Cellular Stress Response Research Articles

BIO 300 Attenuates Whole Blood Transcriptome Changes in Mice Exposed to Total-Body Radiation.

Development of radiation medical countermeasures under the U.S. Food and Drug Administration Animal Rule requires the capability to translate an effective animal-to-human drug dose. One method of human dose translation is using a biomarker and determining drug doses that modulate the biomarker to the desired level. BIO 300 Oral Powder (BIO 300) is a prophylactic radiation medical countermeasure that is currently being developed following the Animal Rule. The present study aimed to identify biomarkers that can be used for human dose conversion by conducting transcriptomics of whole blood collected from BIO 300-treated CD2F1 mice in the presence and absence of total-body irradiation (TBI). Unirradiated mice were treated with vehicle or 50, 100, or 200 mg/kg BIO 300, and irradiated mice were treated with 200 mg/kg or BIO 300 or vehicle prior to TBI. Whole-blood samples were collected after the last dose of the drug and after irradiation. RNA sequencing demonstrated 100 and 200 mg/kg of BIO 300 doses caused significantly more differential gene expression at 48 h after drug dose compared to 50 mg/kg of BIO 300 (7648, 7680, and 55 significantly differently expressed genes, respectively). Interestingly, following TBI, there were no significantly differentially expressed genes between vehicle- and BIO 300-treated mice. Despite the lack of significant changes in gene expression, the transcriptomic profiles in both groups indicated differential changes in signaling pathways. Pathway analysis of the transcriptome profile from vehicle-treated/TBI mice revealed that many inflammatory signaling pathways were activated in these animals. Signaling pathways enriched in BIO 300-treated/TBI mice were involved in cellular stress and immune response and were predicted to be inhibited. In all, four signaling pathways of interest were identified that were differentially enriched in irradiated animals treated with BIO 300: pathogen-induced cytokine storm signaling, S100 family signaling, pulmonary fibrosis idiopathic signaling, and wound-healing signaling. These pathways should be explored to identify potential biomarkers of BIO 300 that can be used for human dose translation.

Investigating long noncoding RNA HA117 and its possible regulatory network in osteosarcoma

Osteosarcoma, a primary malignant bone tumor, is the third most common cancer in children and adolescents under 20 years old. In recent decades, many osteosarcomar elated molecular targets, including long noncoding RNA (lncRNA), have been discovered or confirmed. This study aims to elucidate the gene expression and possible regulatory mechanisms of lncRNA HA117 in osteosarcoma. To achieve this, we downloaded 51 whole-transcriptome osteosarcoma sequencing samples from the NCBI Sequence Read Archive database and performed bioinformatics analysis. Geneexpression analysis of HA117 revealed no significant difference between the tumor and adjacent tissues. However, HA117 exhibited significant down-regulation in bothfresh and formalin‐fixed paraffin-embedded (FFPE) samples after chemotherapy. Bycombining two target gene prediction methods, we identified 11 and 83 target genes for HA117 in fresh and FFPE samples, respectively. Functional analysis indicated that these target genes are mainly located in the cytoplasm and nucleus, with most related to protein binding. In addition, Reactome analysis demonstrated that these target genes participate in the regulation of multiple metabolic pathways, predominantly in cellular responses to stress. Our findings suggest that chemotherapy may regulate downstream target genes by altering the expression of HA117, thereby inducing cellular stress response. Overall, our results indicate that HA117 may not function as an oncogene but could serve as a therapeutic target in osteosarcoma.

Elevated expression of N-myc downstream regulated gene 1 protein in glioblastomas reflects tumor angiogenesis and poor patient prognosis.

