Human herpesvirus-6 and-7 in the brain microenvironment of persons with neurological pathology and healthy people

Funding Information: This research was supported by the Latvian Council of Science Grant Nr.478/2012 and fundamental and applied research project of the Latvian Council of Science LZP-2020/2-0069. The authors would like to thank Svetlana Chapenko for nPCR data curation, and Silvija Roga, certified pathologist, and Ojars Teteris certified pathologist, for collecting of study material. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.During persistent human beta-herpesvirus (HHV) infection, clinical manifestations may not appear. However, the lifelong influence of HHV is often associated with pathological changes in the central nervous system. Herein, we evaluated possible associations between immunoex-pression of HHV-6,-7, and cellular immune response across different brain regions. The study aimed to explore HHV-6,-7 infection within the cortical lobes in cases of unspecified encephalo-pathy (UEP) and nonpathological conditions. We confirmed the presence of viral DNA by nPCR and viral antigens by immunohistochemistry. Overall, we have shown a significant increase (p < 0.001) of HHV antigen expression, especially HHV-7 in the temporal gray matter. Although HHV-infected neurons were found notably in the case of HHV-7, our observations suggest that higher (p < 0.001) cell tropism is associated with glial and endothelial cells in both UEP group and controls. HHV-6, predominantly detected in oligodendrocytes (p < 0.001), and HHV-7, predominantly detected in both astrocytes and oligodendrocytes (p < 0.001), exhibit varying effects on neural homeostasis. This indicates a high number (p < 0.001) of activated microglia observed in the temporal lobe in the UEP group. The question remains of whether human HHV contributes to neurological diseases or are markers for some aspect of the disease process.Peer reviewe

Curcumin effect on copper transport in HepG2 cells

Funding Information: Acknowledgments: The authors appreciate the support and advice of Uldis Berkis. The authors gratefully acknowledge the financial support from EU 7th Framework program project “Unlocking infectious disease research potential at R¯ıga Stradin,š University” (BALTINFECT) (grant agreement No. 316275). Publisher Copyright: © 2018 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.Background and Objective: In Wilson’s disease, copper metabolism is impaired due to defective copper transporting protein ATP7B, resulting in copper accumulation in liver and brain and causing damage to liver and brain tissues. Published data suggest that one of the possible treatments for Wilson’s disease is curcumin—a compound found in the root of Curcuma longa. In this study, we tested whether curcumin affects copper transport and excretion in HepG2 hepatocytes carrying wildtype ATP7B. Materials and Methods: We examined the impact of 5 µM and 25 µM curcumin on the transport of copper in HepG2 cells incubated with 20 µM and 100 µM CuCl2, as well as copper excretion from cells. First, immunofluorescent staining and co-localization analysis were carried out in HepG2 cells using confocal laser scanning microscope and Nikon NIS Elements software. Second, a concentration of copper extracted into cell culture medium was determined using atomic absorption spectrometry. Results: The analysis of the co-localization between Golgi complex and ATP7B revealed that both 5 µM and 25 µM doses of curcumin improve the ability of liver cells to transport copper to plasma membrane at 20 µM CuCl2, but not at 100 µM CuCl2 concentration. However, atomic absorption spectrometry showed that curcumin rather promotes copper absorption into liver cell line HepG2 than excretion of it. Conclusions: Curcumin accelerates the transport of copper within liver cells, but does not promote copper excretion from HepG2 cells.publishersversionPeer reviewe

Mildronate and its Neuroregulatory Mechanisms : Targeting the Mitochondria, Neuroinflammation, and Protein Expression

This review for the first time summarizes the data obtained in the neuropharmacological studies of mildronate, a drug previously known as a cardioprotective agent. In different animal models of neurotoxicity and neurodegenerative diseases, we demonstrated its neuroprotecting activity. By the use of immunohistochemical methods and Western blot analysis, as well as some selected behavioral tests, the new mechanisms of mildronate have been demonstrated: a regulatory effect on mitochondrial processes and on the expression of nerve cell proteins, which are involved in cell survival, functioning, and inflammation processes. Particular attention is paid to the capability of mildronate to stimulate learning and memory and to the expression of neuronal proteins involved in synaptic plasticity and adult neurogenesis. These properties can be useful in neurological practice to protect and treat neurological disorders, particularly those associated with neurodegeneration and a decline in cognitive functions.publishersversionPeer reviewe

Potential of activin b as a clinical biomarker in myalgic encephalomyelitis/chronic fatigue syndrome (Me/cfs)

Funding Information: This research was funded by the Latvian Science Council?s Fundamental and Applied Research project, grant number LZP?2019/1?0380. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Reliable serum biomarkers are of immense need for diagnostic purposes of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—a disabling and complex disease for which diagnosis is mainly based on clinical symptoms. The aim of this study was to evaluate a possible diagnostic potential of activin B by directly comparing 134 cases of ME/CFS with 54 healthy controls. Analyses of human activin B level in plasma samples were performed using a validated human activin B ELISA assay. The results of the study show that activin B levels did not differ statistically significantly between ME/CFS patients and healthy controls (p = 0.6511). No gender or age‐related differences in activin B levels were observed in the ME/CFS group and healthy controls. The level of activin B tended to decrease with increasing visual analogue scale score (r = −0.2004; p = 0.5085) nevertheless the results obtained so far does not support the clinical utility of activin B as a bi-omarker for ME/CFS.Peer reviewe

