Inhibition Of Division Research Articles

FUNDC1/USP15/Drp1 ameliorated TNF-α-induced pulmonary artery endothelial cell proliferation by regulating mitochondrial dynamics.

Mitochondrial dysfunction in pulmonary artery endothelial cells (PAECs) is related to the pathogenesis of pulmonary hypertension (PH). The mitochondrial receptor protein FUN14 domain containing 1 (FUNDC1) was found to be involved in pulmonary artery smooth muscle cell proliferation in PH. However, its role in PAECs remains unclear. We investigated FUNDC1 expression in the pulmonary artery endothelium in both monocrotaline-induced animal models and TNF-α-stimulated cell models. Additionally, the effect of FUNDC1 on PAECs proliferation and its possible mechanism were also investigated. We observed decreased FUNDC1 protein levels in animals and in vitro in PAECs. FUNDC1 deficiency in PAECs upregulated the expression of the deubiquitination enzyme ubiquitin-specific peptidase 15 (USP15), enhanced dynamin-related protein1 (Drp1)-mediated mitochondrial division, and increased mitochondrial ROS levels via the deubiquitination of Drp1. Additionally, FUNDC1 deficiency increased aerobic glycolysis, the production of ATP and lactic acid, and glucose uptake. FUNDC1 overexpression inhibited PAECs proliferation. Moreover, FUNDC1 overexpression in combination with a mitochondrial division or aerobic glycolysis inhibitor enhanced its inhibitory effect on cell proliferation. Our study findings suggest that FUNDC1 deficiency induced by inflammation can promote PAECs proliferation by regulating mitochondrial dynamics and cell energy metabolism via the USP15/Drp1 pathway.

β-arrestin1 protects intestinal tight junction through promoting mitofusin 2 transcription to drive parkin-dependent mitophagy in colitis.

Intestinal barrier defect is an essential inflammatory bowel disease (IBD) pathogenesis. Mitochondrial dysfunction results in energy deficiency and oxidative stress, which contribute to the pathogenesis of IBD. β-arrestin1 (ARRB1) is a negative regulator that promotes G protein-coupled receptors desensitization, endocytosis, and degradation. However, its role in maintaining the intestinal barrier remains unclear. Dextran sulfate sodium-induced colitis was performed in ARRB1 knockout and wild-type mice. Intestinal permeability and tight junction proteins were measured to evaluate the intestinal barrier. Mitochondria function and mitophagic flux in mice and cell lines were detected. Finally, the interaction between ARRB1 and mitofusin 2 was investigated by co-immunoprecipitation and dual luciferase assay. We identified that ARRB1 protected the intestinal tight junction barrier against experimental colitis in vivo. ARRB1 deficiency was accompanied by abnormal mitochondrial morphology, lower adenosine triphosphate (ATP) production, and severe oxidative stress. In vitro, the knockdown of ARRB1 reduced ATP levels and mitochondrial membrane potential while increasing reactive oxygen species levels and oxidative stress. Upon ARRB1 ablation, mitophagy was inhibited, accompanied by decreased LC3BII, phosphatase and tension homologue-induced protein kinase1 (PINK1), and parkin, but increased p62 expression. Mitophagy inhibition via PINK1 siRNA or mitochondrial division inhibitor 1 impaired ARRB1-mediated tight junction protection. The interaction of ARRB1 with E2F1 activated mitophagy by enhancing the transcription of mitofusin 2. Our results suggest that ARRB1 is critical to maintaining the intestinal tight junction barrier by promoting mitophagy. These results reveal a novel link between ARRB1 and the intestinal tight junction barrier, which provides theoretical support for colitis treatment.

