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1.
Nature ; 599(7886): 622-627, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34759320

RESUMO

Zero hunger and good health could be realized by 2030 through effective conservation, characterization and utilization of germplasm resources1. So far, few chickpea (Cicer arietinum) germplasm accessions have been characterized at the genome sequence level2. Here we present a detailed map of variation in 3,171 cultivated and 195 wild accessions to provide publicly available resources for chickpea genomics research and breeding. We constructed a chickpea pan-genome to describe genomic diversity across cultivated chickpea and its wild progenitor accessions. A divergence tree using genes present in around 80% of individuals in one species allowed us to estimate the divergence of Cicer over the last 21 million years. Our analysis found chromosomal segments and genes that show signatures of selection during domestication, migration and improvement. The chromosomal locations of deleterious mutations responsible for limited genetic diversity and decreased fitness were identified in elite germplasm. We identified superior haplotypes for improvement-related traits in landraces that can be introgressed into elite breeding lines through haplotype-based breeding, and found targets for purging deleterious alleles through genomics-assisted breeding and/or gene editing. Finally, we propose three crop breeding strategies based on genomic prediction to enhance crop productivity for 16 traits while avoiding the erosion of genetic diversity through optimal contribution selection (OCS)-based pre-breeding. The predicted performance for 100-seed weight, an important yield-related trait, increased by up to 23% and 12% with OCS- and haplotype-based genomic approaches, respectively.


Assuntos
Cicer/genética , Variação Genética , Genoma de Planta/genética , Análise de Sequência de DNA , Produtos Agrícolas/genética , Haplótipos/genética , Melhoramento Vegetal , Polimorfismo de Nucleotídeo Único/genética
3.
Int J Biometeorol ; 66(6): 1267-1281, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35486200

RESUMO

Field pea is highly sensitive to climatic vagaries, particularly high-temperature stress. The crop often experiences terminal heat stress in tropical climates indicating the need for the development of heat-tolerant cultivars. Characterization and identification of stress-adaptive plant traits are pre-requisites for breeding stress-tolerant/adaptive cultivar(s). In the study, a panel of 150 diverse field pea genotypes was tested under three different temperature environments (i.e., normal sowing time or non-heat stress environment (NSTE), 15 days after normal sowing time or heat stress environment-I (LSHTE-I), and 30 days after normal sowing time or heat stress environment-II (LSHTE-II)) to verify the effect of high-temperature environment, genotype, and genotype × environment interaction on different plant traits and to elucidate their significance in heat stress adaptation/tolerance. The delayed sowing had exposed field pea crops to high temperatures during flowering stage by + 3.5 °C and + 8.1 °C in the LSHTE-I and LSHTE-II, respectively. Likewise, the maximum ambient temperature during the grain-filling period was + 3.3 °C and + 6.1 °C higher in the LSHTE-I and LSHTE-II over the NSTE. The grain yield loss with heat stress was 25.8 ± 2.2% in LSHTE-I, and 59.3 ± 1.5% in LSHTE-II compared to the NSTE. Exposure of crops to a high-temperature environment during the flowering stage had a higher impact on grain yield than the heat stress at the grain filling period. Results suggested that the reduced sink capacity (pod set (pod plant-1), seed set (seed pod-1)) was the primary cause of yield loss under the heat stress environments, while, under the NSTE, yield potential was mostly attributed to the source capacity (plant biomass). The high-temperature stress resulted in forced maturity as revealed by shrinkage in crop period (5-11%) and reproductive period (15-36%), prominently in long-duration genotypes. The failure of pod set in the upper nodes and higher ovule abortion (7-16%) was noticed under the high-temperature environments, particularly in the LSHTE-II. Multivariate analysis results revealed seed set, pods plant-1, last pod bearing node, and plant biomass as a critical yield determinant under the heat stress. The GGE biplot suggested that the genotypes G-112, G-114, and G-33 had higher potential to sustain yield coupled with higher stability across the environments and, thus, could serve as a source for breeding heat-tolerant high yielding cultivars.


