Disrupting D2-NMDA receptor heteromerization blocks the rewarding effects of cocaine but preserves natural reward processing

AbstractAddictive drugs increase dopamine in the nucleus accumbens (NAc), where it persistently shapes excitatory glutamate transmission and hijacks natural reward processing. Herein, we provide evidence, from mice to human, that an underlying mechanism relies on drug-evoked heteromerization of glutamate NMDA receptors (NMDAR) with dopamine receptor 1 (D1R) or 2 (D2R). Using temporally-controlled inhibition of D1R-NMDAR heteromerization, we unraveled their selective implication in early developmental phases of cocaine-mediated synaptic, morphological and behavioral responses. In contrast, preventing D2R-NMDAR heteromerization blocked the persistence of these adaptations. Importantly, interfering with these heteromers spared natural reward processing. Strikingly, we established that D2R-NMDAR complexes exist in human samples and showed that, despite a decreased D2R protein expression in the NAc, psychostimulant-addicts display a higher proportion of D2R forming heteromers with NMDAR. These findings contribute to a better understanding of molecular mechanisms underlying addiction and uncover D2R-NMDAR heteromers as targets with potential therapeutic value.

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Nano-Curcumin Regulates p53 Phosphorylation and PAI-1 Expression during Bleomycin Induced Injury in Alveolar Basal Epithelial Cells

Current Bioactive Compounds ◽

10.2174/1573407214666180727093612 ◽

2020 ◽

Vol 16 (1) ◽

pp. 85-89

Author(s):

Mahesh M. Gouda ◽

Ashwini Prabhu ◽

Varsha Reddy S.V. ◽

Rafa Jahan ◽

Yashodhar P. Bhandary

Keyword(s):

Epithelial Cells ◽

Lung Injury ◽

Molecular Mechanisms ◽

A549 Cells ◽

Plasminogen Activator Inhibitor ◽

Underlying Mechanism ◽

Protective Role ◽

Alveolar Epithelial Cells ◽

Cellular Damage

Background: Bleomycin (BLM) is known to cause DNA damage in the Alveolar Epithelial Cells (AECs). It is reported that BLM is involved in the up-regulation of inflammatory molecules such as neutrophils, macrophages, chemokines and cytokines. The complex underlying mechanism for inflammation mediated progression of lung injury is still unclear. This investigation was designed to understand the molecular mechanisms associated with p53 mediated modulation of Plasminogen Activator Inhibitor-I (PAI-I) expression and its regulation by nano-curcumin formulation. Methods: A549 cells were treated with BLM to cause the cellular damage in vitro and commercially available nano-curcumin formulation was used as an intervention. Cytotoxic effect of nano-curcumin was analyzed using Methyl Thiazolyl Tetrazolium (MTT) assay. Protein expressions were analyzed using western blot to evaluate the p53 mediated changes in PAI-I expression. Results: Nano-curcumin showed cytotoxicity up to 88.5 % at a concentration of 20 μg/ml after 48 h of treatment. BLM exposure to the cells activated the phosphorylation of p53, which in turn increased PAII expression. Nano-curcumin treatment showed a protective role against phosphorylation of p53 and PAI-I expression, which in turn regulated the fibro-proliferative phase of injury induced by bleomycin. Conclusion: Nano-curcumin could be used as an effective intervention to regulate the severity of lung injury, apoptosis of AECs and fibro-proliferation during pulmonary injury.

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Improved response of human gingival fibroblasts to titanium coated with micro-/nano-structured tantalum

International Journal of Implant Dentistry ◽

10.1186/s40729-021-00316-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Chu-nan Zhang ◽

Lin-yi Zhou ◽

Shu-jiao Qian ◽

Ying-xin Gu ◽

Jun-yu Shi ◽

...