HDL-C role in acquired aortic valve stenosis patients and its relationship with oxidative stress

Publisher Copyright: © 2019 by the authors. Licensee MDPI, Basel, Switzerland.Background and objectives: Mechanical stress is currently considered as the main factor promoting calcific aortic valve stenosis (AS) onset. It causes endothelial damage and dysfunction. The chronic inflammatory process causes oxidative stress. Oxidative stress-induced high-density lipoprotein cholesterol (HDL-C) dysfunction is an important component of the development of AS. The aim of the study was to evaluate the role of HDL-C in AS patients in three severity grades and in relation to the biomarkers of oxidative stress, thioredoxin reductase 1 (TrxR1) and myeloperoxidase (MPO). Materials and Methods: 18 patients with mild, 19 with moderate. and 15 with severe AS were included in the study, and 50 individuals were enrolled in the control group. Stenosis severity was determined by echocardiography. The TrxR1 and MPO were analyzed by ELISA, and HDL-C by commercially available tests. Data were analyzed using GraphPad Prism 8. Results: HDL-C in AS patients vs. control substantially decreases and this decline was observed in all three AS severity groups: mild (p = 0.018), moderate (p = 0.0002), and severe (p = 0.004). In both the control and the stenosis group, the HDL-C was higher in women than in men. In comparison to control, the HDL-C level was lower in the AS group, and more pronounced in women (p = 0.0001) than in men (p = 0.049). A higher TrxR1 level was observed in patients with mild (p = 0.0001) and severe AS (p = 0.047). However, a clear correlation between TrxR1 and HDL-C was not obtained. Analysis of MPO showed differences in all severity grades vs. control (p = 0.024 mild stenosis; p = 0.002 moderate stenosis; p = 0.0015 severe stenosis). A negative correlation (p = 0.047; rp = −0.28) was found between MPO and HDL-C, which confirms the adverse effects of MPO resulting in HDL-C dysfunction. Conclusions: In this study, we justified HDL-C level association with AS development process. The results unequivocally substantiated the association between HDL-C and AS in all severity grades in women, but only in moderate AS for men, which we explained by the small number of men in the groups. The obtained correlation between the HDL-C and MPO levels, as well as the concurrent decrease in the HDL-C level and increase in the TrxR1 level, indicate in general an HDL-C association with oxidative stress in AS patients.publishersversionPeer reviewe

Mildronate's protective effects in the peripheral nervous system : Stavudine-induced neuropathy and formalin-induced inflammation

Funding Information: This work was supported by the Latvian Council of Science Grant Nr. 05-1418; ESF Grant ESS2004/3; Contract No. 453, between the Latvian Institute of Organic Synthesis and the Joint Stock Company “Grindex”; Contract No. 2377, between the University of Latvia and the Joint Stock Company “Grindex”; and a L’ORÉAL Latvian “For Women In Science” fellowship with the support of the Latvian National Commission for UNESCO and the Latvian Academy of Sciences.Mildronate, previously known as a cardioprotective drug, recently was found to normalise mitochondrial processes by preventing the dysfunction of complex I in rat liver mitochondria. Previously we have shown also the ability of mildronate to prevent pathologies in the central nervous system by normalizing the expression of different signalling molecules in brain tissue. This allowed us to suggest that mildronate may possess a beneficial role also in peripheral nervous system pathologies. The present study was designed to assess the peripheral tissue damage caused by anti-HIV drug stavudine, as well as pain and inflammation caused by formalin. For this demonstration, we investigated the influence of mildronate: (1) on decreased myelin expression and increased neuron degeneration in rat sciatic nerve tissue caused by stavudine; and (2) on formalin-induced inflammation in mice. We found that mildronate protected the stavudine-induced degeneration of neurons in rat peripheral sciatic nerve without a significant influence on demyelination. In a formalin test, mildronate showed anti-inflammatory action comparable to that of indomethacin, a reference drug. The present results show that mildronate is capable of regulating peripheral nerve damage and peripheral inflammatory responses. We suggest that the multifunctional effects of mildronate can be attributed to its ability to regulate mitochondrial processes. The obtained data indicate protective effects of mildronate in different peripheral neurological pathologies.publishersversionPeer reviewe

Effect of Human Herpesviruses 6 and 7 Infection on the Clinical Course of Rheumatoid Arthritis

