Activation of the endoplasmic reticulum (ER) stress is an adaptive response to disturbed ER homeostasis caused by the accumulation of misfolded or unfolded proteins, or an acute increase in the entry of newly synthesised or mutated proteins into the ER lumen. Overwhelmed or prolonged ER stress causes apoptotic cell death or a maladaptive state of the cell, resulting in various pathological diseases including cancer, inflammation and aging. With a screening of a chemical compound library, here we show that inhibition of histone deacetylases (HDACs) induces ER stress, along with increased retro-translocation of misfolded proteins from the ER lumen to the cytosol for proteasomal degradation. HDAC inhibitors (HDACi) activate the PERK-eIF2α subbranch of the unfolded protein response (UPR), whereas the IRE1α and ATF6 pathways are not affected. Inhibition of the PERK subbranch with specific siRNA or a small molecule inhibitor ameliorates HDACi-induced apoptotic cell death. In addition, a non-phosphorylatable mutant of eIF2α, a critical substrate that transduces the PERK-mediated ER stress response, abolishes apoptosis induced by HDACi, but not by the DNA damage reagent doxorubicin. HDACi reduce the sizes of tumours formed from wildtype but not eIF2αS51A-mutant cells in a xenograft model, further demonstrating the involvement of the PERK subbranch in HDACi-induced ER stress and cell death. Our study reveals novel effects of the well-studied family of HDAC inhibitors, which can be explored further in clinics to treat certain types of cancer manifested with abnormal ER stress conditions.

Epigenetic modifications, including histone post-translational modifications, are central drivers of age-associated structural and functional changes in the genome, influencing gene expression and leading to changes in cellular resilience. Epigenetic modifications are thus a target for therapies to prevent or treat age-related decline in health and lifespan. In this study, we measured the effects of inhibiting histone deacetylases (HDACs) and the histone methyltransferase, SETDB1, on lifespan, reproduction, and stress response in the rotifer Brachionus manjavacas, a model organism for aging studies. Rotifers were exposed to three pharmaceutical compounds, the HDAC inhibitors β-hydroxybutyrate and sodium butyrate and the SETDB1 inhibitor mithramycin A. Changes in global histone modification levels, lifespan, reproduction, and heat stress resistance were quantified. Global histone acetylation levels increased with β-hydroxybutyrate and sodium butyrate treatments. Histone 3 lysine 9 trimethylation (H3K9me3) levels were reduced by treatment with mithramycin A. β-hydroxybutyrate significantly extended lifespan without modifying heat stress resistance. In contrast, mithramycin A increased both lifespan and heat stress tolerance. Sodium butyrate specifically improved heat stress resistance without affecting lifespan. Importantly, none of the three treatments had a significant impact on lifetime reproduction. These findings provide insights into the role of histone modifications in aging and suggest potential interventions targeting epigenetic marks to promote longevity and resilience.

Recent studies emphasize the pivotal role of endoplasmic reticulum (ER) stress in Alzheimer's disease (AD), highlighting the need for further investigation into this critical link. In response to ER stress, cells increase reactive oxygen species (ROS) production, leading to heightened oxidative stress. This interplay has sparked interest in antioxidant molecules such as squalene (SQ) as potential therapeutic agents. The primary objective of this study was to examine the impact of SQ on the unfolded protein response (UPR) pathway triggered by ER stress in an in vitro AD model. Herein, molecular docking analysis was performed to evaluate SQ interactions with target proteins, followed by in vitro assays. Human bone marrow-derived mesenchymal stem cells were differentiated into neuronal-like cells and characterized via immunostaining. The cells were then exposed to Aβ1-42 toxicity to establish an in vitro AD model. To assess the effects of SQ treatment following Aβ1-42 exposure, UPR-related proteins (BIP, p-PERK, PERK, eIF2α, p-eIF2α, ATF4, CHOP) were analysed by Western blotting; ROS levels were quantified to evaluate oxidative stress, and a TUNEL assay was performed to assess apoptosis. Our findings indicate that SQ alters protein expression within the UPR pathway in the AD experimental model. Notably, amyloid-β levels were significantly reduced in the SQ-treated group (p˂0.001). Furthermore, SQ reduced ROS levels. These results suggest that SQ holds potential as a therapeutic agent for mitigating amyloid-β toxicity.

