scholarly journals Dynamic Changes in the Expression of Interferon-Stimulated Genes in Joints of SPF Chickens Infected With Avian Reovirus

2021 ◽  
Vol 8 ◽  
Author(s):  
Sheng Wang ◽  
Liji Xie ◽  
Zhixun Xie ◽  
Lijun Wan ◽  
Jiaoling Huang ◽  
...  
Keyword(s):  
Viral Load ◽  
Zinc Finger Protein ◽  
Transmembrane Protein ◽  
Expression Patterns ◽  
Avian Reovirus ◽  
Protein Kinase R ◽  
Inhibitory Protein ◽  
Viral Challenge ◽  
Interferon Stimulated Genes ◽  
Real Time Quantitative Pcr

Avian reovirus (ARV) can induce many diseases as well as immunosuppression in chickens, severely endangering the poultry industry. Interferons (IFNs) play an antiviral role by inducing the expression of interferon-stimulated genes (ISGs). The effect of ARV infection on the expression of host ISGs is unclear. Specific-pathogen-free (SPF) chickens were infected with ARV strain S1133 in this study, and real time quantitative PCR was used to detect changes in the dynamic expression of IFNs and common ISGs in joints of SPF chickens. The results showed that the transcription levels of IFNA, IFNB, and several ISGs, including myxovirus resistance (MX), interferon-induced transmembrane protein 3 (IFITM3), protein kinase R (PKR), oligoadenylate synthase (OAS), interferon-induced protein with tetratricopeptide repeats 5 (IFIT5), interferon-stimulated gene 12 (ISG12), virus inhibitory protein (VIPERIN), interferon-alpha-inducible protein 6 (IFI6), and integrin-associated protein (CD47), were upregulated in joints on days 1–7 of infection (the levels of increase of MX, IFIT5, OAS, VIPERIN, ISG12, and IFI6 were the most significant, at hundreds-fold). In addition, the expression levels of the ISGs encoding zinc finger protein 313 (ZFP313), and DNA damage–inducible transcript 4 (DDIT4) increased suddenly on the 1st or 2nd day, then decreased to control levels. The ARV viral load in chicken joints rapidly increased after 1 day of viral challenge, and the viral load remained high within 6 days of viral challenge. The ARV viral load sharply decreased starting on day 7. These results indicate that in SPF chicken joints, many ISGs have mRNA expression patterns that are basically consistent with the viral load in joints. IFNA, IFNB, and the ISGs MX, IFITM3, PKR, OAS, IFIT5, ISG12, VIPERIN, IFI6, and CD47 play important roles in defending against ARV invasion, inhibiting ARV replication and proliferation, and promoting virus clearance. These results enrich our understanding of the innate immune response mechanisms of hosts against ARV infection and provide a theoretical basis for prevention and control of ARV infection.

The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse

2021 ◽  
Vol 14 (687) ◽  
pp. eaba0717
Author(s):  
Shunsuke Kataoka ◽  
Priyanka Manandhar ◽  
Judong Lee ◽  
Creg J. Workman ◽  
Hridesh Banerjee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Cell Receptor ◽  
Mapk Signaling ◽  
Inhibitory Protein ◽  
Immune Synapse

Expression of the transmembrane protein Tim-3 is increased on dysregulated T cells undergoing chronic activation, including during chronic infection and in solid tumors. Thus, Tim-3 is generally thought of as an inhibitory protein. We and others previously reported that under some circumstances, Tim-3 exerts paradoxical costimulatory activity in T cells (and other cells), including enhancement of the phosphorylation of ribosomal S6 protein. Here, we examined the upstream signaling pathways that control Tim-3–mediated increases in phosphorylated S6 in T cells. We also defined the localization of Tim-3 relative to the T cell immune synapse and its effects on downstream signaling. Recruitment of Tim-3 to the immune synapse was mediated exclusively by the transmembrane domain, replacement of which impaired the ability of Tim-3 to costimulate T cell receptor (TCR)–dependent S6 phosphorylation. Furthermore, enforced localization of the Tim-3 cytoplasmic domain to the immune synapse in a chimeric antigen receptor still enabled T cell activation. Together, our findings are consistent with a model whereby Tim-3 enhances TCR-proximal signaling under acute conditions.

