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Results for “cellular stress”

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At least 19 recordsLinked to original sources

PubMed2026

Single-cell profiling reveals epithelial and immune responses in BK polyomavirus-infected human kidney biopsies.

INTRODUCTIONBK polyomavirus (BKV) infection is associated with injury and subsequent graft loss due to the extent of injury or rejection. However, the molecular mechanisms driving injury and subsequent adverse outcomes remain poorly understood.METHODSIn a cross-sectional study, single-cell RNA-seq from kidney allograft biopsies was used to assess cell type-specific responses between uninfected controls and 2 distinct phases of BKV infection: peaking (increasing viral blood titers) and resolving (decreasing viral titers following immunosuppression reduction).RESULTSGenes upregulated in BK viral nephropathy (BKVN) were enriched for polyomavirus infection hallmarks, including ribosome biogenesis, translation, and energy restructuring. Additionally, enriched pathways included wound healing, cellular stress, antigen presentation and immune signaling. Even without BKVN (peaking BK viremia alone), epithelial cells expressed signatures for wound healing, cellular stress, and extracellular matrix remodeling. In vivo tubular cell responses at single-cell resolution were validated against single cell transcriptomic data of BKV-infected cells in a cell culture model. Despite similarities, in vivo tubular cells underwent metabolic adaptation favoring fatty acid oxidation and proinflammatory responses not observed in culture models, likely due to an absent innate and adaptive immune system. Despite lymphopenia and immunosuppressive therapies, the proportion of recipient-derived intrarenal adaptive immune cells was increased in biopsies associated with peaking viremia alongside activation of innate immune responses. Adaptive immune cells exhibited persistent inflammatory signaling and remodeling of energy metabolism during the resolving phase of infection.CONCLUSIONThese not previously reported insights into BKV-associated injury may have implications for clinical management and improved allograft outcomes.

Humans↗

PubMed2026

rRNA expansion segments mediate ribosome dimerization as a conserved stress response.

Inhibition of messenger RNA translation is a common feature in proteostatic stress cellular responses. Puromycin, a widely used compound for studying translation, disrupts protein synthesis by mimicking the 3' end of aminoacyl-transfer RNAs. Despite its extensive use as a research tool to probe the connection between translation activity and various physiological and pathological states, the cellular response associated with puromycin-induced translation stress remains incompletely understood. Here, we used electron tomography and topology analysis to define the effects of puromycin on the translation machinery in situ. We show that puromycin-treated neuronal cells exhibit an accumulation of eIF5A-bound ribosomes in a translationally inactive "idle" state, and thereby defining a broader role of eIF5A in ribosome homeostasis. Additionally, the idle ribosomes formed dimeric complexes mediated by ribosomal RNA expansion segments, suggesting an evolved mechanism involving these regions in translational hibernating and protecting idle ribosomes. We further show that the hibernating disome formation is not unique to puromycin administration but represents a conserved mechanism as a response to different cellular stressors including endoplasmic reticulum stress and amino acid depletion. Collectively, our findings illuminate distinct states of mammalian ribosome hibernation and dimerization, providing new insights into the relationship of cellular stress and the dynamic regulation of ribosomal activity.

Ribosomes↗

PubMed2026

Biological Mechanisms Underlying the Cardiovascular Effects of Branched-Chain Amino Acids: A Proteome-Wide Mendelian Randomization Study.

