The choice of effective biocides used for routine hospital practice should consider the role of disinfectants in the maintenance and development of local resistome and how they might affect antibiotic resistance gene transfer within the hospital microbial population. Currently, there is little understanding of how different biocides contribute to eDNA release that may contribute to gene transfer and subsequent environmental retention. Here we investigated how different biocides affected the release of eDNA from mature biofilms of two opportunistic model strains Pseudomonas aeruginosa ATCC 27853 (PA) and Staphylococcus aureus ATCC 25923 (SA) and contribute to the hospital resistome in the form of surface and water contaminants and dust particles. The effect of four groups of biocides including alcohols, hydrogen peroxide, quaternary ammonium compounds, and polymeric guanidines were evaluated using PA and SA biofilms. Most biocides, except for PHMG-Cl and 70% ethanol, caused substantial eDNA release and PHMG-Cl was found to block biofilm development when used at concentrations of 0.5% and 0.1%. This might be associated with the formation of DNA-PHMG-Cl complexes as PHMG-Cl is predicted to bind to AT base pairs by molecular docking assays. PHMG-Cl was found to bind high molecular DNA and plasmid DNA and continued to inactivate DNA on surfaces even after four weeks. PHMG-Cl also effectively inactivated biofilm-associated antibiotic resistance gene eDNA released by a pan-drug-resistant Klebsiella strain which demonstrates the potential of PHMG-Cl as a new surface-active agent to combat the spread of antibiotic resistance in hospital settings.

A challenging problem in the aquaculture industry is bacterial disease outbreaks which results in the global reduction of fish supply and foodborne outbreaks. Biofilms in marine pathogens protect against antimicrobial treatment and host immune defence. Zeolites are minerals of volcanic origin made from crystalline aluminosilicates which are useful in agriculture and in environmental management. In this study, silver ion-exchanged zeolite A of four concentrations; 0.25M (AgZ1), 0.50M (AgZ2), 1.00M (AgZ3)and 1.50M (AgZ4) were investigated for biofilm inhibition and antimicrobial properties against two predominant marine pathogens V. campbelli and V. parahemolyticus by employing the Minimum Inhibitory Concentration(MIC), Crystal Violet Biofilm Quantification assays as well as Scanning Electron Microscopy. In the first instance, all zeolite samples AgZ1-AgZ4 showed antimicrobial activity for both pathogens. For V. campbellii AgZ4 exhibited the highest MIC at 125.00 µg/ml while for V. parahaemolyticus the highest MIC was observed for AgZ3 at 62.50 µg/ml. At sublethal concentration, biofilm inhibition of V. campbelli and V. parahemolyticus by AgZ4 were observed at 60.2% and 77.3% inhibition respectively. Scanning electron microscopy exhibited profound structural alteration of the biofilm matrix by AgZ4. This is the first known study that highlights the potential application of ion-exchanged Zeolite A against marine pathogens and their biofilms.

Abstract: Air-polishing with low abrasiveness powders is fats arising as a valid and mini-invasive instrument for the management of biofilm colonizing dental implants. The reported advantage is the efficient removal of plaque with respect of the titanium integrity. In the present study, we evaluated the in-situ plaque-removal and continual the post-treatment anti-bacterial efficacy of an innovative erythritol/chlorhexidine air-polishing powder and compared it with sodium bicarbonate. Two peri-implantitis-linked biofilm formers strains Staphylococcus aureus and Aggregatibacter actinomycetemcomitans were selected and used to infect titanium disks before and after the air-polishing treatment. Cells number and viability were assayed by colonies forming units (CFUs) count and metabolic-colorimetric (2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide) (XTT) assay. Air-polishing performed with either sodium bicarbonate or erythritol/chlorhexidine was effective in reducing bacteria biofilm viability and number onto pre-infected specimens, while erythritol/ chlorhexidine showed a higher post-treatment biofilm re-growth inhibition. Surface analysis via mechanical profilometry failed to show an increase in titanium roughness, regardless of the powder selected.

The growing increase in infections caused by C. tropicalis, associated with its drug resistance and consequent high mortality, especially in immunosuppressed people, today generates a serious global public health problem. In the search for new potential drug candidates that can be used as treatments or adjuvants in the control of infections by these pathogenic yeasts, the objective of this research was to evaluate the action of isoespintanol (ISO) against the formation of biofilms fungal, the mitochondrial membrane potential (∆Ψm) and its effect on the integrity of the cell wall. We report the ability of ISO to inhibit the formation of biofilms by up to 89.35%, in all cases higher than the values expressed by amphotericin B (AFB). Flow cytometric experiments using rhodamine 123 (Rh123) showed the ability of ISO to cause mitochondrial dysfunction in these cells. Likewise, experiments using calcofluor white (CFW) and analyzed by flow cytometry, showed the ability of ISO to affect the integrity of the cell wall by stimulating chitin synthesis; these changes in the integrity of the wall were also observed through transmission electron microscopy (TEM). These mechanisms are involved in the antifungal action of this monoterpene.

Biofilm-related infections play a significant role in the development and persistence of ventilator-associated pneumonia. Pseudomonas aeruginosa frequently causes biofilm-related infections associated with ventilator tubing. Glucosamine gold nanoparticles (AuNPs) may exhibit antibiofilm properties; however, more studies, including combinatorial therapy with antibiotics, are needed to explore their potential applications in clinical settings. This study aimed to investigate the biofilm inhibition properties of glucosamine AuNPs in combination with meropenem against Pseudomonas aeruginosa ATCC 9027 on the endotracheal tube. A biofilm inhibition assay of glucosamine AuNPs at 0.02 mg/ml, both singly and in combination with meropenem at 1 mg/ml, was carried out against Pseudomonas aeruginosa ATCC 9027 on an endotracheal tube using the tissue culture plate method. Scanning electron microscopy was performed for visualization. Glucosamine AuNPs at 0.02 mg/ml combined with meropenem at 1 mg/ml showed greater biofilm inhibition (72%) than glucosamine nanoparticles at 0.02 mg/ml alone (26%) on the endotracheal tube (p=0.001). The scanning electron microscopic visualization revealed that the untreated Pseudomonas aeruginosa biofilm was denser than the glucosamine nanoparticles-treated biofilm either combined with meropenem or glucosamine nanoparticles alone. The combination of glucosamine AuNPs and meropenem may have the synergistic effect to inhibit biofilm production of Pseudomonas aeruginosa on the endotracheal tube in patient with mechanical ventilation. Conducting additional experiments to explore the impact of combining glucosamine-coated gold nanoparticles (AuNPs) with meropenem on the inhibition of biofilm production by clinical Pseudomonas aeruginosa isolates would be beneficial.