Oxidative crosslinking induced self-reinforcing waterborne polyurethane with tunable structure as multi-synergistic antibacterial biomimetic composite coating

Waterborne polyurethane (WPU) coatings with antibacterial properties have attracted extensive attention. Herein, we proposed a molecular design strategy was used to establish a series of castor oil/tung oil based WPU antibacterial coatings. By introducing conjugated double bonds of tung oil into WPU skeleton, electrostatic interaction by zwitterion and bacterial division inhibition by conjugated double bonds achieved the synergistic antibacterial effects. To our delight, inspired by lotus leaves, the scanning electron microscope test revealed the bionic micro-nano embedded structure was constructed on the surface of WPU using siloxane-modified nanocellulose (CNC@MTES). The destruction of the phosphorus layers and superhydrophobicity grant the material to have quadruple synergistic antibacterial effects. The antibacterial rates of WPU coatings on E. coli and S. aureus were more than 99.6% and played the mildew protection effect. What's more, peroxy bond formed by unique oxidative cross-linking induced self-reinforcing to enhanced the mechanical properties (the stress and Young's modulus of coating enhanced by 122.06% and 2368% respectively). Strong bonding between CNC@MTES and WPU ensured the durability of the coating, which was still effectively antibacterial and hydrophobic after 400 friction cycles. This research offered an innovative and effective method for coating to be widely used in product packaging, medical devices, smart glass and other fields.

Neuron-targeted overexpression of caveolin-1 alleviates diabetes-associated cognitive dysfunction via regulating mitochondrial fission-mitophagy axis

BackgroundType 2 diabetes mellitus (T2DM) induced diabetes-associated cognitive dysfunction (DACD) that seriously affects the self-management of T2DM patients, is currently one of the most severe T2DM-associated complications, but the mechanistic basis remains unclear. Mitochondria are highly dynamic organelles, whose function refers to a broad spectrum of features such as mitochondrial dynamics, mitophagy and so on. Mitochondrial abnormalities have emerged as key determinants for cognitive function, the relationship between DACD and mitochondria is not well understood.MethodsHere, we explored the underlying mechanism of mitochondrial dysfunction of T2DM mice and HT22 cells treated with high glucose/palmitic acid (HG/Pal) focusing on the mitochondrial fission-mitophagy axis with drug injection, western blotting, Immunofluorescence, and electron microscopy. We further explored the potential role of caveolin-1 (cav-1) in T2DM induced mitochondrial dysfunction and synaptic alteration through viral transduction.ResultsAs previously reported, T2DM condition significantly prompted hippocampal mitochondrial fission, whereas mitophagy was blocked rather than increasing, which was accompanied by dysfunctional mitochondria and impaired neuronal function. By contrast, Mdivi-1 (mitochondrial division inhibitor) and urolithin A (mitophagy activator) ameliorated mitochondrial and neuronal function and thereafter lead to cognitive improvement by inhibiting excessive mitochondrial fission and giving rise to mitophagy, respectively. We have previously shown that cav-1 can significantly improve DACD by inhibiting ferroptosis. Here, we further demonstrated that cav-1 could not only inhibit mitochondrial fission via the interaction with GSK3β to modulate Drp1 pathway, but also rescue mitophagy through interacting with AMPK to activate PINK1/Parkin and ULK1-dependent signlings.ConclusionsOverall, our data for the first time point to a mitochondrial fission-mitophagy axis as a driver of neuronal dysfunction in a phenotype that was exaggerated by T2DM, and the protective role of cav-1 in DACD.Graphical Graphic Summary Illustration. In T2DM, excessive mitochondrial fission and impaired mitophagy conspire to an altered mitochondrial morphology and mitochondrial dysfunction, with a consequent neuronal damage, overall suggesting an unbalanced mitochondrial fission-mitophagy axis. Upon cav-1 overexpression, GSK3β and AMPK are phosphorylated respectively to activate Drp1 and mitophagy-related pathways (PINK1 and ULKI), ultimately inhibits mitochondrial fission and enhances mitophagy. In the meantime, the mitochondrial morphology and neuronal function are rescued, indicating the protective role of cav-1 on mitochondrial fission-mitophagy axis.4fVNd5UMHP9GEmZKs4s8VHVideo

Multiomics Reveals Induction of Neuroblastoma SK-N-BE(2)C Cell Death by Mitochondrial Division Inhibitor 1 through Multiple Effects.

