Front Immunol. 2023 Sep 20;14:1212981. doi: 10.3389/fimmu.2023.1212981. eCollection 2023.

ABSTRACT

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory systemic disease with skin manifestations characterized by erythematous, scaly, itchy and/or painful plaques resulting from hyperproliferation of keratinocytes. Certolizumab pegol [CZP], a PEGylated antigen binding fragment of a humanized monoclonal antibody against TNF-alpha, is approved for the treatment of moderate-to-severe plaque psoriasis. Patients with psoriasis present clinical and molecular variability, affecting response to treatment. Herein, we utilized an in silico approach to model the effects of CZP in a virtual population (vPop) with moderate-to-severe psoriasis. Our proof-of-concept study aims to assess the performance of our model in generating a vPop and defining CZP response variability based on patient profiles.

METHODS: We built a quantitative systems pharmacology (QSP) model of a clinical trial-like vPop with moderate-to-severe psoriasis treated with two dosing schemes of CZP (200 mg and 400 mg, both every two weeks for 16 weeks, starting with a loading dose of CZP 400 mg at weeks 0, 2, and 4). We applied different modelling approaches: (i) an algorithm to generate vPop according to reference population values and comorbidity frequencies in real-world populations; (ii) physiologically based pharmacokinetic (PBPK) models of CZP dosing schemes in each virtual patient; and (iii) systems biology-based models of the mechanism of action (MoA) of the drug.

RESULTS: The combination of our different modelling approaches yielded a vPop distribution and a PBPK model that aligned with existing literature. Our systems biology and QSP models reproduced known biological and clinical activity, presenting outcomes correlating with clinical efficacy measures. We identified distinct clusters of virtual patients based on their psoriasis-related protein predicted activity when treated with CZP, which could help unravel differences in drug efficacy in diverse subpopulations. Moreover, our models revealed clusters of MoA solutions irrespective of the dosing regimen employed.

CONCLUSION: Our study provided patient specific QSP models that reproduced clinical and molecular efficacy features, supporting the use of computational methods as modelling strategy to explore drug response variability. This might shed light on the differences in drug efficacy in diverse subpopulations, especially useful in complex diseases such as psoriasis, through the generation of mechanistically based hypotheses.

PMID:37809085 | PMC:PMC10552644 | DOI:10.3389/fimmu.2023.1212981

Front Immunol. 2023 Sep 22;14:1244431. doi: 10.3389/fimmu.2023.1244431. eCollection 2023.

ABSTRACT

Although macrophages are known to be affected by their redox status, oxidation is not yet a well-recognized post-translational modification (PTM) in regulating macrophages and immune cells in general. While it has been described that the redox status of single cysteines in specific proteins is relevant for macrophage functions, global oxidation information is scarce. Hence, we globally assessed the impact of oxidation on macrophage activation using untargeted proteomics and PTM-omics. We exposed THP-1 macrophages to lipopolysaccharide (LPS) for 4 h and 24 h and applied a sequential iodoTMT labeling approach to get information on overall oxidation as well as reversible oxidation of cysteines. Thus, we identified 10452 oxidation sites, which were integratively analyzed with 5057 proteins and 7148 phosphorylation sites to investigate their co-occurance with other omics layers. Based on this integrative analysis, we found significant upregulation of several immune-related pathways, e.g. toll-like receptor 4 (TLR4) signaling, for which 19 proteins, 7 phosphorylation sites, and 39 oxidation sites were significantly affected, highlighting the relevance of oxidations in TLR4-induced macrophage activation. Co-regulation of oxidation and phosphorylation was observed, as evidenced by multiply modified proteins related to inflammatory pathways. Additionally, we observed time-dependent effects, with differences in the dynamics of oxidation sites compared to proteins and phosphorylation sites. Overall, this study highlights the importance of oxidation in regulating inflammatory processes and provides a method that can be readily applied to study the cellular redoxome globally.

PMID:37809076 | PMC:PMC10559879 | DOI:10.3389/fimmu.2023.1244431

Front Immunol. 2023 Sep 22;14:1252765. doi: 10.3389/fimmu.2023.1252765. eCollection 2023.