Pembrolizumab is an important immune checkpoint inhibitor for advanced urothelial carcinoma (aUC). However, there are no established biomarkers to predict its efficacy. Extracellular vesicles (EVs) are liquid bilayer structures released from various cells that contain genetic information such as DNAs, RNAs, and proteins. EVs-derived long non-coding RNAs (lncRNAs) have been reported to be involved play in tumor progression and drug resistance. We investigated whether EVs-derived lncRNA MAFG-AS1 is effective in predicting pembrolizumab efficacy.

Biostimulant use is a promising agricultural strategy to maintain yield while decreasing mineral fertilisers and pesticides. Whereas the positive effect of protein hydrolysates (PH) on growth and yield has already been described, the underlying processes are not well understood. To better identify and characterise the physiological and molecular targets of PH, we first carried out in vitro experiments using the model species Arabidopsis thaliana. PH stimulated Arabidopsis root growth in a dose-dependent manner, with high concentrations inhibiting growth. After having determined a stimulating PH concentration, we performed metabolomic and transcriptomic analyses. We observed that PH application increased amino acid levels in the plants, including a high level of glutamine, although it was only present in trace amounts in PH. These results suggest that amino acids are taken up and metabolized in the plant. PH also had a profound impact on the Arabidopsis transcriptome, with genes involved in nitrate and amino acid transport and assimilation showing a clear up- and down-regulation, respectively. For example, the expression of the high-affinity nitrate transporter NRT2.1 (NITRATE TRANSPORTER 2) was decreased, and consistently high-affinity nitrate uptake and the development of lateral roots were diminished. The PH contained high levels of branched amino acids, which are known to induce the TOR kinase activity, a major driver of growth. Finally, high-throughput phenotyping also showed that PH supply increased shoot growth. In conclusion, our findings show that PH has a clear and robust effect on Arabidopsis growth, but also on the transcriptome, metabolite levels, and physiological processes like nitrogen metabolism.

RSK plays a central role in oncogenic signaling, yet its broader regulatory impact in esophageal squamous cell carcinoma (ESCC) remains unclear. We performed integrated phosphoproteomics and kinase-substrate network analysis to elucidate global signaling alterations following RSK inhibition in ESCC cells. In Eca-109 cells, treatment with a moderate concentration of the selective RSK inhibitor SL0101 effectively suppressed proliferation without inducing apoptosis. To elucidate potential compensatory survival mechanisms, we performed integrated proteomic and phosphoproteomic analyses, which revealed that RSK inhibition provokes broad cellular adaptations. Importantly, the magnitude of these effects varied across pathways. Ribosome biogenesis and mitochondrial organization exhibited substantial perturbation primarily at the proteomic level, reflecting system-level dysregulation. Phosphoproteomic analysis revealed that large-magnitude alterations in nuclear transport and mRNA processing, and more subtle, fine-tuned modulation of mitotic fidelity. Kinase activity inference further identified MAPK14, CDK2, SRPK3, AKT1, PLK1, and PIM2 as principal regulators that may regulate compensatory signaling in response to RSK suppression. Taken together, our study reveals that RSK inhibition reprograms kinase networks to enforce stress adaptation, maintaining oncogenic homeostasis despite perturbations. These findings highlight a potential therapeutic window for early intervention strategies, suggesting that combination strategies may enhance the efficacy of RSK-directed therapies in ESCC.

Hypocrellin A (HA), a photodynamic perylenequinone pigment from Shiraia fruiting bodies, functions as an efficient photosensitizer for clinical photodynamic therapy. Glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme of the pentose phosphate pathway (PPP), governs carbon flux into NADPH production. This study elucidates G6PDH's regulatory role in HA biosynthesis in Shiraia sp. S9. Bamboo polysaccharide (BPS) elicitation (100 mg/L) significantly enhanced HA production to 428.1 mg/L, 1.6-fold higher than controls after 5 days. We cloned the G6PDH gene and demonstrated that BPS upregulated its expression and activity, concomitant with increased reactive oxygen species (ROS; H2O2 and O2•-) and nitric oxide (NO) generation. ROS production was mediated by NADPH oxidase induction, while NO generation was attributed to elevated nitric oxide synthase and nitrate reductase activities. Critically, the G6PDH inhibitor glucosamine (1.0 mM) suppressed both H2O2 and NO production. These ROS/NO signals upregulated key HA biosynthetic (PKS, Omef) and transport (MFS) genes. Our findings establish G6PDH as a central regulator of BPS-induced HA biosynthesis via ROS/NO signaling, revealing novel metabolic crosstalk between the PPP and fungal perylenequinone biosynthesis. This work presents BPS elicitation as a biotechnological strategy for scalable HA production in Shiraia mycelium cultures.

