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1.
Biol Trace Elem Res ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32016827

RESUMO

Cadmium (Cd) is a ubiquitous toxic heavy metal in the natural environment that can cause multiple organ damage to the bodies of animals and humans. Selenium yeast (SeY) is a kind of organic selenium (Se) that has a very strong function against Cd-induced injury to tissues or organs. The aim of the current study was to investigate the roles of inflammatory factors and heat shock proteins (HSPs) in inflammatory injury triggered by Cd and to analyze the protective effects of SeY on Cd-induced damnification in the livers of chickens. Two hundred 120-day-old layers were randomly divided into four groups and raised on a conventional diet, or with Se (0.5 mg/kg SeY), Cd (150 mg/kg CdCl2), or Se + Cd (0.5 mg/kg SeY and 150 mg/kg CdCl2) in their basic diets for 120 days. Then, the liver histopathology, production of nitric oxide (NO), activity of inducible NO synthase (iNOS), and mRNA and protein expression levels of inflammatory factors (iNOS, NF-κB, TNF-α, and PTGE) and heat shock proteins (HSPs 27, 40, 60, 70, and 90) were examined. The results showed that exposure to Cd obviously increased Cd accumulation, NO production, iNOS activity, inflammatory factor, and HSP mRNA and protein expression levels and further caused an inflammatory response. Supplementation with SeY had an antagonistic effect on Cd-induced inflammatory injury in chicken livers. Thus, the present study suggests that SeY can be taken as a potential therapeutic for Cd-induced liver inflammatory injury in chickens.

2.
Chem Commun (Camb) ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32022022

RESUMO

A chiral silver-sulfur nanocluster with a µ8-S inside, Ag18(µ8-S)(p-TBBT)16(PPh3)8, was successfully synthesized and characterized. This nanocluster is composed of a crown-like Ag8S core and an Ag10S16P8 meso-shell. The presence of the core induces symmetry breaking of the nanocluster from S8 to C4, and therefore endows the cluster with chirality.

3.
Oncol Rep ; 43(3): 1010-1018, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020220

RESUMO

The efficacy of chemotherapy for hepatocellular carcinoma (HCC) remains unsatisfactory, primarily due to inherent self­defense mechanisms (e.g., mitophagy and autophagy). In the present study, we aimed to explore the pro­apoptotic effects of targeting mitophagy to potentiate the efficacy of chemotherapy for HCC. HCC cells were subjected to cisplatin, after which cisplatin­induced mitophagy was quantified by immunofluorescence. Mdivi­1, a specific dynamin­related protein 1 (DRP1) inhibitor, was used to study the role of DRP1 in cisplatin­induced HCC mitophagy. The synergistic effect of cisplatin and the DRP1 inhibitor on HCC was assessed in vitro and in vivo. Accordingly, cisplatin induced mitophagy in surviving HCC cells by activating DRP1. The DRP1 inhibitor (Mdivi­1) increased the apoptosis of cisplatin­treated HCC cells by targeting mitophagy. Mechanistically, Mdivi­1 upregulated Bax and downregulated Bcl­xL, leading to an increase in mitochondrial membrane permeability and subsequent release of cytochrome c from mitochondria into the cytosol, thereby aggravating cisplatin­induced apoptosis in HCC cells. Moreover, Mdivi­1 acted synergistically with cisplatin to suppress HCC xenograft growth in vivo. Our results indicate that targeting cisplatin­mediated mitophagy increases HCC apoptosis via DRP1 inhibition, providing preclinical proof of concept for combination therapy targeting mitophagy to potentiate the efficacy of chemotherapy.