Assuntos
Pisum sativum , Termotolerância , Grão Comestível , Resposta ao Choque Térmico/genética , Pisum sativum/genética , Fenótipo , Sementes/genética
4.
Funct Integr Genomics ; 21(2): 251-263, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33635500

RESUMO

Cytoplasmic male sterility (CMS) offers a unique system to understand cytoplasmic nuclear crosstalk, and is also employed for exploitation of hybrid vigor in various crops. Pigeonpea A4-CMS, a predominant source of male sterility, is being used for efficient hybrid seed production. The molecular mechanisms of CMS trait remain poorly studied in pigeonpea. We performed genome-wide transcriptome profiling of A4-CMS line ICPA 2043 and its isogenic maintainer ICPB 2043 at two different stages of floral bud development (stage S1 and stage S2). Consistent with the evidences from some other crops, we also observed significant difference in the expression levels of genes in the later stage, i.e., stage S2. Differential expression was observed for 143 and 55 genes within the two stages of ICPA 2043 and ICPB 2043, respectively. We obtained only 10 differentially expressed genes (DEGs) between the stage S1 of the two genotypes, whereas expression change was significant for 582 genes in the case of stage S2. The qRT-PCR assay of randomly selected six genes supported the differential expression of genes between ICPA 2043 and ICPB 2043. Further, GO and KEGG pathway mapping suggested a possible compromise in key bioprocesses during flower and pollen development. Besides providing novel insights into the functional genomics of CMS trait, our results were in strong agreement with the gene expression atlas of pigeonpea that implicated various candidate genes like sucrose-proton symporter 2 and an uncharacterized protein along with pectate lyase, pectinesterase inhibitors, L-ascorbate oxidase homolog, ATPase, ß-galactosidase, polygalacturonase, and aldose 1-epimerase for pollen development of pigeonpea. The dataset presented here provides a rich genomic resource to improve understanding of CMS trait and its deployment in heterosis breeding in pigeonpea.


Assuntos
Cajanus/genética , Genoma de Planta/genética , Infertilidade das Plantas/genética , Transcriptoma/genética , Hibridização Genômica Comparativa , Citoplasma/genética , Flores/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/genética , Humanos , Melhoramento Vegetal
5.
Planta ; 253(2): 59, 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33538916

RESUMO

MAIN CONCLUSION: Comparative analysis of genome-wide miRNAs and their gene targets between cytoplasmic male sterile (CMS) and fertile lines of pigeonpea suggests a possible role of miRNA-regulated pathways in reproductive development. Exploitation of hybrid vigor using CMS technology has delivered nearly 50% yield gain in pigeonpea. Among various sterility-inducing cytoplasms (A1-A9) reported so far in pigeonpea, A2 and A4 are the two major sources that facilitate hybrid seed production. Recent evidence suggests involvement of micro RNA in vast array of biological processes including plant reproductive development. In pigeonpea, information about the miRNAs is insufficient. In view of this, we sequenced six small RNA libraries of CMS line UPAS 120A and isogenic fertile line UPAS 120B using Illumina technology. Results revealed 316 miRNAs including 248 known and 68 novel types. A total of 637 gene targets were predicted for known miRNAs, while 324 genes were associated with novel miRNAs. Degradome analysis revealed 77 gene targets of predicted miRNAs, which included a variety of transcription factors playing key roles in plant reproduction such as F-box family proteins, apetala 2, auxin response factors, ethylene-responsive factors, homeodomain-leucine zipper proteins etc. Differential expression of both known and novel miRNAs implied roles for both conserved as well as species-specific players. We also obtained several miRNA families such as miR156, miR159, miR167 that are known to influence crucial aspects of plant fertility. Gene ontology and pathway level analyses of the target genes showed their possible implications for crucial events during male reproductive development such as tapetal degeneration, pollen wall formation, retrograde signaling etc. To the best of our knowledge, present study is first to combine deep sequencing of small RNA and degradome for elucidating the role of miRNAs in flower and male reproductive development in pigeonpea.


Assuntos
Cajanus/genética , MicroRNAs , Infertilidade das Plantas/genética , RNA de Plantas/genética , Cajanus/fisiologia , Citoplasma , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Sequenciamento de Nucleotídeos em Larga Escala , MicroRNAs/genética
6.
J Immunol ; 203(7): 1830-1844, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492743

