TNF-α/STAT1/CXCL10 mutual inflammatory axis that contributes to the pathogenesis of experimental models of multiple sclerosis: A promising signaling pathway for targeted therapies.

BACKGROUND: Identifying mutual neuroinflammatory axis in different experimental models of multiple sclerosis (MS) is essential to evaluate the de- and re-myelination processes and improve therapeutic interventions' reproducibility. METHODS: The expression profile data set of EAE (GSE47900) and cuprizone (GSE100663) models were downloaded from the Gene Expression Omnibus database. The R package and GEO2R software processed these raw chip data. Gene Ontology (GO) functional analysis, KEGG pathway analysis, and protein-protein interaction network analysis were performed to investigate interactions between common differentially expressed genes (DEGs) in all models. Finally, the ELISA method assessed the protein level of highlighted mutual cytokines in serum. RESULTS: Our data introduced 59 upregulated [CXCL10, CCL12, and GBP6 as most important] and 17 downregulated [Serpinb1a, Prr18, and Ugt8a as most important] mutual genes. The signal transducer and activator of transcription 1 (STAT1) and CXCL10 were the most crucial hub proteins among mutual upregulated genes. These mutual genes were found to be mainly involved in the TNF-α, TLRs, and complement cascade signaling, and animal models shared 26 mutual genes with MS individuals. Finally, significant upregulation of serum level of TNF-α/IL-1ß/CXCL10 cytokines was confirmed in all models in a relatively similar pattern. CONCLUSION: For the first time, our study revealed the common neuroinflammatory pathway in animal models of MS and introduced candidate hub genes for better evaluating the preclinical efficacy of pharmacological interventions and designing prospective targeted therapies.

Lipocalin-2 Deficiency Diminishes Canonical NLRP3 Inflammasome Formation and IL-1ß Production in the Subacute Phase of Spinal Cord Injury.

Spinal cord injury (SCI) results in the production of proinflammatory cytokines due to inflammasome activation. Lipocalin 2 (LCN2) is a small secretory glycoprotein upregulated by toll-like receptor (TLR) signaling in various cells and tissues. LCN2 secretion is induced by infection, injury, and metabolic disorders. In contrast, LCN2 has been implicated as an anti-inflammatory regulator. However, the role of LCN2 in inflammasome activation during SCI remains unknown. This study examined the role of Lcn2 deficiency in the NLRP3 inflammasome-dependent neuroinflammation in SCI. Lcn2-/- and wild-type (WT) mice were subjected to SCI, and locomotor function, formation of the inflammasome complex, and neuroinflammation were assessed. Our findings demonstrated that significant activation of the HMGB1/PYCARD/caspase-1 inflammatory axis was accompanied by the overexpression of LCN2 7 days after SCI in WT mice. This signal transduction results in the cleaving of the pyroptosis-inducing protein gasdermin D (GSDMD) and the maturation of the proinflammatory cytokine IL-1ß. Furthermore, Lcn2-/- mice showed considerable downregulation in the HMGB1/NLRP3/PYCARD/caspase-1 axis, IL-1ß production, pore formation, and improved locomotor function compared with WT. Our data suggest that LCN2 may play a role as a putative molecule for the induction of inflammasome-related neuroinflammation in SCI.

The interplay between tauopathy and aging through interruption of UPR/Nrf2/autophagy crosstalk in the Alzheimer's disease transgenic experimental models.

PURPOSE: Alzheimer's disease (AD) is the most common form of tauopathy that usually occursduring aging and unfolded protein response (UPR), oxidative stress and autophagy play a crucialrole in tauopathy-induced neurotoxicity. The aim of this study was to investigate the effects oftauopathy on normal brain aging in a Drosophila model of AD. METHOD: We investigated the interplay between aging (10, 20, 30, and 40 days) and human tauR406W (htau)-induced cell stress in transgenic fruit flies. RESULTS: Tauopathy caused significant defects in eye morphology, a decrease in motor function and olfactory memory performance (after 20 days), and an increase in ethanol sensitivity (after 30 days). Our results showed a significant increase in UPR (GRP78 and ATF4), redox signalling (p-Nrf2, total GSH, total SH, lipid peroxidation, and antioxidant activity), and regulatory associated protein of mTOR complex 1 (p-Raptor) activity in the control group after 40 days, while the tauopathy model flies showed an advanced increase in the above markers at 20 days of age. Interestingly, only the control flies showed reduced autophagy by a significant decrease in the autophagosome formation protein (dATG1)/p-Raptor ratio at 40 days of age. Our results were also confirmed by bioinformatic analysis of microarray data from tauPS19 transgenic mice (3, 6, 9, and 12 months), in which tauopathy increased expression of heme oxygenase 1, and glutamate-cysteine ligase catalytic subunit and promote aging in transgenic animals. CONCLUSIONS: Overall, we suggest that the neuropathological effects of tau aggregates may be accelerated brain aging, where redox signaling and autophagy efficacy play an important role.

