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Flumioxazin is a widely applied herbicide for the control of broadleaf weeds, including aquatic plants. Current evidence suggests that flumioxazin could induce cardiac defects (ventricular septal defects) in vertebrates, but the underlining mechanisms remain unclear. Because of the inhibitory effect of flumioxazin on polyphenol oxidase, the assumption is made that flumioxazin‐induced cardiotoxicity is caused by oxidative stress. To verify whether oxidative stress plays an important role in flumioxazin‐induced cardiotoxicity, we compared the differences in heart phenotype, oxidative stress level, apoptosis, and gene expression between flumioxazin exposure and a normal environment, and we also tested whether cardiotoxicity could be rescued with astaxanthin. The results showed that flumioxazin induced both cardiac malformations and the abnormal gene expression associated with cardiac development. Cardiac malformations included pericardial edema, cardiac linearization, elongated heart, cardiomegaly, cardiac wall hypocellularity, myocardial cell atrophy with a granular appearance, and a significant gap between the myocardial intima and the adventitia. An increase in oxidative stress and apoptosis was observed in the cardiac region of zebrafish after exposure to flumioxazin. The antioxidant astaxanthin reversed the cardiac malformations, excessive production of reactive oxygen species (ROS), and expression of genes for cardiac developmental and apoptosis regulation induced by flumioxazin. In addition, flumioxazin also activated aryl hydrocarbon receptor (AhR) signaling pathway genes (aryl hydrocarbon receptor 2 [ahr2], cytochrome p450 family subfamily a [cyp1a1], and b [cyp1b1]) and increased the concentration of porphyrins. The results suggest that excessive ROS production, which could be mediated through AhR, led to apoptosis, contributing to the cardiotoxicity of flumioxazin in zebrafish embryos. Environ Toxicol Chem 2023;42:2737–2746. © 2023 SETAC [ABSTRACT FROM AUTHOR]

eIF3, whose subunits are frequently overexpressed in cancer, regulates mRNA translation from initiation to termination, but mRNA‐selective functions of individual subunits remain poorly defined. Using multiomic profiling upon acute depletion of eIF3 subunits, we observed that while eIF3a, b, e, and f markedly differed in their impact on eIF3 holo‐complex formation and translation, they were each required for cancer cell proliferation and tumor growth. Remarkably, eIF3k showed the opposite pattern with depletion promoting global translation, cell proliferation, tumor growth, and stress resistance through repressing the synthesis of ribosomal proteins, especially RPS15A. Whereas ectopic expression of RPS15A mimicked the anabolic effects of eIF3k depletion, disruption of eIF3 binding to the 5′‐UTR of RSP15A mRNA negated them. eIF3k and eIF3l are selectively downregulated in response to endoplasmic reticulum and oxidative stress. Supported by mathematical modeling, our data uncover eIF3k‐l as a mRNA‐specific module which, through controlling RPS15A translation, serves as a rheostat of ribosome content, possibly to secure spare translational capacity that can be mobilized during stress. Are there mRNA‐selective functions of individual eIF3 subunits? Here, multiomic profiling upon acute depletion of eIF3 subunits uncovers eIF3k‐l as an mRNA‐specific module that serves as a rheostat of ribosome content, securing spare translational capacity that can be mobilized during stress. Acute depletion of eIF3 subunits has subunit‐selective impact on holo‐eIF3 architecture.eIF3k depletion uniquely causes increased tumor growth and ribosome content.eIF3k depletion boosts the translation of RPS15A mRNA through an eIF3‐binding site in the 5′‐UTR.eIF3k and eIF3l are selectively downregulated by cellular stress, thus promoting cell survival. [ABSTRACT FROM AUTHOR]