N-myc downstream regulated gene 1 (NDRG1) is a member of the NDRG family, of which four members (NDRG1, NDRG2, NDRG3, and NDRG4) have been identified. NDRG1 is repressed by c-MYC and N-MYC proto-oncogenes. NDRG1 is translated into a 43 kDa protein that is associated with the regulation of cellular stress responses, proliferation, and differentiation. In this study, we aimed to clarify the relationship between progression of glioblastoma (GB) IDH-wildtype and NDRG1 expression in tumor cells. We assessed the expression of NDRG1 in 41 GBs using immunostaining and evaluated its prognostic significance. NDRG1 expression by GBs was evaluated using Histoscore, which showed high and low scores in 23 and 18 cases, respectively. NDRG1-positive cells were strongly expressed in Ki-67 labeled proliferating tumor cells and CD105 positive proliferating microvessels around the area of palisading necrosis. Statistical analyses showed lower survival rates in the high-score group than the low-score group (P < 0.01). This study indicated that overexpression of NDRG1 by GB reflects tumor angiogenesis and poor patient prognosis.

Extracellular vesicles as mediators of stress response in embryo-maternal communication.

Introduction: The pivotal role of extracellular vesicles (EVs) in facilitating effective communication between the embryo and maternal cells during the preimplantation stage of pregnancy has been extensively explored. Nonetheless, inquiries persist regarding the alterations in EV cargo from endometrial cells under stress conditions and its potential to elicit specific stress responses in trophoblast cells. Thus, the aim of this study was to elucidate the involvement of EV miRNA miRNAs in transmitting stress signals from maternal cells to trophoblasts. Methods: The receptive endometrial epithelium analogue RL95-2 cells were subjected to stress induction with 200µM CoCl2 for 24h before EV isolation. JAr trophoblast spheroids, which serve as embryos, were subjected to treatment with stressed or unstressed EVs derived from RL95-2 cells for 24h. Transcriptomic alterations in the treated JAr spheroids as well as in the untreated group, as a negative control, were investigated by mRNA sequencing. Furthermore, the changes in EV miRNAs were assessed by sequencing EV samples. Results: A comprehensive analysis comparing the miRNA profiles between stressed and unstressed EVs revealed significant changes in 25 miRNAs. Furthermore, transcriptomic analysis of JAr spheroids treated with stressed RL95-2EVs versus unstressed EVs or the untreated group demonstrated 6 and 27 differentially expressed genes, respectively. Pathway enrichment analysis showed that stressed EVs induce alterations in gene expression in trophoblast cells, which is partially mediated by EV microRNAs. Discussion: Our results suggest that EVs can transfer stress signals from endometrial cells to the embryo. These discoveries shed new light on the mechanism underlying implantation failures under stress conditions. Unraveling the role of EVs in transmitting stress signals, can extend our knowledge to pave the way for targeted interventions to manage stress-related implantation failures.

Abstract Tu044: Cardiac Mitochondrial Dysfunction Induces Region-Specific Mitochondrial Stress Response In The Brain To Adapt Neuronal Changes

Background: The hippocampus and cortex are susceptible to changes in blood supply, metabolites, and oxygenation. However, how disrupted cardiac function affects these critical areas of the brain, leading to the cognitive and neurological consequences of heart failure, remains unclear. Hypothesis: We hypothesize that disrupted cardiac function cross-talks with the brain by inducing region-specific mitochondrial stress responses, leading to adaptive changes. Methods: We utilized cardiac-specific LonP1 knockout (LonP1cKO) mice to induce heart failure within 21 days of birth. Alongside cre- control mice, we assessed cerebral blood flow using Laser speckle contrast imaging, locomotor activity through a comprehensive laboratory animal monitoring system (CLAMS), and gene expression profiles in the hippocampus and cortex by RT-PCR. Student’s ‘t’ test determined statistical significance with a p-value&lt;0.05. Results: At 21 days, LonP1cKO mice demonstrated a significant (p&lt;0.0001) reduction in cerebral blood flow (587.1±33.68, n=7) compared to the control (1034±31.26, n=5). Additionally, there were notable decreases in both X and Y-axis ambulatory and total locomotor activities in LonP1cKO mice [XAMB (100.3±6.6 vs 224±13.6 n=16), YAMB) (67.9±4.7 vs 150±8.5 n=16), XTOT (351.8±18.1 vs 534.4±26.3 n=16) and YTOT (190.7±9.6 vs 354.9±17.07 n=16). RT-PCR analysis revealed significant upregulation of genes related to hypoxia and cellular stress (Hif1a, FGf2, Atf6), mitochondrial biogenesis (mtDNA, Tfam, mt-COI, mt-COII), mitochondrial stress response proteases (LonP1, Afg3l2, Spg7, Yme1l1), and downregulation in neurotrophic factors (Bdnf, Ngf, Gfap) in the hippocampus and cortex. Conclusion: The study highlights that cardiac dysfunction in LonP1cKO mice leads to mitochondrial and cellular stress response in the brain to adapt neuronal changes, suggesting a critical link between cardiac health and brain function regulated through mitochondrial stress response pathways.

