N-Glycosylation Facilitates 4-1BB Membrane Localization by Avoiding Its Multimerization

Leveraging the T cell immunity against tumors represents a revolutionary type of cancer therapy. 4-1BB is a well-characterized costimulatory immune receptor existing on activated T cells and mediating their proliferation and cytotoxicity under infectious diseases and cancers. Despite the accumulating interest in implementing 4-1BB as a therapeutic target for immune-related disorders, less is known about the pattern of its intracellular behaviors and regulations. It has been previously demonstrated that 4-1BB is heavily modified by N-glycosylation; however, the biological importance of this modification lacks detailed elucidation. Through biochemical, biophysical, and cell-biological approaches, we systematically evaluated the impact of N-glycosylation on the ligand interaction, stability, and localization of 4-1BB. We hereby highlighted that N-glycan functions by preventing the oligomerization of 4-1BB, thus permitting its membrane transportation and fast turn-over. Without N-glycosylation, 4-1BB could be aberrantly accumulated intracellularly and fail to be sufficiently inserted in the membrane. The N-glycosylation-guided intracellular processing of 4-1BB serves as the potential mechanism explicitly modulating the “on” and “off” of 4-1BB through the control of protein abundance. Our study will further solidify the understanding of the biological properties of 4-1BB and facilitate the clinical practice against this promising therapeutic target.

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Emerging role of G9a in cancer stemness and promises as a therapeutic target

Oncogenesis ◽

10.1038/s41389-021-00370-7 ◽

2021 ◽

Vol 10 (11) ◽

Author(s):

Joshua R. Haebe ◽

Christopher J. Bergin ◽

Tamara Sandouka ◽

Yannick D. Benoit

Keyword(s):

Therapeutic Target ◽

Histone Methyltransferase ◽

Direct Inhibition ◽

Methyltransferase Activity ◽

Cancer Stemness ◽

Promising Therapeutic Target ◽

Context Specific ◽

Different Origins ◽

The Impact

AbstractThe histone methyltransferase G9a is well-documented for its implication in neoplastic growth. However, recent investigations have demonstrated a key involvement of this chromatin writer in maintaining the self-renewal and tumor-initiating capacities of cancer stem cells (CSCs). Direct inhibition of G9a’s catalytic activity was reported as a promising therapeutic target in multiple preclinical studies. Yet, none of the available pharmacological inhibitors of G9a activity have shown success at the early stages of clinical testing. Here, we discuss central findings of oncogenic expression and activation of G9a in CSCs from different origins, as well as the impact of the suppression of G9a histone methyltransferase activity in such contexts. We will explore the challenges posed by direct and systemic inhibition of G9a activity in the perspective of clinical translation of documented small molecules. Finally, we will discuss recent advances in drug discovery as viable strategies to develop context-specific drugs, selectively targeting G9a in CSC populations.

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Skeletal-Muscle Metabolic Reprogramming in ALS-SOD1 G93G Mice Predates Disease Onset and is a Promising Therapeutic Target

SSRN Electronic Journal ◽

10.2139/ssrn.3482152 ◽

2019 ◽

Author(s):

Silvia Scaricamazza ◽

Illari Salvatori ◽

Giacomo Giacovazzo ◽

Jean Philippe Loeffler ◽

Frederique Renè ◽

...

Keyword(s):

Skeletal Muscle ◽

Therapeutic Target ◽

Disease Onset ◽

Metabolic Reprogramming ◽

Promising Therapeutic Target

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miR-124: A Promising Therapeutic Target for Central Nervous System Injuries and Diseases

Cellular and Molecular Neurobiology ◽

10.1007/s10571-021-01091-6 ◽

2021 ◽

Author(s):

Jinying Xu ◽

Yangyang Zheng ◽

Liangjia Wang ◽

Yining Liu ◽

Xishu Wang ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Therapeutic Target ◽

Promising Therapeutic Target

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Histological, Biomechanical, and Biological Properties of Genipin-Crosslinked Decellularized Peripheral Nerves

International Journal of Molecular Sciences ◽

10.3390/ijms22020674 ◽

2021 ◽

Vol 22 (2) ◽

pp. 674

Author(s):

Óscar Darío García-García ◽

Marwa El Soury ◽

David González-Quevedo ◽

David Sánchez-Porras ◽

Jesús Chato-Astrain ◽

...