scholarly journals Probiotics Modulate Tilapia Resistance and Immune Response against Tilapia Lake Virus Infection

Pathogens ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 919
Author(s):  
Pitchaporn Waiyamitra ◽  
Mehmet Arif Zoral ◽  
Aksorn Saengtienchai ◽  
Amorn Luengnaruemitchai ◽  
Olivier Decamp ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Load ◽  
Control Diet ◽  
Expression Patterns ◽  
Economic Damage ◽  
Control Group ◽  
Probiotic Treatment ◽  
Significant Difference ◽  
Bacillus Spp ◽  
Immune Related Genes

Tilapia lake virus (TiLV) causes an emerging viral disease associated with high mortality and economic damage in tilapia farming around the world. The use of probiotics in aquaculture has been suggested as an alternative to antibiotics and drugs to reduce the negative impact of bacterial and viral infections. In this study, we investigate the effect of probiotic Bacillus spp. supplementation on mortality, viral load, and expression of immune-related genes in red hybrid tilapia (Oreochromis spp.) upon TiLV infection. Fish were divided into three groups, and fed with: control diet, 0.5% probiotics-supplemented diet, and 1% probiotics-supplemented diet. After 21 days of experimental feeding, the three groups were infected with TiLV and monitored for mortality and growth performances, while organs were sampled at different time points to measure viral load and the transcription modulation of immune response markers. No significant difference was found among the groups in terms of weight gain (WG), average daily gain (ADG), feed efficiency (FE), or feed conversion ratio (FCR). A lower cumulative mortality was retrieved from fish fed 0.5% and 1% probiotics (25% and 24%, respectively), compared to the control group (32%). Moreover, fish fed with 1% probiotic diet had a significantly lower viral load, than those fed with 0.5% probiotic and control diet at 5, 6, 9, and 12 days post infection-challenge (dpc). The expression patterns of immune-related genes, including il-8 (also known as CXCL8), ifn-γ, irf-3, mx, rsad-2 (also known as VIPERIN) showed significant upregulation upon probiotic treatment during the peak of TiLV pathogenesis (between 9 and 12 dpc) and during most of the study period in fish fed with 1% probiotics-supplemented diet. Taken together, these findings indicate that dietary supplementation using Bacillus spp. probiotics may have beneficial effects to strengthen tilapia immunity and resistance against TiLV infections. Therefore, probiotic treatments may be preventively administered to reduce losses caused by this emerging viral infection in tilapia aquaculture.

scholarly journals Identification of IFITM1 and IFITM3 in Goose: Gene Structure, Expression Patterns, and Immune Reponses against Tembusu Virus Infection

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Anqi Wang ◽  
Lipei Sun ◽  
Mingshu Wang ◽  
Renyong Jia ◽  
Dekang Zhu ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Expression Patterns ◽  
Harderian Gland ◽  
Bursa Of Fabricius ◽  
Poly I:C ◽  
Peripheral Blood Mononuclear ◽  
Interferon Stimulated Genes ◽  
Cecal Tonsil ◽  
Tembusu Virus ◽  
First Time

As interferon-stimulated genes (ISGs), interferon-inducible transmembrane proteins 1 and 3 (IFITM1 and IFITM3) can effectively inhibit the replication of multiple viruses. Here, goose IFITM1 and IFITM3 were cloned and identified for the first time. The two proteins share the same topological structure and several important sites critical for the antiviral functions in other species are conserved in the goose. Goose IFITM1 and IFITM3 are most closely related to their respective orthologs in ducks; these proteins exhibited high mRNA transcript levels in immune-related tissues, including the thymus, bursa of Fabricius, and Harderian gland, compared to other tissues. Moreover, goose IFITM1 was highly constitutively expressed in gastrointestinal tract tissues, while goose IFITM3 was expressed in respiratory organs. Furthermore, goose IFITM3 was activated in goose peripheral blood mononuclear cells (PBMCs) infected with Tembusu virus (TMUV) or treated with Toll-like receptors (TLRs) agonists, while only the R848 and Poly (I:C) agonists induced significant upregulation of goose IFITM1. Furthermore, goose IFITM1 and IFITM3 were upregulated in the sampled tissues, to some extent, after TMUV infection. Notably, significant upregulation of goose IFITM1 and IFITM3 was detected in the cecum and cecal tonsil, where TMUV was primarily distributed. These data provide new insights into the immune effectors in geese and promote our understanding of the role of IFITM1 and IFITM3 in the defense against TMUV.