Exposure to heat stress triggers a well‐defined acute response marked by HSF1‐dependent transcriptional upregulation of heat shock proteins. Cells allowed to recover acquire thermotolerance, but this adaptation is poorly understood. By quantitative proteomics, we discovered selective upregulation of HSP70‐family chaperone HSPA1 and its co‐factors, HSPH1 and DNAJB1, in MCF7 breast cancer cells acquiring thermotolerance. HSPA1 was found to have dual function during heat stress response: (i) During acute stress, it promotes the recruitment of the 26S proteasome to translating ribosomes, thus poising cells for rapid protein degradation and resumption of protein synthesis upon recovery; (ii) during thermotolerance, HSPA1 together with HSPH1 maintains ubiquitylated nascent/newly synthesized proteins in a soluble state required for their efficient proteasomal clearance. Consistently, deletion of HSPH1 impedes thermotolerance and esophageal tumor growth in mice, thus providing a potential explanation for the poor prognosis of digestive tract cancers with high HSPH1 and nominating HSPH1 as a cancer drug target. We propose dual roles of HSPA1 either alone or in complex with HSPH1 and DNAJB1 in promoting quality control of nascent/newly synthesized proteins and cellular thermotolerance. Synopsis: How cells exposed to heat stress acquire thermotolerance is poorly understood. Here, quantitative proteomics identifies upregulation of HSP70‐family chaperone HSPA1, which fulfills dual function in quality control of nascent proteins at translating ribosomes. Proteotoxic stress causes translation arrest, ubiquitylation of nascent/newly synthesized proteins, and proteasome recruitment to ribosomes.Proteasome recruitment to ribosomes is augmented by HSP70 activity independently of nascent chain ubiquitylation.HSPA1 in complex with HSPH1‐DNAJB1 cofactors maintains solubility and proteasomal clearance of ubiquitylated proteins.Low HSPH1 expression impedes nascent‐protein quality control and tumor growth, correlating with favorable outcome. [ABSTRACT FROM AUTHOR]

Sulfometuron methyl (SM) is a widely used herbicide and thus leading to accumulation in the environment. The toxicity assessments of SM in model organisms are currently rare. In the present study, zebrafish were utilized for evaluating the detrimental effects of SM in aquatic vertebrates. Zebrafish embryos were exposed to 0, 10, 20, and 40 mg/L SM from 5.5 to 72 h post-fertilization (hpf), respectively. Consequently, SM exposure resulted in increasing the mortality rate and reducing hatching rate in larval zebrafish at 10, 20, and 40 mg/L SM-treated groups. The reduced numbers of immune cells (neutrophils and macrophages) were observed after SM exposure by a dose-dependent manner. The inflammatory responses (TLR4, MYD88, IL-1β, IL-6, IL-8, IFN-γ, IL-10, and TGF-β) were measured to estimate immune responses. Anti-inflammatory factors (IL-10 and TGF-β) were down-regulated in all the treated groups and significantly altered at 40 mg/L exposure group. Additionally, behavioral tests suggested that SM treatment significantly increased the total distance, average speed, and maximum acceleration of larval zebrafish during light-dark transition and subsequently enzymology test displayed the same trend to locomotor behaviors. The content significantly increased in oxidative stress, as reflected in ROS level in all the treated groups. The numbers of cell apoptosis were significantly increased at 20, and 40 mg/L and the highest concentration group induced the substantial increment (P < 0.001) of apoptosis-related genes including p53, Bax/Bcl-2, caspase-9, and caspase-3. In summary, our results demonstrated that exposure to SM caused toxicity of development, immune system, locomotor behavior, oxidative stress, and cell apoptosis at the early developmental stages of zebrafish. • Sulfometuron-methyl exposure induced the impairment of immune system and the occurrence of apoptotic cells. • Sulfometuron-methyl affected the ROS production and activities of superoxide dismutase, and catalase. • Sulfometuron-methyl significantly altered locomotor behavior in response to light-dark transition by activating AChE activity. [ABSTRACT FROM AUTHOR]

eIF3, a multi-subunit complex with numerous functions in canonical translation initiation, is known to interact with 40S and 60S ribosomal proteins and translation elongation factors, but a direct involvement in translation elongation has never been demonstrated. We found that eIF3 deficiency reduced early ribosomal elongation speed between codons 25 and 75 on a set of ∼2,700 mRNAs encoding proteins associated with mitochondrial and membrane functions, resulting in defective synthesis of their encoded proteins. To promote elongation, eIF3 interacts with 80S ribosomes translating the first ∼60 codons and serves to recruit protein quality-control factors, functions required for normal mitochondrial physiology. Accordingly, eIF3e+/− mice accumulate defective mitochondria in skeletal muscle and show a progressive decline in muscle strength. Hence, eIF3 interacts with 80S ribosomes to enhance, at the level of early elongation, the synthesis of proteins with membrane-associated functions, an activity that is critical for mitochondrial physiology and muscle health. • eIF3—via eIF3e—promotes mRNA selective early translation elongation • eIF3e-dependent mRNAs encode membrane, secretory, and organelle targeted proteins • eIF3 travels with 80S ribosomes until nascent chains emerge for subcellular targeting • In vivo , eIF3e promotes mitochondrial function and skeletal muscle health Lin et al. discovered that, in addition to its function in canonical translation initiation, multi-subunit eIF3 migrates with post-initiation 80S ribosomes to promote early translation elongation of mRNAs encoding organellar, secretory, and membrane-targeted proteins. Loss of eIF3's elongation and subcellular targeting activity leads to mitochondrial and skeletal muscle dysfunction. [ABSTRACT FROM AUTHOR]