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The presenilin-1 (PSEN1) gene is crucial in developing Alzheimer's disease (AD), a progressive neurodegenerative disorder and the most common cause of dementia. Circular RNAs (circRNAs) are non-coding RNA generated through back-splicing, resulting in a covalently closed circular molecule. This study aimed to investigate PSEN1-gene-derived circular RNAs (circPSEN1s) and their potential functions in AD. Our in silico analysis indicated that circPSEN1s (hsa_circ_0008521 and chr14:73614502-73614802) act as sponge molecules for eight specific microRNAs. Surprisingly, two of these miRNAs (has-mir-4668-5p and has-mir-5584-5p) exclusively interact with circPSEN1s rather than mRNA-PSEN1. Furthermore, the analysis of pathways revealed that these two miRNAs predominantly target mRNAs associated with the PI3K-Akt signaling pathway. With sponging these microRNAs, circPSEN1s were found to protect mRNAs commonly targeted by these miRNAs, including QSER1, BACE2, RNF157, PTMA, and GJD3. Furthermore, the miRNAs sequestered by circPSEN1s have a notable preference for targeting the TGF-β and Hippo signaling pathways. We also demonstrated that circPSEN1s potentially interact with FOXA1, ESR1, HNF1B, BRD4, GATA4, EP300, CBX3, PRDM9, and PPARG proteins. These proteins have a prominent preference for targeting the TGF-β and Notch signaling pathways, where EP300 and FOXA1 have the highest number of protein interactions. Molecular docking analysis also confirms the interaction of these hub proteins and Aβ42 with circPSEN1s. Interestingly, circPSEN1s-targeted molecules (miRNAs and proteins) impacted TGF-β, which served as a shared signaling pathway. Finally, the analysis of microarray data unveiled distinct expression patterns of genes influenced by circPSEN1s (WTIP, TGIF, SMAD4, PPP1CB, and BMPR1A) in the brains of AD patients. In summary, our findings suggested that the interaction of circPSEN1s with microRNAs and proteins could affect the fate of specific mRNAs, interrupt the function of unique proteins, and influence cell signaling pathways, generally TGF-β. Further research is necessary to validate these findings and gain a deeper understanding of the precise mechanisms and significance of circPSEN1s in the context of AD. [ABSTRACT FROM AUTHOR]

Tauopathies belong to a heterogeneous class of neuronal diseases resulting in the metabolic disturbance. A disulfide natural compound of Alpha-Lipoic acid (ALA) has shown numerous pharmacologic, antioxidant, and neuroprotective activities under neuropathological conditions. The aim of this study was to investigate the neuroprotective effects of ALA on the tauopathy-induced oxidative disturbance and behavioral deficits. The transgenic Drosophila model of tauopathy induced by human tauR406W using GAL4/UAS system and effects of ALA (0.001, 0.005, and 0.025 % w/w of diet) on the neuropathology of tau in younger (20 days) and older (30 days) adults were investigated via biochemical, molecular, behavioral and in-situ tissue analyses. Expression of apoptosis-related proteins involving Drosophila Cyt-c-d (trigger of intrinsic apoptosis) and DrICE (effector caspase) were upregulated in both ages (20 and 30 days) and DIAP1 (caspase inhibitor) has reduced only in older model flies compared to the controls. Remarkably, all doses of ALA increased DIAP1 and glutathione (GSH) as well as reducing Cyt-c-d and lipid peroxidation (LPO) in the younger flies compared to the model flies. Moreover, the higher doses of ALA were able to decrease thiol concentrations, to increase total antioxidant capacity, and to improve the behavioral deficits (locomotor function, olfactory memory, and ethanol sensitivity) in the younger flies. On the other hand, only a higher dose of ALA was able to decrease DrICE, Cyt-c-d, LPO, and thiol as well as increasing antioxidant capacity and decreasing ethanol sensitivity (ST50, RT50) in the older flies. TUNEL assay showed that all doses of ALA could potentially increase the DIAP1/DrICE ratio and exert anti-apoptotic effects on younger, but not on the older adults. Furthermore, data obtained from the in-situ ROS assay confirmed that only a higher dose of ALA significantly decreased the ROS level at both ages. Our data showed that an effective neuroprotective dose of ALA and its mechanism of action on this model of tauopathy could potentially be influenced by longevity. Moreover, it was shown that ALA prevents apoptosis and decreases the redox homeostasis, and this partially explains the mechanism by which ALA diminishes behavioral deficits. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a prevalent global mental illness with diverse underlying causes. Despite the availability of first-line antidepressants, approximately 10–30 % of MDD patients do not respond to these medications, falling into the category of treatment-resistant depression (TRD). Our study aimed to elucidate the precise molecular mechanisms through which glial cells contribute to depression-like episodes in TRD. We conducted a comprehensive literature search using the PubMed and Scopus electronic databases with search terms carefully selected to be specific to our topic. We strictly followed inclusion and exclusion criteria during the article selection process, adhering to PRISMA guidelines. Additionally, we carried out an in-depth analysis of postmortem brain tissue obtained from patients with TRD using single-nucleus transcriptomics (sn-RNAseq). Our data confirmed the involvement of multiple glia-specific markers (25 genes) associated with TRD. These differentially expressed genes (DEGs) primarily regulate cytokine signaling, and they are enriched in important pathways such as NFκB and TNF-α. Notably, DEGs showed significant interactions with the transcription factor CREB1. sn-RNAseq analysis confirmed dysregulation of nearly all designated DEGs; however, only Cx30/43, AQP4, S100β, and TNF-αR1 were significantly downregulated in oligodendrocytes (OLGs) of TRD patients. With further exploration, we identified the GLT-1 in OLGs as a hub gene involved in TRD. Our findings suggest that glial dysregulation may hinder the effectiveness of existing therapies for TRD. By targeting specific glial-based genes, we could develop novel interventions with minimal adverse side effects, providing new hope for TRD patients who currently experience limited benefits from invasive treatments. [Display omitted] • Glial cells are promising therapeutic targets to improve the efficacy of antidepressants • Dysregulation of glial Cx30/43, AQP4, S100β, and TNF-αR1 are related to TRD. • Oligodendrocyte-specific gene SLC1A2 is a potential cell-specific marker related to TRD. • Glial-specific drug targeting could lead to more efficient, personalized treatment in TRD. [ABSTRACT FROM AUTHOR]

