scholarly journals Strategies and Tools for Studying Microglial-Mediated Synapse Elimination and Refinement

2021 ◽  
Vol 12 ◽  
Author(s):  
Raffaella Morini ◽  
Matteo Bizzotto ◽  
Fabio Perrucci ◽  
Fabia Filipello ◽  
Michela Matteoli
Keyword(s):  
Time Windows ◽  
Developmental Time ◽  
Synapse Elimination ◽  
Pathological Conditions ◽  
Promising Target ◽  
Mice Brain ◽  
Methodological Approaches

The role of microglia in controlling synapse homeostasis is becoming increasingly recognized by the scientific community. In particular, the microglia-mediated elimination of supernumerary synapses during development lays the basis for the correct formation of neuronal circuits in adulthood, while the possible reactivation of this process in pathological conditions, such as schizophrenia or Alzheimer's Disease, provides a promising target for future therapeutic strategies. The methodological approaches to investigate microglial synaptic engulfment include different in vitro and in vivo settings. Basic in vitro assays, employing isolated microglia and microbeads, apoptotic membranes, liposomes or synaptosomes allow the quantification of the microglia phagocytic abilities, while co-cultures of microglia and neurons, deriving from either WT or genetically modified mice models, provide a relatively manageable setting to investigate the involvement of specific molecular pathways. Further detailed analysis in mice brain is then mandatory to validate the in vitro assays as representative for the in vivo situation. The present review aims to dissect the main technical approaches to investigate microglia-mediated phagocytosis of neuronal and synaptic substrates in critical developmental time windows.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Wei-Jin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Cathepsin L ◽  
Human Cells ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals circATP2A2 promotes osteosarcoma progression by upregulating MYH9

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 1749-1761
Author(s):  
Xin Cao ◽  
Xianfeng Meng ◽  
Peng Fu ◽  
Lin Wu ◽  
Zhen Yang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Area Under Curve ◽  
Prognostic Biomarker ◽  
Migration And Invasion ◽  
Promising Target ◽  
Repressive Effect ◽  
Cell Malignancy

Abstract Osteosarcoma (OS) is a highly metastatic primary malignant tumor. CircRNA hsa_circ_0028173 (circATP2A2) has been uncovered to be related to the advancement of OS. However, the biological role of circATP2A2 in OS has not been validated. circATP2A2 and MYH9 were upregulated while miR-335-5p was downregulated in OS. OS patients with high circATP2A2 expression displayed a shorter overall survival and the area under curve of circATP2A2 was 0.77, manifesting that circATP2A2 might be a diagnostic and prognostic biomarker. circATP2A2 silencing repressed OS cell proliferation and glycolysis in vivo and constrained OS cell proliferation, glycolysis, migration, and invasion in vitro. circATP2A2 regulated MYH9 expression through sponging miR-335-5p. MiR-335-5p inhibitor reversed the repressive effect of circATP2A2 knockdown on OS cell malignancy and glycolysis. MYH9 overexpression overturned miR-335-5p upregulation-mediated OS cell malignancy and glycolysis. circATP2A2 accelerated OS cell malignancy and glycolysis through upregulating MYH9 via sponging miR-335-5p, offering a promising target for OS treatment.

scholarly journals Identification of peptides interfering the lrrk2/pp1 interaction

2019 ◽  
Author(s):  
Chang Zhi Dong ◽  
Heriberto Bruzzoni-Giovanell ◽  
Yanhua Yu ◽  
Karim Dorgham ◽  
Christophe Parizot ◽  
...  
Keyword(s):  
Biological Activity ◽  
Elisa Test ◽  
Short Peptides ◽  
Cell Penetrating Peptide ◽  
Original Sequence ◽  
Pathological Conditions ◽  
Cell Penetrating

ABSTRACTSerine/threonine phosphatases are responsible for counteracting the effect of the protein kinases implicated in the development of several pathologies. Here we identified by PEP-scan approach the sequence of a fragment of LRRK2, a Parkinson’s disease associated protein, interacting with the phosphatase PP1. The fragment, that is located in a LRRK2 domain of undefined function, was associated in N-terminal to an optimized cell penetrating peptide in order to study their in vitro and in vivo biological activity. From this original sequence, we developed and studied five interfering peptides (IPs) and identified two peptides able to disrupt the LRRK2/PP1 interaction by in vitro competition in anti-LRRK2 immunoprecipitates. Using FITC-labelled peptides, we confirmed the internalization of the peptides in cell lines as well as in and primary human normal and pathological cells. Finally, we have confirmed by ELISA test the association of Mut3DPT-LRRK2-Long and Mut3DPT-LRRK2-Short peptides to purified PP1 protein in a selective manner. The shortest peptides, MuteDPT-LRRK2-5 to 8 with either N or C-terminal deletions are not able neither disrupt the association LRRK2/PP1 nor to associate to purified PP1 protein. The peptides Mut3DPT-LRRK2-Long and Mut3DPT-LRRK2-Short may be new tools to study the role of LRRK2/PP1 interaction in normal and pathological conditions.

