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"Yu, Yu-qiang"
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SMYD2 targets RIPK1 and restricts TNF-induced apoptosis and necroptosis to support colon tumor growth
SMYD2 is a histone methyltransferase, which methylates both histone H3K4 as well as a number of non-histone proteins. Dysregulation of SMYD2 has been associated with several diseases including cancer. In the present study, we investigated whether and how SMYD2 might contribute to colorectal cancer. Increased expression levels of SMYD2 were detected in human and murine colon tumor tissues compared to tumor-free tissues. SMYD2 deficiency in colonic tumor cells strongly decreased tumor growth in two independent experimental cancer models. On a molecular level, SMYD2 deficiency sensitized colonic tumor cells to TNF-induced apoptosis and necroptosis without affecting cell proliferation. Moreover, we found that SMYD2 targeted RIPK1 and inhibited the phosphorylation of RIPK1. Finally, in a translational approach, pharmacological inhibition of SMYD2 attenuated colonic tumor growth. Collectively, our data show that SMYD2 is crucial for colon tumor growth and inhibits TNF-induced apoptosis and necroptosis.
Journal Article
Tailoring the component of protein corona via simple chemistry
Control over the protein corona of nanomaterials allows them to function better. Here, by taking graphene/gold as examples, we comprehensively assessed the association of surface properties with the protein corona. As revealed by in vitro measurements and computations, the interaction between graphene/gold and HSA/IgE was inversely correlated with the hydroxyl group availability, whereas the interaction between that and ApoE was comparatively less relevant. Molecular simulations revealed that the number and the distribution of surface hydroxyl groups could regulate the manner in which nanomaterials interact with proteins. Moreover, we validated that ApoE pre-adsorption before injection enhances the blood circulation of nanomaterials relative to their pristine and IgE-coated counterparts. This benefit can be attributed to the invulnerability of the complementary system provided by ApoE, whose encasement does not increase cytotoxicity. Overall, this study offers a robust yet simple way to create protein corona enriched in dysopsonins to realize better delivery efficacy.
The interaction between proteins and nanomaterials is complex and of interest for controlling nanoparticle fate. Here, using experimental and computational methods, the authors report on the effect of hydroxyl groups on protein interaction and how they can be used to enhance circulation times.
Journal Article
PGAM5-MAVS interaction regulates TBK1/ IRF3 dependent antiviral responses
Viral infections trigger host innate immune responses, characterized by the production of type-I interferons (IFN) including IFNβ. IFNβ induces cellular antiviral defense mechanisms and thereby contributes to pathogen clearance. Accumulating evidence suggests that mitochondria constitute a crucial platform for the induction of antiviral immunity. Here we demonstrate that the mitochondrial protein phosphoglycerate mutase family member 5 (PGAM5) is important for the antiviral cellular response. Following challenge of HeLa cells with the dsRNA-analog poly(I:C), PGAM5 oligomers and high levels of PGAM5 were found in mitochondrial aggregates. Using immunoprecipitation, a direct interaction of PGAM5 with the mitochondrial antiviral-signaling protein (MAVS) was demonstrated. In addition, PGAM5 deficient cells showed diminished expression of IFNβ and IFNβ target genes as compared to WT cells. Moreover, PGAM5 deficient mouse embryonic fibroblasts (MEFs) exhibited decreased phosphorylation levels of IRF3 and TBK1 when challenged with poly(I:C) intracellularly. Finally, PGAM5 deficient MEFs, upon infection with vesicular stomatitis virus (VSV), revealed diminished IFNβ expression and increased VSV replication. Collectively, our study highlights PGAM5 as an important regulator for IFNβ production mediated via the TBK1/IRF3 signaling pathway in response to viral infection.
Journal Article
Computer simulation of the translocation of nanoparticles with different shapes across a lipid bilayer
Understanding how nanoparticles with different shapes interact with cell membranes is important in drug and gene delivery
1
,
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,
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,
4
, but this interaction remains poorly studied
3
. Using computer simulations, we investigate the physical translocation processes of nanoparticles with different shapes (for example, spheres, ellipsoids, rods, discs and pushpin-like particles) and volumes across a lipid bilayer. We find that the shape anisotropy and initial orientation of the particle are crucial to the nature of the interaction between the particle and lipid bilayer. The penetrating capability of a nanoparticle across a lipid bilayer is determined by the contact area between the particle and lipid bilayer, and the local curvature of the particle at the contact point. Particle volume affects translocation indirectly, and particle rotation can complicate the penetration process. Our results provide a practical guide to geometry considerations when designing nanoscale cargo carriers.