ABSTRACT

BACKGROUND: Bruton's tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the BTK gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. Methods: Patients suspected with X-linked agammaglobulinemia were enrolled during the period of 2010-2018. Clinical summary, and immunological profiles of these patients were recorded. Peripheral blood samples were collected for monocyte BTK protein expression detection and BTK genetic analysis. The medical records between January 2020 and June 2023 were reviewed to investigate COVID-19 in XLA.

RESULTS: Twenty-two patients (from 16 unrelated families) were molecularly diagnosed as XLA. Genetic testing revealed fifteen distinct mutations, including four splicing mutations, four missense mutations, three nonsense mutations, three short deletions, and one large indel mutation. These mutations scattered throughout the BTK gene and mostly affected the kinase domain. All mutations including five novel mutations were predicted to be pathogenic or deleterious by in silico prediction tools. Genetic testing confirmed that eleven mothers and seven sisters were carriers for the disease, while three mutations were de novo. Flow cytometric analysis showed that thirteen patients had minimal BTK expression (0-15%) while eight patients had reduced BTK expression (16-64%). One patient was not tested for monocyte BTK expression due to insufficient sample. Pneumonia (n=13) was the most common manifestation, while Pseudomonas aeruginosa was the most frequently isolated pathogen from the patients (n=4). Mild or asymptomatic COVID-19 was reported in four patients.

CONCLUSION: This report provides the first overview of demographic, clinical, immunological and genetic data of XLA in Malaysia. The combination of flow cytometric assessment and BTK genetic analysis provides a definitive diagnosis for XLA patients, especially with atypical clinical presentation. In addition, it may also allow carrier detection and assist in genetic counselling and prenatal diagnosis.

PMID:37809070 | PMC:PMC10560089 | DOI:10.3389/fimmu.2023.1252765

Front Microbiol. 2023 Sep 22;14:1284540. doi: 10.3389/fmicb.2023.1284540. eCollection 2023.

NO ABSTRACT

PMID:37808289 | PMC:PMC10556730 | DOI:10.3389/fmicb.2023.1284540

Mol Cell Biol. 2023 Oct 8:1-16. doi: 10.1080/10985549.2023.2253131. Online ahead of print.

ABSTRACT

During the inflammatory response, macrophage phenotypes can be broadly classified as pro-inflammatory/classically activated "M1", or pro-resolving/alternatively "M2" macrophages. Although the classification of macrophages is general and assumes there are distinct phenotypes, in reality macrophages exist across a spectrum and must transform from a pro-inflammatory state to a proresolving state following an inflammatory insult. To adapt to changing metabolic needs of the cell, mitochondria undergo fusion and fission, which have important implications for cell fate and function. We hypothesized that mitochondrial fission and fusion directly contribute to macrophage function during the pro-inflammatory and proresolving phases. In the present study, we find that mitochondrial length directly contributes to macrophage phenotype, primarily during the transition from a pro-inflammatory to a proresolving state. Phenocopying the elongated mitochondrial network (by disabling the fission machinery using siRNA) leads to a baseline reduction in the inflammatory marker IL-1β, but a normal inflammatory response to LPS, similar to control macrophages. In contrast, in macrophages with a phenocopied fragmented phenotype (by disabling the fusion machinery using siRNA) there is a heightened inflammatory response to LPS and increased signaling through the ATF4/c-Jun transcriptional axis compared to control macrophages. Importantly, macrophages with a fragmented mitochondrial phenotype show increased expression of proresolving mediator arginase 1 and increased phagocytic capacity. Promoting mitochondrial fragmentation caused an increase in cellular lactate, and an increase in histone lactylation which caused an increase in arginase 1 expression. These studies demonstrate that a fragmented mitochondrial phenotype is critical for the proresolving response in macrophages and specifically drive epigenetic changes via lactylation of histones following an inflammatory insult.

PMID:37807652 | DOI:10.1080/10985549.2023.2253131

Brain Behav Immun. 2023 Oct 6:S0889-1591(23)00285-4. doi: 10.1016/j.bbi.2023.09.022. Online ahead of print.