Recent findings on the role of microRNAs in genetic kidney diseases.

BACKGROUND: MicroRNAs (miRNAs) are non-coding, endogenous, single-stranded, small (21-25 nucleotides) RNAs. Various target genes at the post-transcriptional stage are modulated by miRNAs that are involved in the regulation of a variety of biological processes such as embryonic development, differentiation, proliferation, apoptosis, inflammation, and metabolic homeostasis. Abnormal miRNA expression is strongly associated with the pathogenesis of multiple common human diseases including cardiovascular diseases, cancer, hepatitis, and metabolic diseases. METHODS AND RESULTS: Various signaling pathways including transforming growth factor-ß, apoptosis, and Wnt signaling pathways have also been characterized to play an essential role in kidney diseases. Most importantly, miRNA-targeted pharmaceutical manipulation has represented a promising new therapeutic approach against kidney diseases. Furthermore, miRNAs such as miR-30e-5p, miR-98-5p, miR-30d-5p, miR-30a-5p, miR-194-5p, and miR-192-5p may be potentially employed as biomarkers for various human kidney diseases. CONCLUSIONS: A significant correlation has also been found between some miRNAs and the clinical markers of renal function like baseline estimated glomerular filtration rate (eGFR). Classification of miRNAs in different genetic renal disorders may promote discoveries in developing innovative therapeutic interventions and treatment tools. Herein, the recent advances in miRNAs associated with renal pathogenesis, emphasizing genetic kidney diseases and development, have been summarized.

The neuroprotective effects of polyphenols, their role in innate immunity and the interplay with the microbiota.

Neurodegenerative disorders, particularly in the elderly population, represent one of the most pressing social and health-care problems in the world. Besides the well-established role of both oxidative stress and inflammation, alterations of the immune response have been found to be closely linked to the development of neurodegenerative diseases. Interestingly, various scientific evidence reported that an altered gut microbiota composition may contribute to the development of neuroinflammatory disorders. This leads to the proposal of the concept of the gut-brain-immune axis. In this scenario, polyphenols play a pivotal role due to their ability to exert neuroprotective, immunomodulatory and microbiota-remodeling activities. In the present review, we summarized the available literature to provide a scientific evidence regarding this neuroprotective and immunomodulatory effects and the interaction with gut microbiota of polyphenols and, the main signaling pathways involved that can explain their potential therapeutic application in neurodegenerative diseases.

Investigation of alpha-lipoic acid effect on memory impairment considering strain-dependent differences in mice.

AIMS: Memory impairment is regarded as one of the most challenging neurological disorders. The present study aimed to investigate behavioral and biochemical differences among similar mouse strains following Scopolamine (SCO) exposure as a widespread memory disturbing agent, and a supremely potent antioxidant, alpha-lipoic acid (ALA). MATERIALS AND METHODS: Three sets of mouse strains (i.e. SW, NMRI, and NIH mice) were subjected to 2 mg/kg intraperitoneal SCO and/or 50 mg/kg ALA 30 min before each Morris Water Maze (MWM) trial for five consecutive days. Upon completion of the trials, the hippocampal region of the animals was dissected for histopathological and biochemical analyses. KEY FINDINGS: The results exhibited significant impairments caused by SCO in behavioral tests, including probe test, escape latency, and distance traveled in two strains of NMRI and NIH. Nevertheless, at swimming speed, SCO had no meaningful effect on SW and NIH strains. The level of oxidative stress parameters including MDA, ROS, and SOD increased, FRAP and TTM levels related to the hippocampus decreased. There was also a significant increase in hippocampal acetylcholinesterase levels, ADP/ATP ratio, p-NFkB, and Cyt-c. Conversely, ALA administration resulted in a significant improvement in SCO-induced spatial learning and memory impairments only in the SW and NIH mice, which was associated with a significant reduction in hippocampal AChE activity, ADP/ATP ratio, ROS and MDA levels, and SOD activity. SIGNIFICANCE: In addition of highlighting the efficacious role of ALA in cognitive functions, the findings of this study signified the behavioral dissimilarities among similar animal strains in case of different chemical exposures.