4.
Nat Commun ; 11(1): 679, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015349

RESUMO

Auxin determines the developmental fate of plant tissues, and local auxin concentration is precisely controlled. The role of auxin transport in modulating local auxin concentration has been widely studied but the regulation of local auxin biosynthesis is less well understood. Here, we show that TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS (TAA1), a key enzyme in the auxin biosynthesis pathway in Arabidopsis thaliana is phosphorylated at Threonine 101 (T101). T101 phosphorylation status can act as an on/off switch to control TAA1-dependent auxin biosynthesis and is required for proper regulation of root meristem size and root hair development. This phosphosite is evolutionarily conserved suggesting post-translational regulation of auxin biosynthesis may be a general phenomenon. In addition, we show that auxin itself, in part via TRANS-MEMBRANE KINASE 4 (TMK4), can induce T101 phosphorylation of TAA1 suggesting a self-regulatory loop whereby local auxin signalling can suppress biosynthesis. We conclude that phosphorylation-dependent control of TAA1 enzymatic activity may contribute to regulation of auxin concentration in response to endogenous and/or external cues.

5.
Eur J Immunol ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32068249

RESUMO

Resident cardiac macrophages play important roles in homeostasis, maintenance of cardiac function, and tissue repair. After cardiac injury, monocytes infiltrate the tissue, undergo phenotypic and functional changes, and are involved in inflammatory injury and functional remodelling. However, the fate of cardiac infiltrating/polarized macrophages and the relationship between these cells and resident cardiac macrophage replenishment following injury remain unclear. Our results showed that angiotensin II (ANG II) induces cardiac fibroblast transdifferentiation into cardiac myofibroblasts (MFBs). In co-cultures with MFBs and murine macrophages, the MFBs promoted macrophage polarization to M1 phenotype, followed by selective apoptosis, which was associated with TNF/TNFR1 axis and independent of NO production. Surprisingly, after 36 h of co-culture, the surviving macrophages were converted to M2 phenotype and settled in heart, which was dependent on leptin produced by MFBs or polarized macrophages via the PI3K or Akt pathway. CCR2+ CD45.2+ cells adoptively transferred into CD45.1+ mice with viral myocarditis, differentiated into CD45.2+ CCR2+ CX3CR1+ M2 cells during the resolution of inflammation and settled within the heart. Our data highlight a novel mechanism related to the renewal or replenishment of cardiac resident macrophages following cardiac injury; and suggest that transdifferentiation of cardiac fibroblasts may promote the resolution of inflammation. This article is protected by copyright. All rights reserved.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32023029

RESUMO

A catalytic membrane microreactor is a potential tool for the application in multiphase catalytic reactions. Currently, the installation of a permeable ultrathin membrane to separate the reactants with different phases and the grafting of a catalyst layer on the membrane in a microreactor remain challenging. In this work, a catalytic ultrathin membrane microreactor with an ultrathin freestanding supporting membrane was developed for nitrobenzene hydrogenation, which was formed by the interfacial polycondensation reaction with parallel laminar flow in a microchannel, followed by catalyst layer immobilization on one side of the ultrathin membrane surface using the layer-by-layer self-assembly technique and in situ reduction. The ultrathin freestanding membrane ensured a stable gas/liquid contact interface and good hydrogen permeability. The developed membrane microreactor could exhibit high catalytic performance under mild conditions, demonstrating its superior mass transport. In addition, the effects of the thickness of the ultrathin freestanding membrane, flow rates, and inlet nitrobenzene concentration were investigated to obtain the optimum operating conditions. The experimental results demonstrate that this newly developed membrane microreactor is a promising candidate for multiphase catalytic reactions.

8.
Life Sci ; 244: 117298, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31953163

RESUMO

Long non-coding RNA (lncRNA) is emerging as an essential player in cancer progression. However, its biological function and clinical implication in papillary thyroid carcinoma (PTC) remain poorly understood. In the current study, we found that a novel lncRNA, ASMTL antisense RNA 1 (ASMTL-AS1), was significantly downregulated in PTC. And its downregulation was positively linked to larger tumor size, advanced clinical stage and unfavorable outcome. Overexpression of ASMTL-AS1 evidently inhibited PTC cell proliferation and glycolysis, while knockdown of ASMTL-AS1 resulted in the opposite effect. Regarding the mechanism, ASMTL-AS1 was capable of sponging miR-93-3p and miR-660 to elevate FOXO1 expression, leading to repressing glycolysis and tumorigenesis. In turn, FOXO1 could also increase ASMTL-AS1 expression via directly binding to ASMTL-AS1 promoter, which formed a positive feedback regulation loop. Importantly, the regulatory axis of ASMTL-AS1/miR-93-3p/miR-660/FOXO1 was also identified in vivo. Collectively, our data clearly indicate that ASMTL-AS1 functions as a novel tumor suppressor in PTC through regulation of miR-93-3p/miR-660/FOXO1 pathway. Targeting ASMTL-AS1 and its downstream pathway may be an effective therapeutic approach for patients with PTC.