ABSTRACT

Microbiome science has been one of the most exciting and rapidly evolving research fields in the past two decades. Breakthroughs in technologies including DNA sequencing have meant that the trillions of microbes (particularly bacteria) inhabiting human biological niches (particularly the gut) can be profiled and analysed in exquisite detail. This microbiome profiling has profound impacts across many fields of research, especially biomedical science, with implications for how we understand and ultimately treat a wide range of human disorders. However, like many great scientific frontiers in human history, the pioneering nature of microbiome research comes with a multitude of challenges and potential pitfalls. These include the reproducibility and robustness of microbiome science, especially in its applications to human health outcomes. In this article, we address the enormous promise of microbiome science and its many challenges, proposing constructive solutions to enhance the reproducibility and robustness of research in this nascent field. The optimisation of microbiome science spans research design, implementation and analysis, and we discuss specific aspects such as the importance of ecological principals and functionality, challenges with microbiome-modulating therapies and the consideration of confounding, alternative options for microbiome sequencing, and the potential of machine learning and computational science to advance the field. The power of microbiome science promises to revolutionise our understanding of many diseases and provide new approaches to prevention, early diagnosis, and treatment.

PMID:37806533 | DOI:10.1016/j.bbi.2023.09.022

Int Immunopharmacol. 2023 Oct 6;124(Pt B):110987. doi: 10.1016/j.intimp.2023.110987. Online ahead of print.

ABSTRACT

OBJECTIVE: To develop a new scoring system based on platelet-to-lymphocyte ratio (PLR) and CA199 to predict the prognosis of gastric cancer.

METHODS: PLR-CA199 was identified in a retrospective study that was conducted in a training cohort of 990 gastric cancer patients who underwent curable resection from 2012 to 2014 and validated in a validation cohort of 625 patients between 2015 and 2016.

RESULTS: In the training cohort, PLR-CA199 was related to gender (P = 0.041), age (P = 0.014), tumor location (P = 0.015), tumor size (P < 0.001), Bormann type (P < 0.001), vascular invasion (P < 0.001), perineural invasion (P < 0.001), and TNM staging (P < 0.001). In the validation cohort, PLR-CA199 was related to tumor size (P < 0.001), Bormann type (P = 0.007), vascular invasion (P < 0.001), perineural invasion (P < 0.001), and TNM staging (P < 0.001). Survival analysis showed that in the training cohort the mean disease-free survival (DFS) was 70.699 months for patients PLR-CA199 = 0, 51.223 months for patients PLR-CA199 = 1, and 32.152 months for patients PLR-CA199 = 2 (P < 0.001). The correlation between PLR-CA199 and DFS was further confirmed in the validation cohort (50.640 vs. 41.842 vs. 22.382, P < 0.001). Survival analysis showed that the mean disease special survival (DSS) was 76.668 months for patients PLR-CA199 = 0, 61.218 months for patients PLR-CA199 = 1, and 44.665 months for patients PLR-CA199 = 2 in the training cohort (P < 0.001). The correlation between PLR-CA199 and DSS was further confirmed in the validation cohort (53.858 vs. 46.385 vs. 44.665, P < 0.001). Furthermore, univariate and multivariate analyses showed that PLR-CA199 was an independent prognostic factor for DFS and DSS.

CONCLUSIONS: Preoperative PLR-CA199 may be a useful prognostic indicator, and is a promising tool for predicting the prognosis for gastric cancer.

PMID:37806105 | DOI:10.1016/j.intimp.2023.110987

Biomed Pharmacother. 2023 Oct 6;168:115142. doi: 10.1016/j.biopha.2023.115142. Online ahead of print.

ABSTRACT

Regulatory T cells are a subgroup of T cells with immunomodulatory functions. Different from most cytotoxic T cells and helper T cells, they play a supporting role in the immune system. What's more, regulatory T cells often play an immunosuppressive role, which mainly plays a role in maintaining the stability of the immune system and regulating the immune response in the body. However, recent studies have shown that not only playing a role in autoimmune diseases, organ transplantation, and other aspects, regulatory T cells can also play a role in the immune escape of tumors in the body, through various mechanisms to help tumor cells escape from the demic immune system, weakening the anti-cancer effect in the body. For a better understanding of the role that regulatory T cells can play in cancer, and to be able to use regulatory T cells for tumor immunotherapy more quickly. This review focuses on the research progress of various mechanisms of regulatory T cells in the tumor environment, the related research of tumor cells acting on regulatory T cells, and the existing various therapeutic methods acting on regulatory T cells.