BACKGROUND: Ischemic heart disease (IHD) is the leading cause of morbidity and mortality. Branched-chain amino acids (BCAAs) are associated with higher IHD risk, but the underlying biological pathways remain unclear. OBJECTIVES: This study aims to explore these pathways using 2-step proteome-wide Mendelian randomization. METHODS: We examined the associations between genetic proxies for BCAAs and 2922 proteins in the United Kingdom Biobank Pharma Proteomics Project, supplemented by a meta-analysis with data from deCODE to identify proteins associated with BCAAs. Next, we tested their effects on IHD risk using Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium (122,733 cases and 424,528 controls) and replicated in FinnGen (31,640 cases and 187,152 controls). We conducted sensitivity analyses using genetic instruments from deCODE. Proteins associated with IHD risk and, in a consistent direction, with genetically predicted BCAAs were considered potential mediators. RESULTS: Genetic proxies for BCAAs were associated with 40 proteins. Among these, 6 proteins showed consistent evidence of mediation, including complement C1s subcomponent, coagulation factor II, granulin, proprotein convertase subtilisin/kexin type 9, sex hormone-binding globulin, and V-set and transmembrane domain-containing protein 2-like. These proteins are involved in inflammation, coagulation, lipid metabolism, and cellular stress response. All associations were robust across different analytical methods and replicated in independent datasets. Mediation analysis showed that these proteins accounted for 6.5% to 32.1% of the association between BCAAs and IHD risk. CONCLUSIONS: This study identified 6 proteins that potentially link BCAAs to IHD, implicating pathways related to inflammation, coagulation, lipid metabolism, and cellular stress responses. To our knowledge, these findings provide novel mechanistic insights into the BCAA-IHD relationship and highlight potential protein targets for future prevention and intervention strategies.

Amino Acids, Branched-Chain↗

PubMed2026

Differential gene transcription following intravenous injection of air bubbles in rats with varying resistance to decompression sickness.

Decompression sickness (DCS) is a pathology caused by the appearance of gas emboli in the bloodstream and tissues. However, the weak correlation between the amount of venous gas emboli (VGE) and the development of DCS, as well as the considerable interindividual variability in DCS susceptibility, suggests that a higher DCS resistance could be associated with a better management of VGE-induced stress. To study the effects of VGE independently of the hyperbaric stress induced by diving, Wistar and DCS-resistant male and female rats received 5 mL/kg of a 0.9% NaCl solution containing air microbubbles through the tail vein. After 120 min, the liver and lungs were harvested. Wet-to-dry weight ratio was determined in the lungs. Gene expression was quantified by reverse transcription-polymerase chain reaction in the liver. Compared with standard Wistar, DCS-resistant rats exhibited a lower lung wet-to-dry weight ratio after air microbubble injection, suggesting lower pulmonary fluid accumulation. In the liver, DCS-resistant rats showed higher tissue factor transcription at the basal state and post-air microbubble injection. Tissue factor pathway inhibitor was lower in DCS-resistant rats at the basal state but higher following air microbubble injection. Levels of heat shock protein 70 (HSP70), heat shock protein 27 (HSP27), and early growth response 1 (Egr-1) were higher in DCS-resistant rats after air microbubble injection. At the basal state, only HSP27 was higher in DCS-resistant rats, with HSP70 lower and Egr-1 not different. These results help clarify the pathways involved in the response to VGE and highlight potential mechanisms underlying resistance to DCS, including enhanced anticoagulant pathways and improved cellular stress responses.NEW & NOTEWORTHY This study suggests for the first time that DCS resistance may be associated with a better tolerance to VGE. This greater DCS resistance could be achieved through improved control of the procoagulant effects of bubbles via TFPI-dependent inhibitory mechanisms and an enhanced cellular stress response to VGE by HSP70, HSP27, and EGR-1. It also suggests that it may be possible to stratify the individual DCS risk based on the thromboinflammatory response to bubbles.

Animals↗

PubMed2026

UVB-aged polystyrene microplastics induce enhanced stress responses in human proximal tubular cells.