Hybrid materials are a recent addition in the field of Restorative Dentistry for computer-assisted design/ computer-assisted manufacturing (CAD/CAM) indirect restorations. The long–term clinical success of modern dental restorative materials follows a multifactorial pattern. Among the characteristics, affecting the longevity of a restoration, mechanical properties and physicο – chemical interactions are of utmost importance. While numerous researchers constantly evaluate the mechanical properties, the biological background of resin–based CAD/CAM biomaterials is scarcely investigated and, therefore, less described in the literature. This review aims to analyze the biofilm formation on the surfaces of novel hybrid, resin–based CAD/CAM materials and evaluate the methodological protocols followed to assess microbial growth. It is demonstrated that the surface structure, the composition and the finishing and polishing procedures on the surface of a dental restorative material influence the initial bacterial adhesion; however most studies focus on in vitro protocols, whereas in vivo and/or in situ research of microbiomics in CAD/CAM restorative materials is lacking, obstructing in that manner the accurate understanding of the bioadhesion phenomenon in the oral cavity.

Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer.

Consumption of refined foods and beverages high in sugar make the teeth susceptible to the formation of biofilm, and lead to dental caries and diseases of the oral cavity such as periodontitis and periodontal disease. The aim of the present study was to determine the ability of selected probiotics to inhibit growth and biofilm formation by the cariogenic bacterium Streptococcus mutans in vitro. We screened strains of latic acid bacteria (LAB) (n=120) from the Bioresources Collection and Research Center (BCRC), saliva of healthy adults and infant stool. The antimicrobial activity of LAB in vitro was evaluated by agar spot culture and co-culture of the S. mutans strains. We determined the effect of heating and dilution factors (2- and 4-fold) on the antagonistic activity of LAB. Antagonistic substances in the spent culture suspensions (SCS) of LAB were precipitated by extraction with ammonium sulphate and chloroform to characterise the protein and lipophilic fractions. Results of co-culturing show that the SCS of the three LAB strains (Lactobacillus pentosus 13-1, 13-4 and Lactobacillus crispatus BCRC 14618) subjected to heat treatment showed significantly high antimicrobial activity. We found that substances produced by L. pentosus 13-4 which have the potential to exhibit antimicrobial properties might be lipophilic proteins. Additionally, we infer that the mechanism of reducing biofilm formation by Lactobacillus strains is associated with sucrose-dependent cell–cell adhesion and the gtfC level of glucosyltransferases (Gtfs) in the biofilm. Native LAB strains screened in our study may be used in chewing gums and other processed foods for preventing tooth decay.

Based on screening in computational biology and biological in vitro assays, five natural products isolated from extracts of the herbal medicine toad skin, such as cinobufagin (CBFi), bufalin (BFi), arenobufagin (ABFi), telocinobufagin (TBFi), bufotalin (BFTi), were subjected to molecular docking calculations with the use of SARS-CoV-2 main protease (PDB 6LU7 and 7BTF) and top-scoring ligand-receptor complexes were obtained. The results showed that the binding energy of ABFi to the 3CL protein was -17.044kcal/mol, which was higher than CBFi and TBFi. However, the binding energy of ABFi to the RdRp protease was -23.250 kcal/mol, which was much lower than that of CBFi and TBFi, EVEN lower than that of ABFi to the 3CL protein. ABFi also has polar interactions with amino acids such as Glu811, Ser814, Ser681 and Thr680 of RdRp enzyme. The results revealed that ABFi had a moderate inhibitory effect on the cell proliferation of SARS-CoV-2 in vitro, with an inhibition rate of 61.12%, even weaker than Remdesivir. This new discovery provides us with new ideas for in-depth studies on the development of natural products with this class of structural generalizations as inhibitors of SARS-CoV-2, and provides an experimental basis for the next step of mechanistic studies.

Effective oral care is important to maintain a high quality of life. Therefore, plaque control can prevent the development and recurrence of periodontitis. Brushing with a toothbrush and toothpaste is a common way to remove plaque; however, excessive brushing or brushing with abrasive toothpaste can cause wear and tear on the dental crown. Hence, we aimed to quantitatively compare the plaque-removal efficiency and tooth wear of toothbrushes using bioelectric effect (BE) with those of mechanical electric toothbrushes. To generate the BE signal, an electronic circuit was developed and embedded in a toothbrush. Further, typodonts were coated with cultured artificial plaques and placed in a brushing simulator. A toothpaste slurry was applied, and the typodonts were eluted with tap water after brushing. The plaques of the typodonts were captured, and the images were quantified. For the tooth wear experiment, polymethyl methacrylate disk resin blocks were brushed twice a day, and the thickness of the samples was measured. Subsequently, statistical differences between the experimental toothbrushes and typical toothbrushes were analyzed. The BE toothbrush had a higher plaque-removal efficiency and could minimize tooth wear. This study suggests that the application of BE may be a new solution for oral care.

Atopic dermatitis (AD) is a chronic inflammatory disorder presenting a dysregulated immune response and derangement of the epidermal barrier lipids. The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signal axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D-epidermal equivalents. We used tofacitinib, a low-molecular-mass JAK inhibitor, to screen for the JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4, and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase, and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitate and caused a depletion of triglycerides. This depletion was associated with altered PC profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very long chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by halted homeostasis of FA metabolism.

Cisplatin is a widely used anticancer drug for treating solid tumors, but it is associated with severe side effects, including nephrotoxicity. Various studies have suggested that the nephrotoxicity of cisplatin could be overcome; nonetheless, an effective adjuvant drug has not yet been established. Oleanolic acid acetate (OAA), a triterpenoid isolated from Vigna angularis, is commonly used to treat inflammatory and allergic diseases. This study aimed to investigate the protective effects of OAA against cisplatin-induced apoptosis and necroptosis using TCMK-1 cells and a mouse model. In cisplatin-treated TCMK-1 cells, OAA treatment significantly reduced Bax and cleaved-caspase3 expression, whereas increased Bcl-2 expression. Moreover, in cisplatin-induced kidney injury mouse model, OAA treatment alleviated weight loss in the body and major organs and also relieved cisplatin-induced nephrotoxicity symptoms. RNA sequencing analysis of kidney tissues identified lipocalin-2 as the most upregulated gene by cisplatin. Additionally, necroptosis-related genes such as receptor interacting protein kinase (RIPK) and mixed lineage kinase domain like (MLKL) were identified. In vitro study, the phosphorylation of RIPKs and MLKL was reduced by OAA pretreatment in both cisplatin-treated cells and cells boosted by co-treatment with z-VAD-FMK. In conclusion, OAA could protect the kidney from cisplatin-induced nephrotoxicity and may serve as an anticancer adjuvant.