Cuprizone (Cup) is a copper chelating agent frequently used to study factors that affect oligodendrocytes (OLGs) death and acute demyelination. Triptolide (TP), a nuclear factor-kappaB (NF-κB) blocker, is a major bioactive component of Tripterygium wilfordii Hook f. (TWHf) with various therapeutic activities. In this study, we examined the effects of TP on neuroglia activation, inflammation, apoptosis, demyelination, and behavioral deficits in the Cup-induced toxic model of multiple sclerosis (MS). C57BL/6 J mice were fed with chow containing 0.2% Cup for 6 weeks to induce detectable neuroinflammation and myelin loss. TP was administered intraperitoneally at different doses (125, 250 or 500 μg/kg/day) during the last week of the Cup challenge. Although TP substantially decreased Cup-induced NF-κB extra activation, TNF-α and IL-1 over expression, and gliosis in a dose-dependent manner, only low dose of TP (TP-125) was able to raise the number of OLGs precursor cells (NG-2 + /O4 + ), reduce Bax/Bcl-2 ratio and improve behavioral deficits. In addition, TP-125 decreased NF-κB activation on GFAP + astrocytes more than MAC-3 + microglial and MOG + oligodendrocytes which suggested the possibility of specific dampening of NF-κB signaling in reactive astrocytes. Behavioral assessments by open-field and rota-rod tests showed that only TP-125 notably improved motor function and motor coordination compared to the Cup group. These findings highlight the pivotal role of NF-κB signaling in the oligodendrogenesis and lesion reduction in demyelination diseases such as MS. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) is a common form of drug-resistant epilepsy that sometimes responds to dietary manipulation such as the 'ketogenic diet'. Here we have investigated the effects of metformin in the rat pilocaroin model of TLE. Male rats were treated with intra peritoneal injection of pilocarpine hydrochloride, in dose of 360 mg/kg to induce status epilepticus (SE). At 45 day after induction of SE, metformin was injected intraperitoneally in dose of 250 mg/kg/day for 5 days. We show that metformin potently reduces the progression of seizures and blocks seizure-induced over-expression of brain-derived neurotropic factor (BDNF) and its receptor, Tropomyosin receptor kinase B (TrkB). We have shown that this reduced expression pattern is mediated by the transcriptional co-repressor CtBP (C-terminal binding protein). Moreover, metformin decreased mechanistic target of rapamycin (mTOR) activation through activation of AMP-activated protein kinase (AMPK) signaling pathway. Our findings have been shown that metformin has anticonvulsant and antiepileptic properties, and suggesting that antiglycolytic compounds such as metformin may represent a new class of drugs for treating epilepsy. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS), is a disease that degenerates myelin in central nervous system (CNS). Reactive oxygen species (ROSs) are toxic metabolites, and accumulating data indicate that ROSs-mediated apoptosis of oligodendrocytes (OLGs) plays a major role in the pathogenesis of MS under oxidative stress conditions. In this study, we investigated the role of endogenous antioxidant alpha-lipoic acid (ALA) as ROSs scavenger in the OLGs loss and myelin degeneration during cuprizone (cup)-induced demyelination in the experimental model of MS. Our results have shown that ALA treatment significantly increased population of mature OLGs (MOG cells), as well as decreased oxidative stress (ROSs, COX-2 and PGE2) and apoptosis mediators (caspase-3 and Bax/Bcl2 ratio) in corpus callosum (CC). Surprisingly, ALA significantly stimulates population of NG2 chondroitin sulfate proteoglycan positive glia (NG2 cells or polydendrocytes), from week 4 afterward. Accordingly ALA could prevents apoptosis, delays demyelination and recruits OLGs survival and regeneration mechanisms in CC. We conclude that ALA has protective effects against toxic demyelination via reduction of redox signaling, and alleviation of polydendrocytes vulnerability to excitotoxic challenge. [ABSTRACT FROM AUTHOR]

Context:Ellagic acid (EA) is a natural phenol antioxidant with various therapeutic activities. However, the efficacy of EA has not been examined in neuropathologic conditions. Objective:In vivoneuroprotective effects of EA on cuprizone (cup)-induced demyelination were evaluated. Material and methods:C57BL/6 J mice were fed with chow containing 0.2% cup for 4 weeks to induce oligodendrocytes (OLGs) depletion predominantly in the corpus callosum (CC). EA was administered at different doses (40 or 80 mg/kg body weight/day/i.p.) from the first day of cup diet. Oligodendrocytes apoptosis [TUNEL assay and myelin oligodendrocyte glycoprotein (MOG+)/caspase-3+cells), gliosis (H&E staining, glial fibrillary acidic protein (GFAP+) and macrophage-3 (Mac-3+) cells) and inflammatory markers (interleukin 17 (IL-17), interleukin 11 (IL-11) and stromal cell-derived factor 1 α (SDF-1α) or CXCL12] during cup intoxication were examined. Results:High dose of EA (EA-80) increased mature oligodendrocytes population (MOG+cells,p < 0.001), and decreased apoptosis (p < 0.05) compared with the cup mice. Treatment with both EA doses did not show any considerable effects on the expression of CXCL12, but significantly down-regulated the expression of IL-17 and up-regulated the expression of IL-11 in mRNA levels compared with the cup mice. Only treatment with EA-80 significantly decreased the population of active macrophage (MAC-3+cells,p < 0.001) but not reactive astrocytes (GFAP+cells) compared with the cup mice. Discussion and conclusion:In this model, EA-80 effectively reduces lesions via reduction of neuroinflammation and toxic effects of cup on mature OLGs. EA is a suitable therapeutic agent for moderate brain damage in neurodegenerative diseases such as multiple sclerosis. [ABSTRACT FROM PUBLISHER]