Microplastics (MPs) are increasingly detected in human biological matrices, raising concerns about their potential systemic effects, including on the kidney. However, the cellular responses of renal tubular epithelium to MPs and the role of environmental aging processes in modulating their biological activity remain poorly defined. Under environmental conditions, MPs undergo photo-oxidative transformations that alter their surface chemistry and may influence their interactions with biological systems. In this study, we investigated the effects of 1 µm polystyrene MPs in virgin (MPsV) and UVB-oxidised (MPsOx) forms in a human renal proximal tubular cell line (HK-2). Cells were exposed to MPs (25 and 50 µg/mL), and multiple endpoints related to cellular stress and genomic stability were evaluated, including lysosome-associated responses, oxidative damage, DNA integrity, micronucleus formation, DNA-content distribution profiles as an indirect proxy of proliferative status, and cytoskeletal organisation. Exposure to MPs induced measurable stress responses in tubular cells, with oxidised particles generally eliciting stronger effects than MPsV. These responses were consistent with increased oxidative stress, lysosome-associated cellular responses, genomic instability-associated alterations, activation of stress-responsive molecular pathways, and cytoskeletal perturbation. Collectively, these findings indicate that environmentally aged polystyrene MPs elicit more evident cellular stress responses than their virgin counterparts in HK-2 cells. Our results highlight the importance of incorporating environmentally transformed MPs into toxicological testing frameworks to improve the biological relevance of hazard assessment.

Genotoxicity↗

PubMed2026

Identification of aquaporin (AQP) genes in the noble scallop Chlamys nobilis and characterization of their expression under low-temperature stress.

Aquaporins (AQPs) are transmembrane channel proteins essential for water homeostasis and cellular stress responses. In marine bivalves, their roles in cold tolerance remain poorly understood despite frequent winter mortality events in aquaculture. Here, we identified nine AQP genes in the genome of the economically important noble scallop Chlamys nobilis. Phylogenetic analysis revealed strong conservation with other bivalve AQPs, and structural features, including conserved NPA motifs and ar/R selectivity filters, support their canonical water/glycerol transport functions. Tissue-specific expression profiling showed predominant enrichment in osmoregulatory tissues (gills, intestine) and gonads. Under both chronic and acute low-temperature stress from 23 °C to 9 °C, most CnAQP genes exhibited transient upregulation followed by suppression. Notably, CnAQP4 displayed sustained upregulation, implicating it as a key mediator of long-term cold adaptation. Promoter analysis further revealed abundant cis-elements linked to growth and development as well as immune regulation. Our findings provide the first comprehensive characterization of the AQP family in C. nobilis, highlighting its critical role in maintaining cellular integrity during cold stress and offering molecular targets for selective breeding of cold-tolerant scallop strains.

Animals↗

PubMed2025

Analysis of stress-induced small proteins in Escherichia coli reveals that YoaI mediates cross-talk between distinct signaling systems.

Bacterial small proteins (≤ 50 amino acids) are an emerging class of regulators that modulate the activity of signaling networks that enable bacterial adaptation to stress. The Escherichia coli genome encodes at least 150 small proteins, most of which are functionally uncharacterized. We identified and characterized 17 small proteins induced in E. coli during magnesium (Mg2+) starvation using ribosome profiling, RNA sequencing, and transcriptional reporter assays. Several of these were transcriptionally activated by the PhoQ-PhoP two-component signaling system, which is crucial for Mg2+ homeostasis. Deletion or overexpression of some of these small proteins led to growth defects and changes in cell size under low-Mg2+ conditions, indicating physiological roles in stress adaptation. The small transmembrane protein YoaI, which was transcriptionally induced by the phosphate-responsive PhoR-PhoB signaling pathway, increased in abundance under Mg2+ limitation independently of yoaI transcription or PhoQ-PhoP signaling. YoaI activated a third signaling system, EnvZ-OmpR, which mediates responses to osmotic stress. Overall, this study establishes an initial framework for understanding how small proteins contribute to bacterial stress adaptation by facilitating cross-talk between different signaling systems. Our results suggest these proteins play broader roles in coordinating stress responses, reflecting the interconnected nature of cellular stress networks rather than strictly compartmentalized pathways responding to specific stressors.