An Updated Review of Various Medicinal Applications of p-Co umaric Acid: From Antioxidative and Anti-Inflammatory Properties to Effects on Cell Cycle and Proliferation.

P-Coumaric acid (p-CA) is a hydroxycinnamic acid, an organic compound that is a hydroxyl derivative of cinnamic acid. P-CA is the most abundant isomer in nature and can be found in a wide variety of edible plants such as fungi, peanuts, navy beans, tomatoes, carrots, basil, and garlic. Recently, the therapeutic properties of p-CA have received a great deal of attention from scientific society. Here, we described the medicinal effects of p-CA on various pathological conditions. This review was performed via evaluating PubMed reported studies from January 2010 to January 2020. Also, reference lists were checked to find additional studies. All intermediation or complementarity of animal models, case-control and cohort studies, in vitro studies, and controlled trials (CTs) on p-CA were acceptable. However plant extract studies without indication of main active substances were excluded due to the considerable diversities and heterogeneities. According to recent evidence regarding the beneficial effects of p-CA, numerous diseases such as nephropathies, cardiovascular diseases, neuroinflammatory diseases, liver diseases, cancers, and some metabolic disorders could potentially be controlled by this natural herb. Interestingly, autophagy is a novel molecular mechanism involved in the crosstalk between classic effects of p-CA and introduces alternative therapeutic pathways for this compound. Much work remains in clarifying the main therapeutic properties among the various p-CA effects; these will be the subject of forthcoming work, resulting in presenting further mechanism of action.

Mechanisms and pathogenesis underlying environmental chemical-induced necroptosis.

Necroptosis is a regulated cell death that is governed by mixed lineage kinase domain-like, receptor-interacting serine-threonine kinase 3 and commonly displays with necrosis morphological characteristics. This study examined the molecular mechanisms involved in the chemical-induced necroptosis where a systematic evaluation of experimental studies addressing this issue is missing. We strictly reviewed all scientific reports related to our search terms including "necroptosis" or "programmed necrosis", "environmental chemicals" or "air pollutants" or "pesticides" or "nanoparticles" and "Medicines" from 2009 to 2019. Manuscripts that met the objective of this study were included for further evaluations. Studies showed that several pathological contexts like cancer, neurodegenerative disorders, and inflammatory diseases were related to necroptosis. Furthermore, multiple chemical-induced cytotoxic effects, such as DNA damage, mitochondrial dysregulation, oxidative damage, lipid peroxidation, endoplasmic reticulum disruption, and inflammation are also associated with necroptosis. The main environmental exposures that are related to necroptosis are air pollutants (airborne particulate matter, cadmium, and hydrogen sulfide), nanoparticles (gold, silver, and silica), pesticides (endosulfan, cypermethrin, chlorpyrifos, and paraquat), and tobacco smoke. To sum up, air pollutants, pesticides, and nanoparticles could potentially affect human health via disruption of cell growth and induction of necroptosis. Understanding the exact molecular pathogenesis of these environmental chemicals needs further comprehensive research to provide innovative concepts for the prevention approaches and introduce novel targets for the amelioration of a range of human health problems.

Colorimetric nanoplatform for visual determination of cancer cells via target-catalyzed hairpin assembly actuated aggregation of gold nanoparticles.

According to aptamer-mediated hairpin DNA cascade amplifier and gold nanoparticles aggregation, an optical platform for cancer cells determination has been proposed. High-affinity chimeric aptamers were used for cancer cell detection and also as an initiator for beginning hairpin assembly to construct three-way junction (3WJ) nanostructures. These three hairpins were modified at 3' ends with biotin. In the presence of target cell, chimeric aptamer binds to its ligand on cell surface and initiates 3WJ nanostructures formation. These 3WJ nanostructures interact with streptavidin-modified gold nanoparticles (AuNPs) via non-covalent biotin-streptavidin interactions and create a crossover lattice of nanoparticles. This event leads to AuNPs aggregation and red-shifting. The results were confirmed by gel electrophoresis and UV-visible spectrophotometry. The dynamic range of this assay is 25 to 107 cells with a detection limit of 10 cells which is respectively 9 and 4 times more significant than the sensitivity of AuNP-based approaches without amplification and enzyme-mediated signal amplification. Graphical abstract.