Co-exposure of bisphenol A and selenium deficiency induces pyroptosis via ROS/NLRP3 pathway in chicken spleen

Bisphenol A (BPA) is widely applied in plastic products, which will produce immunotoxicity to organisms after spilling in the environment, and become a kind of endocrine disruptor. Selenium (Se) is an essential trace element and plays an important role in maintaining redox homeostasis and immune function. BPA exposure and Se deficiency often occur together in livestock and poultry farming, however, studies on the effects of joint exposure on chicken immunotoxins have not been reported. Therefore, this study established a chicken spleen and MDCC-MSB1 cell model under the combined effects of BPA exposure or/and Se deficiency. Transcriptomic analysis showed that BPA exposure and/or Se deficiency induced differential enrichment of positive regulatory pathways such as NLRP3 inflammatory complex assembly, inflammatory response and cellular oxidative stress response. In the -Se+BPA group, pathological damage was significantly increased, Se content decreased, BPA accumulation, oxidative stress and pyroptosis. Meanwhile, the roles and mechanisms of oxidative stress and pyroptosis in BPA exposure or/and Se deficiency-induced splenic tissue injury were investigated by using IF and qRT-PCR methods. The results showed that joint BPA exposure with Se deficiency resulted in more significant changes in the above outcomes than one of them. The oxidative stress inhibitor NAC effectually reduced Se deficiency and BPA-induced oxidative stress and pyroptosis, further suggests that oxidative stress mediated Se deficiency or/and BPA-induced pyroptosis. This study revealed that BPA exposure and Se deficiency induced spleen pyroptosis in chickens via the ROS/NLRP3 pathway. These results provide the theoretical basis for the toxicity of BPA in poultry and enrich the toxicological mechanism of combined exposure of Se deficiency and environmental toxins.

Crocetin Enhances Temozolomide Efficacy in Glioblastoma Therapy Through Multiple Pathway Suppression.

Glioblastoma multiforme (GBM) is an aggressive type of brain tumor that is difficult to remove surgically. Research suggests that substances from saffron, namely crocetin and crocin, could be effective natural treatments, showing abilities to kill cancer cells. Our study focused on evaluating the effects of crocetin on glioma using the U87 cell line. We specifically investigated how crocetin affects the survival, growth, and spread of glioma cells, exploring its impact at concentrations ranging from 75-150 μM. The study also included experiments combining crocetin with the chemotherapy drug Temozolomide (TMZ) to assess potential synergistic effects. Crocetin significantly reduced the viability, proliferation, and migration of glioma cells. It achieved these effects by decreasing the levels of Matrix Metallopeptidase 9 (MMP-9) and Ras homolog family member A (RhoA), proteins that are critical for cancer progression. Additionally, crocetin inhibited the formation of cellular structures necessary for tumor growth. It blocked multiple points of the Ak Strain Transforming (AKT) signaling pathway, which is vital for cancer cell survival. This treatment led to increased cell death and disrupted the cell cycle in the glioma cells. When used in combination with TMZ, crocetin not only enhanced the reduction of cancer cell growth but also promoted cell death and reduced cell replication. This combination therapy further decreased levels of high mobility group box 1 (HMGB1) and Receptor for Advanced Glycation End-products (RAGE), proteins linked to inflammation and tumor progression. It selectively inhibited certain pathways involved in the cellular stress response without affecting others. Our results underscore the potential of crocetin as a treatment for glioma. It targets various mechanisms involved in tumor growth and spread, offering multiple avenues for therapy. Further studies are essential to fully understand and utilize crocetin's benefits in treating glioma.