RESUMO

The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant, is a potent ligand for aryl hydrocarbon receptor (AhR). In the current study, we made an exciting observation that naive C57BL/6 mice that were exposed i.p. to TCDD showed massive mobilization of myeloid-derived suppressor cells (MDSCs) in the peritoneal cavity. These MDSCs were highly immunosuppressive and attenuated Con A-induced hepatitis upon adoptive transfer. TCDD administration in naive mice also led to induction of several chemokines and cytokines in the peritoneal cavity and serum (CCL2, CCL3, CCL4, CCL11, CXCL1, CXCL2, CXCL5, CXCL9, G-CSF, GM-CSF, VEGF, and M-CSF) and chemokine receptors on MDSCs (CCR1, CCR5, and CXCR2). Treatment with CXCR2 or AhR antagonist in mice led to marked reduction in TCDD-induced MDSCs. TCDD-induced MDSCs had high mitochondrial respiration and glycolytic rate and exhibited differential microRNA (miRNA) expression profile. Specifically, there was significant downregulation of miR-150-5p and miR-543-3p. These two miRNAs targeted and enhanced anti-inflammatory and MDSC-regulatory genes, including IL-10, PIM1, ARG2, STAT3, CCL11 and its receptors CCR3 and CCR5 as well as CXCR2. The role of miRs in MDSC activation was confirmed by transfection studies. Together, the current study demonstrates that activation of AhR in naive mice triggers robust mobilization of MDSCs through induction of chemokines and their receptors and MDSC activation through regulation of miRNA expression. AhR ligands include diverse compounds from environmental toxicants, such as TCDD, that are carcinogenic to dietary indoles that are anti-inflammatory. Our studies provide new insights on how such ligands may regulate health and disease through induction of MDSCs.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Regulação da Expressão Gênica/imunologia , Tolerância Imunológica , Células Supressoras Mieloides/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Receptores de Interleucina-8B/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Quimiocinas/imunologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Camundongos , MicroRNAs , Células Supressoras Mieloides/patologia , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/agonistas
7.
J Biol Chem ; 294(19): 7669-7681, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-30910812

RESUMO

Although cannabinoid receptor 1 (CB1) antagonists have been shown to attenuate diet-induced obesity (DIO) and associated inflammation, the precise molecular mechanisms involved are not clear. In the current study, we investigated the role of microRNA (miR) in the regulation of adipose tissue macrophage (ATM) phenotype following treatment of DIO mice with the CB1 antagonist SR141716A. DIO mice were fed high-fat diet (HFD) for 12 weeks and then treated daily with SR141716A (10 mg/kg) for 4 weeks while continuing HFD. Treated mice experienced weight loss, persistent reduction in fat mass, improvements in metabolic profile, and decreased adipose inflammation. CB1 blockade resulted in down-regulation of several miRs in ATMs, including the miR-466 family and miR-762. Reduced expression of the miR-466 family led to induction of anti-inflammatory M2 transcription factors KLF4 and STAT6, whereas down-regulation of miR-762 promoted induction of AGAP-2, a negative regulator of the neuroimmune retention cues, Netrin-1 and its coreceptor UNC5B. Furthermore, treatment of primary macrophages with SR141716A up-regulated KLF4 and STAT6, reduced secretion of Netrin-1, and increased migration toward the lymph node chemoattractant CCL19. These studies demonstrate for the first time that CB1 receptor blockade attenuates DIO-associated inflammation through alterations in ATM miR expression that promote M2 ATM polarization and macrophage egress from adipose tissue. The current study also identifies additional novel therapeutic targets for diet-induced obesity and metabolic disorder.


Assuntos
Tecido Adiposo/metabolismo , Quimiotaxia/efeitos dos fármacos , Gorduras na Dieta/efeitos adversos , Macrófagos/metabolismo , MicroRNAs/metabolismo , Obesidade/metabolismo , Receptor CB1 de Canabinoide/antagonistas & inibidores , Rimonabanto/farmacologia , Tecido Adiposo/patologia , Animais , Gorduras na Dieta/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/biossíntese , Macrófagos/patologia , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Receptor CB1 de Canabinoide/metabolismo , Fator de Transcrição STAT6/biossíntese
8.
Theor Appl Genet ; 133(5): 1703-1720, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32253478

RESUMO

KEY MESSAGE: Integration of genomic technologies with breeding efforts have been used in recent years for chickpea improvement. Modern breeding along with low cost genotyping platforms have potential to further accelerate chickpea improvement efforts. The implementation of novel breeding technologies is expected to contribute substantial improvements in crop productivity. While conventional breeding methods have led to development of more than 200 improved chickpea varieties in the past, still there is ample scope to increase productivity. It is predicted that integration of modern genomic resources with conventional breeding efforts will help in the delivery of climate-resilient chickpea varieties in comparatively less time. Recent advances in genomics tools and technologies have facilitated the generation of large-scale sequencing and genotyping data sets in chickpea. Combined analysis of high-resolution phenotypic and genetic data is paving the way for identifying genes and biological pathways associated with breeding-related traits. Genomics technologies have been used to develop diagnostic markers for use in marker-assisted backcrossing programmes, which have yielded several molecular breeding products in chickpea. We anticipate that a sequence-based holistic breeding approach, including the integration of functional omics, parental selection, forward breeding and genome-wide selection, will bring a paradigm shift in development of superior chickpea varieties. There is a need to integrate the knowledge generated by modern genomics technologies with molecular breeding efforts to bridge the genome-to-phenome gap. Here, we review recent advances that have led to new possibilities for developing and screening breeding populations, and provide strategies for enhancing the selection efficiency and accelerating the rate of genetic gain in chickpea.