Targeting Ubiquitin-Proteasome Pathway by Natural Products: Novel Therapeutic Strategy for Treatment of Neurodegenerative Diseases.

Misfolded proteins are the main common feature of neurodegenerative diseases, thereby, normal proteostasis is an important mechanism to regulate the neural survival and the central nervous system functionality. The ubiquitin-proteasome system (UPS) is a non-lysosomal proteolytic pathway involved in numerous normal functions of the nervous system, modulation of neurotransmitter release, synaptic plasticity, and recycling of membrane receptors or degradation of damaged and regulatory intracellular proteins. Aberrant accumulation of intracellular ubiquitin-positive inclusions has been implicated to a variety of neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington disease (HD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Myeloma (MM). Genetic mutation in deubiquitinating enzyme could disrupt UPS and results in destructive effects on neuron survival. To date, various agents were characterized with proteasome-inhibitory potential. Proteins of the ubiquitin-proteasome system, and in particular, E3 ubiquitin ligases, may be promising molecular targets for neurodegenerative drug discovery. Phytochemicals, specifically polyphenols (PPs), were reported to act as proteasome-inhibitors or may modulate the proteasome activity. PPs modify the UPS by means of accumulation of ubiquitinated proteins, suppression of neuronal apoptosis, reduction of neurotoxicity, and improvement of synaptic plasticity and transmission. This is the first comprehensive review on the effect of PPs on UPS. Here, we review the recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders. This review attempts to summarize the latest reports on the neuroprotective properties involved in the proper functioning of natural polyphenolic compounds with implication for targeting ubiquitin-proteasome pathway in the neurodegenerative diseases. We highlight the evidence suggesting that polyphenolic compounds have a dose and disorder dependent effects in improving neurological dysfunctions, and so their mechanism of action could stimulate the UPS, induce the protein degradation or inhibit UPS and reduce protein degradation. Future studies should focus on molecular mechanisms by which PPs can interfere this complex regulatory system at specific stages of the disease development and progression.

Metformin-induced AMPK activation stimulates remyelination through induction of neurotrophic factors, downregulation of NogoA and recruitment of Olig2+ precursor cells in the cuprizone murine model of multiple sclerosis.

PURPOSE: Oligodendrocytes (OLGs) damage and myelin distraction is considered as a critical step in many neurological disorders especially multiple sclerosis (MS). Cuprizone (cup) animal model of MS targets OLGs degeneration and frequently used to the mechanistic understanding of de- and remyelination. The aim of this study was exploring the effects of metformin on the OLGs regeneration, myelin repair and profile of neurotrophic factors in the mice brain after cup-induced acute demyelination. METHODS: Mice (C57BL/6 J) were fed with chow containing 0.2% cup for 5 weeks to induce specific OLGs degeneration and acute demyelination. Next, the cup was withdrawn to allow one-week recovery (spontaneous remyelination). At the end of this period, mature OLGs markers, myelin-associated neurite outgrowth inhibitor protein A (NogoA), premature specific OLGs transcription factor (Olig2), anti-apoptosis marker (survivin), neurotrophic factors, and AMPK activation were monitored in the presence or absence of metformin (50 mg/kg body weight/day) in the corpus callosum (CC). RESULTS: Our finding indicated that consumption of metformin during the recovery period potentially induced an active form of AMPK (p-AMPK) and promoted repopulation of mature OLGs (MOG+ cells, MBP+ cells) in CC through up-regulation of BDNF, CNTF, and NGF as well as down-regulation of NogoA and recruitment of Olig2+ precursor cells. CONCLUSIONS: This study for the first time reveals that metformin-induced AMPK, a master regulator of energy homeostasis, activation following toxic demyelination could potentially accelerate regeneration and supports spontaneous demyelination. These findings suggest the development of new therapeutic strategies based on AMPK activation for MS in the near future. Graphical abstract An overview of the possible molecular mechanisms of action of metformin-mediated remyelinationa.

Investigation of association between CD40 current gene variants (rs4810485, rs1883832 and rs3765459) and serum CD154 protein levels in Iranian migraineurs.