Glucose-Regulated Protein 78, via Releasing β-Catenin from Adherens Junctions, Facilitates Its Interaction with STAT3 in Mediating Retinal Neovascularization

Retinopathy due to neovascularization is one of the major causes of vision loss. To understand the mechanisms underlying retinal neovascularization, using the oxygen-induced retinopathy (OIR) model, we performed two-dimensional gel matrix-assisted laser desorption/ionization time-of-flight/time-of-flight analysis of normoxic and 24-hour post-OIR mice pups' retinas. Two-dimensional gel analysis revealed that glucose-regulated protein 78 (GRP78) is one of the several molecules induced by OIR in the retinal endothelial cells (ECs). Vascular endothelial growth factor A (VEGFA) also induced GRP78 expression independent of endoplasmic reticulum stress response in human retinal microvascular endothelial cells, and depletion of its levels reduced VEGFA-induced EC angiogenic responses. Consistent with these observations, EC-specific deletion of GRP78 inhibited OIR-induced retinal neovascularization. In exploring the mechanisms, we found that GRP78 binds with vascular endothelial-cadherin and releases adherens junction- but not Wnt-mediated β-catenin and that β-catenin, in turn, via interacting with STAT3, triggers cyclin D1 expression. Furthermore, depletion of β-catenin or cyclin D1 levels negated VEGFA-induced EC angiogenic responses and OIR-induced retinal neovascularization. EC-specific deletion of GRP78 also suppressed OIR-induced vascular leakage. In elucidating the upstream signaling, we found that activating transcription factor 6 mediates GRP78 induction in the modulation of VEGFA-induced EC angiogenic responses and OIR-induced retinal neovascularization. Together, these observations reveal that GRP78, independent of its response to endoplasmic reticulum stress, is involved in mediating EC angiogenic responses by VEGFA and retinal neovascularization by OIR. In view of these findings, it appears that GRP78 could be a desirable target for drug development against diabetic retinopathy.

The Stressogenic Impact of Bacterial Secretomes Is Modulated by the Size of the Milk Fat Globule Used as a Substrate.

Milk fat globules (MFGs) are produced by mammary epithelial cells (MECs) and originate from intracellular lipid droplets with a wide size distribution. In the mammary gland and milk, bacteria can thrive on MFGs. Herein, we aimed to investigate whether the response of MECs to the bacterial secretome is dependent on the MFG size used as a substrate for the bacteria, and whether the response differs between pathogenic and commensal bacteria. We used secretomes from both Bacillus subtilis and E. coli. Proinflammatory gene expression in MECs was elevated by the bacteria secretomes from both bacteria sources, while higher expression was found in cells exposed to the secretome of bacteria grown on large MFGs. The secretome of B. subtilis reduced lipid droplet size in MECs. When the secretome originated from E. coli, lipid droplet size in MEC cytoplasm was elevated with a stronger response to the secretome from bacteria grown on large compared with small MFGs. These results indicate that MEC response to bacterial output is modulated by bacteria type and the size of MFGs used by the bacteria, which can modulate the stress response of the milk-producing cells, their lipid output, and consequently milk quality.