Keyword(s):

Molecular Mechanisms ◽

Underlying Mechanism ◽

Cell Number ◽

Human Gingival Fibroblasts ◽

Superior Performance ◽

Control Group ◽

Human Gingival Fibroblast ◽

Gingival Fibroblast ◽

Gingival Fibroblasts ◽

Integrin Β1

Abstract Objectives This study aims to evaluate the ability of tantalum-coated titanium to improve human gingival fibroblasts’ adhesion, viability, proliferation, migration performance, and the potential molecular mechanisms. Materials and methods Titanium plates were divided into two groups: (1) no coating (Ti, control), (2) Tantalum-coated titanium (Ta-coated Ti). All samples were characterized by scanning electronic microscopy, surface roughness, and hydrophilicity. Fibroblasts’ performance were analyzed by attached cell number at 1 h, 4 h, and 24 h, morphology at 1 h and 4 h, viability at 1 day, 3 days, 5 days, and 7 days, recovery after wounding at 6 h, 12 h, and 24 h. RT-PCR, western blot were applied to detect attachment-related genes’ expression and protein synthesis at 4 h and 24 h. Student’s t test was used for statistical analysis. Results Tantalum-coated titanium demonstrates a layer of homogeneously distributed nano-grains with mean diameter of 25.98 (± 14.75) nm. It was found that after tantalum deposition, human gingival fibroblasts (HGFs) adhesion, viability, proliferation, and migration were promoted in comparison to the control group. An upregulated level of Integrin β1 and FAK signaling was also detected, which might be the underlying mechanism. Conclusion In the present study, adhesion, viability, proliferation, migration of human gingival fibroblasts are promoted on tantalum-coated titanium, upregulated integrin β1 and FAK might contribute to its superior performance, indicating tantalum coating can be applied in transmucosal part of dental implant. Clinical significance Tantalum deposition on titanium surfaces can promote human gingival fibroblast adhesion, accordingly forming a well-organized soft tissue sealing and may contribute to a successful osseointegration.

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Beneficial Actions of Orostachys japonica and Its Compounds against Tumors via MAPK Signaling Pathways

Nutrients ◽

10.3390/nu13020555 ◽

2021 ◽

Vol 13 (2) ◽

pp. 555

Author(s):

Soyoung Hur ◽

Eungyeong Jang ◽

Jang-Hoon Lee

Keyword(s):

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Malignant Tumors ◽

Treatment Options ◽

Underlying Mechanism ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Antitumor Effects ◽

Mesenchymal Transition ◽

Perennial Plant

Tumors are one of the most life-threatening diseases, and a variety of cancer treatment options have been continuously introduced in order to overcome cancer and improve conventional therapy. Orostachys japonica (O. japonica), which is a perennial plant belonging to the genus Orostachys of the Crassulaceae family, has been revealed to exhibit pharmacological properties against various tumors in numerous studies. The present review aimed to discuss the biological actions and underlying molecular mechanisms of O. japonica and its representative compounds—kaempferol and quercetin—against tumors. O. japonica reportedly has antiproliferative, anti-angiogenic, and antimetastatic activities against various types of malignant tumors through the induction of apoptosis and cell cycle arrest, a blockade of downstream vascular endothelial growth factor (VEGF)-VEGFR2 pathways, and the regulation of epithelial-to-mesenchymal transition. In addition, emerging studies have highlighted the antitumor efficacy of kaempferol and quercetin. Interestingly, it was found that alterations of the mitogen-activated protein kinase (MAPK) signaling cascades are involved in the pivotal mechanisms of the antitumor effects of O. japonica and its two compounds against cancer cell overgrowth, angiogenesis, and metastasis. In summary, O. japonica could be considered a preventive and therapeutic medicinal plant which exhibits antitumor actions by reversing altered patterns of MAPK cascades, and kaempferol and quercetin might be potential components that can contribute to the efficacy and underlying mechanism of O. japonica.