Clusterin (CLU) protein is involved in various pathophysiological processes including carcinogenesis and tumor progression. In recent years, the role of the secretory isoform has been demonstrated in tumor cells, where it inhibits apoptosis and favors the acquisition of resistance to conventional treatments used to treat cancer. To determine the possible therapeutic potential of inhibiting this protein, numerous studies have been carried out in this field. In this paper, we show the existing knowledge on the inhibition of this protein in different types of cancer and discuss the importance it could have in the development of new therapies directed against this pathology.

The novel coronavirus disease (COVID-19) pandemic has resulted in over 720 million confirmed cases and 7 million deaths worldwide, with insufficient treatment options. Innumerable efforts are being made around the world for faster identification of therapeutic agents to treat the deadly disease. Postacute sequelae of SARS-CoV-2 infection or COVID-19 (PASC), also called Long COVID, is still being understood and lacks treatment options as well. A growing list of drugs are being suggested by various in silico, in vitro and ex vivo models, however currently only two treatment options are widely used: the RNA-dependent RNA polymerase (RdRp) inhibitor remdesivir, and the main protease inhibitor nirmatrelvir in combination with ritonavir. Computational drug development tools and in silico studies involving molecular docking, molecular dynamics, entropy calculations and pharmacokinetics can be useful to identify new targets to treat COVID-19 and PASC, as shown in this work and our recent paper that identified alendronate as a promising candidate. We have now investigated all bisphosphonates which can bind competitively to nidovirus RdRp-associated nucleotidyl (NiRAN) transferase domain, and systematically down selected seven candidates (CHEMBL608526, CHEMBL196676, CHEMBL164344, CHEMBL4291724, CHEMBL4569308, CHEMBL387132, CHEMBL98211), two of which closely resemble the approved drugs minodronate and zoledronate. This work and our recent paper together provide an in silico mechanistic explanation for alendronate and zoledronate users having dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations, and indicate that similar observational studies with minodronate could be valuable.

This study aimed to evaluate the impact of Candida albicans on subgingival biofilm formation on dental implant surfaces. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) were used to compare biofilm structure and microbial biomass in the presence and absence of the fungus after periods of 24, 48, and 72 h. Quantitative polymerase chain reaction (qPCR) was used to quantify the number of viable and total micro-organisms for each of the biofilm-forming strains. A general linear model was applied to compare CLSM and qPCR results between control and test conditions. The biofilm developed with C. albicans at 72 h had a higher bacterial biomass, with a significantly higher cell viability (p < 0.05). After both 48 and 72 h of incubation, in the presence of C. albicans, there was a significant increase in counts of Fusobacterium nucleatum and Porphyromonas gingivalis and in the cell viability of Streptococcus oralis, Aggregatibacter actinomycetemcomitans, F. nucleatum, and P. gingivalis. Using a dynamic in vitro multispecies biofilm model, C. albicans exacerbated the development of the biofilm grown on dental implant surfaces, significantly increasing the number and cell viability of periodontal bacteria.

Enterococcus faecalis is a growing cause of nosocomial and antibiotic-resistant infections. Treating drug-resistant E. faecalis requires novel approaches. The use of bacteriophages (phages) against multidrug-resistant (MDR) bacteria has recently garnered global attention. Biofilms play a vital role in E. faecalis pathogenesis as they enhance antibiotic resistance. Phages eliminate biofilms by producing lytic enzymes, including depolymerases. In this study, Enterococcus phage vB_Efs8_KEN04 (ФKEN04), isolated from a sewage treatment plant in Nairobi, Kenya, was tested against clinical strains of MDR Enterococcus faecalis. This phage had a broad host range against 100% (26/26) of MDR E. faecalis clinical isolates and cross-species activity against Enterococcus faecium. It was able to withstand acidic and alkaline conditions, from pH 3 to 11, as well as temperatures between -80ᵒC and 37ᵒC. It could inhibit and disrupt the biofilms of MDR E. faecalis. Its linear double-stranded DNA genome of 142,402 bp contains 238 coding sequences with a G+C content and coding gene density of 36.01% and 91.46%, respectively. Genomic analyses showed that ФKEN04 belongs to the genus Kochikohdavirus in the family Herelleviridae. It lacked antimicrobial resistance, virulence, and lysogeny genes, and its stability, broad host range, and cross-species lysis indicate strong potential for the treatment of Enterococcus infections.

Shigella and Salmonella have been implicated in neonatal sepsis, food poisoning, and bacteremia. Their increasing resistance to antibiotics has undermined treatment options, constituting a public health crisis. Also, the scarcity of new antibiotics in the development pipeline compounds multidrug-resistance (MDR). Hence, there is a need to potentiate antibiotics to mitigate resistance. This study leveraged riboflavin to re-sensitize fluoroquinolones and carbapenems against MDR Shigella and Salmonella spp. Disk diffusion, microbroth-dilution, chequerboard, and time-kill assays were used to determine resistance profiles and riboflavin-antibiotic activity. Biofilm-formation and bacterial viability (after riboflavin-antibiotic challenge) was determined with crystal-violet and Macrophage infection assays, respectively. Strains exhibited >80% resistance to fluoroquinolones and carbapenems, with 160–320 µg MIC ranges and 0.5–2 FIC, indicating no synergy. At 40–80 µg riboflavin, there was two-fold reduction in bacterial survival, with meropenem-riboflavin exhibiting significant reduction and FIC of 0.075 indicating high synergistic activity. Biofilm-formation was altered (from strong to weak phenotype) with 40 µg riboflavin-antibiotic treatment. There was a 40–70% reduction in bacterial survival in THP-1 cells treated with meropenem-riboflavin after 3 hours, and complete clearance between 24-48 hpi. Riboflavin potentiated fluoroquinolones and meropenem, leading to modulation of the host immune response for the clearance of the strains.

