scholarly journals From Preclinical Stroke Models to Humans: Polyphenols in the Prevention and Treatment of Stroke

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 85
Author(s):  
Edoardo Parrella ◽  
Cristina Gussago ◽  
Vanessa Porrini ◽  
Marina Benarese ◽  
Marina Pizzi
Keyword(s):  
Hemorrhagic Stroke ◽  
Protective Role ◽  
Polyphenolic Compounds ◽  
Preclinical Studies ◽  
Preclinical Models ◽  
Human Diet ◽  
In Vivo Models ◽  
Stroke Models

Polyphenols are an important family of molecules of vegetal origin present in many medicinal and edible plants, which represent important alimentary sources in the human diet. Polyphenols are known for their beneficial health effects and have been investigated for their potential protective role against various pathologies, including cancer, brain dysfunctions, cardiovascular diseases and stroke. The prevention of stroke promoted by polyphenols relies mainly on their effect on cardio- and cerebrovascular systems. However, a growing body of evidence from preclinical models of stroke points out a neuroprotective role of these molecules. Notably, in many preclinical studies, the polyphenolic compounds were effective also when administered after the stroke onset, suggesting their possible use in promoting recovery of patients suffering from stroke. Here, we review the effects of the major polyphenols in cellular and in vivo models of both ischemic and hemorrhagic stroke in immature and adult brains. The results from human studies are also reported.

scholarly journals HDAC2 attenuates airway inflammation by suppressing IL-17A production in HDM-challenged mice

2019 ◽  
Vol 316 (1) ◽  
pp. L269-L279 ◽  
Author(s):  
Tianwen Lai ◽  
Mindan Wu ◽  
Chao Zhang ◽  
Luanqing Che ◽  
Feng Xu ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Inflammatory Cytokines ◽  
Allergic Inflammation ◽  
Allergic Airway Inflammation ◽  
Inflammatory Cells ◽  
Protective Role ◽  
In Vivo Models

Histone deacetylase (HDAC)2 is expressed in airway epithelium and plays a pivotal role in inflammatory cells. However, the role of HDAC2 in allergic airway inflammation remains poorly understood. In the present study, we determined the role of HDAC2 in airway inflammation using in vivo models of house dust mite (HDM)-induced allergic inflammation and in vitro cultures of human bronchial epithelial (HBE) cells exposed to HDM, IL-17A, or both. We observed that HDM-challenged Hdac2+/− mice exhibited substantially enhanced infiltration of inflammatory cells. Higher levels of T helper 2 cytokines and IL-17A expression were found in lung tissues of HDM-challenged Hdac2+/− mice. Interestingly, IL-17A deletion or anti-IL-17A treatment reversed the enhanced airway inflammation induced by HDAC2 impairment. In vitro, HDM and IL-17A synergistically decreased HDAC2 expression in HBE cells. HDAC2 gene silencing further enhanced HDM- and/or IL-17A-induced inflammatory cytokines in HBE cells. HDAC2 overexpresion or blocking IL-17A gene expression restored the enhanced inflammatory cytokines. Collectively, these results support a protective role of HDAC2 in HDM-induced airway inflammation by suppressing IL-17A production and might suggest that activation of HDAC2 and/or inhibition of IL-17A production could prevent the development of allergic airway inflammation.

scholarly journals Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 376
Author(s):  
Chantal B. Lucini ◽  
Ralf J. Braun
Keyword(s):  
Cell Death ◽  
Oxygen Species ◽  
In Vivo Models ◽  
Dependent Cell ◽  
Cell Death Mechanisms ◽  
Sting Pathway ◽  
Mitochondrial Membrane Permeabilization

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

scholarly journals Protective role of methanol extracts of Gentiana asclepiadea L. and G. cruciata L. against genotoxic damage induced by ethyl methanesulfonate

Genetika ◽  
2013 ◽  
Vol 45 (2) ◽  
pp. 329-340 ◽  
Author(s):  
Sanja Matic ◽  
Snezana Stanic ◽  
Slavica Solujic ◽  
Nevena Stankovic ◽  
Milan Mladenovic ◽  
...  
Keyword(s):  
Aerial Part ◽  
Protective Role ◽  
Negative Control ◽  
Ethyl Methanesulfonate ◽  
Recessive Lethal ◽  
Methanol Extracts ◽  
Strong Mutagen ◽  
Gentiana Cruciata

The methanol extracts from the underground and aerial part of the two species of Gentiana genus, Gentiana asclepiadea L. and Gentiana cruciata L. from Serbia, were investigated for their antigenotoxic activity against wellestablished mutagenic agent ethyl methanesulfonate (EMS) using the in vivo sexlinked recessive lethal (SLRL) test on Drosophila melanogaster. For this purpose, three days old Canton S males were treated with the potent mutagen EMS in concentration of 0.75 ppm, alone and combined with methanol extracts obtained from underground or aerial part of G. asclepiadea and G. cruciata in concentration of 5%, separately. Although EMS in concentration of 0.75 ppm increased the mutation frequency in all three broods, post-treatments with methanol extracts obtained from the underground and aerial part of G. asclepiadea and G. cruciata in concentration of 5%, respectively, drastically reduced the frequency of sex-linked recessive lethal mutations induced by EMS. Compared to the sucrose, as a negative control, methanol extract obtained from underground part of G. cruciata showed the most potent antigenotoxic activity. Extracts from the underground and aerial part of the two species of Gentiana genus, G. asclepiadea L. and G. cruciata L. from Serbia used in our experiments showed a clear antimutagenic effect, reducing the frequency of mutations induced by a strong mutagen such as EMS.