LncRNA ILF3-AS1 mediates oxidative stress and inflammation through miR-504-3p/HMGB1 axis in a cellular model of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE), a prevalent neurological disorder, is associated with hippocampal oxidative stress and inflammation. A recent study reveals that the long noncoding RNA ILF3 divergent transcript (ILF3-AS1) level is elevated in the hippocampus of TLE patients; however, the functional roles of ILF3-AS1 in TLE and underlying mechanisms deserve further investigation. Hence, this study aimed to elucidate whether ILF3-AS1 is involved in the pathogenesis of TLE by regulating oxidative stress and inflammation and to explore its underlying mechanism in vitro. Human hippocampal neurons were subjected to a magnesium-free (Mg2+-free) solution to establish an in vitro model of TLE. The potential binding sites between ILF3-AS1 and miRNA were predicted by TargetScan/Starbase and confirmed by dual luciferase reporter assay. Cell viability and damage were assessed by cell counting kit-8 and lactate dehydrogenase assay kits, respectively. Levels of reactive oxygen species, malondialdehyde, and superoxide dismutase were determined by commercial kits. Levels of Interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-alpha were quantified by enzyme-linked immunosorbent assay. The expressions of gene and protein were determined by quantitative real-time polymerase chain reaction and Western blot analysis. In Mg2+-free-treated hippocampal neurons, both ILF3-AS1 and HMGB1 were highly up-regulated, whereas miR-504-3p was down-regulated. ILF3-AS1 knockdown ameliorated Mg2+-free-induced cellular damage, oxidative stress, and inflammatory response. Bioinformatics analysis revealed that miR-504-3p was a target of ILF3-AS1 and was negatively regulated by ILF3-AS1. MiR-504-3p inhibitor blocked the protection of ILF3-AS1 knockdown against Mg2+-free-induced neuronal injury. Further analysis presented that ILF3-AS1 regulated HMGB1 expression by sponging miR-504-3p. Moreover, HMGB1 overexpression reversed the protective functions of ILF3-AS1 knockdown. Our findings indicate that ILF3-AS1 contributes to Mg2+-free-induced hippocampal neuron injuries, oxidative stress, and inflammation by targeting the miR-504-3p/HMGB1 axis. These results provide a novel mechanistic understanding of ILF3-AS1 in TLE and suggest potential therapeutic targets for the treatment of epilepsy.

Genome-wide DNA methylation profiles regulate distinct heat stress response in zebu (Bos indicus) and crossbred (Bos indicus×Bos taurus) cattle.

Epigenetic variations result from long-term adaptation to environmental factors. The Bos indicus (zebu) adapted to tropical conditions, whereas Bos taurusadaptedto temperate conditions; hence native zebu cattle and its crossbred (B indicus×B taurus) show differences in responses to heat stress. The present study evaluated genome-wide DNA methylation profiles of these two breeds of cattle that may explain distinct heat stress responses. Physiological responses to heat stress and estimated values of Iberia heat tolerance coefficient and Benezra's coefficient of adaptability revealed better relative thermotolerance of Hariana compared to the Vrindavani cattle. Genome-wide DNA methylation patterns were different for Hariana and Vrindavani cattle. The comparison between breeds indicated thepresence of 4599 significant differentially methylated CpGs with 756 hypermethylated and 3845 hypomethylated in Hariana compared to the Vrindavani cattle. Further, we found 79 genes that showed both differential methylation and differential expression that are involved in cellular stress response functions. Differential methylations in the microRNA coding sequences also revealed their functions in heat stress responses. Taken together, epigenetic differences represent thepotential regulation of long-term adaptation of Hariana (B indicus) cattle to the tropical environment and relative thermotolerance.

Blue light photobiomodulation induced osteosarcoma cell death by facilitating ferroptosis and eliciting an incomplete tumor cell stress response