Generation of Two Homologous and Intronless Zinc-Finger Protein Genes, Zfp352 and Zfp353, with Different Expression Patterns by Retrotransposition

Genomics ◽  
2002 ◽  
Vol 79 (1) ◽  
pp. 18-23 ◽  
Author(s):  
Huang-Hui Chen ◽  
Tiffany Yi-Chen Liu ◽  
Chiu-Jung Huang ◽  
Kong-Bung Choo
Keyword(s):  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Expression Patterns ◽  
Finger Protein

scholarly journals Vaccination with a Live Attenuated Cytomegalovirus Devoid of a Protein Kinase R Inhibitory Gene Results in Reduced Maternal Viremia and Improved Pregnancy Outcome in a Guinea Pig Congenital Infection Model

2015 ◽  
Vol 89 (19) ◽  
pp. 9727-9738 ◽  
Author(s):  
Mark R. Schleiss ◽  
Craig J. Bierle ◽  
Elizabeth C. Swanson ◽  
Michael A. McVoy ◽  
Jian Ben Wang ◽  
...  
Keyword(s):  
Viral Load ◽  
Protein Kinase ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Congenital Infection ◽  
Virus Genome ◽  
Enzyme Linked Immunosorbent Assay ◽  
Protein Kinase R ◽  
Targeted Deletion ◽  
Pup Mortality

ABSTRACTDevelopment of a vaccine to prevent congenital cytomegalovirus infection is a major public health priority. Live vaccines attenuated through mutations targeting viral mechanisms responsible for evasion of host defense may be both safe and efficacious. Safety and vaccine efficacy were evaluated using a guinea pig cytomegalovirus (GPCMV) model. Recombinant GPCMV with a targeted deletion ofgp145(designated Δ145), a viral protein kinase R (PKR) inhibitor, was generated. Attenuation was evaluated following inoculation of 107PFU of Δ145 or parental virus into guinea pigs immunosuppressed with cyclophosphamide. Efficacy was evaluated by immunizing GPCMV-naive guinea pigs twice with either 105or 106PFU of Δ145, establishing pregnancy, and challenging the guinea pigs with salivary gland-adapted GPCMV. The immune response, maternal viral load, pup mortality, and congenital infection rates in the vaccine and control groups were compared. Δ145 was substantially attenuated for replication in immunocompromised guinea pigs. Vaccination with Δ145 induced enzyme-linked immunosorbent assay (ELISA) and neutralizing antibody levels comparable to those achieved in natural infection. In the higher- and lower-dose vaccine groups, pup mortality was reduced to 1/24 (4%) and 4/29 (14%) pups, respectively, whereas it was 26/31 (81%) in unvaccinated control pups (P< 0.0001 for both groups versus the control group). Congenital infection occurred in 20/31 (65%) control pups but only 8/24 (33%) pups in the group vaccinated with 106PFU (P< 0.05). Significant reductions in the magnitude of maternal DNAemia and pup viral load were noted in the vaccine groups compared to those in the controls. Deletion of a GPCMV genome-encoded PKR inhibitor results in a highly attenuated virus that is immunogenic and protective as a vaccine against transplacental infection.IMPORTANCEPrevious attempts to develop successful immunization against cytomegalovirus have largely centered on subunit vaccination against virion proteins but have yielded disappointing results. The advent of bacterial artificial chromosome technologies has enabled engineering of recombinant cytomegaloviruses (CMVs) from which virus genome-encoded immune modulation genes have been deleted, toward the goal of developing a safe and potentially more efficacious live attenuated vaccine. Here we report the findings of studies of such a vaccine against congenital CMV infection based on a virus with a targeted deletion ingp145, a virus genome-encoded inhibitor of protein kinase R, using the guinea pig model of vertical CMV transmission. The deletion virus was attenuated for dissemination in immunocompromised guinea pigs but elicited ELISA and neutralizing responses. The vaccine conferred protection against maternal DNAemia and congenital transmission and resulted in reduced viral loads in newborn guinea pigs. These results provide support for future studies of attenuated CMV vaccines.