Publisher Copyright: © 2016 by Anda Kadiša. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.Rheumatoid arthritis (RA) is a chronic systemic autoimmune inflammatory disease affecting joints and causing symmetrical chronic progressive aseptic synovitis and erosive-destructive changes. Viruses and viral infections are considered to be the main risk factors for autoimmune disease development (especially for individuals with genetic predisposition). The goal of this study was to evaluate the frequency of HHV-6 and HHV-7 persistent infection and its activity phase in RA and osteoarthritis (OA) patients, and healthy persons. We examined also the influence of HHV-6 and-7 infections on RA activity, aggressiveness, radiographical stage, and frequency of complications as well as the presence of HHV-6 infection markers in synovial fluid and synovial tissues of RA joints of affected patients. Despite the lack of significant correlation between frequency of persistent single HHV-6, single HHV-7, and concurrent HHV-6 and HHV-7 infection and RA clinical course, we found that both active and latent HHV-6 and/or HHV-7 infection increased RA activity and progression in several clinical and laboratory parameters. Regarding the severity of the course of RA, we observed also a high prevalence of RA complications in the patient group with active single HHV-6 infection and also a more severe radiographical stage in RA patients with active concurrent HHV-6 and HHV-7 infection. Moreover, viral infection markers were found in synovial fluid and synovial tissues of affected joints of RA patients. This suggests that HHV-6 and/or HHV-7 infection has effect on the disease clinical course, but virus reactivation may be a consequence of immunosuppressive treatment.Peer reviewe

Plasma levels of Th17-associated cytokines and selenium status in autoimmune thyroid diseases

© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.INTRODUCTION: The contribution of Th17 cytokines to autoimmune thyroid disease (AITD) is generally accepted. However, the roles of Th17 cells in the initiation and progression of Hashimoto's thyroiditis (HT) and Graves' disease (GD) remain unclear. Selenium deficiency, along with genetic predisposition and environmental factors, may have a role in thyroid autoimmunity. AIM: We aimed to assess (1) the Th17 immune response by measuring plasma levels of Th17- and Treg-associated cytokines and (2) the selenium status in treatment-naïve Latvian patients with newly diagnosed GD or HT. METHODS: Eleven GD patients, 41 HT patients, and 26 healthy subjects were recruited for this study. Plasma levels of IL-17a, IL-22, IL-23, IL-6, and IL-10 were detected by xMAP technology, while selenium was detected fluorometrically. RESULTS AND CONCLUSIONS: No significant differences in IL-17a, IL-22, IL-23, IL-6, or IL-10 levels were found among the HT patients, GD patients, and controls. In the HT patients, IL-17a levels were positively correlated with IL-22, IL-23, IL-6, and IL-10, while IL-22 was correlated with IL-6, IL-23, and IL-10. In the GD patients, IL-17a levels were positively correlated with IL-22, IL-23, and IL-10; IL-22 was positively correlated with IL-23, IL-6, and IL-10; FT3 was positively correlated with IL-17a, IL-23, and IL-10; and FT4 was positively correlated with IL-17a and IL-10 levels. Plasma selenium levels were negatively correlated with antithyroid peroxidase antibody titers in the HT patients. Although no difference in selenium levels was observed between the AITD patients and controls, the selenium status of the Latvian patients with GD or HT was at a suboptimal level.publishersversionPeer reviewe

Presence of B19V in Patients with Thyroid Gland Disorders

Background and Objectives: Viral infections are frequently cited as a major environmental factor implicated in thyroid gland diseases. This work aimed to estimate the presence of B19V infection in patients with thyroid gland disorders. Materials and Methods: Thyroid gland tissue and blood samples of 50 patients with autoimmune thyroid gland diseases (AITDs), 76 patients with non-autoimmune thyroid gland diseases (non-AITDs), and 35 deceased subjects whose histories did not show any autoimmune or thyroid diseases (control group) were enrolled in the study. Virus-specific IgM and IgG were detected using ELISA, and the presence and viral load of B19V in the tissue and blood were detected using PCRs. Results: B19V IgG antibodies were detected in 35/50 AITDs patients and in 51/76 non-AITDs patients, and B19V IgM antibodies were detected in 1/50 patients with AITDs and in none of the 76 patients with non-AITDs. The B19V NS sequence was found in the tissue DNA of 10/50 patients with AITDs, in 30/76 with non-AITDs, and in 1/35 control group individuals. The median B19V load in the tissue of patients with AITDs and non-AITDs was 423.00 copies/µg DNA (IQR: 22.50–756.8) and 43.00 copies/µg DNA (IQR: 11.50–826.5), respectively. The viral load in one of the 35 nPCR B19V-positive thyroid tissue samples from the deceased subjects was 13.82 copies/µg DNA. The viral load in the tissue of patients with AITDs was higher than in whole blood, which possibly indicates B19V persistency in thyrocytes (p = 0.0076). Conclusion: The fact that the genoprevalence of B19V NS was significantly higher in patients with non-AITDs compared to the control group and in the thyroid gland tissue of patients with AITDs, and that the non-AITDs viral load was higher than in tissue derived from the control group individuals, suggest the possibility that B19V infection could be involved in the development of thyroid gland diseases

DNA immunization site determines the level of gene expression and the magnitude, but not the type of the induced immune response

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