Contact inhibition (CI) represents a crucial tumor-suppressive mechanism responsible for controlling the unbridled growth of cells, thus preventing the formation of cancerous tissues. CI can be further categorized into two distinct yet interrelated components: CI of locomotion (CIL) and CI of proliferation (CIP). These two components of CI have historically been viewed as separate processes, but emerging research indicates that they share both distinctive and common pathways. Moreover, they exhibit intriguing intersections with mechanotransduction, a process that involves cells sensing and responding to mechanical forces. This review article describes the intricate interplay between mechanical forces and CI, shedding light on how these forces regulate CIL and CIP. Emphasis is placed on filamin A (FLNA)-mediated mechanotransduction, elucidating how FLNA senses mechanical forces and translates them into crucial biochemical signals that regulate cell locomotion and proliferation. In addition to FLNA, trans-acting factors (TAFs) emerge as sensitive players in both CI and the mechanotransduction process. This article presents methods for identifying these TAFs and profiling the associated changes in chromatin structure, offering valuable insights into CI and mechanotransduction regulation. Finally, it addresses unanswered research questions in these fields and delineates their possible future directions.

Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly different. A promising strategy in oncotherapy is targeted therapy, targeting proteins that regulate cell survival and proliferation; such as the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. Inhibitors of these pathways have been tested previously in CCA cell lines. However, these cell lines could not be clearly assigned to ICC or ECC, and results indicated apoptosis induction by targeted therapeutics. We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). We observed cooperative effects of dual inhibition of the two pathways, in accordance with inhibition of phospho-AKT and phospho-ERK1/2 expression. Proliferation was blocked more effectively with dual inhibition than with each single inhibition, but cell numbers did not drop below baseline. Accordingly, we observed G1-phase arrest, but not apoptosis (cleaved caspase-3, AIFM1 regulation, subG1-phase) or necroptosis (phospho-MLKL). We conclude that dual inhibition of MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block proliferation of ICC cell lines, but therapy must certainly be supplemented with standard therapies.

Limited understanding exists regarding the intricate dynamics between the levels of social inhi-bition exhibited by both wives and husbands concerning their perceived family support and de-pressive symptoms, particularly within couples who are parents of children diagnosed with au-tism spectrum disorder (ASD). This study used the actor-partner, interdependence mediation model to analyze data collected from 397 pairs of Chinese parents with children diagnosed with ASD. The findings of the study revealed significant indirect actor effects, indicating that the levels of social inhibition exhibited by both wives and husbands were associated with their own de-pressive symptoms through their respective perceptions of family support. In general, the study did not find significant partner effects, except for some indirect effect (IE) of wives on their hus-bands' depressive symptoms through the wives' perceived social support. This observation sug-gests that cultural norms and role expectations within the family context may influence these dy-namics. These results underscore the potential importance of interventions aimed at addressing social inhibition and enhancing perceived family support to alleviate depressive symptoms in this population. Additionally, interventions targeting fathers should emphasize the importance of their involvement in parenting and collaboration with their partners in caring for children with ASD. Such collaborative efforts may contribute to improved outcomes for both parents and chil-dren within families affected by ASD.

Round bodies in spirochete cultures have been a controversial subject since their description seven decades ago. We report the existence of round bodies (spherical cells) in cultures of Mucispirillum schaedleri, a spiral bacterium phylogenetically distant from spirochetes. Furthermore, when grown in biofilms, M. schaedleri demonstrates a unique morphology known as cording, which has been previously described only in mycobacteria. Thus, M. schaedleri has two distinct features, each previously thought to be unique to two different phylogenetically distant groups of bacteria.

A theoretical model to translate the evolution over time, in early stages, of growth and accumulation of biofilm bacterial mass is introduced. The model implies the solution of a system of differential-difference master equations. The application of an algorithm like Miller´s tree term recurrence, already known for Bessel functions of first kind, allows an exact calculation of the solutions of such equations, for a wide range of parameters values and time. For biofilm model a five term recurrence is deduced and applied in a backwards computation. A suitable normalisation condition completes the reach of the solution.

The chemical investigation of the anti-yeast methanol extract from the stem bark of Terminalia mantaly led to the isolation of seven compounds: 3-O-methyl-4-O-α-rhamnopyranoside ellagic acid (1), 3-O-mehylellagic acid (2), arjungenin or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid (3), arjunglucoside or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid glucopyranoside (4), 2α,3α,24-trihydroxyolean-11,13(18)-dien-28-oïc acid (5), stigmasterol (6), stigmasterol 3-O-β-D-glucopyranoside (7). Their structures were established by means of spectroscopic analysis and comparison with published data. Compounds 1-5 were tested in vitro for activity against three pathogenic yeast isolates, Candida albicans, Candida parapsilosis and Candida krusei. The activity of compounds 1, 2 and 4 were comparable to that of the reference compound fluconazole (MIC values below 32 µg/ml) against the three tested yeast isolates. They were also tested for inhibitory properties against four enzymes of metabolic significance: Glucose-6-Phosphate Deshydrogenase (G6PD), human erythrocyte Carbonic anhydrase I and II (hCA I and hCA II), Glutathione S-transferase (GST). Compound 4 showed highly potent inhibitory property against the four tested enzymes with overall IC₅₀ values below 4 µM and inhibitory constant (Ki) <3 µM.

This paper explores the intricate world of microbial life, focusing on biofilm as a dynamic consortium of bacteria forming complex networks within a self-produced matrix of extracellular polymeric substances (EPS). Analogous to a bacterial house, these structures provide both shelter and support, playing a pivotal role in the microbial realm with dual effects on human and environmental contexts. Biofilm's significance extends beyond its microcosmic architecture, positively contributing to heavy metal removal, electricity generation through microbial fuel cells, and structural remediation, while also posing threats with detrimental formations implicated in conditions from lung to urinary tract infections. Control of biofilm becomes imperative to unlock its positive attributes and mitigate potential negatives, serving as a cornerstone for environmental remediation, sustainable energy, and infrastructure maintenance. Employing a comprehensive bibliographic approach, this study identifies keywords, countries, and organizations influencing biofilm research, proposing innovative avenues like machine learning for future exploration. The aim is not only to contribute to existing knowledge but to pioneer cutting-edge strategies for biofilm optimization and challenge mitigation, shaping its trajectory towards sustainable applications across diverse fields.

Biofilm matrix is akin to bacterial abodes, primarily composed of proteins, polysaccharides, extracellular DNA, and lipids, providing essential structural support to bacteria. While some biofilm matrix offers significant benefits, such as engineered biofilm reactors that assist in water pollutant removal, others pose risks to human health, potentially leading to conditions like lung infections. Realizing the potential of advantageous biofilm matrix and mitigating the harmful effects of detrimental ones necessitates a comprehensive and systematic exploration of this intricate domain. To facilitate this examination, our study leveraged a dataset of the 1000 most pivotal papers in the field and conducted an exhaustive bibliographic review. This paper serves as a valuable resource for understanding the current progress in biofilm matrix research and delving into vital avenues for future exploration in this dynamic field.