Migraine is a chronic neurological disease described by recurrent moderate to severe headaches often in association with neuro-inflammation. As cytokines are affect the immune response and migraine exacerbation, the current study aimed to investigate the possible associations between CD40 polymorphisms and level of soluble CD154 protein with migraine. In a prospective case-control study, we studied blood samples of 190 patients with migraine (migraineurs) and 200 healthy controls (HCs) from southeast Iran. Genotyping for the CD40 (rs4810485-intron, rs1883832-5´-UTR, and rs3765459-intron) gene variants were executed using PCR-RFLP and soluble CD154 protein levels were measured via ELISA method. Among CD40 gene variants, rs1883832 (TC genotype) was significantly associated with migraine (P = 0.007, OR = 2.326, 95% CI = 1.258-4.303).  No significant associations observed between the rs4810485 and rs3765459 SNPs with migraine. The most frequent genotypes for CD40 were GG in rs4810485 (51.5%) and rs3765459 (62.1%) as well as TC in rs1883832 (53.7%). There was no statistically relationship between these gene variants and different subclasses of migraine. Concentration of soluble CD40L among patients with rs1883832 (TC genotype) were significantly (P = 0.027, OR = 0.417, CI = 0.192-0.906) higher in compared to healthy controls. Our findings showed that in CD40 rs1883832, TC genotype may have a role in migraine susceptibility. Therefore, it suggested that in addition to other factors, CD40 rs1883832 (TC genotype) genetic variation may also play a critical role in the etiology of migraine.

Human Cytomegalovirus in Oral Squamous Cell Carcinoma in Southeast of Iran.

BACKGROUND: Carcinogenesis is a multi-step process and the role of infectious agents in this progression has not been fully identified. Since human cytomegalovirus (HCMV) is frequently presented in the gingival sulcus fluid, we hypothesized that this virus would be important in the pathogenesis of oral squamous cell carcinoma (OSCC). OBJECTIVES: The aim of this study was to investigate the presence of active HCMV in different histopathological grades of OSCC in southeast of Iran. MATERIALS AND METHODS: Forty eight individual specimens were evaluated in this study. Serial sections were obtained from paraffin-embedded tissue samples of OSCC biopsies. The frequency of HCMV was investigated using the real-time polymerase change reaction method after DNA extraction from biopsies. RESULTS: The mean age of the patients (66.7% female and 33.3% male) was 58.6 years. Only three cases (6.3%) of the grade I, OSCC biopsies, were positive for active HCMV with average load of 57.7 × 10(3). CONCLUSIONS: According to the low prevalence of HCMV in OSCC, it seems that this virus plays a minor role in this kind of cancer at least in southeast of Iran. More comprehensive studies are needed to investigate the oncomodulatory effect of this virus on OSCC.

In vitro differentiation of rat mesenchymal stem cells to hepatocyte lineage.

OBJECTIVES: Mesenchyme is a type of undifferentiated loose connective tissue that is derived mostly from mesoderm. Recently, mesenchymal stem cells (MSCs), as adult stem cells (ASCs) able to divide into a variety of different cells, are of utmost importance for stem cell research. In this research, ability of the liver extract to induce differentiation of rat derived omentum tissue mesenchymal stem cells (rOT-MSCs) into hepatocyte cells (HCs) was investigated. MATERIALS AND METHODS: After isolation and confirmation of rOT-MSCs they were co-cultured with liver extract and hepatogenic differentiation was monitored. Expressions of mesenchymal stem cell markers were also analyzed via flow cytometry. Moreover, expressions of octamer-binding transcription factor-4 (Oct-4), Wilm's tumor suppressor gene-1 (WT-1), albumin (ALB), alpha fetoprotein (AFP), cytokeratin-18 (CK-18), and mRNAs were analyzed using RT-PCR on days 16, 18 and 21. ALB production was analyzed by immunocytochemistry and western blot. Furthermore, glycogen and urea production were determined via periodic acid-Schiff (PAS) staining and colorimetric assays respectively. RESULTS: The phenotypic characterization revealed the positive expressions of CD90, CD44 and negative expression of CD45 in rOT-MSCs. These cells also expressed mRNA of Oct-4 and WT-1 as markers of omentum tissue. Differentiated rOT-MSCs in presence of 6 µg/ml liver extract expressed ALB, AFP, CK-18, glycogen and urea as specific markers of HCs. CONCLUSION: These observations suggest that liver extract is potentially able to induce differentiation of MSCs into hepatocyte lineage and can be considered an available source for imposing tissue healing on the damaged liver.