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Suppressor Mutations Bypass the Requirement of fluG for Asexual Sporulation and Sterigmatocystin Production in Aspergillus nidulans

Genetics ◽

10.1093/genetics/165.3.1083 ◽

2003 ◽

Vol 165 (3) ◽

pp. 1083-1093

Author(s):

Jeong-Ah Seo ◽

Yajun Guan ◽

Jae-Hyuk Yu

Keyword(s):

Aspergillus Nidulans ◽

Molecular Mechanisms ◽

Dominant Negative ◽

Wild Type ◽

Dominant Mutation ◽

Site Mutation ◽

Asexual Sporulation ◽

Dominant Negative Mutation ◽

Suppressor Mutations ◽

Early Developmental

Abstract Asexual sporulation (conidiation) in the filamentous fungus Aspergillus nidulans requires the early developmental activator fluG. Loss of fluG results in the blockage of both conidiation and production of the mycotoxin sterigmatocystin (ST). To investigate molecular mechanisms of fluG-dependent developmental activation, 40 suppressors of fluG (SFGs) that conidiate without fluG have been isolated and characterized. Genetic analyses showed that an individual suppression is caused by a single second-site mutation, and that all sfg mutations but one are recessive. Pairwise meiotic crosses grouped mutations to four loci, 31 of them to sfgA, 6 of them to sfgB, and 1 each to sfgC and sfgD, respectively. The only dominant mutation, sfgA38, also mapped to the sfgA locus, suggesting a dominant negative mutation. Thirteen sfgA and 1 sfgC mutants elaborated conidiophores in liquid submerged culture, indicating that loss of either of these gene functions not only bypasses fluG function but also results in hyperactive conidiation. While sfg mutants show varying levels of restored conidiation, all recovered the ability to produce ST at near wild-type levels. The fact that at least four loci are defined by recessive sfg mutations indicates that multiple genes negatively regulate conidiation downstream of fluG and that the activity of fluG is required to remove such repressive effects.

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The therapeutic value and molecular mechanisms of lncRNA FENDRR in human cancer

Current Pharmaceutical Design ◽

10.2174/1381612827666210820094702 ◽

2021 ◽

Vol 27 ◽

Author(s):

Wen Xu ◽

Bei Wang ◽

Yuxuan Cai ◽

Jinlan Chen ◽

Enqing Meng ◽

...

Keyword(s):

Noncoding Rna ◽

Molecular Mechanisms ◽

Malignant Tumors ◽

Human Cancer ◽

Tumor Therapy ◽

Pathophysiological Mechanism ◽

Regulatory Processes ◽

Carcinoma Prostate ◽

Therapeutic Value ◽

And Migration

Background: Long noncoding RNA (lncRNA) fetal-lethal non-coding developmental regulatory RNA (FENDRR), a newly known lncRNA, has been reported to be abnormally expressed in diverse tumors. This review is focused on clarifying the mechanism of FENDRR to regulate the biological process of tumors, affirming its value as a target for tumor therapy. Methods: The pathophysiological mechanism of FENDRR acting on tumors has been analyzed and summarized by reviewing PubMed. Results: The expression of lncRNA FENDRR is abnormally altered in clinical cancers, promoting the malignant transformation of a variety of tumors, including colon cancer, cervical cancer, hepatocellular carcinoma, prostate cancer, Malignant melanoma, lung cancer, osteosarcoma, breast cancer, etc. Cellular processions, including proliferation, invasion, apoptosis and migration affected by FENDRR, have been revealed. Conclusion: Specific evidences for the involvement of LncRNA FENDRR in cancer regulatory processes suggest that FENDRR has the potential to be a biomarker or clinical therapeutic target for malignant tumors.