scholarly journals Acute Functional Adaptations in Isolated Presynaptic Terminals Unveil Synaptosomal Learning and Memory

2019 ◽  
Vol 20 (15) ◽  
pp. 3641 ◽  
Author(s):  
Anna Pittaluga
Keyword(s):  
Transmitter Release ◽  
Presynaptic Receptors ◽  
Chemical Stimulation ◽  
Functional Adaptation ◽  
Pathological Conditions ◽  
Chemical Agents ◽  
Important Progress

Synaptosomes are used to decipher the mechanisms involved in chemical transmission, since they permit highlighting the mechanisms of transmitter release and confirming whether the activation of presynaptic receptors/enzymes can modulate this event. In the last two decades, important progress in the field came from the observations that synaptosomes retain changes elicited by both “in vivo” and “in vitro” acute chemical stimulation. The novelty of these studies is the finding that these adaptations persist beyond the washout of the triggering drug, emerging subsequently as functional modifications of synaptosomal performances, including release efficiency. These findings support the conclusion that synaptosomes are plastic entities that respond dynamically to ambient stimulation, but also that they “learn and memorize” the functional adaptation triggered by acute exposure to chemical agents. This work aims at reviewing the results so far available concerning this form of synaptosomal learning, also highlighting the role of these acute chemical adaptations in pathological conditions.

scholarly journals ALPK2 acts as tumor promotor in development of bladder cancer through targeting DEPDC1A

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Yuchen Wang ◽  
Jie Wu ◽  
Wenjie Luo ◽  
Hailiang Zhang ◽  
Guohai Shi ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Malignant Tumors ◽  
Direct Interaction ◽  
In Vivo Experiments ◽  
Tumor Promotor ◽  
Promising Target ◽  
Bladder Cancer Cells

AbstractBladder cancer is one of the most common malignant tumors in the urinary system. The development and improvement of treatment efficiency require the deepening of the understanding of its molecular mechanism. This study investigated the role of ALPK2, which is rarely studied in malignant tumors, in the development of bladder cancer. Our results showed the upregulation of ALPK2 in bladder cancer, and data mining of TCGA database showed the association between ALPK2 and pathological parameters of patients with bladder cancer. In vitro and in vivo experiments demonstrated that knockdown of ALPK2 could inhibit bladder cancer development through regulating cell proliferation, cell apoptosis, and cell migration. Additionally, DEPDC1A is identified as a potential downstream of ALPK2 with direct interaction, whose overexpression/downregulation can inhibit/promote the malignant behavioral of bladder cancer cells. Moreover, the overexpression of DEPDC1A can rescue the inhibitory effects of ALPK2 knockdown on bladder cancer. In conclusion, ALPK2 exerts a cancer-promoting role in the development of bladder cancer by regulating DEPDC1A, which may become a promising target to improve the treatment strategy of bladder cancer.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2020 ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Weijin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Virus Entry ◽  
Cathepsin L ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

SUMMARYTo discover new drugs to combat coronavirus disease 2019 (COVID-19), an understanding of the molecular basis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated and was positively correlated with disease course and severity in COVID-19 patients. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cell lines and human ACE2 transgenic mice, while CTSL overexpression, in turn, enhanced pseudovirus infection. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity and prevented SARS-CoV-2 pseudovirus infection. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals Participation of BMI-1 protein in cancer

2017 ◽  
Vol 71 (0) ◽  
pp. 0-0 ◽  
Author(s):  
Agnieszka Zaczek ◽  
Paweł Jóźwiak ◽  
Anna Krześlak
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
In Vivo Studies ◽  
Histone H2a ◽  
Cellular Processes ◽  
Promising Target ◽  
Polycomb Repressive Complex 1

BMI-1 (B-lymphoma Mo-MLV insertion region 1) protein is a constituent of Polycomb Repressive Complex 1 (PRC1) that via ubiquitination of histone H2A affects expression of many genes. BMI-1 is involved in cellular processes such as DNA repair, proliferation, growth, senescence and apoptosis. BMI-1 plays a key role in biology of stem cells including cancer stem cells by regulation of their self-renewal and differentiation. Accumulating evidence has revealed that overexpression of BMI-1 in many human cancers correlates with disease progression and therapy failure. The results of in vitro and in vivo studies confirm the involvement of BMI-1 in tumor initiation as well as invasion, metastasis and chemoresistance. Taking into account significant role of BMI1 in tumorigenesis, especially associated with cancer stem cells, it seems that this gene may be a promising target of anticancer therapies.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Anti-obesity role of Aster glehni extract: in vivo and in vitro effects

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
HM Lee ◽  
TG Ahn ◽  
CW Kim ◽  
HJ An
Keyword(s):  
In Vitro Effects
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