Staphylococcus aureus and coagulase-negative staphylococci account for about 80% of infections associated with medical devices and are associated with increased virulence due to their ability to form biofilm. In this study, we aimed to construct a comprehensive reference map followed by significant pathway analysis in the proteome of S. aureus biofilm grown for 3-days as compared with 24 h planktonic using a high-resolution TMT based MS. We identified proteins associated with secondary metabolites, ABC transporters, biosynthesis of amino acids, response to stress, and amino sugar and nucleotide sugar metabolism were significantly upregulated in the 3-day biofilm. In contrast, proteins associated with virulence factors, microbial metabolism in diverse environments, translation, and energy metabolism were significantly downregulated. GO functional annotation indicated that more proteins are involved in metabolic processes, catalytic activity, and binding in biofilm, respectively. Among the significantly dysregulated proteins, hyaluronidase (hysA) in conjunction with chitinase may play a significant role in the elimination and/or prevention of biofilm development. This study advances the current S. aureus subproteomes, identified potential pathways significant to biofilm biology and helped to understand their potential role in S. aureus which may shed light on developing new therapeutic regimes including antibiofilm agents in the treatment of biofilm-infections related with implantable medical devices.

There is a growing body of evidence supporting the significant role of bacterial biofilms in the pathogenesis of various human diseases including cancer. Biofilms are polymicrobial communities enclosed within an extracellular matrix composed of polysaccharides, proteins, extracellular DNA, and lipids. This complex matrix provides protection against antibiotics and host immune responses, enabling the microorganisms to establish persistent infections. Moreover, biofilms induce anti-inflammatory responses and metabolic changes in the host, further facilitating their survival. Many of these changes are comparable to those observed in cancer cells. This review will cover recent research on the role of bacterial biofilms in carcinogenesis, especially in colorectal (CRC) and gastric cancers, emphasizing the shared physical and chemical characteristics of biofilms and cancer. This review will also discuss the interactions between bacteria and the tumor microenvironment, which can facilitate oncogene expression and cancer progression. This information will provide insight into developing new therapies to identify and treat biofilm-associated cancers, such as utilizing bacteria as delivery vectors, using bacteria to upregulate immune function, or more selectively targeting biofilms and cancer for their shared traits.

Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1’s important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. Collectively, we report a possible role of REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with significant bearing on cancer treatment regimens.

Helicobacter pylori is a gastric pathogen that infects nearly half of the global population and is recognized as a group 1 carcinogen by the Word Health Organization. The global rise in antibiotic resistance has increased clinical challenges in treating H. pylori infections. Biofilm growth has been proposed to contribute to H. pylori’s chronic colonization of the host stomach, treatment failures, and the eventual development of gastric diseases. Several components of H. pylori have been identified to promote biofilm growth, and several of these may also facilitate antibiotic tolerance, including the extracellular matrix, outer membrane proteins, the coccoid morphology, modulated metabolism, efflux pumps, and virulence factors. Recent developments in therapeutic approaches targeting H. pylori biofilm have shown that synthetic compounds, such as small molecule drugs and plant-derived compounds, are effective at eradicating H. pylori biofilms. These combined topics highlight the necessity for biofilm-based research in H. pylori, to improve current H. pylori targeted therapeutic approaches and alleviate relative public health burden. In this review we discuss recent discoveries that have decoded the life cycle of H. pylori biofilms and current biofilm targeted treatment strategies.

Biofilms are congregations of bacteria on a surface, and they grow into obstacles for the functionalities of any device or machinery involves anything biological. Biofilms are developed through a biochemical system known as ‘Quorum Sensing’ that accounts for the chemical signaling that direct either biofilm formation or inhibition. Computational models that relate chemical and structural features of compounds to their performance properties have been used to aide in the discovery of active small molecules for many decades. These quantitative structure-activity relationship (QSAR) models are also important for predicting the activity of molecules that can have a range of effectiveness in biological systems. This study uses QSAR methodologies combined with and different machine learning algorithms to predict and assess the performance of several different compounds acting in Quorum Sensing. Through computational probing of the quorum sensing molecular interaction, new design rules can be elucidated for countering biofilms.

This study explores the pivotal biofilm life cycle, essential for comprehending intricate processes in biofilm formation and dispersal. With profound implications for medicine, environmental science, and industrial applications, the life cycle involves initial attachment, irreversible attachment, maturation, and dispersion. Employing bibliographic analysis, the paper unravels critical aspects, unveiling key keywords, prominent research countries/regions, and significant research organizations. This comprehensive approach provides insights into the current biofilm research landscape, identifying gaps for future exploration. Biofilm's influence extends to medical conditions, environmental ecosystems, and industrial challenges, accentuating the urgency of understanding its life cycle. The study also delves into global research distribution and influential organizations, guiding collaborative efforts. As a forward-looking initiative, it proposes future research opportunities, aiming to steer advancements and address challenges in biofilm science. Ultimately, this analysis contributes to the ongoing progress of biofilm research, fostering interdisciplinary collaboration and inspiring future initiatives.

This paper explores the multifaceted impact of biofilms, bacterial communities enveloped in extracellular polymeric substance (EPS). Biofilms play a dual role, acting as environmental champions and health threats. They interact with heavy metals, either causing pollution or aiding environmental remediation. Beneficial biofilms generate electricity and repair concrete cracks, offering sustainable solutions. Conversely, they contribute to infections, posing health risks. The study emphasizes the need for in-depth research, utilizing bibliographic methods to analyze global biofilm research. By identifying keywords, core countries, and pivotal organizations, the paper informs future investigations, offering insights into biofilm research evolution and practical applications.

Biofilm-associated proteins (BAPs) are important in the development and resilience of biofilms, which are intricate populations of microbes protected by extracellular matrix. All members of the BAP family are known to possess common characteristics such as high molecular weight and a signal sequence for extracellular secretion. It has been shown that BAPs are directly linked to the pathogenicity of many bacteria. This mini review highlights several potential strategies to target BAPs for drug development.