251 COMPARATIVE ANALYSIS OF GENE EXPRESSION PATTERNS IN PORCINE PRE-IMPLANTATION EMBRYOS DERIVED FROM DIFFERENT ORIGINS

2006 ◽  
Vol 18 (2) ◽  
pp. 233
Author(s):  
J.-G. Kim ◽  
H.-F. Jin ◽  
B.-K. Mohana ◽  
H.-J. Song ◽  
Y.-J. Jeong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Relative Abundance ◽  
Expression Patterns ◽  
Rna Isolation ◽  
Developmental Competence ◽  
Histone H2a ◽  
Cell Stage ◽  
Real Time Quantitative Pcr ◽  
Morula Stage ◽  
Different Origins

The amount of information gathered on the kinetics and quantitative profile of gene expression in nuclear transferred (NT) pre-implantation embryos is still scarce and limited to a handful of genes in pig. In the present study, we compared the relative abundance (RA) of six development-related genes of pre-implantation embryos from different origins. Cumulus-oocyte complexes (COCs) were matured, fertilized and cultured by the method of Abeydeera et al. (2000 Theriogenology 54, 787-797). Parthenogenetic (PA) and NT embryos were produced as described by Kim et al. (2005 Mol. Rep. Dev. 70, 308-313). Sets of 10 embryos each at 4-cell, 8-16-cell, morula, and Day 7 blastocyst stages were used to extract total RNA for analyzing the expression pattern of Bax (pro-apoptotic), Bcl-xl (anti-apoptotic), Oct-4 (pluripotent transcription), Stat3 (cytoplasmic transcription), IFN-tau (implantation) and VEGF (vasculogenesis) genes (three replicates) with real-time quantitative PCR (LightCycler�; Roche Diagnostics, Mannheim, Germany) following RNA isolation (with Dynabeads� mRNA Direct" kit; Dynal, Oslo, Norway) and cDNA amplification (Oligo (dT)12-18 primer and Superscript" III cDNA synthesis kit; Invitrogen, Carlsbad, CA, USA). The expression of each gene was normalized to Histone H2A expression. Statistically significant (P < 0.05) differences in gene expression were analyzed by ANOVA. Oct-4, Stat3, Bax, and Bcl-xl were expressed at the 4-cell stage. However, IFN-tau and VEGF were expressed at the morula stage. The expression patterns of all genes throughout the embryonic development in all types of embryos were similar. However, the relative abundance (RA) of Bax in the 8-16 cell stage of NT and PA was significantly (P < 0.05) increased as compared to that in IVP counterparts. The RA of Oct-4 and Bcl-xl did not differ throughout all stages in NT and PA embryos. There were no significant differences in all types of embryos with respect to the RA of Oct-4 and Bcl-xl with exception of the blastocysts in NT (significantly decreased, P < 0.01). The RA of Stat3 was significantly (P < 0.05) increased in the 8-16 cell stage (NT and PA) and in blastocysts (NT). Similarly, the RA of IFN-tau was significantly (P < 0.05) increased in NT blastocysts. The RA of VEGF was not significantly different in all stages and types of embryos except NT blastocysts (decreased expression, P < 0.01). These results suggest that expression patterns of Bax, Bcl-xl, Oct-4, Stat3, IFN-tau, and VEGF can be used as markers to assess the developmental competence of porcine nuclear transfer embryos. This work was supported by Grant No. 1000520040020000 from Biogreen 21, Republic of Korea.

scholarly journals Tetraspanins TSP-12 and TSP-14 function redundantly to regulate the trafficking of the type II BMP receptor in Caenorhabditis elegans

2020 ◽  
Vol 117 (6) ◽  
pp. 2968-2977
Author(s):  
Zhiyu Liu ◽  
Herong Shi ◽  
Anthony K. Nzessi ◽  
Anne Norris ◽  
Barth D. Grant ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Surface ◽  
Molecular Mechanisms ◽  
Transmembrane Protein ◽  
Expression Patterns ◽  
Bmp Signaling ◽  
Type I ◽  
Type Ii ◽  
Bmp Receptors