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Synthetic Switching Time Statistics

Proceedings of the Human Factors Society Annual Meeting ◽

10.1177/107118137902300150 ◽

1979 ◽

Vol 23 (1) ◽

pp. 201-204 ◽

Cited By ~ 1

Author(s):

David R. Payne ◽

James R. Buck

Keyword(s):

Switching Time ◽

Tracking Task ◽

Time Data ◽

Tracking Errors ◽

Time System ◽

Task Time ◽

Statistical Time ◽

Developmental Phases ◽

Switching Task ◽

Early Developmental

A synthetic (predetermined) time system with expected times and time variances appears to have considerable usefulness in the design of panel layouts and the estimation of operator workloads, particularly during early developmental phases of a system. Accordingly, the study was made to see if a synthetic time system could be devised to predict the time statistics for setting and changing various types of switches as a function of several variables. These variables include: reach distances, type of switch, potential and actual switching uncertainty; both without and with different complexities of a simultaneous tracking task. Time data were collected through computerized instrumentation and the root-mean-square of tracking errors were collected for time intervals between switching task events. Analyses are being made to determine the repeatable predictability of the switching time statistics, the influence of the variables on these statistics, statistical independence of sequential switching times, learning effects on the tracking task, and switching task interferences on the tracking task. Since a synthetic time system requires a number of properties to be a useful technique of statistical time prediction, these tests are needed to show the degree to which these properties hold with switching tasks.

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MicroRNA-8 targets the Wingless signaling pathway in the female mosquito fat body to regulate reproductive processes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1424408112 ◽

2015 ◽

Vol 112 (5) ◽

pp. 1440-1445 ◽

Cited By ~ 50

Author(s):

Keira J. Lucas ◽

Sourav Roy ◽

Jisu Ha ◽

Amanda L. Gervaise ◽

Vladimir A. Kokoza ◽

...

Keyword(s):

Blood Meal ◽

Molecular Mechanisms ◽

Fat Body ◽

Control Strategies ◽

Functional Characterization ◽

Target Prediction ◽

Underlying Mechanism ◽

Female Mosquito ◽

Reproductive Events

Female mosquitoes require a blood meal for reproduction, and this blood meal provides the underlying mechanism for the spread of many important vector-borne diseases in humans. A deeper understanding of the molecular mechanisms linked to mosquito blood meal processes and reproductive events is of particular importance for devising innovative vector control strategies. We found that the conserved microRNA miR-8 is an essential regulator of mosquito reproductive events. Two strategies to inhibit miR-8 function in vivo were used for functional characterization: systemic antagomir depletion and spatiotemporal inhibition using the miRNA sponge transgenic method in combination with the yeast transcriptional activator gal4 protein/upstream activating sequence system. Depletion of miR-8 in the female mosquito results in defects related to egg development and deposition. We used a multialgorithm approach for miRNA target prediction in mosquito 3′ UTRs and experimentally verified secreted wingless-interacting molecule (swim) as an authentic target of miR-8. Our findings demonstrate that miR-8 controls the activity of the long-range Wingless (Wg) signaling by regulating Swim expression in the female fat body. We discovered that the miR-8/Wg axis is critical for the proper secretion of lipophorin and vitellogenin by the fat body and subsequent accumulation of these yolk protein precursors by developing oocytes.

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Betulinic Acid Suppresses Ovarian Cancer Cell Proliferation through Induction of Apoptosis

Biomolecules ◽

10.3390/biom9070257 ◽

2019 ◽

Vol 9 (7) ◽

pp. 257 ◽

Cited By ~ 1

Author(s):