Mitochondrial division inhibitor 1 (Mdivi-1) is a well-known synthetic compound aimed at inhibiting dynamin-related protein 1 (Drp1) to suppress mitochondrial fission, making it a valuable tool for studying mitochondrial dynamics. However, its specific effects beyond Drp1 inhibition remain to be confirmed. In this study, we employed integrative proteomics and phosphoproteomics to delve into the molecular responses induced by Mdivi-1 in SK-N-BE(2)C cells. A total of 3070 proteins and 1945 phosphorylation sites were identified, with 880 of them represented as phosphoproteins. Among these, 266 proteins and 97 phosphorylation sites were found to be sensitive to the Mdivi-1 treatment. Functional enrichment analysis unveiled their involvement in serine biosynthesis and extrinsic apoptotic signaling pathways. Through targeted metabolomics, we observed that Mdivi-1 enhanced intracellular serine biosynthesis while reducing the production of C24:1-ceramide. Within these regulated phosphoproteins, dynamic dephosphorylation of proteasome subunit alpha type 3 serine 250 (PSMA3-S250) occurred after Mdivi-1 treatment. Further site-directed mutagenesis experiments revealed that the dephosphorylation-deficient mutant PSMA3-S250A exhibited a decreased cell survival. This research confirms that Mdivi-1's inhibition of mitochondrial division leads to various side effects, ultimately influencing cell survival, rather than solely targeting Drp1 inhibition.

Local production of reactive oxygen species drives vincristine-induced axon degeneration

Neurological side effects arising from chemotherapy, such as severe pain and cognitive impairment, are a major concern for cancer patients. These major side effects can lead to reduction or termination of chemotherapy medication in patients, negatively impacting their prognoses. With cancer survival rates improving dramatically, addressing side effects of cancer treatment has become pressing. Here, we use iPSC-derived human neurons to investigate the molecular mechanisms that lead to neurotoxicity induced by vincristine, a common chemotherapeutic used to treat solid tumors. Our results uncover a novel mechanism by which vincristine causes a local increase in mitochondrial proteins that produce reactive oxygen species (ROS) in the axon. Vincristine triggers a cascade of axon pathology, causing mitochondrial dysfunction that leads to elevated axonal ROS levels and SARM1-dependent axon degeneration. Importantly, we show that the neurotoxic effect of increased axonal ROS can be mitigated by the small molecule mitochondrial division inhibitor 1 (mdivi-1) and antioxidants glutathione and mitoquinone, identifying a novel therapeutic avenue to treat the neurological effects of chemotherapy.

Balanced cell division is secured by two different regulatory sites in OxyS RNA.

The hydrogen peroxide-induced small RNA OxyS has been proposed to originate from the 3' UTR of a peroxide mRNA. Unexpectedly, phylogenetic OxyS targetome predictions indicate that most OxyS targets belong to the category of "cell cycle," including cell division and cell elongation. Previously, we reported that Escherichia coli OxyS inhibits cell division by repressing expression of the essential transcription termination factor nusG, thereby leading to the expression of the KilR protein, which interferes with the function of the major cell division protein, FtsZ. By interfering with cell division, OxyS brings about cell-cycle arrest, thus allowing DNA damage repair. Cell division and cell elongation are opposing functions to the extent that inhibition of cell division requires a parallel inhibition of cell elongation for the cells to survive. In this study, we report that in addition to cell division, OxyS inhibits mepS, which encodes an essential peptidoglycan endopeptidase that is responsible for cell elongation. Our study indicates that cell-cycle arrest and balancing between cell division and cell elongation are important and conserved functions of the oxidative stress-induced sRNA OxyS.