Anterior-tooth (ANT) contacts induce short latency reflex inhibition of human jaw-closing muscles. The jaw is a rigid class 1 lever for pinpoint-targeting muscle force into a single bite-point, the pivoting food particle. See-saw reflex movements around the food particle fulcrum multiply the food-crushing force. Unpredictable jolts of reaction force caused by food-crushing are subjected to the rostral ANT and caudally to the two articulate ends of the jaw triangle. Compression/distraction strains of food-crushing must be monitored and inhibited by withdrawal reflexes. The mesencephalic ganglion (Vmes), neural myelin sheath, and muscle stretch receptors evolved subsequently to the advent of jaws to improve the velocity of proprioceptive and withdrawal reflexes. In mammalians, the spindles of the taut motor units, stretched by the food-fulcrum send excitatory monosynaptic feedback for the efferent neurons of the respective ipsilateral muscle units, via Vmes. In the Vmes, the spindle-input-mediating afferent neurons are coupled with another source of afferent feedback, which is also excitatory, from the back-tooth (BAT) mechanoreceptors. The two sources of excitatory pulses are summated and targeted for the efferent neurons to boost the stretched and taut motor units. Likewise, the afferent feedback from ANT mechanoreceptors is also coupled in the Vmes with concomitant feedback from spindles. The ANT output, however, is inhibitory to negate the excitatory feedback from the stretched jaw-muscle units. The inhibitory feed from ANT temporarily blocks the excitatory potential of masticatory motor efferent neurons to protect the ANT and jaw-joints from inadvertent strains. The inhibitory inputs from ANT alternate with the excitatory inputs from BAT to determine which jaw-closing muscle units are activated or inhibited at any given instant of food-crushing. The Vmes exists in all jawed vertebrates, and its’ evolution was probably motivated by demands for the control of bite force. The monosynaptic unilateral food-crushing excitatory and inhibitory reflexes (UFCR) override the coexisting bilaterally executed feed for jaw muscles from the central nervous system. Hypothesis: The Vmes-mediated UFCR combine neural inputs from tooth contacts with concomitant feedback from muscle stretch receptors for the control of mammalian food-crushing bite force.

Bacterial biofilms can cause widespread infection. In addition to causing urinary tract infections and pulmonary infections in patients with cystic fibrosis, biofilms can help microorganisms adhere to the surfaces of various medical devices, causing biofilm-associated infections on the surfaces of biomaterials such as venous ducts, joint prostheses, mechanical heart valves, and catheters. Biofilms provide a protective barrier for bacteria and provide resistance to antimicrobial agents, which increases the morbidity and mortality of patients. This review introduces the formation process and drug resistance mechanism of biofilms in detail, and further summarizes the main characteristics of clinical persistent infection caused by biofilms and the many methods of treating biomaterial-related biofilm. This provides ideas and directions for the development of new biofilm infection strategies related to therapeutic materials.

Helicobacter pylori infections are still an urgent and hot topic. This is related to the involvement of H. pylori in human diseases (including gastric diseases, gastric adenocarcinoma, mucosa-associated lymphoid tissue lymphoma, and diabetes), the number of which is constantly increasing. At the same time, agents effective against these bacteria are decreasing due to spreading resistance. Our research focused on extracts of the Rubus genus, commonly present in Central and Eastern Europe and very useful in folk medicine. Results have shown that the extract from Rubus idaeus 'Willamette' shoots, and the extract from R. idaeus 'Poranna Rosa' fruits and R. idaeus 'Laszka' R. occidentalis Litacz' fruits prevent the formation of biofilm by H. pylori on intravenous infusions (they reduce living cells, which was detected using triphenyl tetrazolium chloride (TTC) as a dye) at concentrations of 6.65 and 16.65 mg/mL, respectively. However, the living bacteria in the formed biofilm are affected by the extract from the shoots of R. idaeus 'Willamette' and the fruit of R. idaeus 'Poranna Rosa' at a concentration of 16.65 mg/ml, and the remaining extracts at a concentration of 33.3 mg/ml. The results of the study of interactions of extracts from Rubus sp. and the 2 antibiotics against H. pylori planktonic bacteria showed doxycycline synergism with all tested extracts, but only the extract of R. occidentalis 'Litacz' with levofloxacin. The remaining tested extracts showed indifference with levofloxacin. However, studies on the interaction between antibiotics and extracts of R. idaeus 'Willamette' shoot showed synergy with doxycycline and levofloxacin, additivity with amoxicillin and clarithromycin, and indifference with metronidazole. The tests were carried out on fragments of intravenous infusions with TTC as a dye. The tested extracts may be elements of broadly understood anti-H. pylori therapy.

Biofilm is a complex community of microorganisms that are attached to surfaces and encased in a self-produced extracellular matrix. Machine learning (ML) techniques have been applied to various aspects of biofilm research, such as predicting biofilm formation, identifying key genes, and designing new therapeutic strategies. In this study, we conducted a bibliometric analysis of machine learning in biofilm research to provide a comprehensive overview of the current state of the field. We searched the Web of Science database for articles published included "machine learning biofilm". A total of 126 articles were identified and analysed. Our results showed that the number of publications on machine learning in biofilm has been increasing rapidly over the past decade, indicating a growing interest in the application of ML techniques to biofilm research. The analysis also revealed that the most common research topics in this area were related to biofilm formation, prediction, and control. Furthermore, the most frequently used ML techniques in biofilm research were artificial neural networks and support vector machines. Overall, our study provides valuable insights into the current trends and future directions of machine learning in biofilm research. It also highlights the importance of interdisciplinary collaboration between biofilm researchers and ML experts to drive innovation in this field.

The corrosion inhibition behavior of cetyl pyridinium chloride (CPC) on mild steel (MS) in 0.5 M H₂SO₄ solution was examined using the weight loss method and potentiodynamic polarization method. The experimented MS surface was characterized by Fourier Transform Infrared Spectroscopy (FTIR), Field Emission Scanning Electron Microscopy (FESEM), and Atomic Force Microscopy (AFM). Corrosion rate and corrosion efficiency was calsulated via weight loss and potentiodynamic polarization methods where the corrosion rate in 0.5 M H₂SO₄ , 0.000192 M, and 0.0077 M of CPC solution was 12.09×10^-3, 8.23×10^-3, 6.63×10^-5 (mm/Year), respectively and the inhibition efficiency of 94.42% and 98.54%. FESEM studies demonstrated the corrosion attack on MS surface. Also, the EDX showed the presence of nitrogen of CPC. Thus, CPC acts as an important corrosion inhibitor.