Upon reacting with cellular components, Hg(II) ions elicit the production of reactive oxygen species (ROS). While the ROS-promoted cytotoxic and genotoxic effects induced by Hg(II) have been widely described in eukaryotes, such effects have been less studied in bacteria. In this work, the prokaryotic environmental model Bacillus subtilis was employed to evaluate the cytotoxic and genotoxic impact of Hg(II) over strains proficient or deficient in SOS, general stress and antioxidant responses, as well as the global transcriptional response elicited by this ion. The exposure to HgCl2 significantly increased the mutation frequency to rifampicin resistance (RifR) in WT and mutant strains, suggesting a major contribution of these pathways in counteracting the genotoxic effects of Hg(II). Detection of A → T and C → G transversion mutations in the rpoB gene of Hg(II)-exposed cells suggested the generation of 8-oxo-guanines (8-OxoGs) and other oxidized DNA bases. The RNA-seq study revealed upregulation of genes involved in efflux and/or reduction of metal ions, synthesis of sulfur-containing molecules, and downregulation of genes implicated in iron metabolism and cell envelope stress. Therefore, our results indicate that metal extrusion and scavenging of Hg(II) by thiol-rich molecules may constitute a line of defense of B. subtilis that counteracts the noxious effects of ROS resulting from an imbalance in iron metabolism elicited by this ion.

Thoracic tumors, including lung adenocarcinoma (LUAD) and malignant pleural mesothelioma (MM), remain a leading cause of cancer-related deaths, primarily due to the challenges in treating advanced thoracic tumors. New drugs with optimal efficacy and minimal side effects are required. Traditional Chinese Medicine (TCM) compounds offer a promising alternative. Our study explores the effectiveness of the TCM compound Narciclasine against LUAD and MM. Spheroids derived from LUAD (A549, LuCa1) and MM (MSTO-211H, H2052/484) cell lines were treated with Narciclasine, and efficacy was evaluated through cell morphology analysis, intracellular adenosine triphosphate (ATPi) and lactate dehydrogenase (LDH) assays, RT-qPCR, and western blot analysis. Narciclasine reduced cell viability, with an 80% reduction in viability in MM. It induced cell apoptosis and inhibited proliferation. The IC50 values for Narciclasine ranged from 50 to 150 nM. In silico analysis identified shared gene targets between Narciclasine, LUAD, and MM. Narciclasine modulated the expression of genes associated with ferroptosis and cuproptosis, and the epithelial-to-mesenchymal transition. Narciclasine shows promising efficacy against LUAD and MM spheroid models. These findings warrant further investigation into the mechanisms of action and potential clinical application of Narciclasine for treating thoracic malignancies, offering hope for improved therapeutic options and patient outcomes.

Caffeic acid (CA), 3-O-caffeoylquinic acid (3-CQA), and 5-O-caffeoylquinic acid (5-CQA) were subjected to treating stimulated mouse P815 mast cells to unravel their antiallergic potential. β-Hexosaminidase release, appearance, morphology change, cytokine secretions, and degranulation-related pathway gene expressions, including Mas-related G protein-coupled receptor, member B2 (MRGP receptor B2), and inositol 1,4,5-triphosphate receptor 2 (IP3 receptor 2), in the stimulated mast cells were measured. An ELISA was used to determine the secreted cytokines. The relative gene expression folds were analyzed with reverse transcription real-time quantitative polymerase chain reaction. Correlations between gene expressions and different parameters were analyzed using the Pearson product-moment correlation coefficient (r). The results showed that CA had a superior effect than 3-CQA and 5-CQA on reducing β-hexosaminidase release, IL-4, and IL-6 cytokine secretions by the compound 48/80 (C48/80)- and 5-hydroxymethyl-2-furaldehyde (5-HMF)-stimulated mast cells. CA increased intact mast cell numbers but reduced granule releases, evidencing that CA may soothe activated mast cells. CA reduced IP3 receptor 2 gene expression. There were positive correlations between IP3 receptor 2 gene expression and IL-4 and IL-6 cytokine secretions. Our results conclude that CA might inhibit degranulation, IL-4 and IL-6 cytokine secretions, and IP3 receptor 2 gene expression in C48/80-stimulated mouse P815 mast cells.