Ethylene and ROS mediate root growth inhibition induced by the endocrine disruptor bisphenol A (BPA)

Bisphenol A (BPA) functions as a detrimental substance that disrupts the endocrine system in animals while also impeding the growth and development of plants. In our previous study, we demonstrated that BPA hinders the growth of roots in Arabidopsis by diminishing cell division and elongation, which is ascribed to the increased accumulation and redistribution of auxin. Here, we examined the mediation of ROS and ethylene in BPA-induced auxin accumulation and root growth inhibition. BPA enhanced ROS levels, and ROS increased auxin contents but reduced cell division activity and the expression of EXPA8 involved in root elongation. ROS scavenger treatment reversed BPA-triggered root growth retardation, auxin accumulation, and cell division inhibition. In addition, BPA induced ethylene, and ethylene synthesis inhibitor treatment reversed BPA-triggered root growth retardation and auxin accumulation. Taken together, ROS and ethylene are involved in BPA-inhibited cell elongation and cell division by mediating auxin accumulation and redistribution.

Metabolic Labeling: Snapshot of the Effect of Toxins on the Key Cellular Processes.

Competing bacteria secrete vast variety of toxic effectors via secretion systems. Phospholipase, peptidoglycan-hydrolase, or pore forming toxins often manifest in the bursting of the prey cell. Other toxins reach cytoplasm of the prey where they affect cell division machinery, metabolism, nucleic acid integrity, or protein synthesis. Inhibition of cell division or DNA integrity, which summons SOS response, will often lead to bacterial cell filamentation readily observable under the microscope. However, other toxic activities will not manifest in interpretable phenotypic changes that would readily suggest their mechanism of toxicity. Activity measurements of the three fundamental cellular processes-replication, transcription and translation can pave the way for further understanding of the toxin's activity. Method commonly known as metabolic labeling makes use of radioactive precursors for DNA, RNA and protein synthesis. This method provides highly sensitive snapshot of the activity of key cellular processes.

Fluoroquinolone and beta-lactam antimicrobials induce different transcriptome profiles in Salmonella enterica persister cells

Here, we investigate the transcriptome profiles of two S. Enteritidis and one S. Schwarzengrund isolates that present different persister levels when exposed to ciprofloxacin or ceftazidime. It was possible to note a distinct transcript profile among isolates, time of exposure, and treatment. We could not find a commonly expressed transcript profile that plays a role in persister formation after S. enterica exposure to beta-lactam or fluoroquinolone, as only three DEGs presented the same behavior under the conditions and isolates tested. It appears that the formation of persisters in S. enterica after exposure to ciprofloxacin is linked to the overexpression of genes involved in the SOS response (recA), cell division inhibitor (sulA), iron-sulfur metabolism (hscA and iscS), and type I TA system (tisB). On the other hand, most genes differentially expressed in S. enterica after exposure to ceftazidime appeared to be downregulated and were part of the flagellar assembly apparatus, citrate cycle (TCA cycle), glycolysis/gluconeogenesis, carbon metabolism, bacterial secretion system, quorum sensing, pyruvate metabolism pathway, and biosynthesis of secondary metabolites. The different transcriptome profiles found in S. enterica persisters induced by ciprofloxacin and ceftazidime suggest that these cells modulate their response differently according to each stress.

Time-course adaption strategy of Tetraselmis-based consortia in response to 17α-ethinylestradiol

Estuarine ecosystem constitutes a microenvironment where the abundant green microalga Tetraselmis sp. co-exists with 17α-ethinylestradiol (EE2) pollution. However, the adaption mechanisms of this microalga-based consortia under EE2 shock are rarely recognized. Using extracellular polymeric substance (EPS) characterization, flow cytometry and transcriptomic, this study reveals the time-course response of Tetraselmis-based consortia under EE2 stress. Compared to the insignificant effect of 0.5 mg/L, a high dose of 2.5 mg/L EE2 induces persistent production of reactive oxygen species (ROS) and transiently physiological damages (membrane, chloroplast, organelle morphogenesis, and DNA replication), resulting in cell cycle alteration and division inhibition. These damages could be recovered through active DNA repair and persistently detoxifying processes of enhanced metabolism and ROS quenching. The enhanced EPS production is observed and in line with the significant up-regulation of most key enzymes involved in precursor synthesis and polysaccharides assembling. However, the up-regulation of glycoside hydrolases and most glycosyltransferases, down-regulation of flippases and changed expression of ABC family members indicate the changed EPS composition and synthesis strategy. The resulting increased colloidal polysaccharide is further consumed by associated bacteria whereas protein remains in the co-cultures. These results provide deeper insights into the adverse effects of chemical compounds to microalgae-bacteria and their coadaptation ability.

