scholarly journals Striatal Nurr1 Facilitates the Dyskinetic State and Exacerbates Levodopa-Induced Dyskinesia in a Rat Model of Parkinson’s Disease

2019 ◽  
Author(s):  
RC Sellnow ◽  
K Steece-Collier ◽  
F Altwal ◽  
IM Sandoval ◽  
JH Kordower ◽  
...  
Keyword(s):  
Causative Factor ◽  
Spine Density ◽  
Direct Role ◽  
Lewis Rats ◽  
Fischer 344 ◽  
Therapeutic Development ◽  
Drug Naïve ◽  
Novel Target ◽  
F344 Rats

AbstractBackgroundThe transcription factor Nurr1 has been identified to be ectopically induced in the striatum of dyskinetic rodents expressing L-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression.MethodsWe used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with L-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single unit recordings and dendritic spine analyses in drug-naïve rAAV-injected parkinsonian rats.ResultsrAAV-GFP injected LID-resistant Lewis rats displayed mild LID and no induction of striatal Nurr1. However, Lewis rats transduced to overexpress Nurr1 developed severe LID. Nurr11 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in L-DOPA-naïve rats striatal rAAV-Nurr1 overexpression 1) increased firing activity in dopamine-depleted striatal direct pathway neurons, and 2) decreased spine density and thin-spine morphology on striatal medium spiny neurons, mimicking changes seen in dyskinetic rats. Finally, we provide post-mortem evidence of Nurr1 expression in the striatum of L-DOPA treated PD patients.ConclusionsOur data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.

scholarly journals Rats show a preference for certain unfamiliar strains of rats

2021 ◽  
Author(s):  
Hiroki Kogo ◽  
Yasushi Kiyokawa ◽  
Yukari Takeuchi
Keyword(s):  
Stress Responses ◽  
Wistar Rat ◽  
Sprague Dawley ◽  
Fischer 344 ◽  
The Subject ◽  
Long Evans ◽  
F344 Rats ◽  
Anaesthetised Rats ◽  
Social Behaviours

AbstractHumans show distinct social behaviours when we recognise social similarity in opponents that are members of the same social group. However, little attention has been paid to the role of social similarity in non-human animals. In Wistar subject rats, the presence of an unfamiliar Wistar rat mitigated stress responses, suggesting the importance of social similarity in this phenomenon. We found that the presence of unfamiliar Sprague-Dawley (SD) or Long-Evans (LE) rats, but not an unfamiliar Fischer 344 (F344) rat, similarly mitigated stress in subject rats. It is therefore possible that the subject rats recognised social similarity to unfamiliar SD and LE rats. In this study, we demonstrated that Wistar subject rats were capable of categorizing unfamiliar rats based on their strain, and that Wistar subjects showed a preference for unfamiliar Wistar, SD, and LE rats over F344 rats. However, the subject rats did not show a preference among Wistar, SD, and LE rats. In addition, the results were not due to an aversion to F344 rats, and preference was not affected when anaesthetised rats were presented to subject rats. The findings suggested that rats recognise social similarity to certain unfamiliar strains of rats.

scholarly journals MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Hayley Widden ◽  
Aneta Kaczmarczyk ◽  
Ashok Subedi ◽  
Robert H. Whitaker ◽  
William J. Placzek
Keyword(s):  
Cell Fate ◽  
Cell Cycle Progression ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Direct Role ◽  
Tetramerization Domain ◽  
Apoptotic Protein ◽  
Anti Cancer ◽  
Therapeutic Development

Abstract MCL1, an anti-apoptotic protein that controls chemosensitivity and cell fate through its regulation of intrinsic apoptosis, has been identified as a high-impact target in anti-cancer therapeutic development. With MCL1-specific inhibitors currently in clinical trials, it is imperative that we understand the roles that MCL1 plays in cells, especially when targeting the Bcl-2 homology 3 (BH3) pocket, the central region of MCL1 that mediates apoptotic regulation. Here, we establish that MCL1 has a direct role in controlling p73 transcriptional activity, which modulates target genes associated with DNA damage response, apoptosis, and cell cycle progression. This interaction is mediated through the reverse BH3 (rBH3) motif in the p73 tetramerization domain, which restricts p73 assembly on DNA. Here, we provide a novel mechanism for protein-level regulation of p73 transcriptional activity by MCL1, while also framing a foundation for studying MCL1 inhibitors in combination with platinum-based chemotherapeutics. More broadly, this work expands the role of Bcl-2 family signaling beyond cell fate regulation.