Akt1 is a proto-oncogene that is over active in most cancers. Akt1 activation requires phosphorylation at Thr308; phosphorylation at Ser473 further enhances catalytic activity. Akt1 activity is also regulated via interactions between the kinase domain and the N-terminal auto-inhibitory pleckstrin homology (PH) domain. As it was previously difficult to produce Akt1 in site-specifically phosphorylated forms, the contribution of each activating phosphorylation site to auto-inhibition was unknown. Using a combination of genetic code expansion and in vivo enzymatic phosphorylation, we produced Akt1 variants containing programmed phosphorylation to probe the interplay between Akt1 phosphorylation status and the auto-inhibitory function of the PH domain. Deletion of the PH domain increased the enzyme activity for all three phosphorylated Akt1 variants. For the doubly phosphorylated enzyme, deletion of the PH domain relieved auto-inhibition by 295-fold. We next found that phosphorylation at Ser473 provided resistance to chemical inhibition by Akti-1/2 inhibitor VIII. The Akti-1/2 inhibitor was most effective against pAkt1T308 and showed 4-fold decreased potency with Akt1 variants phosphorylated at Ser473. The data highlight the need to design more potent Akt1 inhibitors that are effective against the doubly phosphorylated and most pathogenic form of Akt1.

Cellulose nanocrystals (CNCs) are cellulose-derived nanomaterials that can be easily obtained, e.g., from vegetable wastes produced by circular economies. They show promising antimicrobial activity and the absence of side effects and toxicity. This study investigated the ability of CNCs to reduce microbial adherence and biofilm formation using in vitro microbiological models reproducing the oral environment. Microbial adherence by microbial strains of oral interest, Streptococcus mutans and Candida albicans was evaluated on the surfaces of salivary pellicle-coated enamel disks in the presence of different aqueous solutions of CNCs. The antibiofilm activity of the same CNC solutions was tested against S. mutans and an oral microcosm model based on mixed plaque inoculum using a continuous-flow bioreactor. Results showed an excellent anti-adherent activity of the CNCs against the tested strains from the lowest concentration tested (0.032 wt.%). Such activity was significantly higher against S. mutans than C. albicans, suggesting a selective anti-adherent activity against pathogenic strains. At the same time, there was a minimal albeit significant antibiofilm activity (at least 0.5 and 4 wt.% CNC solution for S. mutans and oral microcosm, respectively). This makes CNCs particularly interesting as anticaries agents, encouraging their use in the oral field.

Biofilm serves as the residence for bacteria, wherein bacteria attach to surfaces and produce extracellular polymeric substances, including proteins, polysaccharides, and extracellular DNA. In recent years, biofilm reactors have gained increasing significance, playing a crucial role, for instance, in immobilizing heavy metals from waterways. This paper employs a bibliographic study to analyze the most important keywords and organizations in the field of biofilm reactors, identifying recent significant papers. Additionally, the paper discusses the opportunities for the future development of biofilm reactors. Through this study, a better understanding of key factors in biofilm reactor research is achieved, providing valuable guidance for future studies and applications in this field.

Bioelectric effect is known as combinatorial biofilm treatment with low dose of antibiotics with small electricity. When external electric field or current are applied, biofilms can be affected by the electrostatic force, non-uniform distribution of essential electrolytes, induction of low activity of enzyme, and increase of permeability of biofilms. In this work, we have focused on the reduction of applied electric power consumption that could avoid water electrolysis which was one of major challenges for biomedical applications. We have developed a new type of electrical signal that enhances the efficacy of biofilm removal. The results show combination of alternating and direct current remove biofilm effectively without causing electrolysis. We further developed an oral healthcare device as a bioelectric toothbrush and tested in dental clinic. The results demonstrated 75% reduction of gingivitis. In addition, we have tested a mimicked air conditioner biofilms that are root causes of aerobic hygiene infection. The result demonstrates 81.8% increased biofilm removal. In conclusion, a new bioelectric technology has been developed and demonstrated the biofilm removal efficacy without the electrolysis.

Biofilm-mediated infection is a major cause of bone prosthesis failure. The lack of molecules able to act in biofilms has driven research aimed at identifying new anti-biofilm agents via chemical screens. However, to be able to accommodate a large number of compounds, the testing conditions of these screenings end up being typically far from the clinical scenario. In this study, we assess the potential applicability of three anti-biofilm compounds (based on natural compounds) as part of implanted medical devices by testing them on in vitro systems that more faithfully resemble the clinical scenario. To that end, we used a competition model based on the co-culture of SaOS-2 mammalian cells and Staphylococcus aureus (collection and clinical strains) on a titanium surface. Additionally, we studied whether these derivatives of natural compounds enhance the previously proven protective effect of pre-incubating the titanium surface with SaOS-2 cells. Out of the three tested leads, one showed the highest potential, and can be regarded as a promising agent for incorporation into bone implants. This study emphasizes and demonstrates the importance of using meaningful experimental models, where potential antimicrobials ought to be tested for protection of biomaterials in translational applications.

This study was performed to evaluate the efficacy of nicotinic acid against Streptococcus pneumoniae biofilm. The experimental results indicate that S. pneumoniae forms biofilms, particularly at the liquid-air interface, as evidenced by the pellicle assay. Nicotinic acid demonstrated significant inhibition of S. pneumoniae biofilm formation at 6 h and 18 h, with higher concentrations leading to lower biofilm biomass, suggesting a concentration-dependent response. However, minimal biofilm inhibition was observed at 12 h. Treatment with nicotinic acid induced FTIR spectral changes in protein biomolecules of S. pneumoniae biofilm at 6 h and 18 h, evidenced by alterations in spectral peaks at 750 cm-1, 906 cm-1, 1540 cm-1, 1548 cm-1, and 1644 cm-1. Notably, no FTIR spectral changes were detected in 12 h S. pneumoniae biofilm following exposure to nicotinic acid. These findings suggest that nicotinic acid inhibits biofilm formation in a time and concentration-dependent manner, possibly by altering the structure of protein biomolecules within the biofilm.

Effective oral care is a critical requirement to maintain high quality of life. Most oral diseases are caused by plaque (oral biofilm), which is also correlated with systemic diseases. A common method to remove biofilm is brushing teeth with a toothpaste. However, 3.5 billion people in the world have oral diseases, meaning that more efficient methods of removing biofilms are needed. We have developed a toothbrush applying bioelectric effect (BE) utilizing an electric force for biofilm removal. It demonstrated significantly higher biofilm removal efficiency than non-BE manual toothbrushes. Tests were performed in saline and toothpaste conditions using various pressure. Results showed that the BE toothbrush had a significantly higher biofilm removal efficiency in saline (0.5 N: 215.43 ± 89.92 %, 2.5 N: 116.77 ± 47.02 %) and in a toothpaste slurry (0.5 N: 104.96 ± 98.93 %, 2.5 N: 96.23 ± 35.16 %) than non-BE manual toothbrushes. Results also showed that BE toothbrushes were less dependent on toothpaste. This study suggests that the application of BE can be a new solution to plaque problems in oral care.