Inhibition of host cell division by T5 protein 008 (Hdi).

Bacteriophages (phages) have evolved effective methods of exploiting host-cell machinery by redirecting molecular pathways. In this study, we describe an inhibitor of bacterial growth, T5.008, encoded by the T5 phage. High-throughput sequencing of genomic DNA from bacterial mutants resistant to T5.008 identified mutations in the Escherichia coli ftsZ gene, suggesting that T5.008 targets the cell division protein FtsZ. We validated this finding by replacing a residue in FtsZ with one that confers protection from T5.008 inhibition. We used time-lapse microscopy to show that T5.008 interferes with FtsZ ring formation and stability, thereby inhibiting division. We also demonstrated that phages expressing T5.008 can prevent host division before lysis much more efficiently than those lacking T5.008. We also showed that T5.008 provides a competitive advantage to the T5 phage. This strategy of inhibiting division during phage infection likely enables T5 phage to utilize host-cell resources efficiently.IMPORTANCEWe have identified a novel phage-encoded inhibitor of the major cytoskeletal protein in bacterial division, FtsZ. The inhibition is shown to confer T5 bacteriophage with a growth advantage in dividing hosts. Our studies demonstrate a strategy in bacteriophages to maximize their progeny number by inhibiting escape of one of the daughter cells of an infected bacterium. They further emphasize that FtsZ is a natural target for bacterial growth inhibition.

Zearalenone promotes porcine ESCs apoptosis by enhancing Drp1-mediated mitochondrial fragmentation and activating the JNK pathway

Zearalenone (ZEA) is widely present in food and feed, and pigs are susceptible to its effects. This study explored the underlying function of ZEA-induced apoptosis in porcine endometrial stromal cells (ESCs) through activation of the JNK signaling pathway and mitochondrial division. This study utilized ESCs to explore the impact of exposure to ZEA. A mitochondrial division inhibitor (Mdivi) was also included as a reference. The results indicated a gradual decrease in cell viability with increasing ZEA concentration. In addition, ZEA can modify the growth status of porcine ESCs, disrupt their ultrastructure, and lead to apoptosis of porcine ESCs via the mitochondrial division pathway and JNK signaling pathway. In summary, our study found the critical targets of ZEA infected with pig ESCs, which provided a conceptual foundation to prevent and control ZEA.

Mdivi1 ameliorates mitochondrial dysfunction in non-alcoholic steatohepatitis by inhibiting JNK/MFF signaling.

