N6-methyladenosine (m6A) is an abundant mRNA modification that affects multiple biological processes, including those involved in the cell stress response and viral infection. YTH domain family 2 ...(YTHDF2) is an m6A-binding protein that affects the localization and stability of targeted mRNA. RNA-binding proteins (RBPs) can regulate the stability of inflammatory gene mRNA transcripts, thus participating in the regulation of inflammatory processes. As an RBP, the role of YTHDF2 in the LPS-induced inflammatory reaction has not been reported. To elucidate the function of YTHDF2 in the inflammatory response of macrophages, we first detected the expression level of YTHDF2 in RAW 264.7 cells, and found that it was upregulated after LPS stimulation. YTHDF2 knockdown significantly increased the LPS-induced IL-6, TNF-α, IL-1β, and IL-12 expression and the phosphorylation of p65, p38, and ERK1/2 in NF-κB and MAPK signaling. Moreover, the upregulated expression of TNF-α and IL-6 in cells with silenced YTHDF2 expression was downregulated by the NF-κB, p38, and ERK inhibitors. YTHDF2 depletion increased the expression and stability of MAP2K4 and MAP4K4 mRNAs. All of these results suggest that YTHDF2 knockdown increases mRNA expression levels of MAP2K4 and MAP4K4 via stabilizing the mRNA transcripts, which activate MAPK and NF-κB signaling pathways, which promote the expression of proinflammatory cytokines and aggravate the inflammatory response in LPS-stimulated RAW 264.7 cells.
Dental pulp inflammation is a widespread public health problem caused by oral bacterial infections and can progress to pulp necrosis and periapical diseases. N6‐methyladenosine (m6A) is a prevalent ...epitranscriptomic modification in mRNA. Previous studies have demonstrated that m6A methylation plays important roles in cell differentiation, embryonic development and stress responses. However, whether m6A modification affects dental pulp inflammation remains unknown. To address this issue, we investigated the expression of m6A and N6‐adenosine methyltransferase (METTL3, METTL14) as well as demethylases (FTO, ALKBH5) and found that the levels of m6A and METTL3 were up‐regulated in human dental pulp cells (HDPCs) stimulated by lipopolysaccharide (LPS). Furthermore, we knocked down METTL3 and demonstrated that METTL3 depletion decreased the expression of inflammatory cytokines and the phosphorylation of IKKα/β, p65 and IκBα in the NF‐κB signalling pathway as well as p38, ERK and JNK in the MAPK signalling pathway in LPS‐induced HDPCs. The RNA sequencing analysis revealed that the vast number of genes affected by METTL3 depletion was associated with the inflammatory response. Previous research has shown that METTL3‐dependent N6‐adenosine methylation plays an important role in mRNA splicing. In this study, we found that METTL3 knockdown facilitated the expression of MyD88S, a splice variant of MyD88 that inhibits inflammatory cytokine production, suggesting that METTL3 might inhibit the LPS‐induced inflammatory response of HDPCs by regulating alternative splicing of MyD88. These data shed light on new findings in epitranscriptomic regulation of the inflammatory response and open new avenues for research into the molecular mechanisms of dental pulp inflammation.
Osteoclast differentiation and function are crucial for maintaining bone homeostasis and preserving skeletal integrity. N6-methyladenosine (m
A) is an abundant mRNA modification that has recently ...been shown to be important in regulating cell lineage differentiation. Nevertheless, the effect of m
A on osteoclast differentiation remains unknown. In the present study, we observed that the m
A level and methyltransferase METTL3 expression increased during osteoclast differentiation.
knockdown resulted in an increased size but a decreased bone-resorbing ability of osteoclasts. The expression of osteoclast-specific genes (
,
,
,
and
) was inhibited by
depletion, while the expression of the cellular fusion-specific gene
was upregulated. Mechanistically,
knockdown elevated the mRNA stability of
and the same result was obtained when the m
A-binding protein YTHDF2 was silenced. Moreover, the phosphorylation levels of key molecules in the MAPK, NF-κB and PI3K-AKT signaling pathways were reduced upon
deficiency. Depletion of
maintained the retention of
mRNA in the nucleus and reduced the protein levels of TRAF6. Taken together, our data suggest that METTL3 regulates osteoclast differentiation and function through different mechanisms involving
mRNA degradation mediated by YTHDF2 and
mRNA nuclear export. These findings elucidate the molecular basis of RNA epigenetic regulation in osteoclast development.