Journal Article↗

PubMed2025

DDX3X acts as a selective dual switch regulator of mRNA translation in acute ER stress.

Regulation of eukaryotic mRNA translation initiation greatly impacts gene expression and is critical for cellular stress response. DDX3X is a ubiquitous DEAD-box RNA helicase whose precise role in scanning and translation regulation in non-stressed and stressed cells remains incompletely understood. Here, we show that DDX3X associates with thousands of mRNAs as part of the eIF4F-mediated 48S scanning complex and exerts dual regulatory effects, promoting or repressing translation of select mRNAs under basal conditions and reversing this regulation during acute endoplasmic reticulum stress. Initiation profiling reveals mechanistically distinct modes of DDX3X action linked to its binding patterns across the 5' UTR and coding sequence. We further uncover that mRNAs selectively regulated by DDX3X exhibit specific patterns of cytidine N4-acetylation near start codons, with shared de-repression observed upon NAT10 knockdown. Together, our findings reveal DDX3X as a context-sensitive regulator that has a possible functional connection with epitranscriptomic features in translation control.

DEAD-box RNA Helicases↗

PubMed2026

Twenty-Five Years of the Environmental Stress Response and the Enduring Power of Yeast in Stress Biology.

All organisms must be able to sense and respond to adverse environments, especially those that threaten cellular integrity. The age of genomics clarified the breadth and specificity of cellular stress responses, including in free-living microbes directly exposed to a changing environment. The environmental stress response (ESR) in Saccharomyces cerevisiae was among the first responses defined at the transcriptome-wide level as a common program triggered by diverse types of stress. Since its original publication over 25 years ago, many studies have explored the role, regulation, and evolution of the ESR and underlying principles of stress defense. This perspective reviews the history of the ESR, recent insights and perspectives into its purpose and regulation, and remaining questions in stress biology primed for the power of yeast experimentation.

Saccharomyces cerevisiae↗

PubMed2026

Comparative toxicoproteomics reveals distinct proteostasis and ribosomal stress signatures of CMIT and PHMG.

Methylchloroisothiazolinone (CMIT) and polyhexamethylene guanidine (PHMG) are antimicrobial biocides associated with pulmonary toxicity, although their comparative cellular stress mechanisms remain unclear. Here, we investigated how CMIT and PHMG differentially alter the proteome of human alveolar epithelial A549 cells under subcytotoxic conditions. Cells were exposed to CMIT or PHMG, and global proteomic profiling was performed using label-free liquid chromatography-tandem mass spectrometry. Differentially expressed proteins (DEPs) were identified at a 1% false discovery rate with an absolute log2 fold change ≥1. Functional analyses were conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Ingenuity Pathway Analysis, and selected proteins were validated by western blotting. Comparative toxicoproteomics revealed distinct stress-response signatures induced by the two biocides. CMIT preferentially altered proteins associated with proteostasis, oxidative stress, and protein quality control, whereas PHMG was characterized by coordinated depletion of ribosome-associated and translation-related proteins. A total of 73 and 155 DEPs were identified in CMIT- and PHMG-treated cells, respectively, with 22 proteins shared between treatments. Western blotting confirmed PSMD3, TUBB2A, and GLRX1 as CMIT-responsive proteins and THRAP3, DHX15, and RPL4 as PHMG-responsive markers. These findings provide comparative mechanistic insight into how CMIT and PHMG induce distinct epithelial stress responses and identify candidate protein markers that may support future in vitro assessment of biocide-induced pulmonary toxicity.

CMIT↗

PubMed2026

Dysregulated adult hippocampal neurogenesis in major depressive disorder.