Tetraspanins are a unique family of 4-pass transmembrane proteins that play important roles in a variety of cell biological processes. We have previously shown that 2 paralogous tetraspanins in Caenorhabditis elegans, TSP-12 and TSP-14, function redundantly to promote bone morphogenetic protein (BMP) signaling. The underlying molecular mechanisms, however, are not fully understood. In this study, we examined the expression and subcellular localization patterns of endogenously tagged TSP-12 and TSP-14 proteins. We found that TSP-12 and TSP-14 share overlapping expression patterns in multiple cell types, and that both proteins are localized on the cell surface and in various types of endosomes, including early, late, and recycling endosomes. Animals lacking both TSP-12 and TSP-14 exhibit reduced cell-surface levels of the BMP type II receptor DAF-4/BMPRII, along with impaired endosome morphology and mislocalization of DAF-4/BMPRII to late endosomes and lysosomes. These findings indicate that TSP-12 and TSP-14 are required for the recycling of DAF-4/BMPRII. Together with previous findings that the type I receptor SMA-6 is recycled via the retromer complex, our work demonstrates the involvement of distinct recycling pathways for the type I and type II BMP receptors and highlights the importance of tetraspanin-mediated intracellular trafficking in the regulation of BMP signaling in vivo. As TSP-12 and TSP-14 are conserved in mammals, our findings suggest that the mammalian TSP-12 and TSP-14 homologs may also function in regulating transmembrane protein recycling and BMP signaling.

Expression patterns of gpNMB in breast cancer (BC): Retrospective evaluation of tumor tissue from the phase II EMERGE study.

2015 ◽  
Vol 33 (28_suppl) ◽  
pp. 129-129
Author(s):  
Denise A. Yardley ◽  
Michelle E. Melisko ◽  
Andres Forero ◽  
Rebecca G. Bagley ◽  
Joshua Zhang ◽  
...  
Keyword(s):  
Phase Ii ◽  
Tumor Tissue ◽  
Transmembrane Protein ◽  
Expression Patterns ◽  
Objective Response ◽  
Progression Free Survival ◽  
Antibody Drug Conjugate ◽  
Free Survival ◽  
Disease Characteristics ◽  
Clinical Trial Information

129 Background: Glycoprotein NMB (gpNMB) is an internalizable transmembrane protein overexpressed in ~20% of BC. gpNMB promoted BC metastases in a murine model and is a poor prognostic marker in BC patients (pts) (Rose 2010). Glembatumumab vedotin (GV, CDX-011) is a novel antibody-drug conjugate targeting gpNMB+ cancer cells with the potent cytotoxin monomethyl auristatin E. In a Phase I/II and in the Phase II EMERGE study, GV was well-tolerated (treatment-related toxicity included rash, neutropenia, and neuropathy) with promising activity in gpNMB+ BC tumors including TNBC. In EMERGE, GV vs. investigator’s choice chemotherapy, demonstrated an objective response rate of 30% (7/23) vs. 9% (1/11) in pts with tumor gpNMB overexpression (gpNMB in > 25% of tumor cells); 18% (5/28) vs. 0% (0/11) in TNBC; and 40% (4/10) vs. 0% (0/6) in gpNMB-overexpressing TNBC. Improvements in progression-free survival (hazard ratio (HR) = 0.11) and overall survival (HR = 0.14) in gpNMB-overexpressing TNBC were noted. Methods: This retrospective analysis of the EMERGE study examined frequency of gpNMB overexpression by various baseline and disease characteristics. Tumors were centrally assessed by immunohistochemistry (IHC) and included data for 328 pts. Results: Tumor gpNMB overexpression was present in 21% (69/328) of screened and 40% (38/96) of TNBC pts. gpNMB overexpression was consistent in progesterone, estrogen, or HER2+ expressing tumors at rates of 12-15%. gpNMB overexpression was not observed among 17 lobular tumors, but was present in 21% (57/270) of ductal tumors. gpNMB overexpression was seen across organ sites, including lung (43%, 3/7), lymph node (31%, 12/39), chest wall (23%, 3/13), breast (21%, 44/209), bone (13%, 1/8), and liver (13%, 3/24). There were no apparent differences in gpNMB overexpression by age, race or disease setting (early vs. advanced) at tissue collection. Analysis is ongoing to determine if prior treatments may upregulate gpNMB expression. Conclusions: gpNMB overexpression in BC, especially in TNBC, appears consistent in archival primary and/or metastatic BC, regardless of age. A randomized multicenter study of GV in gpNMB overexpressing metastatic TNBC (METRIC) is ongoing. Clinical trial information: NCT01156753.