To investigate the potential of blue light photobiomodulation (PBM) in inducing ferroptosis, a novel form of regulated cell death, in OS cells, considering its known effectiveness in various cancer models. In this investigation, we exposed human OS cell lines, HOS and MG63, to different wavelengths (420, 460 and 480 nm) of blue light at varying irradiances, and examined cellular responses such as viability, apoptosis, levels of reactive oxygen species (ROS), and mitochondrial membrane potential (MMP). Transcriptome sequencing was employed to unravel the molecular mechanisms underlying blue light-induced effects, with validation via quantitative real-time PCR (qRT-PCR). Our findings revealed a wavelength- and time-dependent decrease in cell viability, accompanied by increased apoptosis and oxidative stress. Transcriptomic analysis identified differential expression of genes associated with ferroptosis, oxidative stress, and iron metabolism, further validated by qRT-PCR. These results implicated ferroptosis as a significant mechanism in the blue light-induced death of OS cells, potentially mediated by ROS generation and disruption of iron homeostasis. Also, An incomplete stress response was observed in MG63 cells induced by blue light exposure. Hence, blue light PBM holds promise as a therapeutic approach in OS clinical investigations; however, additional exploration of its underlying mechanisms remains imperative.

Assessing the phytotoxic effects of class A foam application on northern Europe tree species: a short-term study on implications for wildfire management and ecosystem health

Wildfires are an ever-increasing issue due to the driving forces of climate change. Weather events that lead to higher wildfire potential are likely to increase and thus new fire management methods via more sustainable fire suppressant class A foams rather than retardants are being developed. However, despite their adherence to regulations, foam impact on targeted ecosystems, namely forests and forest trees is poorly studied. We aimed to investigate how three tree species (Pinus sylvestris, Alnus glutinosa and Picea abies) will react to a one-time class A foam application. Two separate trials were conducted. During the first the foam was applied to seeds and during the other – to 1-year-old seedlings. Tree growth and physiological status were evaluated. Stress criteria for cellular damage, non-antioxidant and antioxidant stress response and photosynthesis efficacy were measured. Results showed an obvious species effect, as all three reacted differently. The dose effect was also notable, with the higher application rate leading to a proportionally bigger response. Overall, pines were negatively impacted, spruce were positively affected, and alders didn’t experience a notable change. This leads us to conclude that pending the limitation of this experiment the tested foam while phytotoxic in some cases, is unlikely to affect tree survival rates under field conditions and any physiological responses are likely transient in nature.

SGK1 promotes the lipid accumulation via regulating the transcriptional activity of FOXO1 in bovine

ObjectivesSerum/glucocorticoid-inducible kinase 1 (SGK1) gene encodes a serine/threonine protein kinase that plays an essential role in cellular stress response and regulation of multiple metabolic processes. However, its role in bovine adipogenesis remains unknown. In this study, we aimed to clarify the role of SGK1 in bovine lipid accumulation and improvement of meat quality.MethodsPreadipocytes were induced to differentiation to detect the temporal expression pattern of SGK1. Heart, liver, lung, spleen, kidney, muscle and fat tissues were collected to detect its tissue expression profile. Recombinant adenovirus and the lentivirus were packaged for overexpression and knockdown. Oil Red O staining, quantitative real-time PCR, Western blot analysis, Yeast two-hybrid assay, luciferase assay and RNA-seq were performed to study the regulatory mechanism of SGK1.ResultsSGK1 showed significantly higher expression in adipose and significantly induced expression in differentiated adipocytes. Furthermore, overexpression of SGK1 greatly promoted adipogenesis and inhibited proliferation, which could be shown by the remarkable increasement of lipid droplet, and the expression levels of adipogenic marker genes and cell cycle-related genes. Inversely, its knockdown inhibited adipogenesis and facilitated proliferation. Mechanistically, SGK1 regulates the phosphorylation and expression of two critical proteins of FoxO family, FOXO1/FOXO3. Importantly, SGK1 attenuates the transcriptional repression role of FOXO1 for PPARγ via phosphorylating the site S256, then promoting the bovine fat deposition.ConclusionsSGK1 is a required epigenetic regulatory factor for bovine preadipocyte proliferation and differentiation, which contributes to a better understanding of fat deposition and meat quality improvement in cattle.