Major depressive disorder (MDD) is associated with reduced hippocampal volume, altered connectivity and negative memory bias, suggesting disrupted hippocampal plasticity. Dysregulated adult hippocampal neurogenesis is a potential contributor, but its relevance in humans and role in MDD remain unclear. Here we investigated the molecular basis of hippocampal dysfunction in nonmedicated individuals with MDD by integrating analyses of neurogenic trajectories, cell-type- and subfield-specific gene expression, chromatin accessibility and protein expression. We identify a neurogenic lineage in the adult human hippocampal subgranular zone and provide evidence for a stalled neurogenic process in MDD, associated with transcriptional regulation, stress-related reprogramming and interferon signaling across developmental stages. Excitatory and inhibitory neurons show dysregulation of transcription factor networks affecting cell states. Cellular stress, excitatory-inhibitory imbalance, impaired synaptic plasticity, reduced metabolic capacity and immune activation, underlie impaired neurogenesis and reduced hippocampus circuit plasticity. Findings indicate genetic and epigenetic regulation of gene expression in MDD, and overlapping pathogenetic mechanisms with autoimmune, neurodevelopmental and neurodegenerative diseases. This work provides a new understanding of the pathogenesis of hippocampus-dependent cognitive symptoms in MDD and suggests potential therapeutic targets.

Journal Article↗

PubMed2026

Differentiation-independent activation of HPV genome replication by the lncRNA DINO.

Human papillomaviruses (HPVs) rely on multiple host cell factors to replicate the viral genome, yet the contribution of host long non-coding RNAs (lncRNAs) to viral genome maintenance and amplification in the productive life cycle remains poorly understood. In this study, we show that the lncRNA damage-induced long non-coding RNA (DINO) is a driver of HPV DNA replication. DINO levels increase during keratinocyte differentiation, and ectopic expression of DINO promotes both HPV genome replication and the formation of replication foci, and this is independent of keratinocyte differentiation signals. Ectopic DINO expression increases select early viral transcript levels, including E1^E4, E1, and E2. Notably, DINO's subcellular localization is also context-dependent: during DNA damage, DINO is predominantly cytoplasmic, but during keratinocyte differentiation, nuclear retention is observed. This differential localization suggests that DINO has distinct functional roles in keratinocyte differentiation and HPV biology. Our findings highlight DINO as a lncRNA that promotes HPV genome replication and suggest that lncRNAs may play underappreciated roles in host-virus interactions. This work provides a foundation for further exploration of lncRNAs as potential therapeutic targets in HPV-associated diseases.IMPORTANCEHuman papillomaviruses (HPVs) are the causative agents of many anogenital tract and oral cancers, yet the host factors that trigger and support viral genome replication during the productive life cycle are incompletely understood. This study identifies the long non-coding RNA DINO as a host regulator that promotes HPV DNA replication, replication focus formation, and early viral gene expression independently of keratinocyte differentiation. We further show that DINO exhibits context-dependent subcellular localization, suggesting distinct functional roles in cellular stress responses and HPV biology. These findings reveal an underappreciated role for host lncRNAs in virus-host interactions and provide new insight into cellular pathways that support HPV genome replication.

Virus Replication↗

PubMed2026

m6A-Mediated epitranscriptomic control of mitochondrial dysfunction in neurodegeneration.

Mitochondrial dysfunction is a common pathology of neurodegenerative diseases, which contributes to neuronal vulnerability via excessive oxidative stress, impaired bioenergetics, and dysregulated apoptosis. Emerging studies highlighted the critical role of epitranscriptomic RNA modifications, particularly N6-methyladenosine (m6A), in mitochondrial gene expression regulation and cellular stress responses. m6A modifications are installed by methyltransferases ("writers," METTL3/METTL14), recognized by reader proteins (YTH domain family proteins, IGF2BPs), and removed by demethylases ("erasers," FTO, ALKBH5), collectively orchestrating mRNA splicing, localization, stability, and translation. Recent evidence demonstrates that m6A modifications modulate both nuclear-encoded and mitochondrially encoded transcripts and regulate key mitochondrial processes, including fission/fusion dynamics, oxidative phosphorylation, mitophagy, and apoptosis. Dysregulation of m6A machinery disrupts mitochondrial homeostasis, exacerbates oxidative stress and neuroinflammation, and promotes neuronal loss. Importantly, pharmacological or genetic modulation of m6A regulators can restore mitochondrial function, inhibit caspase activation, and dampen pro-inflammatory signaling, underscoring their therapeutic potential. This review consolidates current insights into mitochondrial epitranscriptomics, emphasizing how m6A modifications act as central regulators of mitochondrial stress responses and neurodegeneration.