Keyword(s):

Ex Vivo ◽

Nerve Repair ◽

Wistar Rat ◽

Biomechanical Properties ◽

Biological Properties ◽

Suitable Alternative ◽

Promising Alternative ◽

Histological Pattern ◽

The Impact

Acellular nerve allografts (ANGs) represent a promising alternative in nerve repair. Our aim is to improve the structural and biomechanical properties of biocompatible Sondell (SD) and Roosens (RS) based ANGs using genipin (GP) as a crosslinker agent ex vivo. The impact of two concentrations of GP (0.10% and 0.25%) on Wistar rat sciatic nerve-derived ANGs was assessed at the histological, biomechanical, and biocompatibility levels. Histology confirmed the differences between SD and RS procedures, but not remarkable changes were induced by GP, which helped to preserve the nerve histological pattern. Tensile test revealed that GP enhanced the biomechanical properties of SD and RS ANGs, being the crosslinked RS ANGs more comparable to the native nerves used as control. The evaluation of the ANGs biocompatibility conducted with adipose-derived mesenchymal stem cells cultured within the ANGs confirmed a high degree of biocompatibility in all ANGs, especially in RS and RS-GP 0.10% ANGs. Finally, this study demonstrates that the use of GP could be an efficient alternative to improve the biomechanical properties of ANGs with a slight impact on the biocompatibility and histological pattern. For these reasons, we hypothesize that our novel crosslinked ANGs could be a suitable alternative for future in vivo preclinical studies.

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Hypoxia Conditioning as a Promising Therapeutic Target in Parkinson's Disease?

Movement Disorders ◽

10.1002/mds.28544 ◽

2021 ◽

Author(s):

Johannes Burtscher ◽

Muhammed Muazzam Kamil Syed ◽

Hilal A. Lashuel ◽

Grégoire P. Millet

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Therapeutic Target ◽

Promising Therapeutic Target

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Earthworms as an Ecological Indicator of Soil Recovery after Mechanized Logging Operations in Mixed Beech Forests

Forests ◽

10.3390/f12010018 ◽

2020 ◽

Vol 12 (1) ◽

pp. 18

Author(s):

Hadi Sohrabi ◽

Meghdad Jourgholami ◽

Mohammad Jafari ◽

Farzam Tavankar ◽

Rachele Venanzi ◽

...

Keyword(s):

Soil Properties ◽

Soil Depth ◽

Biological Properties ◽

Economic Benefits ◽

Ecological Indicator ◽

Traffic Intensity ◽

Soil Biological Properties ◽

Density And Biomass ◽

Soil Recovery ◽

The Impact

Soil damage caused by logging operations conducted to obtain and maximize economic benefits has been established as having long-term effects on forest soil quality and productivity. However, a comprehensive study of the impact of logging operations on earthworms as a criterion for soil recovery has never been conducted in the Hyrcanian forests of Iran. The aim of this study was to determine the changes in soil biological properties (earthworm density and biomass) and its recovery process under the influence of traffic intensity, slope and soil depth in various intervals according to age after logging operations. Soil properties were compared among abandoned skid trails with different ages (i.e., 3, 10, 20, and 25 years) and an undisturbed area. The results showed that earthworm density and biomass in the high traffic intensity and slope class of 20–30% at the 10–20 cm depth of the soil had the lowest value compared to the other treatments. Twenty-five years after the logging operations, the earthworm density at soil depth of 0–10 and 10–20 cm was 28.4% (0.48 ind. m−2) and 38.6% (0.35 ind. m−2), which were less than those of the undisturbed area, respectively. Meanwhile, the earthworm biomass at a soil depth of 0–10 and 10–20 cm was 30.5% (2.05 mg m−2) and 40.5% (1.54 mg m−2) less than the values of the undisturbed area, respectively. The earthworm density and biomass were positively correlated with total porosity, organic carbon and nitrogen content, while negatively correlated with soil bulk density and C/N ratio. According to the results, 25 years after logging operations, the earthworm density and biomass on the skid trails were recovered, but they were significantly different with the undisturbed area. Therefore, full recovery of soil biological properties (i.e., earthworm density and biomass) takes more than 25 years. The conclusions of our study reveal that the effects of logging operations on soil properties are of great significance, and our understanding of the mechanism of soil change and recovery demand that harvesting operations be extensively and properly implemented.

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