Assuntos
Cicer/crescimento & desenvolvimento , Cicer/genética , Genoma de Planta , Genômica/métodos , Melhoramento Vegetal/normas , Plantas Geneticamente Modificadas/genética , Locos de Características Quantitativas , Genética Populacional , Fenótipo , Plantas Geneticamente Modificadas/crescimento & desenvolvimento
9.
Am J Physiol Gastrointest Liver Physiol ; 315(2): G220-G230, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29672155

RESUMO

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that affects millions of people with high morbidity and health care costs. The precise etiology of IBD is unknown, but clear evidence suggests that intestinal inflammation is caused by an excessive immune response to mucosal antigens. Recent studies have shown that activation of the aryl hydrocarbon receptor (AhR) induces regulatory T cells (Tregs) and suppresses autoimmune diseases. In the current study, we investigated if a nontoxic ligand of AhR, 2-(1' H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), can attenuate dextran sodium sulfate-induced colitis. Our studies demonstrated that in mice that received ITE treatment in vivo, colitis pathogenesis, including a decrease in body weight, was significantly reversed along with the systemic and intestinal inflammatory cytokines. ITE increased the expression of Tregs in spleen, mesenteric lymph nodes (MLNs), and colon lamina propria lymphocytes (cLPL) of mice with colitis when compared with controls. This induction of Tregs was reversed by AhR antagonist treatment in vitro. ITE treatment also increased dendritic cells (CD11c+) and decreased macrophages (F4/80+) from the spleen, MLNs, and cLPL in mice with colitis. ITE also reversed the systemic and intestinal frequency of CD4+ T cells during colitis and suppressed inflammatory cytokines including IFN-γ, TNF-α, IL-17, IL-6, and IL-1 as well as induced IL-10 levels. These findings suggest that ITE attenuates colitis through induction of Tregs and reduction in inflammatory CD4+ T cells and cytokines. Therefore, our work demonstrates that the nontoxic endogenous AhR ligand ITE may serve as a therapeutic modality to treat IBD. NEW & NOTEWORTHY We report the novel finding that activation of the aryl hydrocarbon receptor with the nontoxic ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) induces regulatory T cells (Tregs) and suppresses inflammatory bowel disease (IBD). Our data suggest that ITE diminishes colitis pathology through induction of Tregs; reduces inflammatory cytokines, inflammation score, and macrophage frequency; and induces DCs resulting in amelioration of colitis. Therefore, nontoxic endogenous ITE promotes the induction of Tregs and may be useful for the treatment of IBD.


Assuntos
Colite , Indóis , Interleucinas/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Linfócitos T Reguladores/imunologia , Tiazóis , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacologia , Autoimunidade/imunologia , Colite/imunologia , Colite/metabolismo , Indóis/imunologia , Indóis/farmacologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Ligantes , Camundongos , Tiazóis/imunologia , Tiazóis/farmacologia
10.
Eur J Immunol ; 47(7): 1188-1199, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28543188

RESUMO

Dysbiosis in gut microbiome has been shown to be associated with inflammatory and autoimmune diseases. Previous studies from our laboratory demonstrated the pivotal role played by CD44 in the regulation of EAE, a murine model of multiple sclerosis. In the current study, we determined whether these effects resulted from an alteration in gut microbiota and the short-chain fatty acid (SCFA) production in CD44 knockout (CD44KO) mice. Fecal transfer from naïve CD44KO but not C57BL/6 wild type (CD44WT) mice, into EAE-induced CD44WT mice, led to significant amelioration of EAE. High-throughput bacterial 16S rRNA gene sequencing, followed by clustering sequences into operational taxonomic units (OTUs) and biochemical analysis, revealed that EAE-induced CD44KO mice showed significant diversity, richness, and evenness when compared to EAE-induced CD44WT mice at the phylum level, with dominant Bacteroidetes (68.5%) and low Firmicutes (26.8%). Further, data showed a significant change in the abundance of SCFAs, propionic acid, and i-butyric acid in EAE-CD44KO compared to EAE-CD44WT mice. In conclusion, our results demonstrate that the attenuation of EAE seen following CD44 gene deletion in mice may result from alterations in the gut microbiota and SCFAs. Furthermore, our studies also demonstrate that the phenotype of gene knock-out animals may be shaped by gut microbiota.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Microbioma Gastrointestinal/imunologia , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/imunologia , Animais , Bacteroidetes/genética , Bacteroidetes/imunologia , Bacteroidetes/isolamento & purificação , Modelos Animais de Doenças , Disbiose , Encefalomielite Autoimune Experimental/fisiopatologia , Ácidos Graxos Voláteis/imunologia , Transplante de Microbiota Fecal , Fezes/microbiologia , Firmicutes/genética , Firmicutes/imunologia , Firmicutes/isolamento & purificação , Microbioma Gastrointestinal/genética , Deleção de Genes , Metagenômica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Propionatos/metabolismo , RNA Ribossômico 16S
11.
J Immunol ; 196(3): 1108-22, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26712945