Computer simulations show that the shape and initial orientation of nanoparticles on a lipid bilayer can affect the way they penetrate it, thus offering new insights for the design of nanocarriers for various biological applications.
Journal Article
The Role of Programmed Necrosis in Colorectal Cancer
For quite a long time, necrosis was considered a chaotic and unorganized form of cell death. However, studies conducted during the past few decades unveiled multiple types of programmed necrosis, such as necroptosis, pyroptosis and ferroptosis. These types of programmed necrosis have been shown to play crucial roles in mediating pathological processes, including tumorigenesis. Almost all key mediators, such as RIPK3 and MLKL in necroptosis, GSDMD and caspase 1/11 in pyroptosis and GPX4 in ferroptosis, are highly expressed in intestinal epithelial cells (IECs). An aberrant increase or decrease in programmed necrosis in IECs has been connected to intestinal disorders. Here, we review the pathways of programmed necrosis and the specific consequences of regulated necrosis in colorectal cancer (CRC) development. Translational aspects of programmed necrosis induction as a novel therapeutic alternative against CRC are also discussed.
Journal Article
SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial Cells
The COVID-19 pandemic caused by SARS-CoV-2 has lasted for more than two years. Despite the presence of very effective vaccines, the number of virus variants that escape neutralizing antibodies is growing. Thus, there is still a need for effective antiviral treatments that target virus replication independently of the circulating variant. Here, we show for the first time that deficiency or pharmacological inhibition of the cellular lysine-methyltransferase SMYD2 decreases TMPRSS2 expression on both mRNA and protein levels. SARS-CoV-2 uses TMPRSS2 for priming its spike protein to infect target cells. Treatment of cultured cells with the SMYD2 inhibitors AZ505 or BAY598 significantly inhibited viral replication. In contrast, treatment of Vero E6 cells, which do not express detectable amounts of TMPRSS2, had no effect on SARS-CoV-2 infection. Moreover, by generating a recombinant reporter virus that expresses the spike protein of the Delta variant of SARS-CoV-2, we demonstrate that BAY598 exhibits similar antiviral activity against this variant of concern. In summary, SMYD2 inhibition downregulates TMPRSS2 and blocks viral replication. Targeting cellular SMYD2 represents a promising tool to curtail SARS-CoV-2 infection.
Journal Article
Constraining Palatini–Horndeski theory with gravitational waves after GW170817
In this paper, we investigate the possible parameter space of Palatini–Horndeski theory with gravitational waves in a spatially flat Universe. We develop a general method for obtaining the speed of gravitational waves in the Palatini formalism in the cosmological background and we find that if the theory satisfies the following condition: in any spatially flat cosmological background, the tensor gravitational wave speed is the speed of light
c
, then only
S
=
∫
d
4
x
-
g
[
K
(
ϕ
,
X
)
-
G
3
(
ϕ
,
X
)
□
~
ϕ
+
G
4
(
ϕ
)
R
~
]
is left as the possible action in Palatini–Horndeski theory. We also find that when
G
5
(
ϕ
,
X
)
≠
0
, the tensor part of the connection will propagate and there are two different tensor gravitational wave speeds.
Journal Article
Apoptosis, autophagy, necroptosis, and cancer metastasis
Metastasis is a crucial hallmark of cancer progression, which involves numerous factors including the degradation of the extracellular matrix (ECM), the epithelial-to-mesenchymal transition (EMT), tumor angiogenesis, the development of an inflammatory tumor microenvironment, and defects in programmed cell death. Programmed cell death, such as apoptosis, autophagy, and necroptosis, plays crucial roles in metastatic processes. Malignant tumor cells must overcome these various forms of cell death to metastasize. This review summarizes the recent advances in the understanding of the mechanisms by which key regulators of apoptosis, autophagy, and necroptosis participate in cancer metastasis and discusses the crosstalk between apoptosis, autophagy, and necroptosis involved in the regulation of cancer metastasis.
Journal Article
Classification of gravitational waves in higher-dimensional space-time and possibility of observation
The direct detection of gravitational waves opens the possibility to test general relativity and its alternatives in the strong field regime. Here we focus on the test of the existence of extra dimensions. The classification of gravitational waves in metric gravity theories according to their polarizations in higher-dimensional space-time and the possible observation of these polarizations in three-dimensional subspace are discussed in this work. We also show that the difference in the response of gravitational waves in detectors with and without extra dimensions can serve as evidence for the existence of extra dimensions.
Journal Article