scholarly journals Purification, characterization and molecular cloning of glycosylphosphatidylinositol-anchored arginine-specific ADP-ribosyltransferases from chicken

2005 ◽  
Vol 389 (3) ◽  
pp. 853-861 ◽  
Author(s):  
Masaharu Terashima ◽  
Harumi Osago ◽  
Nobumasa Hara ◽  
Yoshinori Tanigawa ◽  
Makoto Shimoyama ◽  
...  
Keyword(s):  
Molecular Cloning ◽  
Expression Patterns ◽  
Post Translational Modification ◽  
Rnase Protection ◽  
Functional Roles ◽  
Chicken Tissues ◽  
Adp Ribosylation ◽  
Real Time Quantitative Pcr ◽  
Specific Distribution ◽  
Rapid Amplification

Mono-ADP-ribosylation is a post-translational modification that regulates the functions of target proteins or peptides by attaching an ADP-ribose moiety. Here we report the purification, molecular cloning, characterization and tissue-specific distribution of novel arginine-specific Arts (ADP-ribosyltransferases) from chicken. Arts were detected in various chicken tissues as GPI (glycosylphosphatidylinositol)-anchored forms, and purified from the lung membrane fraction. By molecular cloning based on the partial amino acid sequence using 5′- and 3′-RACE (rapid amplification of cDNA ends), two full-length cDNAs of chicken GPI-anchored Arts, cgArt1 (chicken GPI-anchored Art1) and cgArt2, were obtained. The cDNA of cgArt1 encoded a novel polypeptide of 298 amino acids which shows a high degree of identity with cgArt2 (82.9%), Art6.1 (50.2%) and rabbit Art1 (42.1%). In contrast, the nucleotide sequence of cgArt2 was identical with that of Art7 cloned previously from chicken erythroblasts. cgArt1 and cgArt2 proteins expressed in DT40 cells were shown to be GPI-anchored Arts with a molecular mass of 45 kDa, and these Arts showed different enzymatic properties from the soluble chicken Art, Art6.1. RNase protection assays and real-time quantitative PCR revealed distinct expression patterns of the two Arts; cgArt1 was expressed predominantly in the lung, spleen and bone marrow, followed by the heart, kidney and muscle, while cgArt2 was expressed only in the heart and skeletal muscle. Thus GPI-anchored Arts encoded by the genes cgArt1 and cgArt2 are expressed extensively in chicken tissues. It may be worthwhile determining the functional roles of ADP-ribosylation in each tissue.

scholarly journals Disruption of the Circadian Clock Alters Antioxidative Defense via the SIRT1-BMAL1 Pathway in 6-OHDA-Induced Models of Parkinson’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Yali Wang ◽  
Dongjun Lv ◽  
Wenwen Liu ◽  
Siyue Li ◽  
Jing Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Circadian Clock ◽  
Antioxidative Activity ◽  
Expression Patterns ◽  
Antioxidative Defense ◽  
Real Time Quantitative Pcr ◽  
6 Hydroxydopamine

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is known to involve circadian dysfunction and oxidative stress. Although antioxidative defense is regulated by the molecular circadian clock, few studies have examined their function in PD and their regulation by silent information regulator 1 (SIRT1). We hypothesize that reduced antioxidative activity in models of PD results from dysfunction of the molecular circadian clock via the SIRT1 pathway. We treated rats and SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) and measured the expression of core circadian clock and associated nuclear receptor genes using real-time quantitative PCR as well as levels of SIRT1, brain and muscle Arnt-like protein 1 (BMAL1), and acetylated BMAL1 using Western blotting. We found that 6-OHDA treatment altered the expression patterns of clock and antioxidative molecules in vivo and in vitro. We also detected an increased ratio of acetylated BMAL1:BMAL1 and a decreased level of SIRT1. Furthermore, resveratrol, an activator of SIRT1, decreased the acetylation of BMAL1 and inhibited its binding with CRY1, thereby reversing the impaired antioxidative activity induced by 6-OHDA. These results suggest that a dysfunctional circadian clock contributes to an abnormal antioxidative response in PD via a SIRT1-dependent BMAL1 pathway.

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