Assuntos
Proteína Forkhead Box O1/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicólise , MicroRNAs/genética , RNA Longo não Codificante/genética , Câncer Papilífero da Tireoide/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Feminino , Seguimentos , Proteína Forkhead Box O1/genética , Humanos , Masculino , Metiltransferases/antagonistas & inibidores , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , RNA Antissenso/genética , Taxa de Sobrevida , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Int J Mol Sci ; 21(2)2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31941098

RESUMO

Lysozymes are key antimicrobial peptides in the host innate immune system that protect against pathogen infection. In this study, the full-length cDNAs of two c-type lysozymes (gfLyz-C1 and gfLyz-C2) were cloned from goldfish (Carassius auratus). The structural domains, three-dimensional structures, and amino acid sequences of gfLyz-C1 and gfLyz-C2 were highly comparable, as the two proteins shared 89.7% sequence identity. The gfLyz-C1 and gfLyz-C2 recombinant proteins were generated in the insoluble fractions of an Escherichia coli system. Based on the results of lysoplate and turbidimetric assays, gfLyz-C1 and gfLyz-C2 showed broad-spectrum antimicrobial properties with high levels of activity against Micrococcus lysodeikticus, Vibrio parahemolyticus, and Edwardsiella tarda, and relatively low activity against E. coli. Both gfLyz-C1 and gfLyz-C2 mRNAs were mainly expressed in the trunk kidney and head kidney, and gfLyz-C1 was expressed at much higher levels than gfLyz-C2 in the corresponding tissues. The expression of the gfLyz-C1 and gfLyz-C2 transcripts in the trunk kidney and head kidney was induced in these tissues by challenge with heat-inactivated E. coli and lipopolysaccharides (LPS), and the transcriptional responses of gfLyz-C1 were more intense. In goldfish primary trunk kidney cells, the levels of the gfLyz-C1 and gfLyz-C2 transcripts were upregulated by heat-inactivated E. coli, V. parahemolyticus, and E. tarda, as well as LPS, and downregulated by treatment with dexamethasone and leptins. Overall, this study may provide new insights that will improve our understanding of the roles of c-type lysozymes in the innate immunity of cyprinid fish, including the structural and phylogenetic characteristics, antimicrobial effects, and regulatory mechanism.

11.
J Mol Graph Model ; 96: 107526, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31901678

RESUMO

The oncogenic receptor tyrosine kinase family ErbB consists of four members (ErbB1, ErbB2, ErbB3 and ErbB4); they are involved in the tumorgenesis of diverse cancers. A variety of missence mutations have been clinically observed in ErbB kinases, which would shift drug sensitivity to these kinases and cause drug resistance in targeted cancer therapy. In this study, systematic inhibitor response to ErbB missense mutations in gastric cancer (GC) is investigated by combining computational analysis and experimental assay. The response profile is created for 6 ATP-competitive, reversible inhibitors against 9, 17, 5 and 17 GC-associated missense mutations of ErbB1, ErbB2, ErbB3 and ErbB4 kinase domains, respectively. From the profile a number of potential resistant and sensitive responses are identified theoretically. It is suggested that most ErbB mutations have only a modest effect on inhibitor binding, but few that are located around the kinase active site can influence the binding significantly. Structural examination reveals that steric hindrance and allosteric effect are primarily responsible for inhibitor resistance and sensitivity, respectively. Two ErbB2 mutations, namely V777L and T862A, are predicted to cause effective resistance on inhibitors TAK285 and Lapatinib, respectively. Kinase assays consistently observe that the mutations can reduce inhibitor activity by 4.9-fold and 2.4-fold, with IC50 changing from 29 to 16 nM (wild type) to 83 and 39 nM (mutant) for TAK285 and Lapatinib, respectively.