PMID:37806087 | DOI:10.1016/j.biopha.2023.115142

Curr Opin Biotechnol. 2023 Oct 6;84:102996. doi: 10.1016/j.copbio.2023.102996. Online ahead of print.

ABSTRACT

The tumor microenvironment (TME) consists of a network of metabolically interconnected tumor and immune cell types. Macrophages influence the metabolic composition within the TME, which directly impacts the metabolic state and drug response of tumors. The accumulation of oncometabolites, such as succinate, fumarate, and 2-hydroxyglutarate, represents metabolic vulnerabilities in cancer that can be targeted therapeutically. Immunometabolites are emerging as metabolic regulators of the TME impacting immune cell functions and cancer cell growth. Here, we discuss recent discoveries on the potential impact of itaconate on the TME. We highlight how itaconate influences metabolic pathways relevant to immune responses and cancer cell proliferation. We also consider the therapeutic implications of manipulating itaconate metabolism as an immunotherapeutic strategy to constrain tumor growth.

PMID:37806082 | DOI:10.1016/j.copbio.2023.102996

Trends Parasitol. 2023 Oct 6:S1471-4922(23)00230-1. doi: 10.1016/j.pt.2023.09.009. Online ahead of print.

ABSTRACT

Recent studies have proposed that Trichomonas vaginalis, the causative agent of trichomoniasis [the most common nonviral sexually transmitted infection (STI) in humans] can establish persistent infections in the vagina. T. vaginalis infections are often asymptomatic but can have adverse consequences such as increased risk of HIV-1 infection and cervical cancer. Despite this, it remains an understudied infection. A potential agent of persistent infections is the 'pseudocyst', a spherical form of T. vaginalis identified by several laboratories and linked to persistence in related species such as the avian parasite Trichomonas gallinae and cattle parasite Tritrichomonas foetus. Additional robust and reproducible research on pseudocysts and persistent T. vaginalis infections is required, which may ultimately shed light on how to better diagnose and treat trichomoniasis.

PMID:37806787 | DOI:10.1016/j.pt.2023.09.009

Mol Ther. 2023 Oct 6:S1525-0016(23)00545-2. doi: 10.1016/j.ymthe.2023.10.004. Online ahead of print.

ABSTRACT

In vivo apoptosis of human mesenchymal stromal cells (MSCs) plays a critical role in delivering immunomodulation. Yet, caspase activity not only mediates the dying process but also death-independent functions that may shape the immunogenicity of apoptotic cells. Therefore, a better characterization of the immunological profile of apoptotic MSCs (ApoMSCs) could shed light on their mechanistic action and therapeutic applications. We analyzed the transcriptomes of MSCs undergoing apoptosis and identified several immunomodulatory factors and chemokines dependent on caspase activation following Fas stimulation. The ApoMSC secretome inhibited human T cell proliferation and activation, and chemoattracted monocytes in vitro. Both immunomodulatory activities were dependent on the cyclooxygenase2 (COX2)/prostaglandin E2 (PGE2) axis. To assess the clinical relevance of ApoMSC signature, we used the peripheral blood mononuclear cells (PBMCs) from a cohort of fistulizing Crohn's Disease (CD) patients who had undergone MSC treatment (ADMIRE-CD). Compared to healthy donors, MSCs exposed to patients' PBMCs underwent apoptosis and released PGE2 in a caspase-dependent manner. Both PGE2 and apoptosis were significantly associated with clinical responses to MSCs. Our findings identify a new mechanism whereby caspase activation delivers ApoMSC immunosuppression. Remarkably, such molecular signatures could implicate translational tools for predicting patients' clinical responses to MSC therapy in CD.

PMID:37805713 | DOI:10.1016/j.ymthe.2023.10.004

Sci Data. 2023 Oct 7;10(1):681. doi: 10.1038/s41597-023-02558-5.