Bone mesenchymal stem cells (BMSCs) can be a useful cell resource for developing biological treatment strategies for bone repair and regeneration, and their therapeutic applications hinge on an ...understanding of their physiological characteristics. N⁶-methyl-adenosine (m⁶A) is the most prevalent internal chemical modification of mRNAs and has recently been reported to play important roles in cell lineage differentiation and development. However, little is known about the role of m⁶A modification in the cell differentiation of BMSCs. To address this issue, we investigated the expression of N⁶-adenosine methyltransferases (Mettl3 and Mettl14) and demethylases (Fto and Alkbh5) and found that Mettl3 was upregulated in BMSCs undergoing osteogenic induction. Furthermore, we knocked down
and demonstrated that
knockdown decreased the expression of bone formation-related genes, such as
and
. The alkaline phosphatase (ALP) activity and the formation of mineralized nodules also decreased after
knockdown. RNA sequencing analysis revealed that a vast number of genes affected by
knockdown were associated with osteogenic differentiation and bone mineralization. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed that the phosphatidylinositol 3-kinase/AKT (PI3K-Akt) signaling pathway appeared to be one of the most enriched pathways, and Western blotting results showed that Akt phosphorylation was significantly reduced after
knockdown. Mettl3 has been reported to play an important role in regulating alternative splicing of mRNA in previous research. In this study, we found that
knockdown not only reduced the expression of
but also decreased the level of its splice variants,
and
, in
-deficient BMSCs. These findings might contribute to novel progress in understanding the role of epitranscriptomic regulation in the osteogenic differentiation of BMSCs and provide a promising perspective for new therapeutic strategies for bone regeneration.
White teas are produced in the simple process of withering and drying the tender leaves of the plant
Camellia sinensis.
Tea aroma created in this way exhibits a unique profile. Studies were carried ...out on the molecular contributors to the aroma character of the four well-known traditional white teas: Baihaoyingzhen (BHYZ), Baimudan (BMD), Gongmei (GM), and Shoumei (SM). Volatiles of the tea infusions were enriched by solvent partitioning followed by solid-phase extraction (SPE). The highly volatile compounds were captured by headspace solid-phase microextraction (HS SPME). Gas chromatography–olfactometry (GC-O) experiments discovered 37 odor-active components. Quantitation of aroma compounds was achieved using the method of standard addition (SAM). Calculation of odor activity value (OAV) and aroma reconstitution experiments revealed that the aroma profiles of the four white teas were attributed by 15 compounds, although a total of 179 volatile components were found in the extracts. BHYZ had distinct floral, fruity, and sweet characters, while BMD, GM, and SM had stronger woody and fermented notes. The major aroma contributors to the floral and sweet characters were geraniol and linalool for BHYZ and BMD; 2-phenylethanol and phenylacetaldehyde for GM and SM. The compounds produced from amino acid reactions during tea manufacturing, e.g. dimethyl sulfide, 3-methylbutanal, phenylacetaldehyde, etc., formed the basis of fruity and refreshing attributes. Degradation products of glycosides and carotenoids, such as geraniol, linalool, and ionones, contributed to the essential floral and sweet characters of the white teas.