12.
Phys Chem Chem Phys ; 22(5): 2930-2937, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31951227

RESUMO

The Al concentration and distribution have a great influence on the hydrothermal stability of the H-SSZ-13 zeolites in experiments. In this work, first-principles calculations are performed to clarify the decomposition mechanism of an H-SSZ-13 framework with adjacent Al atom pair distribution under hydrothermal conditions. It is found that the adjacent Al atoms have a tendency to occupy the para-sites of the 4-membered rings (4MRs) in the framework. Water molecules are chemisorbed onto the Al atom one by one, and the hydroxylation of the neighboring O atoms induces the breaking of the Al-O bonds, which causes the first dealumination in 4MRs. The other Al atom in the para-site can be easily removed from the framework once the first one is lost. The feasible subsequent dealumination of adjacent Al atoms would break the linker of 6MRs in the framework, which is responsible for the degraded hydrothermal stability. Moreover, the partial substitution of metal ions (such as Na+ and Cu+) for the protons in the framework will greatly stabilize the Al-O bonds and enlarge the energy barrier of para-site Al dealumination, which leads to the improved hydrothermal stability of H-SSZ-13.

13.
J Cell Mol Med ; 24(3): 2087-2097, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31916698

RESUMO

Cellular senescence represents the state of irreversible cell cycle arrest during cell division. Cellular senescence not only plays a role in diverse biological events such as embryogenesis, tissue regeneration and repair, ageing and tumour occurrence prevention, but it is also involved in many cardiovascular, renal and liver diseases through the senescence-associated secretory phenotype (SASP). This review summarizes the molecular mechanisms underlying cellular senescence and its possible effects on a variety of renal diseases. We will also discuss the therapeutic approaches based on the regulation of senescent and SASP blockade, which is considered as a promising strategy for the management of renal diseases.

14.
Phytomedicine ; 68: 153169, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31999976

RESUMO

BACKGROUND: Activation of NLRP3 inflammasome plays a key role in cardiac dysfunction for acute myocardial ischemia-reperfusion injury. Scutellarin (Scu) is a flavonoid purified from Erigeron breviscapus. Whether Scu has any influence on the activation of NLRP3 inflammasome in cardiomyocytes remains unknown. PURPOSE: We aimed to examine the therapeutic effect of Scu on cardiomyocyte ischemia-reperfusion (I/R) injury and its effect on NLRP3 inflammasome in rats with acute myocardial I/R injury and anoxia/reoxygenation (A/R)-induced H9c2 injuries. METHODS: Heart injuries were induced through 30 min of ischemia followed by 24 h of reperfusion. Scu was intraperitoneally administered 15 min before vascular ligation. Effects of Scu on cardiac injury were detected by echocardiograms, TTC staining, and histological and immunohistochemical analyses. The effects of Scu on biochemical parameters were analyzed. H9c2 cells were pretreated with different concentrations of Scu for 6 h before A/R exposure. Afterward, cell viability, LDH release, and Hoechst 33342 and peromide iodine double staining were determined. Western blot analyses of proteins, including those involved in autophagy, NLRP3, mTOR complex 1 (mTORC1), and Akt signaling, were conducted. RESULTS: In vivo study revealed that Scu improved diastolic dysfunction, ameliorated myocardium structure abnormality, inhibited myocyte apoptosis and inflammatory response, and promoted autophagy. Scu reduced NLRP3 inflammasome activation, inhibited mTORC1 activity, and increased Akt phosphorylation. In vitro investigation showed the same results. The Scu-mediated NLRP3 inflammasome and mTORC1 inhibition and cardioprotection were abolished through the genetic silencing of Akt by siRNA. CONCLUSIONS: The cardioprotective effect of Scu was achieved through its anti-inflammatory effect. It suppressed the activation of NLRP3 inflammasome. In addition, inflammasome restriction by Scu was dependent on Akt activation and mTORC1 inhibition.