The hypothalamus is a key regulator of fundamental physiological processes and a site of adult neurogenesis. Allopregnanolone (ALLO) is a neurosteroid that mitigates the adverse effects of stress on the central nervous system and also affects neurogenesis. This study examined the effects of acute stress and ALLO administration (separately or in combination) into the third brain ventricle on the expression of neurotrophins and Trkβ receptor in distinct hypothalamic areas of sexually active female sheep. Expression of genes encoding brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4) and the Trkβ receptor was analyzed in the medial basal hypothalamus (MBH), arcuate nucleus (ARC), anterior hypothalamus (AHA), paraventricular nucleus (PVN), and preoptic area (POA). Acute stress stimulated the expression of neurotrophins (BDNF, NGF, and NT-3) in the ARC and PVN, while inhibitory effects predominated in the MBH, AHA and POA. ALLO alone mainly suppressed neurotrophins expression, while stimulatory effects were limited to the BDNF-Trkβ system in the ARC and Trkβ in the AHA. When combined with stress, ALLO either counteracted stress-induced increases in neurotrophins expression or produced no effect. The results demonstrate that acute stress can differentially modify neurotrophins mRNA expression in hypothalamic regions, activating neurotrophic activity in specific nuclei. The predominant inhibitory effect of ALLO on neurotrophin synthesis, particularly under conditions of acute stress, may help prevent excessive neuronal activation. Conversely, the upregulation of the BDNF-Trkβ system in the ARC indicates a positive relationship between this neurosteroid and hypothalamic adult neurogenesis.

On acid soils, aluminum (Al3+) is typically toxic to plants, though certain species like Pogostemon cablin (patchouli) show growth stimulation. This study reveals that Al functions as a root development stimulant in patchouli under acidic conditions. Treatment with 1.0 mM AlCl3 for 34 days significantly enhanced root architecture, increasing total root length by 172.12% and root dry weight by 161.75%, without affecting shoot biomass. Structural analysis showed Al accumulation in root tip meristems and lateral root primordia, triggering a 103.77% increase in meristem activity and a 111.9% promotion of cell elongation. Physiological assays showed that Al treatment reduced H2O2 and malondialdehyde (MDA) levels by 49.2% and 67.6%, respectively, while boosting glutathione (GSH) content by 187.5%, thereby mitigating oxidative membrane damage mainly through the non-enzymatic antioxidant system. Moreover, Al deprivation impaired lateral root elongation, highlighting its functional importance. Gene expression profiling further indicated that Al regulated pathways related to cell proliferation, cell wall remodeling, and lateral root development. Taken together, our findings uncover a novel mechanism by which Al, traditionally regarded as toxic, acts as a stimulator of root development in patchouli, providing new insights into the molecular networks underlying plant abiotic stress responses.

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperactivation and dysregulated cytokine signaling, with nuclear factor kappa B (NF-κB), a master transcription factor that regulates immune and inflammatory gene expression, playing a central role. Adalimumab, a monoclonal antibody that inhibits tumor necrosis factor alpha (TNF-α), is widely used in psoriasis therapy, yet its molecular effects on NF-κB-associated genes and microRNAs (miRNAs) in keratinocytes remain insufficiently defined. In this study, immortalized human keratinocytes (HaCaT cells) were exposed to lipopolysaccharide (LPS) to induce inflammatory stress and treated with adalimumab for 2, 8, and 24 h. Transcriptome-wide profiling was performed using messenger RNA (mRNA) and miRNA microarrays, followed by validation with reverse transcription quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). Bioinformatic analyses included prediction of miRNA-mRNA interactions, construction of protein-protein interaction (PPI) networks, and gene ontology (GO) enrichment. Adalimumab reversed LPS-induced upregulation of NF-κB-associated genes, including inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB), interleukin-1 receptor-associated kinase 1 (IRAK1), TNF receptor-associated factor 2 (TRAF2), mitogen-activated protein kinase kinase kinase 7 (MAP3K7), and TNF alpha-induced protein 3 (TNFAIP3), with concordant changes observed at the protein level. Several regulatory miRNAs, notably miR-1297, miR-30a, miR-95-5p, miR-125b, and miR-4329, showed reciprocal expression changes consistent with anti-inflammatory activity. STRING analysis identified IKBKB as a central hub in the PPI network, while GO enrichment highlighted immune regulation, apoptosis, and NF-κB signaling. These findings demonstrate that adalimumab modulates NF-κB activity in keratinocytes through coordinated regulation of gene, protein, and miRNA expression, providing mechanistic insight into TNF-α blockade in psoriasis.