Dahae Lee ◽

Seoung Rak Lee ◽

Ki Sung Kang ◽

Yuri Ko ◽

Changhyun Pang ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cell ◽

Betulinic Acid ◽

Molecular Mechanisms ◽

Underlying Mechanism ◽

Nuclear Staining ◽

Dependent Manner ◽

Meoh Extract ◽

Concentration Dependent Manner ◽

Induction Of Apoptosis

Ovarian cancer is one of the leading causes of cancer deaths worldwide in women, and the most malignant cancer among the different gynecological cancers. In this study, we explored potentially anticancer compounds from Cornus walteri (Cornaceae), the MeOH extract of which has been reported to show considerable cytotoxicity against several cancer cell lines. Phytochemical investigations of the MeOH extract of the stem and stem bark of C. walteri by extensive application of chromatographic techniques resulted in the isolation of 14 compounds (1–14). The isolated compounds were evaluated for inhibitory effects on the viability of A2780 human ovarian carcinoma cells and the underlying molecular mechanisms were investigated. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was employed to assess the anticancer effects of compounds 1–14 on A2780 cells, which showed that compound 11 (betulinic acid) reduced the viability of these cells in a concentration-dependent manner and had an half maximal (50%) inhibitory concentration (IC50) of 44.47 μM at 24 h. Nuclear staining and image-based cytometric assay were carried out to detect the induction of apoptosis by betulinic acid. Betulinic acid significantly increased the condensation of nuclei and the percentage of apoptotic cells in a concentration-dependent manner in A2780 cells. Western blot analysis was performed to investigate the underlying mechanism of apoptosis. The results indicated that the expression levels of cleaved caspase-8, -3, -9, and Bax were increased in A2780 cells treated with betulinic acid, whereas those of Bcl-2 were decreased. Thus, we provide the experimental evidence that betulinic acid can induce apoptosis in A2780 cells through both mitochondria-dependent and -independent pathways and suggest the potential use of betulinic acid in the development of novel chemotherapeutics for ovarian cancer therapy.

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The Development and Influence of Parasocial Relationships With Television Characters: A Longitudinal Experimental Test of Prejudice Reduction Through Parasocial Contact

Communication Research ◽

10.1177/0093650219900632 ◽

2020 ◽

pp. 009365021990063

Author(s):

Bradley J. Bond

Keyword(s):

Intergroup Contact ◽

Behavioral Responses ◽

Underlying Mechanism ◽

Prejudice Reduction ◽

Experimental Conditions ◽

Parasocial Relationships ◽

Attitudes And Behaviors ◽

Television Characters ◽

Extended Exposure ◽

Over Time

The current study investigates parasocial relationships as the underlying mechanism explaining prejudice reduction following extended exposure to mediated outgroups. Heterosexual participants viewed a fictional television series for 10 weeks depicting outgroup (gay) characters in which the outgroup attribute (sexuality) was accentuated or sanitized. Parasocial relationships with outgroup characters grew significantly over the course of the study regardless of condition. White participants and participants who reported the strongest pretest prejudice experienced the most intense growth. Outgroup prejudice decreased significantly over time for participants in both experimental conditions. Parasocial relationships predicted both prejudice reduction over time and behavioral responses to the outgroup. Parasocial relationships with an ingroup character engaged in intergroup contact did not contribute to prejudice reduction beyond parasocial relationships with outgroup characters. This research suggests that audiences can develop socioemotional bonds with outgroup television characters that can influence attitudes and behaviors much the same as direct, interpersonal intergroup contact.

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The Developmental Phases of Zebrafish Myogenesis

Journal of Developmental Biology ◽

10.3390/jdb7020012 ◽

2019 ◽

Vol 7 (2) ◽

pp. 12 ◽

Cited By ~ 5

Author(s):

Samuel R. Keenan ◽

Peter D. Currie

Keyword(s):

Molecular Mechanisms ◽

Muscle Growth ◽

Data Sets ◽

Vertebrate Lineage ◽

New Findings ◽

Muscle Groups ◽

Teleost Muscle ◽

Axial Musculature ◽

Developmental Phases ◽

Type Specification

The development and growth of vertebrate axial muscle have been studied for decades at both the descriptive and molecular level. The zebrafish has provided an attractive model system for investigating both muscle patterning and growth due to its simple axial musculature with spatially separated fibre types, which contrasts to complex muscle groups often deployed in amniotes. In recent years, new findings have reshaped previous concepts that define how final teleost muscle form is established and maintained. Here, we summarise recent findings in zebrafish embryonic myogenesis with a focus on fibre type specification, followed by an examination of the molecular mechanisms that control muscle growth with emphasis on the role of the dermomyotome-like external cell layer. We also consider these data sets in a comparative context to gain insight into the evolution of axial myogenic patterning systems within the vertebrate lineage.

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