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-1β 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. [ABSTRACT FROM AUTHOR]

Background. Recently, it has been suggested that human herpes virus 6 (HHV6) may play a role in the pathogenesis of multiple sclerosis (MS). Our purpose is to determine the incidence of reactivated HHV6 in MS patients. Methods. Viral sequence analyzed by qPCR in the peripheral blood mononuclear cells (PBMCs), serum, and saliva samples of different subtypes of MS patients (n = 78) and healthy controls (n = 123). HHV6 IgG and IgM antibody levels measured by ELISA technique in the plasma samples of both groups. Likewise, cerebrospinal fluid (CSF) samples of some MS patients (n = 38) were analyzed for viral sequence. Results. Results demonstrate increased levels of anti-HHV6-IgG (78.2% versus 76.4% in controls; ), and IgM (34.6% versus 6.5% in controls; ) in MS patients. Furthermore, RRMS and SPMS patients showed relatively higher anti-HHV6 IgG and IgM compared to PPMS (P < 0.001). Moreover, load of cell-free viral DNA was higher in RRMS and SPMS patients and detected in 60.2% (47/78) of MS patients, compared with 14.6% (18/123) of healthy controls (P < 0.001). Moreover, load of cell-free viral DNA was higher in RRMS and SPMS patients and detected in 60.2% (47/78) of MS patients, compared with 14.6% (18/123) of healthy controls (P = 0.001). Conclusions. The results extend the observation of an increased frequency of systemic reactivated HHV6 infection in MS patients with developed stages of disease. [ABSTRACT FROM AUTHOR]

Abstract: Objectives : Elaidic acid, the predominant trans-fatty acid in industrially hydrogenated oils, exists on high levels in Iranian hydrogenated oils and margarines. This study was undertaken to investigate the effect of elaidic acid and its cis-counterpart oleic acid on expression of ICAM-1 and VCAM-1 on human bone marrow endothelial cells (HBMECs). Design and methods : HBMEC were pre-treated with TNF-α or LPS for induction of the adhesion molecules expression, and then treated with elaidic acid or oleic acid. Soluble and cell associated forms of ICAM-1 and VCAM-1 were quantified by ELISA and Western blot. Results : Our findings indicated that oleic acid suppresses VCAM-1 and ICAM-1 expression on HBMEC near to the basal level. Conversely, elaidic acid maintained the level of VCAM-1 and ICAM-1 up-regulated by TNF-α or LPS. Conclusions : It is suggested that elaidic acid could keep the HBMEC at the stimulated phenotype. These findings provide further support on the detrimental effects of elaidic acid in promotion and induction of cardiovascular diseases (CVD). [Copyright &y& Elsevier]

Introduction: Obesity is among the most severe challenges of our era, with significant health consequences and a high economic burden for health systems. Therefore, many countries have developed political agendas to cope with this ever-rising challenge. Along with chemical medications developed to manage obesity, researchers have focused on some natural ingredients and herbal extracts that are effective in reducing weight. The current study investigated the association between Foeniculum vulgar (fennel) extracts and body weight, lipid profile, and leptin. Methods: In total, 35 adult male BALB/c mice were investigated in sham, fennel 50 mg/kg, fennel 100 mg/kg, and fennel 200 mg/kg (n=7) groups. The mice were administered fennel extracts for fourteen days while weighted at the intervention's beginning and end. Then, their weight, lipid profile, serum leptin, and expression of leptin protein in the hypothalamus were measured. Results: After providing the intervention, leptin receptor protein expression was increased in all groups, while serum leptin didn't change significantly. Moreover, a significant decrease was observed in the cholesterol dose of 100 mg/kg/day, triglycerides in 100 and 200 mg/kg/day, and LDL in 50 and 100 mg/kg/day. Serum HDL was increased significantly in a dose of 100 mg/kg/day. Conclusion: Fennel extract can decrease the lipid profile by changing the expression of the leptin receptor. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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-1β. Furthermore, Lcn2−/− mice showed considerable downregulation in the HMGB1/NLRP3/PYCARD/caspase-1 axis, IL-1β 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. [ABSTRACT FROM AUTHOR]

Abstract Purpose Method Results Conclusions 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.We investigated the interplay between aging (10, 20, 30, and 40 days) and human tauR406W (htau)-induced cell stress in transgenic fruit flies.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.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. [ABSTRACT FROM AUTHOR]