RESUMO

Aryl hydrocarbon receptor (AhR) has been shown to have profound influence on T cell differentiation, and use of distinct AhR ligands has shown that whereas some ligands induce regulatory T cells (Tregs), others induce Th17 cells. In the present study, we tested the ability of dietary AhR ligands (indole-3-carbinol [I3C] and 3,3'-diindolylmethane [DIM]) and an endogenous AhR ligand, 6-formylindolo(3,2-b)carbazole (FICZ), on the differentiation and functions of Tregs and Th17 cells. Treatment of C57BL/6 mice with indoles (I3C or DIM) attenuated delayed-type hypersensitivity (DTH) response to methylated BSA and generation of Th17 cells while promoting Tregs. In contrast, FICZ exacerbated the DTH response and promoted Th17 cells. Indoles decreased the induction of IL-17 but promoted IL-10 and Foxp3 expression. Also, indoles caused reciprocal induction of Tregs and Th17 cells only in wild-type (AhR(+/+)) but not in AhR knockout (AhR(-/-)) mice. Upon analysis of microRNA (miR) profile in draining lymph nodes of mice with DTH, treatment with I3C and DIM decreased the expression of several miRs (miR-31, miR-219, and miR-490) that targeted Foxp3, whereas it increased the expression of miR-495 and miR-1192 that were specific to IL-17. Interestingly, treatment with FICZ had precisely the opposite effects on these miRs. Transfection studies using mature miR mimics of miR-490 and miR-1192 that target Foxp3 and IL-17, respectively, or scrambled miR (mock) or inhibitors confirmed that these miRs specifically targeted Foxp3 and IL-17 genes. Our studies demonstrate, to our knowledge for the first time, that the ability of AhR ligands to regulate the differentiation of Tregs versus Th17 cells may depend on miR signature profile.


Assuntos
Hipersensibilidade Tardia/imunologia , Indóis/imunologia , MicroRNAs/biossíntese , Receptores de Hidrocarboneto Arílico/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Carbazóis/imunologia , Carbazóis/farmacologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Dieta , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Hipersensibilidade Tardia/genética , Indóis/farmacologia , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real
13.
Brain Behav Immun ; 59: 147-157, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27592314

RESUMO

Social stress is a risk factor for psychiatric disorders, however only a subset of the population is susceptible while others remain resilient. Inflammation has been linked to the pathogenesis of psychosocial disorders in humans and may underlie these individual differences. Using a resident-intruder paradigm capable of revealing individual differences in coping behavior and inflammatory responses, the present study determined if resveratrol (RSV; 0, 10, 30mg/kg/day) protected against persistent stress-induced inflammation in socially defeated rats. Furthermore, the antidepressant efficacy of RSV was evaluated using the sucrose preference test. Active coping rats were characterized by more time spent in upright postures and increased defeat latencies versus passive coping rats. Five days after defeat, flow cytometry revealed enhanced stimulation of proinflammatory proteins (IL-ß, TNF-α) in spleen cells of passive rats as compared to active coping and controls, an effect that was blocked by both doses of RSV. Furthermore, only passive coping rats exhibited increased proinflammatory proteins (IL-1ß, TNF-α, GM-CSF) in the locus coeruleus (LC), a noradrenergic brain region implicated in depression. Notably, only 30mg/kg RSV blocked LC neuroinflammation and importantly, was the only dose that blocked anhedonia. Alternatively, while stress had minimal impact on resting cytokines in the dorsal raphe (DR), RSV dose-dependently reduced DR cytokine expression. However, this did not result in changes in indoleamine 2,3-dioxygenase activity or serotonin levels. Taken together, these data suggest that social stress-induced depressive-like behavior evident in passive coping rats may be driven by stress-induced neuroinflammation and highlight natural anti-inflammatory agents to protect against social stress-related consequences.


