measured in 15 patients operated on with reduced hemodynamic parameters (hypotensive group) and in 10 individuals operated on under normotensive conditions (normotensive group). Concentrations of NSE and S-100 were assessed preoperatively, as well as 24 h and 48 h postsurgery. Blood flow velocity in the MCA was evaluated with transcranial color Doppler sonography. RESULTS: An increase in NSE concentration was demonstrated in 5 out of 6 patients from the hypotensive group in whom BFV in the MCA dropped below normal reference range during surgery. An association between both phenomena was confirmed on statistical analysis. Neither the rise of S-100 concentration nor postoperative neurological deficits were detected in any of the studied individuals. CONCLUSIONS: Controlled hypotension during skull base procedures can result in postoperative increase in NSE serum concentration, a phenomenon suggestive for a degree of brain ischemia. Noticeably, the rise of NSE level occurs in subjects in whom BFV in the MCA decreased below normal reference limit during the surgery. Although neither S-100 protein level increase nor neurological deficits were detected postoperatively, further studies of the safety of hypotension applied during endoscopic skull base operations are warranted.

The Role of Visinin-Like Protein-1 in the Pathophysiology of Alzheimer's Disease.

Calcium ions are crucial in the process of information transmission and integration in the central nervous system (CNS). These ions participate not only in intracellular mechanisms but also in intercellular processes. The changes in the concentration of Ca2 + ions modulate synaptic transmission, whereas neuronal activity induces calcium ion waves. Disturbed calcium homeostasis is thought to be one of the main features in the pathophysiology of Alzheimer's disease (AD), and AD pathogenesis is closely connected to Ca2 + signaling pathways. The effects of changes in neuronal Ca2 + are mediated by neuronal calcium sensor (NCS) proteins. It has been revealed that NCS proteins, with special attention to visinin-like protein 1 (VILIP-1), might have a connection to the etiology of AD. In the CNS, VILIP-1 influences the intracellular neuronal signaling pathways involved in synaptic plasticity, such as cyclic nucleotide cascades and nicotinergic signaling. This particular protein is implicated in calcium-mediated neuronal injury as well. VILIP-1 also participates in the pathological mechanisms of altered Ca2 + homeostasis, leading to neuronal loss. These findings confirm the utility of VILIP-1 as a useful biomarker of neuronal injury. Moreover, VILIP-1 plays a vital role in linking calcium-mediated neurotoxicity and AD-type pathological changes. The disruption of Ca2 + homeostasis caused by AD-type neurodegeneration may result in the damage of VILIP-1-containing neurons in the brain, leading to increased cerebrospinal fluid levels of VILIP-1. Thus, the aim of this overview is to describe the relationships of the NCS protein VILIP-1 with the pathogenetic factors of AD and neurodegenerative processes, as well as its potential clinical usefulness as a biomarker of AD. Moreover, we describe the current and probable therapeutic strategies for AD, targeting calcium-signaling pathways and VILIP-1.

Evaluation of visinin-like protein 1 concentrations in the cerebrospinal fluid of patients with mild cognitive impairment as a dynamic biomarker of Alzheimer's disease.

BACKGROUND: The correlations between pathology of neurodegenerative diseases, especially Alzheimer's disease (AD), and concentrations of neuronal calcium sensor proteins, such as visinin-like protein 1 (VILIP-1), in cerebrospinal fluid (CSF) have been discussed in the literature but its utility as biomarker of AD in comparison with mild cognitive impairment (MCI) has not been studied yet. OBJECTIVE: Therefore, the aim of our study was to assess the clinical utility of the measurement of CSF concentrations of VILIP-1 in patients with AD, MCI subjects, and non-demented controls. The clinical and neuropsychological diagnoses were supported by CSF biomarkers of neurochemical dementia diagnostics: decreased concentrations of Aß1-42 and/or Aß42/40 ratio and increased concentrations of Tau and pTau181 proteins. METHODS: The study included 33 AD patients, 15 subjects with MCI, and 18 elderly individuals without cognitive deficits. The CSF concentrations of biomarkers tested were determined by using the ELISA method. RESULTS: Concentrations of VILIP-1 in CSF were significantly higher in AD patients compared to the MCI subjects and elderly individuals without cognitive impairment. Increased concentrations of VILIP-1 correlated significantly with reduced Aß42/40 ratio and higher pTau181 in AD group. CONCLUSION: Our findings suggest that VILIP-1 may play a role in the AD pathophysiology and is a good candidate for dynamic biomarker of AD, although this issue requires further investigation.

Concentrations of matrix metalloproteinases and their tissue inhibitors in the cerebrospinal fluid of patients with Alzheimer's disease.

BACKGROUND: A growing body of evidence shows the involvement of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in neurodegeneration processes, but reports of their concentrations in the cerebrospinal fluid (CSF) are inconsistent. OBJECTIVE: Therefore, the aim of our study was to evaluate the CSF concentrations of MMP-2, MMP-3, MMP-9, and their inhibitors (TIMP-1 and TIMP-2) in carefully selected groups of patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and non-demented controls, whose clinical and neuropsychological diagnoses were confirmed by the corresponding CSF biomarkers of neurochemical dementia diagnostics: decreased concentrations of Aß1-42 and/or Aß42/40 ratio, and increased concentrations of Tau and pTau181 proteins. METHODS: The study included 33 AD patients, 15 subjects with MCI, and 18 elderly individuals without cognitive deficits. The CSF concentrations of MMPs and TIMPs were determined with ELISAs. RESULTS: CSF concentrations of MMP-9 were significantly lower, and the concentrations of MMP-3 significantly higher in AD patients compared to the controls. Neither MMP-2 nor TIMPs showed significant changes among the groups investigated. CONCLUSION: Altered concentrations of two out of three MMPs investigated in this study suggest that this family of biomolecules may play a role in the AD pathophysiology. Further studies are needed to establish their potential diagnostic utility.