Anxiety-related disorders (ARDs) are chronic neuropsychological diseases and the sixth leading cause of disability in the world. As dysregulation of microRNAs (miRs) are observed in the pathological course of neuropsychiatric disorders, the present study aimed to introduce miRs that underlie anxiety processing in the brain. First, we collected the experimentally confirmed anxiety-related miRNAs (ARmiRs), predicted their target transcripts, and introduced critical cellular pathways with key commune hub genes. As a result, we have found nine anxiolytic and ten anxiogenic ARmiRs. The anxiolytic miRs frequently target the mRNA of Acyl-CoA synthetase long-chain family member 4 (Acsl4), AFF4-AF4/FMR2 family member 4 (Aff4), and Krüppel like transcription factor 4 (Klf4) genes, where miR-34b-5p and miR-34c-5p interact with all of them. Moreover, the anxiogenic miRs frequently target the mRNA of nine genes; among them, only two miR (miR-142-5p and miR-218-5p) have no interaction with the mRNA of trinucleotide repeat-containing adaptor 6B (Tnrc6b), and miR-124-3p interacts with all of them where MAPK is the main signaling pathway affected by both anxiolytic and anxiogenic miR. In addition, the anxiolytic miR commonly target E2F transcription factor 5 (E2F5) in the TGF-β signaling pathway, and the anxiogenic miR commonly target Ataxin 1 (Atxn1), WASP-like actin nucleation promoting factor (Wasl), and Solute Carrier Family 17 Member 6 (Slc17a6) genes in the notch signaling, adherence junction, and synaptic vesicle cycle pathways, respectively. Taken together, we conclude that the most important anxiolytic (miR-34c, Let-7d, and miR-17) and anxiogenic (miR-19b, miR-92a, and 218) miR, as hub epigenetic modulators, potentially influence the pathophysiology of anxiety, primarily via interaction with the MAPK signaling pathway. Moreover, the role of E2F5 as a novel putative target for anxiolytic miRNAs in ARDs disorders deserves further exploration. [ABSTRACT FROM AUTHOR]

Background: Migraine is a chronic neurological disease characterized by recurrent moderate to severe headaches commonly in association with neuro-inflammation. Interleukin-4 (IL-4), an anti-inflammatory cytokine, plays an important role in modulating pain threshold and has an essential role in stimulation of pain receptors in the trigeminal nerve fibers. Aim of the study: The current study aimed to investigate the possible associations between IL-4 single nucleotide polymorphisms (SNPs) and susceptibility to migraine in Iranian patients. Patients and methods: In a prospective case-control study, we studied blood samples of 190 patients with migraine (migraineurs) and 200 healthy controls (HCs) for analysis of gene variants. Genotyping for the IL-4 SNPs: C-589T (rs2243250), T+2979G (rs2227284), and C-33T (rs2070874) were performed using PCR-RFLP. Statistical analysis was performed using the SPSS version 21.0 (SPSS, Chicago) and SNPStats version 1.14.0. Results and conclusion: Among IL-4 SNPs, rs2243250 (TC genotype, OR = 0.25, 95% CI = 0.13-0.50, P = 0.001) and rs2227284 (TG and TT genotypes, OR = 0.44, 95% CI = 0.23- 0.92, P = 0.029 and OR = 0.38, 95% CI = 0.18-0.79, P = 0.009 respectively) were significantly [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system. Although remarkable progress has been made in treating MS, current therapies are less effective in protecting against the progression of the disease. Since cucurbitacins have shown an extreme range of pharmacological properties, in this study, we aimed to investigate the prophylactic effect of cucurbitacin B (CuB) in the experimental MS model. Experimental autoimmune encephalomyelitis (EAE) induced by subcutaneous immunization of MOG35-55 in C57BL/6 mice. CuB interventions (0.5 and 1 mg/kg, i.p.) were performed every other day from the first day of EAE induction. Assessment of clinical scores and motor function, inflammatory responses, and microglial activation were assessed by qRT-PCR, western blotting, and immunohistochemical (IHC) analyses. CuB (1 mg/kg) significantly decreased the population of CD45+ (P < 0.01), CD11b+ (P < 0.01) and CD45+/CD11b+ (P < 0.05) cells in cortical lesions of EAE mice. In addition, activation of STAT3 (P < 0.001), expression of IL-17 A and IL-23 A (both mRNA and protein), and transcription of Iba-1 significantly decreased. On the contrary, CuB (1 mg/kg) significantly increased the transcription of MBP and Olig-2. Furthermore, a significant decrease in the severity of EAE (P < 0.05), and an improvement in motor function (P < 0.05) and coordination (P < 0.05) were observed after treatment with a high dose of CuB. Our results suggest that CuB may have a wide-ranging effect on autoimmune responses in MS via a reduction in STAT3 activation, microgliosis, and adaptation of the IL-23/IL-17 axis. Further studies are needed to investigate the exact effect of CuB in glial cells and its efficiency and bioavailability in other neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]

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 × 103 and 38.5 × 103 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. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) is the most prevalent infectious agent that can induce severe liver disease. Patients infected with long-term HBV, including chronic, asymptomatic and occult forms, cannot clear HBV from infected hepatocytes completely. It is not clear why some people can clear the infection while others cannot. Furthermore, the main mechanisms responsible for progression of the infections are not fully understood. It has been hypothesised that differences in genetic and immunological parameters between patients and subjects who successfully clear HBV infections are responsible for inducing the long-term forms of the infection. Previous investigations showed that Toll-like receptors (TLRs) play important roles in immune responses, especially innate immunity, against viral infections, including hepatitis B. TLR9 detects intracellular viral dsDNA, which results in the activation of an immune response against HBV. However, defects in this system may result in an attenuated response ultimately leading to long-term HBV infections. Targeting the defects in TLR9 or reactivating the downstream pathways that are normally switched on by TLR9 in response to HBV infection is a new approach to the treatment of long-term HBV infection. However, the pathways and defects seen in patients with long-term HBV need to be thoroughly explored before therapeutics can be applied in the clinical setting. Furthermore, the apparently multigenic nature of long-term HBV infection suggests that treatment of patients may need to be personalised. [ABSTRACT FROM AUTHOR]