Assuntos
Antioxidantes/uso terapêutico , Citocinas/metabolismo , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/psicologia , Meio Social , Estilbenos/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Adaptação Psicológica , Anedonia , Animais , Transtorno Depressivo/metabolismo , Relação Dose-Resposta a Droga , Locus Cerúleo/metabolismo , Masculino , Núcleos da Rafe/metabolismo , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Resveratrol , Baço/metabolismo , Estresse Psicológico/psicologia
14.
Brain Behav Immun ; 59: 10-20, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27327245

RESUMO

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), which is thought to result from immune-mediated inflammatory disorders, leads to high morbidity and health care cost. Fatty acid amide hydrolase (FAAH) is an enzyme crucially involved in the modulation of intestinal physiology through anandamide (AEA) and other endocannabinoids. Here we examined the effects of an FAAH inhibitor (FAAH-II), on dextran sodium sulphate (DSS)-induced experimental colitis in mice. Treatments with FAAH-II improved overall clinical scores by reversing weight loss and colitis-associated pathogenesis. The frequencies of activated CD4+ T cells in spleens, mesenteric lymph nodes (MLNs), Peyer's patches (PPs), and colon lamina propiria (LP) were reduced by FAAH inhibition. Similarly, the frequencies of macrophages, neutrophils, natural killer (NK), and NKT cells in the PPs and LP of mice with colitis declined after FAAH blockade, as did concentrations of systemic and colon inflammatory cytokines. Microarray analysis showed that 26 miRNAs from MLNs and 217 from PPs had a 1.5-fold greater difference in expression after FAAH inhibition. Among them, 8 miRNAs were determined by reverse-transcription polymerase chain reaction (RT-PCR) analysis to have anti-inflammatory properties. Pathway analysis demonstrated that differentially regulated miRNAs target mRNA associated with inflammation. Thus, FAAH-II ameliorates experimental colitis by reducing not only the number of activated T cells but also the frequency of macrophages, neutrophils, and NK/NKT cell, as well as inflammatory miRNAs and cytokine at effector sites in the colon. These studies demonstrate for the first time that FAAH-II inhibitor may suppress colitis through regulation of pro-inflammatory miRNAs expression.


Assuntos
Amidoidrolases/antagonistas & inibidores , Anti-Inflamatórios/farmacologia , Colite/prevenção & controle , Inibidores Enzimáticos/uso terapêutico , RNA Mensageiro/biossíntese , Animais , Colite/induzido quimicamente , Colite/patologia , Colo/patologia , Sulfato de Dextrana , Feminino , Doenças Inflamatórias Intestinais/prevenção & controle , Mucosa Intestinal/patologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/efeitos dos fármacos , Redução de Peso/efeitos dos fármacos
15.
Immunology ; 147(4): 488-98, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26780721

RESUMO

The role of microRNA in the regulation of encephalitogenic T-cell development is of interest in understanding the pathogenesis of multiple sclerosis (MS). Direct binding of microRNAs to their target mRNAs usually suppresses gene expression and facilitates mRNA degradation. In this study, we observed that the expression of several microRNAs was significantly altered in patients with MS. Interestingly, the expression of miR-140-5p, among other microRNAs, was significantly decreased in the peripheral blood mononuclear cells of patients with MS, and this microRNA may regulate encephalitogenic T helper type 1 (Th1) cell differentiation. The expression level of miR-140-5p was inversely correlated with disease severity with greater reduction in relapsing disease compared with remitting disease. Transfection of synthetic miR-140-5p in peripheral blood mononuclear cells suppressed encephalitogenic Th1 differentiation. Signal transducer and activator of transcription 1 (STAT1) was the functional target of miR-140-5p - transfection of the synthetic miR-140-5p suppressed activation of STAT1 and the expression of its downstream target, T-bet. Our results suggested that miR-140-5p is probably involved in the regulation of encephalitogenic T cells in the pathogenesis of MS.


Assuntos
Regulação da Expressão Gênica , MicroRNAs/genética , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Adulto , Sequência de Bases , Sítios de Ligação , Estudos de Casos e Controles , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Análise por Conglomerados , Progressão da Doença , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Masculino , MicroRNAs/química , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/patologia , Interferência de RNA , Fator de Transcrição STAT1/química , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Proteínas com Domínio T/genética , Células Th1/citologia , Ativação Transcricional
16.
Cytokine ; 77: 44-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26520877