Capability of Cartilage Extract to In Vitro Differentiation of Rat Mesenchymal Stem Cells (MSCs) to Chondrocyte Lineage.

The importance of mesenchymal stem cells (MSCs), as adult stem cells (ASCs) able to divide into a variety of different cells is of utmost importance for stem cell researches. In this study, the ability of cartilage extract to induce differentiation of rat derived omentum tissue MSCs (rOT-MSCs) into chondrocyte cells (CCs) was investigated. After isolation of rOT-MSCs, they were co-cultured with different concentrations of hyaline cartilage extract and chondrocyte differentiation was monitored. Expression of MSCs markers was analyzed via flow cytometry. Moreover, expression of octamer- binding transcription factor-4 (Oct-4), Wilm's tumor suppressor gene-1 (WT-1), aggrecan (AG), collagen type-II (CT-II) and collagen type-X (CT-X) was analyzed using RT-PCR on 16, 18 and 21 days. Furthermore, immunocytochemistry and western blot were performed for CT-II production. Finally, proteoglycans (PGs) were examined using toluidine blue and alcian blue staining. The phenotypic characterization revealed the positive expression of CD90, CD44 and negative expression of CD45 in rOT-MSCs. These cells also expressed mRNA of Oct-4 and WT-1 as markers of omentum tissue. Differentiated rOT-MSCs in the presence of 20 µg/ ml cartilage extract expressed AG, CT-II, CT-X, and PGs as specific markers of CCs. These observations suggest that cartilage extract is potentially able to induce differentiation of MSCs into chondrocyte lineage and may be considered as an available source for imposing tissue healing on the damaged cartilage. More investigations are needed to prove in vivo cartilage repair via cartilage extract or its effective factors.

Human herpesvirus-6 and epstein-barr virus infections at different histopathological grades of oral squamous cell carcinomas.

BACKGROUND: The aim of this study was to determine the prevalence and viral load of Epstein-Barr virus (EBV) and Human herpesvirus-6 (HHV-6) in different histopathologic grades of oral squamous cell carcinoma (OSCC). METHODS: Forty-five formalin-fixed paraffin-embedded tissue section of OSCC patients were analyzed by quantitative real-time polymerase chain reaction for detection of EBV and HHV-6. RESULTS: The mean age of the patients was 58.6 years, 69% of whom were female, and 31% were male. Overall, the positive rate for EBV and HHV-6 were 16.7% and 27.1%, respectively; and the mean viral load EBV was 27.9 × 10(3) and 38.5 × 10(3) for HHV-6. No correlation was demonstrated between the viral load of EBV DNA (P = 0.35) and HHV-6 (P = 0.38) at the different OSCC histopathologic grades. CONCLUSIONS: These findings neither lend support to the hypothesis that EBV and HHV-6 are directly involved in OSCC nor rule out the possibility that these viruses play an indirect role in carcinogenesis in this area.

Relationship between metalloproteinase 2 and 9 concentrations and soluble CD154 expression in Iranian patients with multiple sclerosis.

Matrix metalloproteinases (MMPs) play a critical role in the blood-brain barrier permeability and in invasion of the leukocytes into the central nervous system during multiple sclerosis (MS). In this respect, in the present study, we have evaluated the possible role of MMP-9 and MMP-2 on the expression of soluble CD154 (sCD154) and membrane-bound isoform of the CD154 in Iranian MS patients. The expressions of the aforementioned protein-related genes were analyzed at the levels of messenger RNA and proteins by real-time reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting. The results showed a high expression of CD154 isoforms, MMP-9 and MMP-2, in MS patients in contrast to controls (p < 0.001). We found an increase in sCD154 concentration (i.e., >3-fold) in patients with a higher MMPs/tissue inhibitor of metalloproteinase 1 (TIMP-1) ratio. Furthermore, secondary-progressive MS patients with exacerbate period showed higher positive correlation between increasing sCD154 concentration and overexpression of MMP-2 (p < 0.001). Our data demonstrate that following the exacerbation period, sCD154 concentration is increased in patients, which is mutually related to the MMPs/TIMP-1 ratio. This relationship may represent a new link between sCD154 concentration and the MMPs/TIMP-1 ratio with prognostic implications.