ABSTRACT

Zoonotic spillover of sarbecoviruses (SarbeCoVs) from non-human animals to humans under natural conditions has led to two large-scale pandemics, the severe acute respiratory syndrome (SARS) pandemic in 2003 and the ongoing COVID-19 pandemic. Knowledge of the genetic diversity, geographical distribution, and host specificity of SarbeCoVs is therefore of interest for pandemic surveillance and origin tracing of SARS-CoV and SARS-CoV-2. This study presents a comprehensive repository of publicly available animal-associated SarbeCoVs, covering 1,535 viruses identified from 63 animal species distributed in 43 countries worldwide (as of February 14,2023). Relevant meta-information, such as host species, sampling time and location, was manually curated and included in the dataset to facilitate further research on the potential patterns of viral diversity and ecological characteristics. In addition, the dataset also provides well-annotated sequence sets of receptor-binding domains (RBDs) and receptor-binding motifs (RBMs) for the scientific community to highlight the potential determinants of successful cross-species transmission that could be aid in risk estimation and strategic design for future emerging infectious disease control and prevention.

PMID:37805633 | DOI:10.1038/s41597-023-02558-5

Sci Rep. 2023 Oct 7;13(1):16906. doi: 10.1038/s41598-023-43948-4.

ABSTRACT

The design of popular disposable electronic cigarettes (ECs) was analyzed, and the concentrations of WS-23, a synthetic coolant, in EC fluids were determined for 22 devices from 4 different brands. All products contained WS-23 in concentrations that ranged from 1.0 to 40.1 mg/mL (mean = 21.4 ± 9.2 mg/mL). To determine the effects of WS-23 on human bronchial epithelium in isolation of other chemicals, we exposed EpiAirway 3-D microtissues to WS-23 at the air liquid interface (ALI) using a cloud chamber that generated aerosols without heating. Proteomics analysis of exposed tissues revealed that the cytoskeleton was a major target of WS-23. BEAS-2B cells were exposed to WS-23 in submerged culture to validate the main results from proteomics. F-actin, which was visualized with phalloidin, decreased concentration dependently in WS-23 treated BEAS-2B cells, and cells became immotile in concentrations above 1.5 mg/mL. Gap closure, which depends on both cell proliferation and migration, was inhibited by 0.45 mg/mL of WS-23. These data show that WS-23 is being added to popular EC fluids at concentrations that can impair processes dependent on the actin cytoskeleton and disturb homeostasis of the bronchial epithelium. The unregulated use of WS-23 in EC products may harm human health.

PMID:37805554 | DOI:10.1038/s41598-023-43948-4

Environ Res. 2023 Oct 5:117117. doi: 10.1016/j.envres.2023.117117. Online ahead of print.

ABSTRACT

INTRODUCTION: Colorectal cancer (CRC) is one of the most malignant tumors and in which various efforts for screening is inconclusive.The intracrine FGF panel, the non-tyrosine kinase receptors (NTKR) FGFs and affiliated antisenses play a pivotal role in FGF signaling.The expression levels of coding and non-coding intracrine FGFs were assessed in CRC donors.Also, substantial costs and slow pace of drug discovery give high attraction to repurpose of previously discovered drugs to new opportunities.

OBJECTIVES: The aim of present study was to evaluate the potential role of the coding and non-coding intracrine FGFs as a new biomarkers for CRC cases and defining drug repurposing to alleviate FGF down regulation.

METHODS: RNA-seq data of colon adenocarcinomas (COAD) was downloaded using TCGA biolinks package in R.The DrugBank database (https://go.drugbank.com/) was used to extract interactions between drugs and candidate genes. A total of 200 CRC patients with detailed criteria were enrolled.RNAs were extracted with TRIzol-based protocol and amplified via LightCycler® instrument.FGF11 and FGF13 proteins validation was performed by used of immunohistochemistry technique in tumor and non-tumoral samples.Pearson's correlation analysis and ROC curve plotted by Prism 8.0 software.