Fusarium species and the mycotoxins produced by them represent a significant problem for agriculture and human health. Thus, the development of novel management strategies and tools is of high importance. Spray-induced gene silencing (SIGS), based on the natural mechanism of RNA interference (RNAi), has been considered as a highly specific and ecologically safe alternative to chemical fungicides, the use of which is restricted by the emergence of resistant strains and environmental concerns. At the same time, massive application of SIGS is challenged by the degradability of RNA molecules in the environment. Nanoparticles have been widely applied to protect RNA from degradation and improve its action. The aims of this study were to evaluate whether RNAi-mediated silencing of the regulatory FgVe1 gene leads to inhibition of growth, mycotoxin production, and pathogenicity of Fusarium graminearum and whether the use of CaP nanoparticles (CaPs) as double-stranded RNA (dsRNA) carriers enhances and prolongs the silencing effect. It was shown that dsRNA treatment of fungal liquid cultures resulted in 19.78-fold silencing of FgVe1 expression as well as inhibition of expression of genes related to secondary metabolism, including those involved in trichothecene and aurofusarin biosynthesis, thus leading to a reduction in DON accumulation and changes in culture color. The results also demonstrated that naked dsRNA and CaPs:dsRNA nanocomplexes differed in their abilities to induce a high silencing effect at different time points. Naked dsRNA proved more effective in inducing silencing in the early stages of fungal growth, whereas application of nanocomplexes provided a prolonged effect up to 10 days in liquid cultures and up to 14 days on detached leaves. The obtained data can be considered as a basis for the further development of new efficient SIGS-based plant protection strategies.

For patients with metastatic uveal melanoma (UM), tebentafusp is currently the only systemic therapy approved by the EMA and FDA, but its use is limited to HLA-A*02:01-positive individuals. Immune checkpoint blockade (ICB) represents another option, though only a small subgroup of patients benefits, and no reliable predictive biomarkers are available to date. The aim of this study was therefore to identify parameters associated with favorable ICB response. Tumor samples and clinical data from 30 patients were analyzed. Group A (n = 16) showed clinical benefit, while Group B (n = 14) experienced disease progression. NanoString® analyses revealed 258 upregulated genes in Group A, including IDO1, CD28, and CCL8. The enriched pathways were predominantly linked to immune activation, leukocyte adhesion, and responses to external stimuli. Immunohistochemistry confirmed significantly higher CD28 expression on infiltrating immune cells in Group A, while a machine learning approach identified CCL8 as a predictive marker with ~78% accuracy. Overall survival differed significantly between the groups. These findings indicate that patients responding to ICB display tumors with enhanced immune activation. CD28 and CCL8 emerged as promising candidates and should be validated in prospective studies to determine their clinical utility.

The emergence of multidrug-resistant Pseudomonas aeruginosa strains is increasingly becoming a critical threat to global health. Among the resistance mechanisms, the MexAB-OprM efflux pump confers P. aeruginosa with an efficient method to export a broad spectrum of antibiotics. The antimicrobial peptide Esc (1-21)-1c was shown to downregulate this efflux system, though its mechanism of action has not been unveiled thus far. Here, we employed a combination of molecular modeling and experimental methods to investigate the precise peptide inhibitory mechanism. Functional proteomic experiments revealed the P. aeruginosa protein Q9I5H3, homologous to E. coli QseB, as a putative key target of Esc(1-21)-1c. Molecular docking predicted stable peptide-protein interactions, which were experimentally validated through fluorescence spectroscopy. Furthermore, electrophoretic mobility shift assays demonstrated that Q9I5H3 specifically binds the MexAB-OprM promoter and that Esc(1-21)-1c competitively inhibits this interaction in a dose-dependent manner. These findings reveal a previously uncharacterized regulatory pathway for efflux pump control and highlight Q9I5H3 as a promising therapeutic target against multidrug-resistant P. aeruginosa.

Interferon Regulatory Factor 5 plays an important role in the regulation of innate immune responses by amplifying the Nuclear Factor κB response, which is critical in gout inflammation. Furthermore, the rs4728141 polymorphism C allele was associated with both increased IRF5 expression and susceptibility to gout. We examine the association between rs4728141 and cytokine production in response to various Toll-Like Receptor ligands and describe the transcriptomic and proteomic changes observed in patients with gout and controls in relation to this polymorphism. We examine the transcriptome of freshly isolated peripheral blood mononuclear cells (PBMCs) from 93 normouricemic donors and 63 gout patients as well as serum inflammatory proteome in 197 control and 195 gout samples. Stimulation experiments of freshly isolated human PBMCs were performed over 24 h, followed by RNA-sequencing in gout patients and cytokine production measurement by ELISA in normouricemic donors and gout patients. The rs4728141 C allele was associated with increased IL-1β expression in unstimulated PBMCs of controls, but not in gout. No association between the polymorphism and serum inflammatory proteome was found. As expected, an increased IRF5 expression was observed in stimulated PBMCs of rs4728141 C allele carriers in response to several stimulations. Interestingly, IL-1β production was specifically enhanced in association to the rs4728141 C allele when cells were stimulated with palmitate with or without monosodium urate crystals. This pattern of cytokine production shows a functional impact of rs4728141 in gout through altered IL-1β production.