Mitochondrial dysfunction plays a crucial role in the progression of non-alcoholic steatohepatitis (NASH). Mitochondrial division inhibitor 1 (Mdivi1) is a potential inhibitor of dynamin-related protein (Drp1) and mitochondrial fission. However, the therapeutic effect of Mdivi1 against NASH and its underlying molecular mechanisms remain unclear. In this study, we established mouse models of NASH by inducing high-fat/high-cholesterol (HFHC) or methionine- and choline-deficient (MCD) diets and treated the animals with 5mg/kg/day Mdivi1 or placebo. Treatment with Mdivi1 significantly alleviated diet-induced fatty liver phenotypes, including increased liver weight/body weight ratio, insulin resistance, hepatic lipid accumulation, steatohepatitis, and liver injury. Furthermore, Mdivi1 treatment suppressed HFHC or MCD diet-induced changes in the expression of genes related to lipid metabolism and inflammatory cytokines. Additionally, Mdivi1 reduced macrophage infiltration in the injured liver and promoted polarization of macrophages towards the M1 phenotype. At the molecular level, Mdivi1 attenuated mitochondrial fission by reducing Drp1 activation and expression, thereby decreasing mitochondrial reactive oxygen species accumulation and mitochondrial DNA damage. Moreover, Mdivi1-treated mice exhibited elevated levels of phosphorylated-c-Jun N-terminal kinase (p-JNK), mitochondrial fission factor (MFF), cleaved caspase 3 protein, and TUNEL-positive cell expression in the liver, suggesting that Mdivi1 might ameliorate mitochondrial dysfunction and reduce hepatocyte apoptosis by inhibiting the JNK/MFF pathway. Collectively, Mdivi1 protected against diet-induced NASH by restoring mitochondrial homeostasis and function, potentially through its inhibitory effect on the JNK/MFF pathway. Consequently, further investigation of Mdivi1 as a promising drug for NASH treatment is warranted.

Immunolocalization of Jasmonates and Auxins in Pea Roots in Connection with Inhibition of Root Growth under Salinity Conditions.

Inhibition of root elongation is an important growth response to salinity, which is thought to be regulated by the accumulation of jasmonates and auxins in roots. Nevertheless, the mechanisms of the interaction of these hormones in the regulation of the growth response to salinity are still not clear enough. Their better understanding depends on the study of the distribution of jasmonates and auxins between root cells. This was achieved with the help of immunolocalization of auxin (indoleacetic acid) and jasmonates on the root sections of pea plants. Salinity inhibited root elongation and decreased the size of the meristem zone and the length of cells in the elongation zone. Immunofluorescence based on the use of appropriate, specific antibodies that recognize auxins and jasmonates revealed an increased abundance of both hormones in the meristem zone. The obtained data suggests the participation of either auxins or jasmonates in the inhibition of cell division, which leads to a decrease in the size of the meristem zone. The level of only auxin and not jasmonate increased in the elongation zone. However, since some literature evidence argues against inhibition of root cell division by auxins, while jasmonates have been shown to inhibit this process, we came to the conclusion that elevated jasmonate is a more likely candidate for inhibiting root meristem activity under salinity conditions. Data suggests that auxins, not jasmonates, reduce cell size in the elongation zone of salt-stressed plants, a suggestion supported by the known ability of auxins to inhibit root cell elongation.

Parkin-Mediated Mitophagy by TGF-β Is Connected with Hepatic Stellate Cell Activation.

Hepatic stellate cells (HSCs) are the main contributors to the development and progression of liver fibrosis. Parkin is an E3 ligase involved in mitophagy mediated by lysosomes that maintains mitochondrial homeostasis. Unfortunately, there is little information regarding the regulation of parkin by transforming growth factor-β (TGF-β) and its association with HSC trans-differentiation. This study showed that parkin is upregulated in fibrotic conditions and elucidated the underlying mechanism. Parkin was observed in the cirrhotic region of the patient liver tissues and visualized using immunostaining and immunoblotting of mouse fibrotic liver samples and primary HSCs. The role of parkin-mediated mitophagy in hepatic fibrogenesis was examined using TGF-β-treated LX-2 cells with mitophagy inhibitor, mitochondrial division inhibitor 1. Parkin overexpression and its colocalization with desmin in human tissues were found. Increased parkin in fibrotic liver homogenates of mice was observed. Parkin was expressed more abundantly in HSCs than in hepatocytes and was upregulated under TGF-β. TGF-β-induced parkin was due to Smad3. TGF-β facilitated mitochondrial translocation, leading to mitophagy activation, reversed by mitophagy inhibitor. However, TGF-β did not change mitochondrial function. Mitophagy inhibitor suppressed profibrotic genes and HSC migration mediated by TGF-β. Collectively, parkin-involved mitophagy by TGF-β facilitates HSC activation, suggesting mitophagy may utilize targets for liver fibrosis.