Abstract: Specific and predictable hybridization of the polynucleotide sequences to their complementary counterparts plays a fundamental role in the rational design of new nucleic acid nanodevices. Generally, nucleic acid hybridization can be performed using two major strategies, namely hybridization of DNA or RNA targets to surface-tethered oligonucleotide probes (solid-phase hybridization) and hybridization of the target nucleic acids to randomly distributed probes in solution (solution-phase hybridization). Investigations into thermodynamic and kinetic parameters of these two strategies showed that hybridization on surfaces is less favorable than that of the same sequence in solution. Indeed, the efficiency of DNA hybridization on surfaces suffers from three constraints: (1) electrostatic repulsion between DNA strands on the surface, (2) steric hindrance between tethered DNA probes, and (3) nonspecific adsorption of the attached oligonucleotides to the solid surface. During recent years, several strategies have been developed to overcome the problems associated with DNA hybridization on surfaces. Optimizing the probe surface density, application of a linker between the solid surface and the DNA-recognizing sequence, optimizing the pH of DNA hybridization solutions, application of thiol reagents, and incorporation of a polyadenine block into the terminal end of the recognizing sequence are among the most important strategies for enhancing DNA hybridization on surfaces. [Copyright &y& Elsevier]

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). 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. 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. 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. [ABSTRACT FROM AUTHOR]

• There is a complex interplay between gut microbiota, nervous and immune system. • This relationship leads to introduce the concept of the gut-brain-immune axis. • Evidence reported the role of polyphenols in modulating the gut-brain-immune axis. • Polyphenols may be effective in management of gut-brain-immune axis-related diseases. 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. [ABSTRACT FROM AUTHOR]

Cuprizone (cup) model targets oligodendrocytes (OLGs) degeneration and is frequently used for the mechanistic understanding of de- and remyelination. Improperly, this classic model is time-consuming and the extent of brain lesions and behavioral deficits are changeable (both temporally and spatially) within a mouse strain. We aimed to offer an alternative, less time-consuming, and more reproducible cup model. Mice (C57BL/6) were treated with cup (400 mg kg−1 day−1/gavage) for three consecutive weeks to induce OLGs degeneration with or without YM155 (1 mg kg−1 day−1) to examine the effects of this molecule in cup neurotoxicity. Co-administration of cup and YM155 (cuYM) accelerated the intrinsic apoptosis of mature OLGs (MOG positive cells) through the upregulation of caspase-9 and caspase-3. In addition to the stimulation of oxidative stress via reduction of glutathione peroxidase and induction of malondialdehyde, behavioral deficits in both Open-field and Rota-rod tests were worsened by cuYM. In the cuYM group, the expression of BIRC5, BIRC4 and NAIP was reduced, but no significant changes were observed in the abundance of the other inhibitor of apoptosis proteins (cIAP1 and cIAP2) in comparison with the cup group. Moreover, in silico analysis validated that YM155 directly interrupts the binding sites of certain transcription factors, such as krüppel-like family (Klf), specificity proteins (SPs), myeloid zinc fingers (MZFs), zinc finger proteins (ZNFPs), and transcription factor activating enhancer-binding proteins (TFAPs), on the promoters of target genes. In conclusion, this modified model promotes cup-induced redox and apoptosis signaling, elevates behavioral deficits, saves time, minimizes variations, and can be employed for early evaluation of novel neuroprotective agents in oligodendropathies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

[Display omitted] • CXCL10, CCL12, and GBP6 were the important upregulated mutual genes in all models. • STAT1, and CXCL10, were the most crucial hub proteins among mutual genes. • Mutual genes were involved in the TNF-α, TLRs, and complement cascade signaling. • Serum level of TNF-α/IL-1β/CXCL10 cytokines increased in all models. 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. 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-1β/CXCL10 cytokines was confirmed in all models in a relatively similar pattern. 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. [ABSTRACT FROM AUTHOR]