Humans↗

PubMed2024

Nonlethal deleterious mutation-induced stress accelerates bacterial aging.

Random mutagenesis, including when it leads to loss of gene function, is a key mechanism enabling microorganisms' long-term adaptation to new environments. However, loss-of-function mutations are often deleterious, triggering, in turn, cellular stress and complex homeostatic stress responses, called "allostasis," to promote cell survival. Here, we characterize the differential impacts of 65 nonlethal, deleterious single-gene deletions on Escherichia coli growth in three different growth environments. Further assessments of select mutants, namely, those bearing single adenosine triphosphate (ATP) synthase subunit deletions, reveal that mutants display reorganized transcriptome profiles that reflect both the environment and the specific gene deletion. We also find that ATP synthase α-subunit deleted (ΔatpA) cells exhibit elevated metabolic rates while having slower growth compared to wild-type (wt) E. coli cells. At the single-cell level, compared to wt cells, individual ΔatpA cells display near normal proliferation profiles but enter a postreplicative state earlier and exhibit a distinct senescence phenotype. These results highlight the complex interplay between genomic diversity, adaptation, and stress response and uncover an "aging cost" to individual bacterial cells for maintaining population-level resilience to environmental and genetic stress; they also suggest potential bacteriostatic antibiotic targets and -as select human genetic diseases display highly similar phenotypes, - a bacterial origin of some human diseases.

Escherichia coli↗

PubMed2026

Cloning of two Hsp70 genes and association analysis between SNP haplotypes and high temperature tolerance trait in red swamp crayfish (Procambarus clarkii).

Aquaculture is suffering the challenge from high temperature climate. Two Hsp70 genes, PcHsp70-1 and PcHsp70-2, as key genes involved in the high temperature tolerance of red swamp crayfish (Procambarus clarkii) were identified and cloned in this study. Their molecular features and expression patterns were characterized, revealing the distinct tissue-specific upregulation expression under high temperature stress (33 °C). Two SNPs, PcHsp70-1 (SNP258) and PcHsp70-2 (SNP555) were examined to associate with high temperature tolerance in three populations (n = 675). The genotypes of PcHsp70-1-SNP258 (GA) and PcHsp70-2-SNP555 (TT) were significantly associated with stronger high temperature tolerance. Notably, individuals carrying the haplotype of Hap I (GG + TT) showed a survival rate exceeding 70% under high temperature stress, whereas, the Hap VIII (AA + CT) showed it at 5.2%. RNA interference of PcHsp70-1 resulted in a significant decrease expression of the gene GSH-Px and its encoding protein (glutathione peroxidase) activity, and damage in intestinal tissue under high temperature stress. The transcriptome result revealed that PcHsp70-1 participates in regulation of the pathways related to cytoskeletal construction, immune response, apoptosis, and antioxidant defense. These findings indicate that PcHsp70 genes are crucial for the cellular stress response under high temperature stress. The developed Kompetitive Allele Specific PCR (KASP) markers provide valuable tools for the marker-assisted selection of high temperature tolerant crayfish varieties, supporting the sustainable development of aquaculture under the challenge of global warming.

Animals↗

PubMed2026

Selenoprotein S associates with complexes governing membrane protein biogenesis and translation-associated processes.