Serum levels and tissue expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinases 2 (TIMP-2) in colorectal cancer patients.

The objective of the study was the assessment of serum levels and tissue expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of matrix metalloproteinases 2 (TIMP-2) in patients with colorectal cancer (CRC). The study included 72 CRC patients and 68 healthy subjects. The serum levels of MMP-2 and TIMP-2 were measured using enzyme-linked immunosorbent assay (ELISA) method, whereas tissue expression of MMP-2 and TIMP-2 in cancer cells, interstitial inflammatory cells, and adjacent normal colorectal mucosa were examined by immunohistochemical staining of tumor samples. The serum levels of MMP-2 and TIMP-2 in cancer patients were significantly lower than those in control group, but the percentage of positive immunoreactivity of these proteins were higher in malignant and inflammatory cells as compared to normal tissue. There was a significant correlation between MMP-2 immunoreactivity in inflammatory cells and the presence of distant metastases and between TIMP-2 expression in inflammatory cells and tumor size, nodal involvement, and distant metastases. Area under receiver operating characteristic (ROC) curve (AUC) for serum MMP-2 was higher than for serum TIMP-2. Moreover, positive tissue expression of MMP-2 was a significant prognostic factor for CRC patients' survival. Our findings suggest that MMP-2 and TIMP-2 might play a role in the process of colorectal cancer invasion and metastasis, but the significance of their interactions with tumor stroma and interstitial inflammatory infiltration in colorectal neoplasia require further elucidation.

The role of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the pathophysiology of neurodegeneration: a literature study.

Matrix metalloproteinases (MMPs) and their natural tissue inhibitors (TIMPs) are involved in cell signaling processes and the release of extracellular matrix (ECM) and non-ECM molecules. Nonregulated MMP activity and an imbalance between metalloproteinases and their inhibitors might contribute to various disorders, including neurodegenerative diseases such as Alzheimer's disease (AD), which is the most common cause of dementia. There is a complex relationship between MMPs and TIMPs with AD. It has been shown that MMPs and TIMPs are localized in neuritic senile plaques and neurofibrillary tangles in the postmortem brains of patients with AD. Some MMPs have also been shown to induce tau aggregation and the formation of neurofibrillary tangles in vitro. Moreover, MMPs contribute to AD pathogenesis via the disruption of the blood-brain barrier and promotion of neurodegeneration. However, MMPs can degrade both soluble and fibrillar forms of amyloid-ß (Aß). It has also been shown that Aß enhances the expression of MMPs in neuroglial cultures and induces the release of TIMP-1 by brain cells. Inhibition of Aß-induced MMP activity resulted in an improvement of performance tests in mice. Moreover, simultaneous examination of MMP-9, MMP-2, and TIMP-1 in the CSF contributed to the ability to differentiate between AD and other types of dementia. Thus, the aim of this literature study was to describe the role of MMPs and TIMPs in neurodegeneration, as well as their potential usefulness as CSF or plasma biomarkers in the diagnosis of AD as well as other neurodegenerative disorders and vascular dementia.

Serum matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinases 2 in esophageal cancer patients.

The positive expression of MMP-2 and TIMP-2 were found in esophageal cancer (EC) tissue and correlated with cancer stage and clinico-pathological features of tumor and patients' survival. However, little is known about serum levels of those proteins in EC patients. The aim of the present study was to investigate the diagnostic significance of MMP-2 and TIMP-2 serum levels in EC patients in relation to clinico-pathological features of cancer. The study included 53 EC patients and 92 healthy controls. The serum levels of MMP-2, TIMP-2 and classical tumor markers CEA (carcinoembryonic antigen) and SCC (squamous cell carcinoma antigen) were assayed. The prognostic values and diagnostic criteria for the biomarkers tested were defined. Serum levels of MMP-2, TIMP-2 in EC patients were significantly lower, whereas CEA and SCC significantly higher than in control group. The diagnostic sensitivity of TIMP-2 (57%) was higher than those for other biomarkers tested and increased in combination with SCC (70%). Area under ROC curve for TIMP-2 (0.8698) was larger than for other proteins. In Cox's univariate analysis only SCC serum levels were significant prognostic factors for EC patients' survival. The results suggest the limited value of serum analyses of MMP-2 for tumor staging and prognosis in EC and the better usefulness of TIMP-2 than MMP-2 as a tumor marker in the diagnosis of EC, especially in combined use with SCC.

Interleukin 6 and C-reactive protein in esophageal cancer.

Esophageal cancer (EC) is one of the most aggressive malignant tumors of the gastrointestinal tract. It is well known that cancer initiation and tumor development are closely linked with inflammation. C-reactive protein (CRP) and interleukin-6 (IL-6) are acute-phase proteins involved in cancer development. It was suggested that CRP and IL-6 play potential roles in the growth and progression of malignant tumors, including EC. The aim of the study was to describe the significance of IL-6 and CRP in the development of esophageal cancer and to assess the potential role of their serum levels as prognostic indicators of EC patient's survival.