Glyphosate is one of the most widely used herbicides in agricultural, horticultural, and urban environments. However, its residue accumulation and oxidative damage pose serious threats to crop health and food safety. In this study, we evaluated the potential of epigallocatechin gallate, a natural polyphenol derived from tea, to alleviate glyphosate-induced stress in melon (Cucumis melo L.). LC-MS/MS analysis revealed that EGCG significantly reduced glyphosate residues in plant tissues. Transcriptome analysis indicated that glyphosate induced extensive transcriptional reprogramming, activating genes involved in detoxification and antioxidant defense. Co-treatment with glyphosate and EGCG partially mitigated this stress response and redirected gene expression toward secondary metabolic pathways, particularly flavonoid and phenylalanine biosynthesis. Under herbicide stress, EGCG restored the transcription of key flavonoid biosynthetic genes, including PAL, C4H, CHI, and OMT. Meanwhile, EGCG also modulated the expression of APX, SOD, and GST, suggesting a selective effect on antioxidant systems. Co-expression network analysis identified key hub genes associated with oxidative stress and flavonoid metabolism. These findings demonstrate the dual regulatory role of EGCG in suppressing acute oxidative stress while enhancing metabolic adaptability, highlighting its potential as a natural additive for reducing herbicide residues in fruit crops.

Pressure overload in non-treated or resistant hypertension (HTN) increases the risk of heart failure (HF) as well as the occurrence of fatal ventricular arrhythmias and stroke-provoking atrial fibrillation (AF), while perturbed connexin-43 (Cx43) and Cx40 might be involved. In addition, kidney dysfunction may facilitate hemodynamic volume overload and congestive HF. We investigated the impact of volume overload on Cx43 and Cx40 in right and left heart atria of hypertensive pressure overloaded Ren-2 transgenic (TGR) strain and normotensive Hannover Sprague Dawley (HSD) rats, as well as the efficacy of renin-angiotensin blockade with trandolapril and losartan. Key novel findings revealed lower levels of Cx43 and Cx40 proteins in left as well as right heart atria in pressure overloaded hypertensive rats compared to normotensive rats. There was a significant decrease in Cx43 and Cx40 proteins due to volume overload in both atria of normotensive as well as hypertensive rats. Treatment with trandolapril increased Cx43 and Cx40 levels in right and left heart atria of normotensive as well as hypertensive volume overloaded rats. While losartan increased Cx43 and did not affect Cx40 in left and right heart atria of volume overloaded rats. Findings of this study point out that right heart atria of normotensive as well as hypertensive rats are more susceptible to volume overload comparing to the left heart atria. Trandolapril attenuated pro-arrhythmic downregulation of Cx43 and Cx40 in atria of volume overloaded normotensive as well as hypertensive rats. This fact as well as examining AF inducibility requires further investigation.

Micro- and nanoplastic particles (MNPLs) present in the environment have recently become a potential health hazard factor due to the ability to penetrate living organisms, their organs, and cells. MNPLs interact with and absorb chemicals and elements, including metals, such as iron, copper, and zinc, and transport them into the cells. The cells subsequently respond with the altered gene expression profiles. In this study, we applied freely accessible online bioinformatic tools to draw out the sets of genes modulated by the metal ions and MNPLs. We focused on the gene interactome as revealed by The Comparative Toxicogenomics Database (CTD). To achieve a deeper insight into the biological processes that are potentially modulated, the retrieved CTD lists of genes, whose expression was influenced by MNPLs and metals, were subsequently analyzed using online tools: Metascape and String database. The genes from the revealed networks were arranged into functional clusters, annotated mainly as inflammation and immune system activity, regulation of apoptosis, oxidative stress response, Wingless-related Integration Site (WNT) signaling and ferroptosis. The complexity of the interactions between the gene sets altered by MNPLs and metal ions illustrates their pleiotropic effects on living systems.