The interplay between H2S and nitric oxide (NO) is thought to contribute to renal functions. The current study was designed to assess the role of NO in mediating the renoprotective effects of hydrogen sulfide in the 5/6 nephrectomy (5/6 Nx) animal model. Forty rats were randomly assigned to 5 experimental groups: (a) Sham; (b) 5/6 Nx; (c) 5/6Nx+sodium hydrosulfide‐a donor of H 2S, (5/6Nx+sodium hydrosulfide [NaHS]); (d) 5/6Nx+NaHS+ L‐NAME (a nonspecific nitric oxide synthase [NOS] inhibitor); (e) 5/6Nx+NaHS+aminoguanidine (a selective inhibitor of inducible NOS [iNOS]). Twelve weeks after 5/6 Nx, we assessed the expressions of iNOS and endothelial NOS (eNOS), oxidative/antioxidant status, renal fibrosis, urine N‐acetyl‐b‐glucosaminidase (NAG) activity as the markers of kidney injury and various markers of apoptosis, inflammation, remodeling, and autophagy. NaHS treatment protected the animals against chronic kidney injury as depicted by improved oxidative/antioxidant status, reduced apoptosis, and autophagy and attenuated messenger RNA (mRNA) expression of genes associated with inflammation, remodeling, and NAG activity. Eight weeks Nω‐nitro‐l‐arginine methyl ester (L‐NAME) administration reduced the protective effects of hydrogen sulfide. In contrast, aminoguanidine augmented the beneficial effects of hydrogen sulfide. Our finding revealed some fascinating interactions between NO and H 2S in the kidney. Moreover, the study suggests that NO, in an isoform‐dependent manner, can exert renoprotective effects in 5/6 Nx model of CKD. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a devastating chronic autoimmune demyelinating disease of the central nervous system (CNS), thought to affect more than 2.5 million people worldwide. Regulation of the sleep-wake cycle might influence disease activity and the frequency of relapses in patients. As melatonin (or sleep hormone) involves the regulation of circadian rhythms, much attention has been paid to the management of MS symptoms with melatonin. This review describes the pharmacological mechanisms underlying the neuroprotective effects of melatonin and recent clinical evidence from MS patients. Apparent risks and benefits of melatonin therapies are also discussed. Various in vivo and clinical data presented in this up-to-date review suggest that melatonin may possibly possess a protective role against the behavioral deficits and neuropathological characteristics of MS. Multiple mechanisms of the neuroprotective effects of melatonin such as mitochondrial protection and antioxidant, anti-inflammatory, and anti-apoptotic properties, as well as its anti-demyelinating function are also discussed. A large body of evidence shows that melatonin potently regulates the immune system, demyelination, free radical generation, and inflammatory responses in neural tissue, which are mediated by multiple signal transduction cascades. In the present article, we focus on different pathways that are targeted by melatonin to prevent the development and progression of MS. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a major public health problem worldwide and is associated with spatial learning deficits. The aim of the present study was to evaluate the protective effects of hydrogen sulfide (H2S) on CKD-mediated behavioral deficits with emphasis to the role of nitric oxide (NO) in these effects. Fifty rats were randomly allocated to five experimental groups including: sham, Five-sixth (5/6) nephrectomy (Nx), 5/6Nx + NaHS, 5/6Nx + NaHS+L-nitroarginine methyl ester (L-NAME), and 5/6Nx + NaHS+aminoguanidine (AMG). Twelve weeks after 5/6Nx, we evaluated proteinuria, creatinine clearance (CrCl), oxidative/antioxidant status, and hippocampus neuro-inflammation and NO synthase genes in all groups. Furthermore, training trials of all animals were conducted in the Morris water maze (MWM) task one day before animal euthanizing. As predicted, 5/6Nx induced several injuries, including enhancement of proteinuria and reduction of CCr, oxidant/antioxidant imbalance and up-regulation of TNF-α and IL-1β gene expressions in the hippocampus tissues. As predicted, 5/6Nx resulted in learning and memory impairments, and increased escape latency during acquisition trials in the MWM task. Interestingly, NaHS (H2S donor) improved behavioral deficits, renal dysfunction, accelerated anti-oxidant/anti-inflammatory responses and increased eNOS and decreased iNOS. Moreover, these effects of NaHS were prevented by L-NAME but not AMG co-administration. In conclusion, H2S ameliorates CKD-mediated brain dysfunctions, through interaction with NO signaling in the hippocampus. [ABSTRACT FROM AUTHOR]

The efficiency of interferon beta (IFNβ)-based drugs is considerably limited due to their undesirable properties, especially high immunogenicity. In this study, for the first time we investigated the impact of a computationally designed peptide mimetic of IFNβ, called MSPEP27, in the animal model of MS. A peptide library was constructed using the Rosetta program based on the predominant IFNAR1-binding site of IFNβ. Molecular docking studies were carried out using ClusPro and HADDOCK tools. The GROMACS package was subsequently used for molecular dynamics (MD) simulations. Validation of peptide-receptor interaction was carried out using intrinsic fluorescence measurements. To explore in silico findings further, experimental autoimmune encephalomyelitis (EAE) was induced by subcutaneous immunization of myelin oligodendrocyte glycoprotein (MOG35-55). Mice were then separated into distinct groups and intravenously received 10 or 20 mg kg − 1 of MSPEP27 or IFNβ. The inflammatory mediators were monitored by immunohistochemistry (IL17, CD11b, CD45), quantitative real-time PCR (MMP2, MMP9, TIMP-1) and enzyme-linked immunosorbent assay (IL1β, TNFα) methods. Among the library of tolerated peptides, MSPEP27, a peptide with favorable physicochemical properties, was chosen for further experiments. This peptide was shown to significantly interact with IFNAR1 in a dose-dependent manner. Like IFNβ, MSPEP27 could efficiently bind to IFNAR1 and form a stable peptide-receptor complex during 30 ns MD simulations. In vivo analyses revealed that MSPEP27 could lessen inflammation by modulating the levels of inflammatory mediators. According to our results, MSPEP27 peptide could efficiently bind to IFNAR1 and suppress neuroinflammation in vivo. We conclude that MSPEP27 has protective effects against MOG-induced EAE via reduction of immune dysfunction and inflammation. [ABSTRACT FROM AUTHOR]