Differential in vitro cytotoxic effects and metabolomic insights into raw and powdered Manuka honey through UPLC-Q-TOF-MS

Manuka honey (MH) has garnered much attention due to its remarkable antimicrobial, anticancer, immunomodulatory and wound-healing properties. This study compared the antiproliferative effects of raw and powdered MH (pMH) on various human and murine cancer cell lines. A detailed metabolomics analysis was also carried out using untargeted ultrahigh-performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry (UPLC-Q-TOF-MS) to compare the constituents in raw MH and pMH. The results of the viability studies showed that both raw MH and pMH caused a dose-dependent inhibition of tumor cell growth at concentrations of > 1% w/v (equivalent to ~ 10 mg/ml). A differential susceptibility to MH was observed among the cell lines with the human MDA-MB-231 and A549 cells and murine B16.F10 cells being relatively resistant to MH while the murine MC38 colorectal adeno-carcinoma cells showing the most sensitivity. The effect of raw MH and pMH on cell viability was validated using 2 indepndent assays. Metabolomics analysis detected 2440 compounds, out of which 833 were successfully identified. Among these, 90 phytochemical compounds, predominantly comprising terpenoids, flavonoids, coumarins and derivatives, and phenylpropanoic acids, and 79 lipids were identifiable. Significant differences in 5 metabolite classes, including flavonoids, phenols, terpenoids, carbohydrates, and organic acids were observed between the raw and pMH. Moreover, several altered metabolic pathways were identified in pMH compared to raw MH, such as energy metabolism, amino acid metabolism, and various other pathways that collectively influence biological functions associated with cellular growth, signaling, and stress response.

Effects of inhibitors of DNA repair enzymes OGG1 and MTH1 on the replication of African swine fever virus

African swine fever virus (ASFV), as a contagious viral pathogen, is responsible for the occurrence of African swine fever (ASF), a rapidly spreading and highly lethal disease. Since ASFV was introduced into China in 2018, it has been quickly spread to many provinces, which brought great challenges to the pig industry in China. Due to the limited knowledge about the pathogenesis of ASFV, neither vaccines nor antiviral drugs are available. We have found that ASFV infection can induce oxidative stress responses in cells, and DNA repair enzymes play a key role in this process. This study employed RNA interference, RT-qPCR, Western blotting, Hemadsorption (HAD), and flow cytometry to investigate the effects of the inhibitors of DNA repair enzymes OGG1 and MTH1 on ASFV replication and evaluated the anti-ASFV effects of the inhibitors. This study provides reference for the development of anti-viral drugs.

Oxidative stress elicits the remodeling of vimentin filaments into biomolecular condensates

The intermediate filament protein vimentin performs an essential role in cytoskeletal interplay and dynamics, mechanosensing and cellular stress responses. In pathology, vimentin is a key player in tumorigenesis, fibrosis and infection. Vimentin filaments undergo distinct and versatile reorganizations, and behave as redox sensors. The vimentin monomer possesses a central α-helical rod domain flanked by N- and C-terminal low complexity domains. Interactions between this type of domains play an important function in the formation of phase-separated biomolecular condensates, which in turn are critical for the organization of cellular components. Here we show that several oxidants, including hydrogen peroxide and diamide, elicit the remodeling of vimentin filaments into small particles. Oxidative stress elicited by diamide induces a fast dissociation of filaments into circular, motile dots, which requires the presence of the single vimentin cysteine residue, C328. This effect is reversible, and filament reassembly can occur within minutes of oxidant removal. Diamide-elicited vimentin droplets recover fluorescence after photobleaching. Moreover, fusion of cells expressing differentially tagged vimentin allows the detection of dots positive for both tags, indicating that vimentin dots merge upon cell fusion. The aliphatic alcohol 1,6-hexanediol, known to alter interactions between low complexity domains, readily dissolves diamide-elicited vimentin dots at low concentrations, in a C328 dependent manner, and hampers reassembly. Taken together, these results indicate that vimentin oxidation promotes a fast and reversible filament remodeling into biomolecular condensate-like structures, and provide primary evidence of its regulated phase separation. Moreover, we hypothesize that filament to droplet transition could play a protective role against irreversible damage of the vimentin network by oxidative stress.