RESULTS: RNA-seq data from TCGA was analyzed by normalizing with edgeR.Differentially expressed gene (DEG) analysis was generated. WCC algorithm extracted the most significant genes with a total of 47 genes. Expression elevation of iFGF antisenses (12AS,13As,14AS) compared with the normal colon tissue were observed (P = 0.0003,P = 0.042,P = 0.026, respectively). Moreover,a significant decrease in expression of the corresponding sense iFGF genes was detected (P < 0.0001).Plotted receiver operating characteristic (ROC) curves for iFGF components' expression showed an area of over 0.70 (FGF11-13: 0.71% and FGF12-14: 0.78%, P < 0.001) for sense mRNA expression, with the highest sensitivity for FGF12 (92.8%) and lowest for FGF11 (61.41%).The artificial intelligence (AI) revealed the valproic acid as a repurposing drug to relief the down regulation of FGF12 and 13 in CRC patients.

CONCLUSION: Intracrine FGFs panel was down regulated versus up regulation of dependent antisenses. Thus, developing novel biomarkers based on iFGF can be considered as a promising strategy for CRC screening.In advanced, valporic acid detected by AI as a repurposing drug which may be applied in clinical trials for CRC treatment.

PMID:37805185 | DOI:10.1016/j.envres.2023.117117

J Theor Biol. 2023 Oct 5:111632. doi: 10.1016/j.jtbi.2023.111632. Online ahead of print.

ABSTRACT

Elementary flux modes (EFMs) are minimal, steady state pathways characterizing a flux network. Fundamentally, all steady state fluxes in a network are decomposable into a linear combination of EFMs. While there is typically no unique set of EFM weights that reconstructs these fluxes, several optimization-based methods have been proposed to constrain the solution space by enforcing some notion of parsimony. However, it has long been recognized that optimization-based approaches may fail to uniquely identify EFM weights and return different feasible solutions across objective functions and solvers. Here we show that, for flux networks only involving single molecule transformations, these problems can be avoided by imposing a Markovian constraint on EFM weights. Our Markovian constraint guarantees a unique solution to the flux decomposition problem, and that solution is arguably more biophysically plausible than other solutions. We describe an algorithm for computing Markovian EFM weights via steady state analysis of a certain discrete-time Markov chain, based on the flux network, which we call the cycle-history Markov chain. We demonstrate our method with a differential analysis of EFM activity in a lipid metabolic network comparing healthy and Alzheimer's disease patients. Our method is the first to uniquely decompose steady state fluxes into EFM weights for any unimolecular metabolic network.

PMID:37804942 | DOI:10.1016/j.jtbi.2023.111632

Cell Metab. 2023 Sep 29:S1550-4131(23)00341-8. doi: 10.1016/j.cmet.2023.09.010. Online ahead of print.

ABSTRACT

The intestinal epithelium has a high turnover rate and constantly renews itself through proliferation of intestinal crypt cells, which depends on insufficiently characterized signals from the microenvironment. Here, we showed that colonic macrophages were located directly adjacent to epithelial crypt cells in mice, where they metabolically supported epithelial cell proliferation in an mTORC1-dependent manner. Specifically, deletion of tuberous sclerosis complex 2 (Tsc2) in macrophages activated mTORC1 signaling that protected against colitis-induced intestinal damage and induced the synthesis of the polyamines spermidine and spermine. Epithelial cells ingested these polyamines and rewired their cellular metabolism to optimize proliferation and defense. Notably, spermine directly stimulated proliferation of colon epithelial cells and colon organoids. Genetic interference with polyamine production in macrophages altered global polyamine levels in the colon and modified epithelial cell proliferation. Our results suggest that macrophages act as "commensals" that provide metabolic support to promote efficient self-renewal of the colon epithelium.

PMID:37804836 | DOI:10.1016/j.cmet.2023.09.010

Cell. 2023 Sep 26:S0092-8674(23)01032-2. doi: 10.1016/j.cell.2023.09.011. Online ahead of print.

ABSTRACT

Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.

PMID:37804830 | DOI:10.1016/j.cell.2023.09.011

Pathol Res Pract. 2023 Oct 2;251:154838. doi: 10.1016/j.prp.2023.154838. Online ahead of print.