RESUMO

Crohn's disease (CD) and ulcerative colitis (UC), two forms of inflammatory bowel disease (IBD), are chronic, relapsing, and tissue destructive lesions that are accompanied by the uncontrolled activation of effector immune cells in the mucosa. Recent estimates indicate that there are 1.3 million annual cases of IBD in the United States, 50% of which consists of CD and 50% of UC. Chemokines and cytokines play a pivotal role in the regulation of mucosal inflammation by promoting leukocyte migration to sites of inflammation ultimately leading to tissue damage and destruction. In recent years, experimental studies in rodents have led to a better understanding of the role played by these inflammatory mediators in the development and progression of colitis. However, the clinical literature on IBD remains limited. Therefore, the aim of this study was to evaluate systemic concentrations of key chemokines and cytokines in forty-two IBD patients with a range of disease activity compared to levels found in ten healthy donors. We found a significant increase in an array of chemokines including macrophage migration factor (MIF), CCL25, CCL23, CXCL5, CXCL13, CXCL10, CXCL11, MCP1, and CCL21 in IBD patients as compared to normal healthy donors (P<0.05). Further, we also report increases in the inflammatory cytokines IL-16, IFN-γ, IL-1ß and TNF-α in IBD patients when compared to healthy donors (P<0.05). These data clearly indicate an increase in circulating levels of specific chemokines and cytokines that are known to modulate systemic level through immune cells results in affecting local intestinal inflammation and tissue damage in IBD patients. Blockade of these inflammatory mediators should be explored as a mechanism to alleviate or even reverse symptoms of IBD.


Assuntos
Quimiocinas/sangue , Citocinas/sangue , Mediadores da Inflamação/sangue , Doenças Inflamatórias Intestinais/sangue , Adulto , Idoso , Colite Ulcerativa/sangue , Doença de Crohn/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
17.
Plant Cell Rep ; 35(5): 967-93, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26905724

RESUMO

KEY MESSAGE: A comprehensive understanding of CMS/Rf system enabled by modern omics tools and technologies considerably improves our ability to harness hybrid technology for enhancing the productivity of field crops. Harnessing hybrid vigor or heterosis is a promising approach to tackle the current challenge of sustaining enhanced yield gains of field crops. In the context, cytoplasmic male sterility (CMS) owing to its heritable nature to manifest non-functional male gametophyte remains a cost-effective system to promote efficient hybrid seed production. The phenomenon of CMS stems from a complex interplay between maternally-inherited (mitochondrion) and bi-parental (nucleus) genomic elements. In recent years, attempts aimed to comprehend the sterility-inducing factors (orfs) and corresponding fertility determinants (Rf) in plants have greatly increased our access to candidate genomic segments and the cloned genes. To this end, novel insights obtained by applying state-of-the-art omics platforms have substantially enriched our understanding of cytoplasmic-nuclear communication. Concomitantly, molecular tools including DNA markers have been implicated in crop hybrid breeding in order to greatly expedite the progress. Here, we review the status of diverse sterility-inducing cytoplasms and associated Rf factors reported across different field crops along with exploring opportunities for integrating modern omics tools with CMS-based hybrid breeding.


Assuntos
Quimera/genética , Infertilidade das Plantas/genética , Plantas/genética , Pólen/genética , Cruzamento , Núcleo Celular/genética , Citoplasma/genética , Fertilidade/genética , Marcadores Genéticos/genética , Sementes/genética , Sementes/fisiologia
18.
Mol Pharmacol ; 87(5): 842-54, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25753120

RESUMO

Prenatal exposure to diethylstilbestrol (DES) is known to cause an increased susceptibility to a wide array of clinical disorders in humans. Previous studies from our laboratory demonstrated that prenatal exposure to DES induces thymic atrophy and apoptosis in the thymus. In the current study, we investigated if such effects on the thymus result from alterations in the expression of microRNA (miR). To that end, pregnant C57BL/6 mice who were exposed to DES and miR profiles in thymocytes of both the mother and fetuses on postnatal day 3 (gestation day 17) were studied. Of the 609 mouse miRs examined, we noted 59 altered miRs that were common for both mothers and fetuses, whereas 107 altered miRs were specific to mothers only and 101 altered miRs were specific to fetuses only. Upon further analyses in the fetuses, we observed that DES-mediated changes in miR expression may regulate genes involved in important functions, such as apoptosis, autophagy, toxicity, and cancer. Of the miRs that showed decreased expression following DES treatment, miR-18b and miR-23a were found to possess complementary sequences and binding affinity for 3' untranslated regions of the Fas ligand (FasL) and Fas, respectively. Transfection studies confirmed that DES-mediated downregulation of miR-18b and miR-23a led to increased FasL and Fas expression. These data demonstrated that prenatal DES exposure can cause alterations in miRs, leading to changes in the gene expression, specifically, miR-mediated increased expression in FasL and Fas causing apoptosis and thymic atrophy.