The sea urchin embryo and the cell stress responses: new perspectives

In addition to many industrial activities that release pollutants in coastal areas, numerous human behaviors contribute to climate change, inducing global warming, which can also reshape the environmental impacts of some pollutants. Therefore, it is extremely important to develop new tools that can detect pollutants and environmental changes quickly and easily with high levels of sensitivity. The sea urchin embryo is a well-known model used worldwide in many research fields, including marine ecotoxicology, as a huge range of contaminants can affect its embryonic development with species-specific sensitivity. Morphological abnormalities are already considered biomarkers to evaluate the effects of pollutants, and, indeed, the sea urchin has long been used as one of the key species in a battery of bioassays to assess the toxicity of many pollutants and dredged sediments. At the cellular level, the molecular mechanisms activated against a stress agent constitute what is known as the “cell stress response,” analyzed here within a whole organism, namely, the sea urchin embryo. In this minireview, we have reported the available molecular biomarkers linked to morphological abnormalities and the genes affected by environmental changes and emerging pollutants, highlighting those studies that use high-throughput screening approaches to evaluate the effects of environmental conditions on sea urchin embryos.

Reversible acetylation of HDAC8 regulates cell cycle

HDAC8, a member of class I HDACs, plays a pivotal role in cell cycle regulation by deacetylating the cohesin subunit SMC3. While cyclins and CDKs are well-established cell cycle regulators, our knowledge of other regulators remains limited. Here we reveal the acetylation of K202 in HDAC8 as a key cell cycle regulator responsive to stress. K202 acetylation in HDAC8, primarily catalyzed by Tip60, restricts HDAC8 activity, leading to increased SMC3 acetylation and cell cycle arrest. Furthermore, cells expressing the mutant form of HDAC8 mimicking K202 acetylation display significant alterations in gene expression, potentially linked to changes in 3D genome structure, including enhanced chromatid loop interactions. K202 acetylation impairs cell cycle progression by disrupting the expression of cell cycle-related genes and sister chromatid cohesion, resulting in G2/M phase arrest. These findings indicate the reversible acetylation of HDAC8 as a cell cycle regulator, expanding our understanding of stress-responsive cell cycle dynamics.

Do tunneling nanotubes drive chemoresistance in solid tumors and other malignancies?

Intercellular communication within the tumor microenvironment (TME) is essential for establishing, mediating, and synchronizing cancer cell invasion and metastasis. Cancer cells, individually and collectively, react at the cellular and molecular levels to insults from standard-of-care treatments used to treat patients with cancer. One form of cell communication that serves as a prime example of cellular phenotypic stress response is a type of cellular protrusion called tunneling nanotubes (TNTs). TNTs are ultrafine, actin-enriched contact-dependent forms of membrane protrusions that facilitate long distance cell communication through transfer of various cargo, including genetic materials, mitochondria, proteins, ions, and various other molecules. In the past 5-10 years, there has been a growing body of evidence that implicates TNTs as a novel mechanism of cell-cell communication in cancer that facilitates and propagates factors that drive or enhance chemotherapeutic resistance in a variety of cancer cell types. Notably, recent literature has highlighted the potential of TNTs to serve as cellular conduits and mediators of drug and nanoparticle delivery. Given that TNTs have also been shown to form in vivo in a variety of tumor types, disrupting TNT communication within the TME provides a novel strategy for enhancing the cytotoxic effect of existing chemotherapies while suppressing this form of cellular stress response. In this review, we examine current understanding of interplay between cancer cells occurring via TNTs, and even further, the implications of TNT-mediated tumor-stromal cross-talk and the potential to enhance chemoresistance. We then examine tumor microtubes, an analogous cell protrusion heavily implicated in mediating treatment resistance in glioblastoma multiforme, and end with a brief discussion of the effects of radiation and other emerging treatment modalities on TNT formation.