CCR5 plays important roles in hepatitis B infection.

In humans, hepatitis B virus (HBV) is the most prevalent and the main infectious agent that leads to liver disease. Previous investigations identified that long-term HBV-infected patients are unable to eradicate HBV completely from hepatocytes. The main mechanisms responsible for long-term forms of the infections are yet to be clarified. However, researchers believe that the differences in genetic and immunological parameters in the patients in comparison to subjects who successfully clear HBV infections may be the causes for long-term infection. Previous studies demonstrated that chemokines play important roles in the regulation of immune cell migration and activation, which is crucial for a comprehensive immune response against HBV. RANTES, MIP-1α, and MIP-1ß are important CC chemokines which act through CC chemokines receptor 5 (CCR5). This receptor is expressed on several effector immune cells including NK cells, T lymphocytes, and macrophages, and plays a crucial role in the regulation of activation and migration of the immune cells during immune responses against viruses, including HBV. Therefore, alterations in its expression or functions could be associated with attenuated immune responses against HBV. In addition, previous studies identified that a 32 base pair deletion (Δ32) in exon 1, as well as three polymorphisms in the promoter region of the CCR5 gene results in downregulation of the molecule. Previous studies revealed that CCR5 expression was altered in hepatitis B but the role of the CCR5 Δ32 mutation and CCR5 promoter polymorphisms in this disease is controversial. This review addresses the recent information regarding the status of CCR5 expression on immune cells and the association of CCR5 promoter polymorphisms with HBV-infected patients.

Evaluation of reactive Epstein-Barr virus (EBV) in Iranian patient with different subtypes of multiple sclerosis (MS)

OBJECTIVES: Epstein-Barr virus has been recently associated with the onset of multiple sclerosis, yet understanding how it elicits autoimmunity remains elusive. We investigated the relation between Epstein-Barr virus reactivation and disease development in different subtypes of multiple sclerosis. METHODS: In the present research, we have determined the Epstein-Barr virus-DNA load by quantitative real-time polymerase chain reaction and Epstein-Barr virus antibody levels by EIA technique in both multiple sclerosis patients (n = 78) and healthy controls (n = 123). RESULTS: Our results demonstrated increased titer of both anti-Epstein-Barr virus-IgG and IgM antibodies in patients (91.02% vs 82.11% in controls, p < 0.001 and 14.1% vs 4.06% in controls, p < 0.001, respectively). Overall, Epstein-Barr virus reactivation was found in 68.75% of subtypes of multiple sclerosis, 4.54% of multiple sclerosis primary subtype, and in only 3.25% of healthy control subjects. Moreover, in samples of patients with disease relapse (exacerbation) cell free viral DNA was elevated in contrast to other patients (p < 0.001). CONCLUSIONS: These findings provide further support for the detrimental effects of Epstein- Barr virus in the reactivation of multiple sclerosis attacks.

Evaluation of reactive Epstein-Barr Virus (EBV) in Iranian patient with different subtypes of multiple sclerosis (MS).

OBJECTIVES: Epstein-Barr virus has been recently associated with the onset of multiple sclerosis, yet understanding how it elicits autoimmunity remains elusive. We investigated the relation between Epstein-Barr virus reactivation and disease development in different subtypes of multiple sclerosis. METHODS: In the present research, we have determined the Epstein-Barr virus-DNA load by quantitative real-time polymerase chain reaction and Epstein-Barr virus antibody levels by EIA technique in both multiple sclerosis patients (n=78) and healthy controls (n=123). RESULTS: Our results demonstrated increased titer of both anti-Epstein-Barr virus-IgG and IgM antibodies in patients (91.02% vs 82.11% in controls, p<0.001 and 14.1% vs 4.06% in controls, p<0.001, respectively). Overall, Epstein-Barr virus reactivation was found in 68.75% of subtypes of multiple sclerosis, 4.54% of multiple sclerosis primary subtype, and in only 3.25% of healthy control subjects. Moreover, in samples of patients with disease relapse (exacerbation) cell free viral DNA was elevated in contrast to other patients (p<0.001). CONCLUSIONS: These findings provide further support for the detrimental effects of Epstein-Barr virus in the reactivation of multiple sclerosis attacks.