The current study aimed to examine the renoprotective effects of long-term treatment with sodium hydrosulfide (NaHS), a prominent hydrogen sulfide donor, in 5/6 nephrectomy animal model. Twenty-four rats were randomly divided into 3 groups including sham-operated group (Sham), 5/6-nephrectomized group (5/6 Nx), and NaHStreated group (5/6Nx+NaHS). NaHS (30 micromol/l) was added twice daily into the drinking water and renal failure was induced by 5/6 nephrectomy. Twelve weeks after surgical procedure, blood pressure, creatinine clearance (CCr), urine concentration of neutrophil gelatinase associated lipocalin (NGAL) and tissue concentration of malondialdehyde (MDA), superoxide dismutase (SOD), as well as renal morphological changes, apoptosis (cleaved caspase-3) and inflammation (p-NF-κB) were measured. Five-sixth nephrectomy induced severe renal damage as indicated by renal dysfunction, hypertension and significant histopathological injury which were associated with increased NGAL and MDA levels, oxidant/antioxidant imbalance, decreased SOD activity and CCr and also overexpression of p-NF-κB and cleaved caspase-3 proteins. Instead, NaHS treatment attenuated renal dysfunction through reduction of NGAL concentration, hypertension, CCr, oxidant/antioxidant imbalance, inflammation and apoptosis. These findings suggest that long term NaHS treatment can be useful in preventing the progression of CKD by improving oxidant/antioxidant balance and reducing inflammation and apoptosis in the kidney. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ferroptosis involves iron-mediated lipid peroxidation and cell death. • Ferroptosis links cell metabolism, redox imbalance, and human diseases. • Ferroptosis is controlled by numerous cellular metabolic processes. • Ferroptosis modulation carries excellent treatment potential for a variety of diseases. Ferroptosis is a type of iron-mediated cell death merging cell metabolism, redox status, and human disease. Reactive oxygen species (ROS) are formed after exposure to xenobiotics and normal metabolism; depending on their level, ROS can serve as intracellular redox messengers and regulators of cell fate, while excessive ROS amounts cause cellular oxidative changes, suppress protein activity, and trigger cell death. At the intracellular level, several redox mechanisms, such as the pyridine nucleotide redox systems involving thioredoxin and glutathione, are connected with ROS signaling and therefore contribute to cell status and function. Living in polluted conditions with an increased presence of fossil fuels, negatively affects human health and makes humans vulnerable to debilitating problems such as cancer and infectious diseases. The present understanding of ferroptosis in toxicity-mediated environmental exposures remains incomplete, and the underlying basis for the chemical stressors that trigger ferroptosis remains unclear. This review summarized the effects of environmental chemical exposure on cellular redox signaling, ferroptosis, and cell death providing critical information to stop the impact of ferroptosis on human health. [ABSTRACT FROM AUTHOR]

Salient evidence testifies the link between organophosphorus (OPs) exposure and the formation of free radical oxidants; and it is well accepted that free radicals are one of the basic concerns of senescence. To show the oxidative features of phosalone (PLN) as a key member of OPs, to induce senescence in rat embryonic fibroblast (REF) cells and to demonstrate the beneficial effects of the known antioxidant ellagic acid (EA) in diminishing the PLN-induced toxic effects, the levels of cell viability, oxidative stress markers, inflammatory cytokines, telomerase activity, and the expression of the genes related to senescence were investigated. Our results lend support to the hypothesis that PLN enhances the entire premature senescence parameters of REF cells. This accounts for the mechanistic approval of the role of OPs in induction of senescence in rat fibroblasts. Moreover, incorporation of EA diminished PLN toxicity mainly through suppression of p38 and p53 at gene and protein levels, and tempered the inflammation factors (TNF-α, IL-1β, IL-6 and NF-κB), which further affected cell division. Analysis of cell cycle showed that the percentage of G0/G1 arrest, in REF cells treated by EA was elevated as compared to control and PLN treated cells. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a debilitating neurological condition often associated with chronic neuroinflammation and redox imbalance. Oxidative stress is one of the main hallmark of secondary injury of SCI which is tightly regulated by nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling. In this study, we aimed at investigating the interplay between inflammation-related miRNAs and the Nrf2 pathway in animal model of SCI. The expression of selected four validated miRNA-target pairs (miRNA223-3p, miRNA155-5p, miRNA145-5p, and miRNA124-3p) was examined at different time points (6 h, 12 h, 1 day, 3 day and 7 day) after SCI. Further, using GFAP-specific kelch-like ECH-associated protein 1 deletion (Keap1−/−) and whole-body Nrf2−/− knockout mice, we investigated the potential interplay between each miRNA and the Keap1/Nrf2 signaling system. The expression of all miRNAs except miRNA155-5p significantly increased 24 h after SCI and decreased after 7 days. Interestingly, Keap1−/− mice only showed significant increase in the miRNA145-5p after 24 h SCI compared to the WT group. In addition, Keap1−/− mice showed significant decrease in CXCL10/12 (CXCL12 increased in Nrf2−/− mice), and TNF-α, and an increase in Mn-SOD and NQO-1 (Mn-SOD and NQO-1 decreased in Nrf2−/− mice) compared to WT mice. Our results suggest that astrocytic hyperactivation of Nrf2 exert neuroprotective effects at least in part through the upregulation of miRNA145-5p, a negative regulator of astrocyte proliferation, and induction of ARE in early phase of SCI. Further studies are needed to investigate the potential interplay between Nrf2 and miRNA145-5p in neuroinflammatory condition. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Purpose:Some functional limitations and economic burden of therapeutic antibodies indicated that introducing of alternative therapeutic compounds with same or different mechanism of action could be worthwhile. In this regard small-molecule antagonists can have a wide range of impacts, so in this research, we examine the prophylactic effects of BIO-1211 [Very Late Antigen-4 (VLA4) blocker], in experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis in comparison with commercial available medicine, Natalizumab (NTZ)]. Methods:EAE was induced by subcutaneous immunization of myelin oligodendrocyte glycoprotein (MOG35-55) in 8-week-old C57BL/6 mice. During EAE induction, mice were separated to distinct groups and provided either BIO-1211 (5 and 10 mg/kg) or NTZ (5 mg/kg) and co-administration of these two compounds. After 21 days, neuro-inflammatory responses were analyzed using qRT-PCR, western blot, and ELISA methods. Pervade of immune cells to brain was examined by Evans blue staining and immunohistochemistry (IHC) analysis of specific markers of microglia/monocytes (CD11b) and leukocytes (CD45). Results:Targeted disruption of VLA4/VCAM1 interactions, by BIO-1211 agonist in mice, results in reduced cytokines expression, leukocyte trafficking, and inhibition of inflammatory responses in EAE (p < 0.01) in a dose-independent manner (data not shown). Mice treated with both BIO-1211 and NTZ exhibited a considerable depletion in the EAE clinical score, which correlated with decreased expression of TNF-α, IL-17, IFN-γ and pervade of CD11b+and CD45+cells into the cerebral cortex. Conclusion:Our results indicated that BIO12-11 compound would be an useful tool to further understand the biological roles of VLA4/VCAM1 interactions, and could also be considered as EAE-suppressing agent. [ABSTRACT FROM PUBLISHER]