Assuntos
Carcinogênese/efeitos dos fármacos , Dietilestilbestrol/farmacologia , Feto/efeitos dos fármacos , MicroRNAs/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Transcriptoma/efeitos dos fármacos , Regiões 3' não Traduzidas/efeitos dos fármacos , Regiões 3' não Traduzidas/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Carcinogênese/genética , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Proteína Ligante Fas/genética , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Mães , Neoplasias/genética , Gravidez , Timócitos/efeitos dos fármacos , Timo/efeitos dos fármacos , Transcriptoma/genética , Receptor fas/genética
19.
Biotechnol Lett ; 37(8): 1529-39, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25851953

RESUMO

Unprecedented developments in legume genomics over the last decade have resulted in the acquisition of a wide range of modern genomic resources to underpin genetic improvement of grain legumes. The genome enabled insights direct investigators in various ways that primarily include unearthing novel structural variations, retrieving the lost genetic diversity, introducing novel/exotic alleles from wider gene pools, finely resolving the complex quantitative traits and so forth. To this end, ready availability of cost-efficient and high-density genotyping assays allows genome wide prediction to be increasingly recognized as the key selection criterion in crop breeding. Further, the high-dimensional measurements of agronomically significant phenotypes obtained by using new-generation screening techniques will empower reference based resequencing as well as allele mining and trait mapping methods to comprehensively associate genome diversity with the phenome scale variation. Besides stimulating the forward genetic systems, accessibility to precisely delineated genomic segments reveals novel candidates for reverse genetic techniques like targeted genome editing. The shifting paradigm in plant genomics in turn necessitates optimization of crop breeding strategies to enable the most efficient integration of advanced omics knowledge and tools. We anticipate that the crop improvement schemes will be bolstered remarkably with rational deployment of these genome-guided approaches, ultimately resulting in expanded plant breeding capacities and improved crop performance.


Assuntos
Produtos Agrícolas/genética , Genoma de Planta , Genômica/métodos , Análise de Sequência de DNA , Biologia Computacional
20.
J Biol Chem ; 288(52): 36810-26, 2013 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-24202177

RESUMO

Δ(9)-Tetrahydrocannabinol (THC), the major bioactive component of marijuana, has been shown to induce functional myeloid-derived suppressor cells (MDSCs) in vivo. Here, we studied the involvement of microRNA (miRNA) in this process. CD11b(+)Gr-1(+) MDSCs were purified from peritoneal exudates of mice administered with THC and used for genome-wide miRNA profiling. Expression of CD31 and Ki-67 confirmed that the THC-MDSCs were immature and proliferating. THC-induced MDSCs exhibited distinct miRNA expression signature relative to various myeloid cells and BM precursors. We identified 13 differentially expressed (>2-fold) miRNA in THC-MDSCs relative to control BM precursors. In silico target prediction for these miRNA and pathway analysis using multiple bioinformatics tools revealed significant overrepresentation of Gene Ontology clusters within hematopoiesis, myeloid cell differentiation, and regulation categories. Insulin-like growth factor 1 signaling involved in cell growth and proliferation, and myeloid differentiation pathways were among the most significantly enriched canonical pathways. Among the differentially expressed, miRNA-690 was highly overexpressed in THC-MDSCs (∼16-fold). Transcription factor CCAAT/enhancer-binding protein α (C/EBPα) was identified as a potential functional target of miR-690. Supporting this, C/EBPα expression was attenuated in THC-MDSCs as compared with BM precursors and exhibited an inverse relation with miR-690. miR-690 knockdown using peptide nucleic acid-antagomiR was able to unblock and significantly increase C/EBPα expression establishing the functional link. Further, CD11b(+)Ly6G(+)Ly6C(+) and CD11b(+)Ly6G(-)Ly6C(+) purified subtypes showed high levels of miR-690 with attenuated C/EBPα expression. Moreover, EL-4 tumor-elicited MDSCs showed increased miR-690 expression. In conclusion, miRNA are significantly altered during the generation of functional MDSC from BM. Select miRNA such as miR-690 targeting genes involved in myeloid expansion and differentiation likely play crucial roles in this process and therefore in cannabinoid-induced immunosuppression.


Assuntos
Analgésicos não Narcóticos/farmacologia , Proteínas Estimuladoras de Ligação a CCAAT/biossíntese , Dronabinol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Tolerância Imunológica/efeitos dos fármacos , Células Mieloides/metabolismo , Animais , Antígenos de Diferenciação/biossíntese , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/imunologia , Células Cultivadas , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Tolerância Imunológica/genética , Camundongos , Células Mieloides/citologia , Células Mieloides/imunologia
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