15.
Analyst ; 145(2): 440-444, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31793929

RESUMO

Polymerase chain reaction (PCR) and isothermal amplification methods such as LAMP and RPA are widely used for genetic detection. However, there are some shortcomings of these methods such as dependence on thermocycler instruments for PCR, complexity of primer design, the possibility for nonspecific amplification in LAMP and complexity of components in RPA. We develop a novel isothermal DNA detection system named Recombinase Assisted Loop-mediated Amplification (RALA). Recombinase from Thermus thermophilus (TthRecA) was used to open target double-stranded DNA to initiate loop-mediated amplification under isothermal conditions, which simplified the primer design and circumvented pre-denaturation. A FRET sensor named ProofMan and a proofreading enzyme Pfu were introduced to produce fluorescence signals by cleaving the sensor from the 3' end. Consequently, sequence-specific detection based on the RALA system was achieved, and even a single nucleotide polymorphism (SNP) could be identified. By introducing additional loop primers, the fast RALA version can amplify 102 DNA targets in 30 minutes. In addition to high sensitivity and specificity, the flexibility of choosing different reporting sensors makes this method versatile in either quantitative or qualitative DNA detection.

16.
Bioresour Technol ; 297: 122426, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31776106

RESUMO

Nitrite has a key role in nitrogen conversion during composting. In this study, the dynamic changes in the NO2- contents, abundances of nirS and nxrA, and the bacteria that harbored these genes were determined during composting. NO2- accumulated during the initial composting stage. The nirS gene was abundant throughout composting, whereas the nxrA gene was only abundant in the late composting phases. Ralstonia sp. and Thauera sp. were the dominant denitrifiers that harbored nirS, and Nitrobacter winogradskyi Nb-255 was the dominant nitrifier that harbored nxrA. Structural equation modeling showed that NO2- was mainly reduced by nirS in the early phases, and oxidized by nxrA in the late phases, but especially in the maturity phase. Network analysis showed that the dominant bacteria harboring nirS and nxrA were hubs in the modules related to the reduction and oxidation of NO2-, and they had competitive relationships during the cooling and maturity phases.


Assuntos
Compostagem , Nitrobacter , Animais , Bactérias , Esterco , Nitritos , Suínos
17.
Stem Cells Dev ; 29(3): 169-176, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31797736

RESUMO

In mammals, spermatogenesis is closely related to intercellular interactions of germ cells and surrounding Sertoli cells, that is, blood-testis barrier and gap junction, which are subjected to hormone signals in testicular seminiferous tubules. Androgen signal plays pivotal role in regulating spermatogenesis, but the underlying mechanism is largely unknown. Our recent study demonstrated a novel regulatory pattern of androgen in regulation of spermatogonia differentiation, in which androgen indirectly regulates the expression of ITGB1 on Sertoli Cells through intermediate molecule Wilms tumor-1 (Wt-1) during spermatogenesis. In this study, we identified that Connexin 43 (Cx43), the key component for gap junction distributed between spermatogonia and Sertoli cells, was also regulated by androgen signal. Chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) demonstrated that WT1 occupied Cx43 promoter in Sertoli cells, suggesting WT1 as an intermediate molecule in regulation of Cx43. Finally, we revealed a regulatory pattern of Cx43 by androgen in Sertoli cells, and the Sertoli cells in germ cell depleted microenvironment were sensitive to androgen signal, which enhances the understanding of the mechanism of spermatogenesis.