Expand and Sensitize: Guanidine‐Functionalized Exopolysaccharide Nanoparticles Cause Bacterial Cell Expansion and Antibiotic Sensitization

AbstractConventional antibacterial agents and mechanisms are frequently observed to be ineffective due to the evolution of bacteria to the strains with stronger antibiotic resistance, and hence developing alternative antibacterial materials and mechanisms is urgently needed. Here, guanidine‐functionalized exopolysaccharide (EPS) nanoparticles (termed EPGNs) with durable antibacterial and antibiofilm activities are developed. Very interestingly, the EPGNs obtained by the reaction of EPS, epichlorohydrin, and polyhexamethylene guanidine hydrochloride exhibit an unconventional antibacterial mechanism, i.e., they can induce substantial bacterial cell expansion by upregulating the SulA and DicB proteins that are responsible for cell division inhibition, along with the increase of reactive oxygen species production, bacterial cell surface disruption, and bacterial ribosomal RNA degradation. The transcriptome analysis reveals that EPGNs can hinder cell motility, induce loss of cell integrity, decrease the resistance of bacteria to oxidative stress, and finally lead to cell death. Moreover, EPGNs can effectively accelerate the bacteria‐infected wound healing. This work provides the first example that nanomaterials can cause bacterial cell expansion by affecting intracellular structures and inhibiting cell division, and it may inspire other researchers to investigate the effect of antibacterial materials on the change of bacterial volume and design unconventional antibacterial materials/strategies.

Phage-antibiotic synergy: Cell filamentation is a key driver of successful phage predation.

Phages are promising tools to fight antibiotic-resistant bacteria, and as for now, phage therapy is essentially performed in combination with antibiotics. Interestingly, combined treatments including phages and a wide range of antibiotics lead to an increased bacterial killing, a phenomenon called phage-antibiotic synergy (PAS), suggesting that antibiotic-induced changes in bacterial physiology alter the dynamics of phage propagation. Using single-phage and single-cell techniques, each step of the lytic cycle of phage HK620 was studied in E. coli cultures treated with either ceftazidime, cephalexin or ciprofloxacin, three filamentation-inducing antibiotics. In the presence of sublethal doses of antibiotics, multiple stress tolerance and DNA repair pathways are triggered following activation of the SOS response. One of the most notable effects is the inhibition of bacterial division. As a result, a significant fraction of cells forms filaments that stop dividing but have higher rates of mutagenesis. Antibiotic-induced filaments become easy targets for phages due to their enlarged surface areas, as demonstrated by fluorescence microscopy and flow cytometry techniques. Adsorption, infection and lysis occur more often in filamentous cells compared to regular-sized bacteria. In addition, the reduction in bacterial numbers caused by impaired cell division may account for the faster elimination of bacteria during PAS. We developed a mathematical model to capture the interaction between sublethal doses of antibiotics and exposition to phages. This model shows that the induction of filamentation by sublethal doses of antibiotics can amplify the replication of phages and therefore yield PAS. We also use this model to study the consequences of PAS on the emergence of antibiotic resistance. A significant percentage of hyper-mutagenic filamentous bacteria are effectively killed by phages due to their increased susceptibility to infection. As a result, the addition of even a very low number of bacteriophages produced a strong reduction of the mutagenesis rate of the entire bacterial population. We confirm this prediction experimentally using reporters for bacterial DNA repair. Our work highlights the multiple benefits associated with the combination of sublethal doses of antibiotics with bacteriophages.