Human selenoprotein S (selenos) is part of the integrated cellular stress response and linked to protein quality control and signaling pathways. Consequently, genetic polymorphisms of selenos are associated with increased risks for diabetes, dyslipidemia, and cardiovascular diseases. Determining the specific roles of selenos in these cellular pathways and diseases has been challenging, as selenos associates with a wide range of protein complexes. Thus, to map the cellular functions of selenos and uncover their interconnections, we used affinity purification and in vivo crosslinking to stabilize transient protein interactions, followed by proteomics to record the resulting selenos interactome. Through mapping of selenos protein partners, we found evidence that selenos associates with complexes responsible for the insertion of membrane proteins into the endoplasmic reticulum (ER) bilayer and their connected quality control components. Furthermore, selenos is also part of metabolic, trafficking, and mitochondrial pathways. Notably, proteins involved in translation preferentially associate with selenos when its C-terminal intrinsically disordered segment containing the redox-active motif is accessible. Together, these results identify the C-terminal redox loop of selenos as a central interaction hub connecting translation with ER membrane protein biogenesis and quality control.

Selenoproteins↗

PubMed2026

Chaperone-mediated autophagy as a regulator of hallmarks of cancer.

Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that maintains cellular homeostasis by degrading soluble proteins containing KFERQ-like motifs. Although CMA has traditionally been recognized for its role in protein quality control and cellular stress adaptation, increasing evidence shows that it is frequently altered in cancer, where it regulates multiple processes that promote tumor initiation, progression, and therapy resistance. The growing number of identified CMA substrates involved in cell proliferation, apoptosis, metabolism, DNA damage response, immune regulation, inflammation, and cellular plasticity suggests that CMA is much more than a protein degradation pathway; it is an important regulator of tumor adaptation. In this review, we bring together current evidence to provide a comprehensive understanding of how CMA contributes to the Hallmarks of Cancer, including sustained proliferative signaling, resistance to cell death, metabolic reprogramming, invasion and metastasis, immune evasion, and the enabling characteristics of genome instability and tumor-promoting inflammation. We further explore the emerging roles of CMA in cellular plasticity and cancer stem cell maintenance, two interconnected processes that drive tumor progression, metastasis, and therapeutic resistance. By integrating evidence from diverse tumor types, this review provides a comprehensive understanding of how CMA shapes multiple hallmarks of cancer by selectively degrading key regulatory proteins. Finally, we highlight the context-dependent roles of CMA, identify key gaps in our current understanding, and discuss the opportunities and challenges of targeting CMA for cancer therapy. Overall, this hallmark-based perspective provides an integrated understanding of how CMA contributes to multiple hallmarks of cancer and supports its potential as a therapeutic target.

autophagy↗

PubMed2026

Dietary Titanium Dioxide (E171) Alters the Colon Transcriptome-Evidence From a Human Dietary Intervention Study.

Food-grade titanium dioxide (E171) has been removed from the European food market due to concerns about its potential genotoxicity, yet human evidence remains limited. Given its continuous use outside the European Union, clarifying its potential hazard is essential for human risk assessment. In a randomized crossover study, 31 adults consumed 2 mg/kg body weight/day of E171 for 2 weeks, with biospecimens collected after both control and exposure periods. Oral intake resulted in elevated titanium concentrations in feces (CTRL: 6.3 mg/kg; E171: 377 mg/kg). Particle characterization showed a median size of 228 nm, with 9% <100 nm. Systemic oxidative stress increased, evidenced by increased superoxide radical levels in whole blood (p = 0.057). Transcriptomic profiling of colon biopsies revealed activation of 73 pathways linked to oxidative stress, cellular metabolism, and colorectal cancer-associated processes. The observed transcriptional changes were consistent with findings of its proposed mode of action. This human intervention study characterizes the effects of dietary E171 following human gastrointestinal digestion and provides evidence that exposure to dietary E171 induces systemic oxidative stress and transcriptional changes in the colon. These findings strengthen regulatory concerns about E171 as a food additive and its potentially harmful effects on human gastrointestinal health.

Humans↗