18.
Eur Radiol ; 30(2): 1054-1061, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31630235

RESUMO

PURPOSE: To identify the diagnostic performance of magnetic resonance (MR) imaging for patients with adnexal torsion and to develop a predictive model for necrosis related to torsion. METHODS: The institutional ethics committee approved this retrospective study. A total of 56 women with a preoperative pelvic MR scan and a surgical and pathologic diagnosis of adnexal torsion were enrolled from five institutions. Three radiologists reviewed the MR images independently. The kappa value of interrater agreement was assessed. Differences between patients treated with conservative surgery and adnexectomy were evaluated by univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curve analysis was used to assess the ability of the model to predict ovarian necrosis. RESULTS: Fifty-six patients were divided into the conservative surgery group (24/56, 42.9%) or the adnexectomy group (32/56, 57.1%) depending on the surgical outcomes. The radiographic features related to torsion were interpreted by three raters retrospectively with substantial interrater agreement (kappa > 0.60). Older reproductive age and pedicle hemorrhagic infarction were significantly associated with adnexectomy (p < 0.05). At multivariate analysis, pedicle hemorrhagic infarction (odds ratio = 10.476 [95% confidence interval 1.103, 99.504; p = 0.041]) was associated with adnexectomy. Using the predictive model (older reproductive age and pedicle hemorrhagic infarction), a receiver operating characteristic curve was generated with an area under the curve (AUC = 0.870 ± 0.049). CONCLUSION: The presence of pedicle hemorrhagic infarction and older reproductive age can predict necrosis of adnexal torsion and may be used to guide the optimal treatment strategy. KEY POINTS: • Pedicle hemorrhagic infarction and older reproductive age are predictors of necrosis in adnexal torsion in patients of reproductive age (AUC = 0.870 ± 0.049). • Cystic wall thickening, enlarged vascular pedicle, tubal thickening, and uterine deviation are associated with a high risk for adnexal torsion, occurring in more than half of the cases in this study. • MR findings are useful for the definitive diagnosis of adnexal torsion and for the prediction of adnexal necrosis.

19.
J Hazard Mater ; 385: 121596, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31732342

RESUMO

Covalent organic frameworks (COFs) are emerging and promising adsorbents for the adsorptive removal of many types of pollutants. However, most COFs fabricated by various methods are in the form of microcrystalline powders, making them difficult in separation. In this study, magnetic COFs were prepared by a simple impregnation method. The as-prepared samples with Ms = 5.2 emu g-1 showed a good magnetic separation capability. Additionally, the adsorption performance of magnetic COFs towards antibiotics (e.g., diclofenac and sulfamethazine) was also studied. Various adsorption kinetic models (e.g., the pseudo first-order, the pseudo second-order, and mixed-order models) and adsorption isotherm models (e.g., the Freundlich, the Langmuir, and the Sips models) were used to study their adsorption kinetics and isotherms. Furthermore, density functional theory (DFT) was utilized to predict the interaction between adsorbents and adsorbates and to explain the partial adsorption mechanisms.

20.
Brain Res ; 1727: 146552, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31726041

RESUMO

The mesocorticolimbic system is comprised of dopaminergic neurons in the ventral tegmental area (VTA) and their projection targets in the ventral striatum, amygdala, prefrontal cortex, and hippocampus, among others. Regulation of dopamine transmission within this system is achieved in part through a negative feedback mechanism via dopamine D2 autoreceptors located on somatodendrites and terminals of VTA dopaminergic neurons. Dysregulation of this mechanism has been implicated in addiction and other psychiatric disorders, although the biological bases for these associations are unclear. In order to elucidate the functional consequences of VTA D2 receptor dysregulation, this study investigated alterations in local cerebral glucose utilization throughout the brain following Drd2 knockdown in the VTA. Male Sprague-Dawley rats received bilateral injections of lentivirus encoding shRNAs against the rat dopamine D2 receptor, scrambled shRNA or phosphate buffered saline. The autoradiographic 2-[14C]deoxyglucose metabolic mapping procedure was conducted 22 days post-infection. Brains were sectioned for autoradiography and glucose utilization was measured across distinct regions throughout the brain. Local cerebral glucose utilization was found to be elevated in the Drd2 knockdown group as compared to control groups. These greater levels of metabolic activity following Drd2 knockdown in the VTA were observed not only in the mesocorticolimbic system and associated dopamine pathways, but also in a global pattern that included many areas with far less concentrated VTA dopamine inputs. This suggests that even a partial Drd2 deletion in the VTA can have widespread consequences and impact information flow in diverse networks that process sensory, cognitive, motor and emotional information.

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