RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy.

Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding of pathophysiology, and inspiring development of therapeutics. As a crucial component of epigenetics at post-transcription level, RNA modification significantly determines RNA fates, further affecting various biological processes and cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts. In this review, we characterize the distribution features, modifying mechanisms and biological functions of 8 RNA modifications, including N6-methyladenosine (m6A), N6,2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively the most studied types. Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described, categorized as glucose, lipid, amino acid, and mitochondrial metabolism. And we highlight the regulation of RNA modifications on immunometabolism, further influencing immune responses. Above all, we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy, progression of RNA modification-targeted agents, and its potential in RNA-targeted therapeutics. Eventually, we give legitimate perspectives for future researches in this field from methodological requirements, mechanistic insights, to therapeutic applications.

METTL16-mediated N6-methyladenosine modification of Soga1 enables proper chromosome segregation and chromosomal stability in colorectal cancer.

N6-methyladenosine (m6A) is the most prevalent internal modification in mammalian messenger RNAs and is associated with numerous biological processes. However, its role in chromosomal instability remains to be established. Here, we report that an RNA m6A methyltransferase, METTL16, plays an indispensable role in the progression of chromosome segregation and is required to preserve chromosome stability in colorectal cancer (CRC) cells. Depletion or inhibition of the methyltransferase activity of METTL16 results in abnormal kinetochore-microtubule attachment during mitosis, leading to delayed mitosis, lagging chromosomes, chromosome mis-segregation and chromosomal instability. Mechanistically, METTL16 exerts its oncogenic effects by enhancing the expression of suppressor of glucose by autophagy 1 (Soga1) in an m6A-dependent manner. CDK1 phosphorylates Soga1, thereby triggering its direct interaction with the polo box domain of PLK1. This interaction facilitates PLK1 activation and promotes mitotic progression. Therefore, targeting the METTL16-Soga1 pathway may provide a potential treatment strategy against CRC because of its essential role in maintaining chromosomal stability.

Identification and Detection of Intracellular Reactive Sulfur Species Using a Reaction-Mediated Dual-Recognition Strategy.

Reactive sulfur species (RSS) are emerging as a potential key gasotransmitter in diverse physiological processes linking two signaling molecules H2S and SO2. However, the exact roles of H2S and SO2 remain unclear. A major hurdle is the shortage of accurate and robust approaches for sensing of H2S and SO2 in biological systems. Herein, we report a reaction-mediated dual-recognition strategy-based nanosensor, silver nanoparticles (AgNPs)-loaded MIL-101 (Fe) (ALM) hybrids, for the simultaneous detection of H2S and SO2 in a living cell. Upon exposure to H2S, AgNPs can be oxidized to form Ag2S, causing a decrease of surface enhanced Raman spectroscopy (SERS) signals of p,p'-dimercaptoazobenzene. Moreover, SO2 reacts with the amino moiety of MIL-101 to form charge-transfer complexes, resulting in an increment of fluorescent (FL) intensity. The ALM with dual-modal signals can simultaneously analyze H2S and SO2 at a concentration as low as 2.8 × 10-6 and 0.003 µM, respectively. Most importantly, the ALM sensing platform enables targeting mitochondria and detection multiple RSS simultaneously in living cells under external stimulation, as well as displays indiscernible crosstalk between SERS and FL signals, which is very beneficial for the comprehension of physiological issues related with RSS.

Colorimetric/fluorescent/Raman trimodal sensing of zinc ions with complexation-mediated Au nanorod.

Accurate and selective in-field detection of metal ions in complex media has gained wide interests due to the complexed matrices and weak affinity towards sensing surface. Herein, we develop a first trimodal method for sensing of Zn2+ in complex matrices by stimuli-responsive N-[6-piperazinyl-2-pyridinyl]-N-(2-pyridinylmethyl)-2-Pyridinemethanamine dithiocarbamates (DPY) modified gold nanorods (GNRs-DPY). The presence of Zn2+ triggers the aggregation of GNRs-DPY, leading to increment of color and fluorescence intensity of the sensing system, which could be visually discerned with bare eye. Moreover, the intensive electromagnetic enhancement among "hot spots" of GNRs, generated during self-aggregation of the GNRs-DPY caused by Zn2+, lowers the detection limit of SERS assay to 6 × 10-3 pM. It is noteworthy that GNRs-DPY based sensing platform not only enables distinguishing Zn2+ from Cd2+, with simplicity and rapidity, but also demonstrates as trimodal nanoprobe for sensitive and selective quantitative determination of Zn2+ in different matrices. Therefore, the GNRs-DPY provides a new strategy for accurate and credible on-spot determination of Zn2+ in complicated specimens, as well as offering multiple applications in point-of-care monitoring.