Genotoxicity and acute toxicity of 2-amino-5-benzylthiazole in complex with polymeric nanocarrier in Allium bioassay

Background. The search for optimal methods of selective and integral determination of various cytotoxic compounds in biological fluids and tissues, which would have high sensitivity and allow for quick and reliable assessment and detection of potentially cytotoxic components of substances with biologically active action, remains relevant today. It is known that chemotherapeutic agents can be released into the environment (air, surface water, sediments and soil) and cause adverse consequences (impact on the stability of ecosystems due to reduced viability of species). The aim of this work was to investigate the effect of thiazole derivative N-(5-benzyl-1,3-thiazol-2-yl)-3,5-dimethyl1-benzofuran-2-carboxamide (BF1) conjugated with PEG-based polymeric nanoparticles (PEG-PN – Th1) on genotoxicity and acute toxicity in allium bioassay. Materials and Methods. Allium cepa ana-telophase assay was applied to monitor genotoxicity of the studied compounds. The acute toxic effects such as inhibition of cell division, seed germination and growth of Allium roots were estimated. A. cepa seeds (15 per each point) were germinated on the studied solutions of BF1, Th1 and Th2 (10 μM) for 5 days at 22 °C. The root growth and the percentage of inhibition of seed germination were calculated. In order to establish cyto- and genotoxicity of the studied compounds, we have determined the mitotic index and the relative amount of chromosomal aberrations. Results. BF1 had a significant inhibitory effect on root growth and seed germination at a concentration of 10 μM. The effect was eliminated when it was influenced by BF1 complex with a polymeric carrier. The free polymer does not have a negative effect on the studied parameters either. A significant decrease in the mitotic index and increase in the percentage of chromosomal aberrations was observed under the action of BF1 at a concentration of 10 µM. There was no significant change in the value of mitoitic index and percentage of chromosomal aberrations under the action of Th2 comp­lex or polymeric carrier Th1. Conclusions. The thiazole derivative in complex with a polymeric carrier at a concentration of 10 µM did not show acute toxicity in Allium cepa bioassay. Polymer carrier based on polyethylene glycol neutralized the negative effect of BF1 on the mitotic and phase indices of Allium root meristem cells; it also decreased the percentage of chromosomal aberrations.

Impact of aqueous extract of Viscum album on different organisms

The phytochemical and pharmacological potential of Viscum album extracts are widely used for the treatment of various diseases in many countries. The effect of aqueous extract from different mistletoe host trees (Abies alba, Acer saccharinum, Malus domestica, Pinus sylvestris) on model objects (Allium cepa and Drosophila milanogaster), bacteria (Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus), and fungi (Aspergillus niger, Heterobasidion annosum, Inonotus obliquus) was evaluated. The influence of mistletoe extracts on A. cepa, D. melanogaster and basidiomycetes species H. annosum and I. obliquus was demonstrated for the first time. The study findings revealed that the impact of mistletoe aqueous extract exhibits considerable variation, influenced by multiple factors. These factors include the specific tree from which mistletoe is obtained, the concentration used, and the organism targeted. Mistletoe extracts caused the appearance of cells with pathologies in the meristematic tissues of A. cepa at different stages of the plant cell cycle. A clear cytostatic effect on A. cepa and D. melanogaster was shown, with the highest effect of mistletoe extract obtained from A. saccharinum. The main action of the solution on cells is probably manifested in the inhibition of cell division according to the results of the cytotoxicity assessment of aqueous extracts of mistletoe. Antibacterial activity of concentated mistletoe extract obtained from A. saccharinum was found only against S. aureus with zone of growth inhibition 11.0 ± 0.1 mm. In the assay on agar plates the tested extracts stimulated the mycelial growth of A. niger 1.85 times higher compared to the control, but inhibited the growth of H. annosum, I. obliquus at 65.5% and 62.2%, respectively. However, the biomass production of H. annosum was strongly dependent on the host mistletoe tree of the aqueous extract, and both the inhibition of mycelial synthesis of the wood-destroying fungus and its stimulating effect on mycelial accumulation were found. A negative effect (1.46 times decrease in biomass ) of H. annosum was found in the case of application of mistletoe extract obtained from A. saccharinum. The highest stimulation effect on fungus (1.53 times increase in biomass) was established by using mistletoe extract prepared from A. alba. In this study the main effects on living organisms used were indirectly caused by the host trees of mistletoe extracts. The overall negative impact was associated with the host tree Acer saccharinum.