Recent studies have revealed robust metabolic changes during cell differentiation. Mitochondria, the organelles where many vital metabolic reactions occur, may play an important role. Here, we report ...the involvement of SIRT3-regulated mitochondrial stress in osteoblast differentiation and bone formation. In both the osteoblast cell line MC3T3-E1 and primary calvarial osteoblasts, robust mitochondrial biogenesis and supercomplex formation were observed during differentiation, accompanied by increased ATP production and decreased mitochondrial stress. Inhibition of mitochondrial activity or an increase in mitochondrial superoxide production significantly suppressed osteoblast differentiation. During differentiation, SOD2 was specifically induced to eliminate excess mitochondrial superoxide and protein oxidation, whereas SIRT3 expression was increased to enhance SOD2 activity through deacetylation of K68. Both SOD2 and SIRT3 knockdown resulted in suppression of differentiation. Meanwhile, mice deficient in SIRT3 exhibited obvious osteopenia accompanied by osteoblast dysfunction, whereas overexpression of SOD2 or SIRT3 improved the differentiation capability of primary osteoblasts derived from SIRT3-deficient mice. These results suggest that SIRT3/SOD2 is required for regulating mitochondrial stress and plays a vital role in osteoblast differentiation and bone formation.
Paraprofessionals have increasingly served as a support service for students with disabilities. Yet, scholars have urged caution in the overuse of assigning paraprofessional supports. Furthermore, it ...is unclear how states provide guidance to local stakeholders in determining the best use of paraprofessionals. Thus, in this study, we conducted a state-by-state analysis of documents depicting guidance for paraprofessional supports. We identified states that offered comprehensive frameworks to support practitioners while allowing teams to maintain the autonomy to make decisions on a case-by-case basis. However, we also found that few states offered guidance, particularly with regard to navigating tensions between student need and potential risks. We rely on a Disability Studies framework to discuss implications for policy, practice, and future research, particularly in how states might provide robust guidance that assists schools in building an accommodating and inclusive environment rather than focusing solely on student characteristics framed as deficits.
The traditional recognition of mitochondria as powerhouses that generate ATP and reactive oxygen species (ROS) via oxidative phosphorylation and the tricarboxylic acid cycle has ceased ...
Gliomas are the most common primary malignant tumor of the central nervous system. At the present time, radiotherapy (RT) is the cornerstone of therapeutic approaches, but the worldwide research ...trends in RT for gliomas in the world are unclear. This bibliometric analysis aimed to investigate trends in glioma RT research since 2011.
The Web of Science database was searched, and SigmaPlot 14.0 and VOSviewer software were used to analyze and visualize the trends.
Bibliometric analysis of 5106 articles was conducted. While the number of publications per year was relatively steady, the number of citations grew exponentially from 356 in 2011 to 21,051 in 2020. Articles originated from 89 countries, with the majority from the United States. Journal of Neuro-Oncology and Texas A&M University were the journal and institution, respectively, with the highest number of publications. The articles mainly involved oncology, neurology, radiology, and surgery.
This bibliometric analysis found an increased focus on glioblastoma, survival, and chemotherapy in glioma RT research.
Abstract
Succinate dehydrogenase, which is known as mitochondrial complex II, has proven to be a fascinating machinery, attracting renewed and increased interest in its involvement in human diseases. ...Herein, we find that succinate dehydrogenase assembly factor 4 (SDHAF4) is downregulated in cardiac muscle in response to pathological stresses and in diseased hearts from human patients. Cardiac loss of
Sdhaf4
suppresses complex II assembly and results in subunit degradation and complex II deficiency in fetal mice. These defects are exacerbated in young adults with globally impaired metabolic capacity and activation of dynamin-related protein 1, which induces excess mitochondrial fission and mitophagy, thereby causing progressive dilated cardiomyopathy and lethal heart failure in animals. Targeting mitochondria via supplementation with fumarate or inhibiting mitochondrial fission improves mitochondrial dynamics, partially restores cardiac function and prolongs the lifespan of mutant mice. Moreover, the addition of fumarate is found to dramatically improve cardiac function in myocardial infarction mice. These findings reveal a vital role for complex II assembly in the development of dilated cardiomyopathy and provide additional insights into therapeutic interventions for heart diseases.
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