Utilizing Ag-Au core-satellite structures for colorimetric and surface-enhanced Raman scattering dual-sensing of Cu (II).

This study develops a dual-channel colorimetric and surface-enhanced Raman scattering (SERS) strategy for detection of Cu2+ utilizing Ag-Au core-satellite nanostructures. 4-mercaptobenzoic acid (MBA) modified Ag nanoparticles (AgNPs@MBA) and 4-mercaptopyridine (Mpy) capped AuNPs (GNPs@Mpy) are first designed via metal-sulfur bonds, respectively. Benefiting from the Cu2+-triggered NPs self-aggregation, the dispersion of AgNPs-GNPs (AgNPs@MBA + GNPs@Mpy) is turned into AgNPs-Cu2+-GNPs core-satellite structures. Because of the presence of pyridyl nitrogen and carboxy group which have specific coordination ability towards Cu2+, induces a certain aggregation of NPs. As well it can be obviously discerned by the visual assay and easily captured by SERS analysis. The UV-Vis method exhibits good linearity in the ranging from 0.1 µM-200 µM for Cu2+, while SERS method displays good linear response from 1 pM to 100 µM. The detection limit of Cu2+ is 0.032 µM by colorimetry and 0.6 pM by SERS method, which is significantly lower than the acceptable limit of Cu2+ in drinking water (20 µM) set by the US EPA. Furthermore, colorimetric and SERS assay based on AgNPs-Cu2+-GNPs core-satellite structures is used to determine Cu2+ in various waters and soils, and the detection results are consistent with the traditional atomic analysis methods. This work offers a new method for detecting Cu2+ in environmental samples, and the plasmonic nanostructure provides new entry point for development of multiplexed sensing platform for in-field application.

An Integrated Method for Coding Trees, Measuring Tree Diameter, and Estimating Tree Positions.

Accurately measuring tree diameter at breast height (DBH) and estimating tree positions in a sample plot are important in tree mensuration. The main aims of this paper include (1) developing a new, integrated device that can identify trees using the quick response (QR) code technique to record tree identifications, measure DBH, and estimate tree positions concurrently; (2) designing an innovative algorithm to measure DBH using only two angle sensors, which is simple and can reduce the impact of eccentric stems on DBH measures; and (3) designing an algorithm to estimate the position of the tree by combining ultra-wide band (UWB) technology and altitude sensors, which is based on the received signal strength indication (RSSI) algorithm and quadrilateral localization algorithm. This novel device was applied to measure ten 10 × 10 m square plots of diversified environments and various tree species to test its accuracy. Before measuring a plot, a coded sticker was fixed at a height of 1.3 m on each individual tree stem, and four UWB module anchors were set up at the four corners of the plot. All individual trees' DBHs and positions within the plot were then measured. Tree DBH, measured using a tree caliper, and the values of tree positions, measured using tape, angle ruler, and inclinometer, were used as the respective reference values for comparison. Across the plots, the decode rate of QR codes was 100%, with an average response time less than two seconds. The DBH values had a bias of 1.89 mm (1.88% in relative terms) and a root mean square error (RMSE) of 5.38 mm (4.53% in relative terms). The tree positions were accurately estimated; the biases on the x-axis and the y-axis of the tree position were -8.55-14.88 cm and -12.07-24.49 cm, respectively, and the corresponding RMSEs were 12.94-33.96 cm and 17.78-28.43 cm. The average error between the estimated and reference distances was 30.06 cm, with a standard deviation of 13.53 cm. The device is cheap and friendly to use in addition to its high accuracy. Although further studies are needed, our method provides a great alternative to conventional tools for improving the efficiency and accuracy of tree mensuration.