scholarly journals The role of the immune system in idiopathic nephrotic syndrome

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Agnes Hackl ◽  
Seif El Din Abo Zed ◽  
Paul Diefenhardt ◽  
Julia Binz-Lotter ◽  
Rasmus Ehren ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Immune System ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Idiopathic Nephrotic Syndrome ◽  
Cell Subset ◽  
Causative Factor ◽  
Direct Role ◽  
Filtration Barrier

AbstractIdiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia and usually responds well to steroids. However, relapses are frequent, which can require multi-drug therapy with deleterious long-term side effects. In the last decades, different hypotheses on molecular mechanisms underlying INS have been proposed and several lines of evidences strongly indicate a crucial role of the immune system in the pathogenesis of non-genetic INS. INS is traditionally considered a T-cell-mediated disorder triggered by a circulating factor, which causes the impairment of the glomerular filtration barrier and subsequent proteinuria. Additionally, the imbalance between Th17/Tregs as well as Th2/Th1 has been implicated in the pathomechanism of INS. Interestingly, B-cells have gained attention, since rituximab, an anti-CD20 antibody demonstrated a good therapeutic response in the treatment of INS. Finally, recent findings indicate that even podocytes can act as antigen-presenting cells under inflammatory stimuli and play a direct role in activating cellular pathways that cause proteinuria. Even though our knowledge on the underlying mechanisms of INS is still incomplete, it became clear that instead of a traditionally implicated cell subset or one particular molecule as a causative factor for INS, a multi-step control system including soluble factors, immune cells, and podocytes is necessary to prevent the occurrence of INS. This present review aims to provide an overview of the current knowledge on this topic, since advances in our understanding of the immunopathogenesis of INS may help drive new tailored therapeutic approaches forward.

Airway arginase expression and Nω-hydroxy-nor-arginine effect on methacholine-induced bronchoconstriction differentiate Lewis and Fischer rat strains

2014 ◽  
Vol 116 (6) ◽  
pp. 621-627
Author(s):  
Paul-André Risse ◽  
Anouk Lavoie-Lamoureux ◽  
Taisuke Jo ◽  
Kimitake Tsuchiya ◽  
Sana Siddiqui ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Arginase Activity ◽  
Tracheal Smooth Muscle ◽  
Lewis Rats ◽  
Fischer 344 ◽  
Smooth Muscle Proliferation ◽  
Fischer 344 Rat ◽  
Fischer Rats

Innate airway hyperresponsiveness (AHR) is well modeled by two strains of rat, the hyperresponsive Fischer 344 rat and the normoresponsive Lewis rat. Arginase has been implicated in AHR associated with allergic asthma models. We addressed the role of arginase in innate AHR using the Fischer-Lewis model. In vivo arginase inhibition with Nω-hydroxy-nor-arginine (nor-NOHA) was evaluated on methacholine-induced bronchoconstriction in the Fischer and the Lewis rats. Arginase activity and mRNA expression were quantified in structural and resident cells of the proximal airway tree. The effect of nor-NOHA was evaluated on cultured tracheal smooth muscle proliferation. Fischer rats exhibited significantly greater changes in respiratory resistance and elastance in response to methacholine compared with Lewis rats. nor-NOHA reduced the methacholine-induced bronchoconstriction in the central airways of Lewis rats, while it did not change the innate AHR of Fischer rats. Lewis rats exhibited greater arginase activity in tracheal smooth muscle but a lower proliferation rate compared with Fischer rats. Smooth muscle proliferation was not affected by nor-NOHA in either strain of rats. The strain-specific arginase expression in the smooth muscle may contribute to the differences in sensitivity of the methacholine challenged airways of Lewis and Fischer rats to inhibition of arginase.

scholarly journals Involvement of pro-inflammatory cytokines and growth factors in the pathogenesis of Dupuytren's contracture: a novel target for a possible future therapeutic strategy?

2015 ◽  
Vol 129 (8) ◽  
pp. 711-720 ◽  
Author(s):  
Enrica Bianchi ◽  
Samanta Taurone ◽  
Lia Bardella ◽  
Alberto Signore ◽  
Elena Pompili ◽  
...  
Keyword(s):  
Growth Factors ◽  
Inflammatory Cytokines ◽  
Therapeutic Strategy ◽  
Dupuytren’S Contracture ◽  
Direct Role ◽  
Dupuytren's Disease ◽  
Novel Target ◽  
Tgf Β1 ◽  
Pro Inflammatory Cytokines

