Global research trends and prospects of cellular metabolism in colorectal cancer

BACKGROUND An increasing number of studies have focused on the role of cellular metabolism in the development of colorectal cancer(CRC).However,no work is currently available to synthesize the field through bibliometrics.AIM To analyze the development in the field of“glucose metabolism”(GM),“amino acid metabolism”(AM),“lipid metabolism”(LM),and“nucleotide metabolism”(NM)in CRC by visualization.METHODS Articles within the abovementioned areas of GM,AM,LM and NM in CRC,which were published from January 1,1991,to December 31,2022,are retrieved from the Web of Science Core Collection and analyzed by CiteSpace 6.2.R4 and VOSviewer 1.6.19.RESULTS The field of LM in CRC presented the largest number of annual publications and the fastest increase in the last decade compared with the other three fields.Meanwhile,China and the United States were two of the most prominent contri-butors in these four areas.In addition,Gang Wang,Wei Jia,Maria Notar-nicola,and Cornelia Ulrich ranked first in publication numbers,while Jing-Yuan Fang,Senji Hirasawa,Wei Jia,and Charles Fuchs were the most cited authors on average in these four fields,respectively.“Gut microbiota”and“epithelial-mesenchymal transition”emerged as the newest burst words in GM,“gut microbiota”was the latest outburst word in AM,“metastasis”,“tumor microenvironment”,“fatty acid metabolism”,and“metabolic reprogramming”were the up-to-date outbreaking words in LM,while“epithelial-mesenchymal transition”and“apoptosis”were the most recently occurring words in NM.CONCLUSION Research in“cellular metabolism in CRC”is all the rage at the moment,and researchers are particularly interested in exploring the mechanism to explain the metabolic alterations in CRC.Targeting metabolic vulnerability appears to be a promising direction in CRC therapy.

Cellular metabolism: A key player in cancer ferroptosis

Cellular metabolism is the fundamental process by which cells maintain growth and self-renewal.It produces energy,furnishes raw materials,and intermedi-ates for biomolecule synthesis,and modulates enzyme activity to sustain normal cellular functions.Cellular metabolism is the foundation of cellular life processes and plays a regulatory role in various biological functions,including pro-grammed cell death.Ferroptosis is a recently discovered form of iron-dependent programmed cell death.The inhibition of ferroptosis plays a crucial role in tumorigenesis and tumor progression.However,the role of cellular metabolism,particularly glucose and amino acid metabolism,in cancer ferroptosis is not well understood.Here,we reviewed glucose,lipid,amino acid,iron and sele-nium metabolism involvement in cancer cell ferroptosis to elucidate the impact of different metabolic pathways on this process.Additionally,we provided a detailed overview of agents used to induce cancer ferroptosis.We explained that the metabolism of tumor cells plays a crucial role in maintaining intracellu-lar redox homeostasis and that disrupting the normal metabolic processes in these cells renders them more susceptible to iron-induced cell death,resulting in enhanced tumor cell killing.The combination of ferroptosis inducers and cel-lular metabolism inhibitors may be a novel approach to future cancer therapy and an important strategy to advance the development of treatments.

Redox and metabolic regulation of epigenetic modifications:an emerging toxic action mechanism

Epigenetic modifications modulate conformational structure of chromatin and consequently gene expression by enzyme-mediated chemical modifications of DNA and histones.The activities of epigenetic modifying enzymes depend on many co-substrates and cofactors,such as 2-oxoglutarate(2-OG),iron,S-adenosylmethionine(SAM),nicotinamide adenine dinucleotide(NAD+),flavin adenine dinucleotide(FAD),and acetyl-CoA.These factors are inter-connecting molecules that integrate cellular nutrient metabolism and redox homeostasis,two key regulators of cell proliferation,cell survival,and cell functions.Dysregulation of such delicate regulatory network has been implicated in many pathological conditions and also been increasingly recognized as an emerging mechanism responsible for environmental pollutant-induced adverse effects.In this review,we first summarize DNA and histone modifying enzymes and their essential factors,then discuss the metabolic sources and the redox regulatory roles of these enzymatic factors,and finally elaborate the mechanisms of how targeting such factors by environmental pollutants influences epigenetic regulation and perturbs cellular functions.

Development of cell metabolite analysis on microfluidic platform

Cell metabolite analysis is of great interest to analytical chemists and physiologists, with some metabolites having been identified as important indicators of major diseases such as cancer. A highthroughput and sensitive method for drug metabolite analysis will largely promote the drug discovery industry. The basic barrier of metabolite analysis comes from the interference of complex components in cell biological system and low abundance of target substances. As a powerful tool in biosample analysis, microfluidic chip enhances the sensitivity and throughput by integrating multiple functional units into one chip. In this review, we discussed three critical steps of establishing functional microfluidic platform for cellular metabolism study. Cell in vitro culture model, on chip sample pretreatment, and microchip combined detectors were described in details and demonstrated by works in five years. And a brief summary was given to discuss the advantages as well as challenges of applying microchip method in cell metabolite and biosample analysis.

GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal squamous cell carcinoma

Treating patients with esophageal squamous cell carcinoma(ESCC)is challenging due to the high chemoresistance.Growth differentiation factor 15(GDF15)is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research.In this study,the link between GDF15 and chemotherapy resistance in ESCC was further explored.The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies.ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response.GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2.Through an in vivo study,we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin.Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A.AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A,indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin.The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy,resulting in beneficial therapeutic outcomes.

α-ketoglutarate promotes the specialization of primordial germ cell-like cells through regulating epigenetic reprogramming

There is growing evidence that cellular metabolism can directly participate in epigenetic dynamics and consequently modulate gene expression.However,the role of metabolites in activating the key gene regulatory network for specialization of germ cell lineage remains largely unknown.Here,we identified some cellular metabolites with significant changes by untargeted metabolomics between mouse epiblast-like cells(EpiLCs)and primordial germ cell-like cells(PGCLCs).More importantly,we found that inhibition of glutaminolysis by bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide(BPTES)impeded PGCLC specialization,but the impediment could be rescued by addition ofα-ketoglutarate(αKG),the intermediate metabolite of oxidative phosphorylation and glutaminolysis.Moreover,adding aKG alone to the PGCLC medium accelerated the PGCLC specialization through promoting H3 K27 me3 demethylation.Thus,our study reveals the importance of metabolite aKG in the germ cell fate determination and highlights the essential role of cellular metabolism in shaping the cell identities through epigenetic events.

PROBING THE IMPACT OF GAMMA-IRRADIATION ON THE METABOLIC STATE OF NEURAL STEM AND PRECURSOR CELLS USING DUAL-WAVELENGTH INTRINSIC SIGNAL TWO-PHOTON EXCITED FLUORESCENCE

Two-photon excitedfluorescence(TPEF)spectroscopy and imaging were used to investigate the effects of gamma-irradiation on neural stem and precursor cells(NSPCs).While the observed signal from reduced nicotinamide adenine dinucleotide(NADH)was localized to the mitochondria,the signal typically associated with oxidizedflavoproteins(Fp)was distributed diffusely throughout the cell.The measured TPEF emission and excitation spectra were similar to the established spectra of NAD(P)H and Fp.Fpfluorescence intensity was markedly increased by addition of the electron transport chain(ETC)modulator menadione to the medium,along with a concomitant decrease in the NAD(P)H signal.Three-dimensional(3D)neurospheres were imaged to obtain the cellular metabolic index(CMI),calculated as the ratio of Fp to NAD(P)Hfluorescence intensity.Radiation effects were found to differ between low-dose(
50 cGy)and high-dose(50 cGy)exposures.Low-dose irradiation caused a marked drop in CMI values accompanied by increased cellular proliferation.At higher doses,both NAD(P)H and Fp signals increased,leading to an overall elevation in CMI values.Thesefindings underscore the complex relationship between radiation dose,metabolic state,and proliferation status in NSPCs and highlight the ability of TPEF spectroscopy and imaging to characterize metabolism in 3D spheroids.

Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection

The coronavirus disease 2019(COVID-19)pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is spread primary via respiratory droplets and infects the lungs.Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines(transformed or cancer cells)and species differences between animals and humans.Organoids are stem cell-derived selforganized three-dimensional culture in vitro and model the physiological conditions of natural organs.Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells(hESCs)-derived lung organoids,including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs.The infected ceils were ciliated,club,and alveolar type 2(AT2)cells,which were sequentially located from the proximal to the distal airway and terminal alveoli,respectively.Additionally,RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes,especially lipid metabolism,in addition to the well-known upregulation of immune response.Further,Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids.Therefore,human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.

Hydrogel platform with tunable stiffness based on magnetic nanoparticles cross-linked GelMA for cartilage regeneration and its intrinsic biomechanism

Cartilage injury affects numerous individuals,but the efficient repair of damaged cartilage is still a problem in clinic.Hydrogel is a potent scaffold candidate for tissue regeneration,but it remains a big challenge to improve its mechanical property and figure out the interaction of chondrocytes and stiffness.Herein,a novel hybrid hydrogel with tunable stiffness was fabricated based on methacrylated gelatin(GelMA)and iron oxide nanoparticles(Fe_(2)O_(3))through chemical bonding.The stiffness of Fe_(2)O_(3)/GelMA hybrid hydrogel was controlled by adjusting the concentration of magnetic nanoparticles.The hydrogel platform with tunable stiffness modulated its cellular properties including cell morphology,microfilaments and Young’s modulus of chondrocytes.Interestingly,Fe_(2)O_(3)/GelMA hybrid hydrogel promoted oxidative phosphorylation of mitochondria and facilitated catabolism of lipids in chondrocytes.As a result,more ATP and metabolic materials generated for cellular physiological activities and organelle component replacements in hybrid hydrogel group compared to pure GelMA hydrogel.Furthermore,implantation of Fe_(2)O_(3)/GelMA hybrid hydrogel in the cartilage defect rat model verified its remodeling potential.This study provides a deep understanding of the bio-mechanism of Fe_(2)O_(3)/GelMA hybrid hydrogel interaction with chondrocytes and indicates the hydrogel platform for further application in tissue engineering.