ABSTRACT

The interaction between long non-coding RNAs (lncRNAs), miRNAs and mRNAs has implications in the pathogenesis of different cancer, including breast cancer. In the current study, we developed an in-silico approach to ascertain the competing endogenous RNA (ceRNA) network in breast cancer. Our approach led to identification of 1816 differentially expressed (DE) mRNAs, including 1039 downregulated DEmRNAs (such as LEP and ADIPOQ) and 777 upregulated DEmRNAs (such as COL11A1 and COL10A1), 19 DElncRNAs, including 15 downregulated DElncRNAs (such as CARMN and COPG2IT1) and 4 upregulated DElncRNAs (such as MALAT1 and NRAV) and 27 DEmiRNAs, including 15 downregulated DEmiRNAs (such as MIR452 and MIR224) and 12 upregulated DEmiRNAs (such as MIR6787 and MIR21). Pathway analysis revealed down-regulation of PPAR, Fatty acid metabolism, Adipocytokine, Vascular smooth muscle contraction and Metabolism of xenobiotics by cytochrome P450, while up-regulation of Pyrimidine metabolism, p53 signaling pathway, Cell cycle, Oocyte meiosis and RNA transport pathways in breast cancer. Finally, we constructed an lncRNA/miRNA/mRNA ceRNA network consisted of 2 lncRNAs, 15 mRNAs, and 4 miRNAs. This network represents an appropriate target for design of anti-cancer modalities and documentation of novel markers for breast cancer.

PMID:37804544 | DOI:10.1016/j.prp.2023.154838

Plant Physiol. 2023 Oct 7:kiad535. doi: 10.1093/plphys/kiad535. Online ahead of print.

ABSTRACT

During photosynthesis, plants must manage strong fluctuations in light availability on different time scales, leading to long-term acclimation and short-term responses. However, little is known about the regulation and coordination of these processes and the modulators involved. In this study, we used proteomics, metabolomics, and reverse genetics to investigate how different light environmental factors, such as intensity or variability, affect long-term and short-term acclimation responses of Arabidopsis (Arabidopsis thaliana) and the importance of the chloroplast redox network in their regulation. In the wild type, high light, but not fluctuating light, led to large quantitative changes in the proteome and metabolome, accompanied by increased photosynthetic dynamics and plant growth. This finding supports light intensity as a stronger driver for acclimation than variability. Deficiencies in NADPH-thioredoxin reductase C (NTRC) or thioredoxins m1/m2, but not thioredoxin f1, almost completely suppressed the reengineering of the proteome and metabolome, with both the induction of proteins involved in stress and redox responses and the repression of those involved in cytosolic and plastid protein synthesis and translation being strongly attenuated. Moreover, the correlations of protein or metabolite levels with light intensity were severely disturbed, suggesting a general defect in the light-dependent acclimation response, resulting in impaired photosynthetic dynamics. These results indicate a previously unknown role of NTRC and thioredoxins m1/m2 in modulating light acclimation at proteome and metabolome levels to control dynamic light responses. NTRC, but not thioredoxins m1/m2 or f1, also improves short-term photosynthetic responses by balancing the Calvin-Benson cycle in fluctuating light.

PMID:37804523 | DOI:10.1093/plphys/kiad535

Microb Biotechnol. 2023 Oct 7. doi: 10.1111/1751-7915.14346. Online ahead of print.

ABSTRACT

Iron is an essential element for all eukaryote organisms because of its redox properties, which are important for many biological processes such as DNA synthesis, mitochondrial respiration, oxygen transport, lipid, and carbon metabolism. For this reason, living organisms have developed different strategies and mechanisms to optimally regulate iron acquisition, transport, storage, and uptake in different environmental responses. Moreover, iron plays an essential role during microbial infections. Saccharomyces cerevisiae has been of key importance for decrypting iron homeostasis and regulation mechanisms in eukaryotes. Specifically, the transcription factors Aft1/Aft2 and Yap5 regulate the expression of genes to control iron metabolism in response to its deficiency or excess, adapting to the cell's iron requirements and its availability in the environment. We also review which iron-related virulence factors have the most common fungal human pathogens (Aspergillus fumigatus, Cryptococcus neoformans, and Candida albicans). These factors are essential for adaptation in different host niches during pathogenesis, including different fungal-specific iron-uptake mechanisms. While being necessary for virulence, they provide hope for developing novel antifungal treatments, which are currently scarce and usually toxic for patients. In this review, we provide a compilation of the current knowledge about the metabolic response to iron deficiency and excess in fungi.

PMID:37804207 | DOI:10.1111/1751-7915.14346