scholarly journals A neuroprotective role for microglia in prion diseases

2016 ◽  
Vol 213 (6) ◽  
pp. 1047-1059 ◽  
Author(s):  
Caihong Zhu ◽  
Uli S. Herrmann ◽  
Jeppe Falsig ◽  
Irina Abakumova ◽  
Mario Nuvolone ◽  
...  
Keyword(s):  
Prion Diseases ◽  
Protective Role ◽  
Proteinase K ◽  
Immune Effector ◽  
Effector Cells ◽  
The Central Nervous System ◽  
Cultured Slices ◽  
Simplex Virus

Microglial activation is a hallmark of most neurodegenerative disorders, and is particularly conspicuous in prion diseases. However, the role of microglia, which function as both primary immune effector cells and professional phagocytes in the central nervous system, remains contentious in the context of neurodegeneration. Here, we evaluated the effect of microglial depletion/deficiency on prion pathogenesis. We found that ganciclovir-mediated microglial ablation on tga20/CD11b-thymidine kinase of Herpes simplex virus (HSVTK) cerebellar organotypic cultured slices markedly aggravated prion-induced neurotoxicity. A similar deterioration of disease was recapitulated in in vivo microglial depletion in prion-infected tga20/CD11b-HSVTK mice. Additionally, deficiency of microglia in interleukin 34 knockout (IL34−/−) mice again resulted in significantly augmented proteinase K–resistant prion protein deposition and accelerated prion disease progression. These results provide unambiguous evidence for a general protective role of microglia in prion pathogenesis.

The Role of the Host in the Development of in vivo Models for Carcinogenesis Studies

1973 ◽  
pp. 20-47
Author(s):  
Carrie E. Whitmire ◽  
Charles F. Demoise ◽  
Richard E. Kouri
Keyword(s):  
In Vivo Models

scholarly journals The Role of Merlin/NF2 Loss in Meningioma Biology

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1633 ◽  
Author(s):  
Sungho Lee ◽  
Patrick J. Karas ◽  
Caroline C. Hadley ◽  
James C. Bayley V ◽  
A. Basit Khan ◽  
...  
Keyword(s):  
Early Recognition ◽  
Neurofibromatosis Type ◽  
Genetic Alterations ◽  
In Vivo Models ◽  
Inhibition Of Proliferation ◽  
Nf2 Gene ◽  
Sequencing Studies

Mutations in the neurofibromin 2 (NF2) gene were among the first genetic alterations implicated in meningioma tumorigenesis, based on analysis of neurofibromatosis type 2 (NF2) patients who not only develop vestibular schwannomas but later have a high incidence of meningiomas. The NF2 gene product, merlin, is a tumor suppressor that is thought to link the actin cytoskeleton with plasma membrane proteins and mediate contact-dependent inhibition of proliferation. However, the early recognition of the crucial role of NF2 mutations in the pathogenesis of the majority of meningiomas has not yet translated into useful clinical insights, due to the complexity of merlin’s many interacting partners and signaling pathways. Next-generation sequencing studies and increasingly sophisticated NF2-deletion-based in vitro and in vivo models have helped elucidate the consequences of merlin loss in meningioma pathogenesis. In this review, we seek to summarize recent findings and provide future directions toward potential therapeutics for this tumor.

scholarly journals Exploiting GRK2 Inhibition as a Therapeutic Option in Experimental Cancer Treatment: Role of p53-Induced Mitochondrial Apoptosis

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3530
Author(s):  
Jessica Gambardella ◽  
Antonella Fiordelisi ◽  
Gaetano Santulli ◽  
Michele Ciccarelli ◽  
Federica Andrea Cerasuolo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Nude Mice ◽  
Specific Inhibitor ◽  
Cancer Cell Proliferation ◽  
In Vivo Models ◽  
P53 Expression

The involvement of GRK2 in cancer cell proliferation and its counter-regulation of p53 have been suggested in breast cancer even if the underlying mechanism has not yet been elucidated. Furthermore, the possibility to pharmacologically inhibit GRK2 to delay cancer cell proliferation has never been explored. We investigated this possibility by setting up a study that combined in vitro and in vivo models to underpin the crosstalk between GRK2 and p53. To reach this aim, we took advantage of the different expression of p53 in cell lines of thyroid cancer (BHT 101 expressing p53 and FRO cells, which are p53-null) in which we overexpressed or silenced GRK2. The pharmacological inhibition of GRK2 was achieved using the specific inhibitor KRX-C7. The in vivo study was performed in Balb/c nude mice, where we treated BHT-101 or FRO-derived tumors with KRX-C7. In our in vitro model, FRO cells were unaffected by GRK2 expression levels, whereas BHT-101 cells were sensitive, thus suggesting a role for p53. The regulation of p53 by GRK2 is due to phosphorylative events in Thr-55, which induce the degradation of p53. In BHT-101 cells, the pharmacologic inhibition of GRK2 by KRX-C7 increased p53 levels and activated apoptosis through the mitochondrial release of cytochrome c. These KRX-C7-mediated events were also confirmed in cancer allograft models in nude mice. In conclusion, our data showed that GRK2 counter-regulates p53 expression in cancer cells through a kinase-dependent activity. Our results further corroborate the anti-proliferative role of GRK2 inhibitors in p53-sensitive tumors and propose GRK2 as a therapeutic target in selected cancers.

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