Present study studies pro-inflammatory cytokines and growth factors involved in the Dupuytren's disease. Our data showed the expression of TGF-β1, IL-1β and VEGFa in DC nodules suggesting a direct role of these markers in progression and recurrence of the disease.

scholarly journals Overview on the Different Patterns of Tumor Vascularization

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 639
Author(s):  
Domenico Ribatti ◽  
Francesco Pezzella
Keyword(s):  
Vasculogenic Mimicry ◽  
Endothelial Cell Proliferation ◽  
Published Data ◽  
Alternative Mechanism ◽  
Tumor Vascularization ◽  
Angiogenic Therapy ◽  
Physiological Processes ◽  
Inhibition Of Angiogenesis ◽  
Therapeutic Development

Angiogenesis is a crucial event in the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads to the formation of a vascular network of tumor-associated capillaries promoting survival and proliferation of the tumor cells. Starting with the hypothesis formulated by Judah Folkman that tumor growth is angiogenesis-dependent, this area of research has a solid scientific foundation and inhibition of angiogenesis is a major area of therapeutic development for the treatment of cancer. Over this period numerous authors published data of vascularization of tumors, which attributed the cause of neo-vascularization to various factors including inflammation, release of angiogenic cytokines, vasodilatation, and increased tumor metabolism. More recently, it has been demonstrated that tumor vasculature is not necessarily derived by endothelial cell proliferation and sprouting of new capillaries, but alternative vascularization mechanisms have been described, namely vascular co-option and vasculogenic mimicry. In this article, we have analyzed the mechanisms involved in tumor vascularization in association with classical angiogenesis, including post-natal vasculogenesis, intussusceptive microvascular growth, vascular co-option, and vasculogenic mimicry. We have also discussed the role of these alternative mechanism in resistance to anti-angiogenic therapy and potential therapeutic approaches to overcome resistance.

scholarly journals The Association of Human Herpesviruses with Malignant Brain Tumor Pathology and Therapy: Two Sides of a Coin

2021 ◽  
Vol 22 (5) ◽  
pp. 2250
Author(s):  
Evita Athanasiou ◽  
Antonios N. Gargalionis ◽  
Fotini Boufidou ◽  
Athanassios Tsakris
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Comprehensive Evaluation ◽  
Tumor Development ◽  
Scientific Data ◽  
Malignant Brain Tumor ◽  
Direct Role ◽  
Tumor Pathology ◽  
Human Herpesviruses

The role of certain viruses in malignant brain tumor development remains controversial. Experimental data demonstrate that human herpesviruses (HHVs), particularly cytomegalovirus (CMV), Epstein–Barr virus (EBV) and human herpes virus 6 (HHV-6), are implicated in brain tumor pathology, although their direct role has not yet been proven. CMV is present in most gliomas and medulloblastomas and is known to facilitate oncomodulation and/or immunomodulation, thus promoting cancer cell proliferation, invasion, apoptosis, angiogenesis, and immunosuppression. EBV and HHV-6 have also been detected in brain tumors and high-grade gliomas, showing high rates of expression and an inflammatory potential. On the other hand, due to the neurotropic nature of HHVs, novel studies have highlighted the engagement of such viruses in the development of new immunotherapeutic approaches in the context of oncolytic viral treatment and vaccine-based strategies against brain tumors. This review provides a comprehensive evaluation of recent scientific data concerning the emerging dual role of HHVs in malignant brain pathology, either as potential causative agents or as immunotherapeutic tools in the fight against these devastating diseases.

The Costs of Seeking Shelter for Renters With Discrediting Background Records

2021 ◽  
pp. 153568412110124
Author(s):  
Anna Reosti
Keyword(s):  
Financial Burden ◽  
Rental Housing ◽  
Application Process ◽  
Direct Role ◽  
Screening Process ◽  
Housing Search ◽  
Housing Options ◽  
Depth Interviews ◽  
Rental Housing Market

This study illuminates an understudied pathway through which disadvantage is reproduced in the rental housing market: the housing search, application, and tenant screening process. Using in-depth interviews with 25 housing-seekers with criminal conviction records, past evictions, and damaged credit histories, this article examines the direct role of the rental housing search and application process in reproducing economic precarity and social disadvantage among renters with discrediting background records, beyond delimiting their housing options. Its findings suggest that navigating the housing search from a position of acute market disadvantage comes with significant costs for this population, including the financial burden of repeated application fees and the psychological strains associated with the specter of indefinite housing insecurity. The findings also demonstrate how the housing search process may undermine the willingness of stigmatized renters to contest exploitative or unlawful rental practices by reinforcing awareness of their degraded status in the rental market.

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