Objective(s): 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. [ABSTRACT FROM AUTHOR]

IL-1B is released by monocytes, astrocytes and brain endothelial cells and seems to be involved in inflammatory reactions of the central nervous system (CNS) in multiple sclerosis (MS). This study aims to evaluate the expression level of IL-1B mRNA in peripheral blood mononuclear cells (PBMCs), genotype the rs16944 SNP and find out the role of this SNP on the expression level of IL-1B in MS patients. We found that the expression level of IL-1B in MS patients increased 3.336 times more than controls in PBMCs but the rs16944 SNP in the promoter region of IL-1B did not affect the expression level of this gene and there was not association of this SNP with MS in the examined population. Also, our data did not reveal any correlation between normalized expressions of IL-1B gene with age of participants, age of onset, and disease duration. [ABSTRACT FROM AUTHOR]

• Intra-NAc shell infusion of CART induced CPP or CPA dose-dependently. • Aversive CART + rewarding morphine produced neither CPP nor CPA. • IHC showed NR1 reduction in NAc and hippocampus, but not in PFC in above experiment. • Sub-rewarding both CART and morphine induced CPP, NR1 increased in all above areas. • There might be an interaction between opioids, CART and NMDA in NAc-shell framework. The addictive properties of opioids may be mediated to some extent by cocaine-and amphetamine-regulated transcript (CART) in the reward pathway. Moreover, some claims CART interacts with the glutamate system. Here, we evaluated whether intra-nucleus accumbens (NAc) shell infusions of CART induces Conditioned Place Preference (CPP) or Conditioned Place Aversion (CPA) and affects morphine reward. We also measured NR1 subunit expressions of the N -methyl- d -aspartate (NMDA) receptor in various parts of the reward pathway (NAc, prefrontal cortex and hippocampus) after conditioning tests. Animals with bilateral intra-NAc shell cannulas were place-conditioned with several doses of subcutaneous morphine prior to intra-NAc shell infusions of artificial cerebrospinal fluid (aCSF). Immunohistochemistry (IHC) showed a dose-dependent increase in the NR1 expression in all examined parts. When rats were conditioned with intra-NAc shell infusions of CART, CPP and CPA induced with 2.5 and 5 μg/side respectively and IHC showed NR1elevation with 2.5 and reduction with 5 μg/side in all areas. Sub-rewarding dose of CART administration (1.25 μg/side) prior to sub-rewarding dose of morphine (2.5 mg/kg) induced CPP and NR1 increased in all examined tissues in IHC. However, infusion of an aversive dose of CART (5 μg/side) prior to the rewarding dose of morphine (5 mg/kg) produced neither CPP nor CPA and NR1 in the NAc and hippocampus decreased significantly. It seems that the rewarding or aversive effects of intra-NAc shell CART and its facilitating or inhibiting effects on morphine reward are dose-dependent. Additionally, NMDA may be closely involved in the affective properties of opioids and CART in the reward pathway. [ABSTRACT FROM AUTHOR]

• Alzheimer's disease (AD) is highly prevalent neurodegenerative pathology. • Chronic oral microbiota alterations have been associated with the risk of AD. • Oral microbiota releases inflammatory mediators that can cause neuroinflammation. • Oral health care is essential to prevent oral microbiota dysbiosis. Alzheimer's disease (AD) is a progressive neurodegenerative pathology affecting milions of people worldwide associated with deposition of senile plaques. While the genetic and environmental risk factors associated with the onset and consolidation of late onset AD are heterogeneous and sporadic, growing evidence also suggests a potential link between some infectious diseases caused by oral microbiota and AD. Oral microbiota dysbiosis is purported to contribute either directly to amyloid protein production, or indirectly to neuroinflammation, occurring as a consequence of bacterial invasion. Over the last decade, the development of Human Oral Microbiome database (HOMD) has deepened our understanding of oral microbes and their different roles during the human lifetime. Oral pathogens mostly cause caries, periodontal disease, and edentulism in aged population, and, in particular, alterations of the oral microbiota causing chronic periodontal disease have been associated with the risk of AD. Here we describe how different alterations of the oral microbiota may be linked to AD, highlighting the importance of a good oral hygiene for the prevention of oral microbiota dysbiosis. [ABSTRACT FROM AUTHOR]

As a group of progressive, chronic, and disabling disorders, neurodegenerative diseases (NDs) affect millions of people worldwide, and are on the rise. NDs are known as the gradual loss of neurons; however, their pathophysiological mechanisms have not been precisely revealed. Due to the complex pathophysiological mechanisms behind the neurodegeneration, investigating effective and multi-target treatments has remained a clinical challenge. Besides, appropriate neuroprotective agents are still lacking, which raises the need for new therapeutic agents. In recent years, several reports have introduced naturally-derived compounds as promising alternative treatments for NDs. Among natural entities, flavonoids are multi-target alternatives affecting different pathogenesis mechanisms in neurodegeneration. Naringenin is a natural flavonoid possessing neuroprotective activities. Increasing evidence has attained special attention on the variety of therapeutic targets along with complex signaling pathways for naringenin, which suggest its possible therapeutic applications in several NDs. Here, in this review, the neuroprotective effects of naringenin, as well as its related pharmacological targets, signaling pathways, molecular mechanisms, and clinical perspective, are described. Moreover, the need to develop novel naringenin delivery systems is also discussed to solve its widespread pharmacokinetic limitation. [ABSTRACT FROM AUTHOR]