Salmonella can cause acute and chronic infections in humans. Salmonella species are known to cause food poisoning and other diseases in developing countries. Their role in the pathogenesis of these diseases has received increased international attention. Despite numerous advances in sanitation, they still can infect humans and cause outbreaks in developed countries. For example, Salmonella causes about 1.2 million illnesses in the US each year with over 450 deaths. Additionally, Salmonella outbreaks cause significant losses to chicken producers globally. The Salmonella species is also prone to acquiring resistance to various classes of antibiotics. Hence, the need for a paradigm shift from antibiotics to bacteriophages to manage, control and treat bacterial infections. The ɛ34 phage belongs to Podoviruses and categorized into the P22-like phages. The P22-like phages include ɛ34, ES18, P22, ST104, and ST64T. In this work, we investigated the antibacterial property of ɛ34 phage tailspike protein against Salmonella newington (S. newington). We demonstrate here that, the phage’s tailspike protein enzymatic property as a LPS hydrolase synergizes with Vero Cell culture supernatant in killing S. newington. Using decellularized cartilage scaffold as an ex vivo tissue model, the ɛ34 TSP protected the scaffold from S. newington biofilm formation. Computational analysis of the ɛ34 TSP interaction with membrane proteins of S. newington demonstrated a higher probability (0.7318) of binding to ompA of S. newington, and when docked to ompA extracellular component, it produced a high free energy of -11.3kcal/mol. We also demonstrate the resistance/sensitivity of the tailspike to the digestive enzyme trypsin. The data obtained in this work indicates that the trypsin resistant tailspike protein of Ɛ34 phage can be formulated as a novel antibacterial agent against S. newington.

Histone deacetylase 6 (HDAC6) regulates many physiological processes that are involved in cancer development and progression such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, by deacetylation of multiple substrates and association with interacting proteins. Due to its the ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cells survival. HDAC6 is often overexpressed in tumors, including colorectal cancer (CRC) and is correlated with poor disease prognosis. However, it has been shown in animal models that HDAC6 is not essential for normal mammalian development. Therefore, it represents a good target for the development of novel cancer therapeutics. Selective inhibition of HDAC6 impairs growth and progression of many tumors without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown potential to reduce tumor progression and to enhance the therapeutic effect of other drugs. As HDAC6 is involved in regulation of immune responses, HDAC6 inhibitors have shown potential to improve antitumor immunity by increasing immunogenicity of tumor cells, augmenting immune cell activity and alleviating immunosuppression in tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect and to overcome resistance to immunotherapy.

Bacteria of the genus Staphylococcus are a significant a challenge for medicine, as many species are resistant to multiple antibiotics and even to all of the antibiotics used. One of the approaches to develop new therapeutics to treat staphylococcal infections is the use of bacteriophages specif-ic to these bacteria or lysins of such bacteriophages capable to hydrolyze the cell walls of these bacteria. In this study, a new bacteriophage St_134 specific to Staphylococcus epedermidis was de-scribed. This small podophage belonging to the Andhravirus genus showed relatively wide host range and was able to infect more than 60 strain of Staphylococcus spp., including a clinical strain from the Staphylococcus aureus complex. Two genes encoding different phage lysins were identi-fied in the Ste134 genome. Both lysins LysSte134_1 and LysSte134_2 were produced in Escherichia coli cells. Endolysin LysSte134_1 was demonstrated catalytic activity against a wide panel of staphylococcal peptidoglycans (4 species, 6 strains), was active against S. aureus and S. epidermidis planktonic cultures and destroyed biofilms formed by clinical strains of S. aureus and S. epider-midis.

Membrane biofouling is an inevitable challenge in membrane-based water treatment systems such as membrane bioreactors. Recent studies have shown that biological approaches based on bacterial signaling can effectively control biofilm formation. Quorum quenching (QQ) is known to inhibit biofilm growth by disrupting quorum sensing (QS) signaling, while nitric oxide (NO) signaling helps to disperse biofilms. In this study, batch biofilm experiments were conducted to investigate the impact of simultaneously applying NO signaling and QQ for biofilm control, using Pseudomonas aeruginosa PAO1 as a model microorganism. The NO treatment involved the injection of NONOates (NO donor compounds) into mature biofilms, while QQ was implemented by immobilizing QQ bacteria (Escherichia coli TOP10-AiiO or Rhodococcus sp. BH4) in alginate or polyvinyl alcohol/alginate beads to preserve the QQ activity. When AiiO and BH4 beads were applied together with (Z)-1-[N-(3-aminopropyl)-N-(n-propyl) amino] diazen-1-ium-1,2-diolate (PAPA NONOate), they achieved higher biofilm reduction compared to their individual applications. These findings highlight the significant potential of combining QQ and NO technologies for effective biofilm control across a variety of processes that require enhanced biofilm inhibition.

The emergence of antimicrobial resistance remains one of the greatest public health concerns. Biofilm formation has been postulated as a mechanism of microbial pathogens to resist antimicrobial agents. Lactic Acid Bacteria (LAB) and their metabolites have been proposed to combat bacterial biofilms, due to their antimicrobial activity. In this vein, the aim of the present study was to investigate the biofilm removal potential of cell-free supernatant (CFS) of five wild-type Lacticaseibacillus rhamnosus LAB strains, isolated from Greek natural products, in comparison to the commercial available L. rhamnosus GG strain, formed by common foodborne pathogens (Salmonella Enteritidis, Salmonella Typhimurium, Escherichia coli, Listeria monocytogenes, and Staphylococcus aureus). Biofilm removal activity of LAB was assessed on two-days mature biofilm using a microtiter plate-based procedure. Both non-neutralized and neutralized CFSs removed biofilms in a concentration-dependent manner. Biofilm removal activity of the non-neutralized CFSs was significantly higher compared to the neutralized CFSs, as expected, ranging 40 – 90% and 10 – 78%, respectively. Biofilm removal efficiency of L. rhamnosus OLXAL-3 was signifanctly higher among the wild-type L. rhamnosus strains tested (20 – 100% v/v). In conclusion, our results suggested the great potential of application of wild-type Lacticaseibacillus rhamnosus strains CFSs as effective natural agents against pathogenic bacterial biofilms.

BUB1 is overexpressed in most human solid cancers including breast cancer. Higher BUB1 levels are associated with poor prognosis especially in patients with triple-negative breast cancer (TNBC). Women with TNBC often develop resistance to chemotherapy and radiotherapy, which are still the mainstay of treatment for TNBC. Our previous studies demonstrated that BUB1 kinase inhibitor (BAY1816032) reduced tumor cell proliferation and significantly enhanced radiotherapy efficacy in TNBC. In this study, we evaluated the effectiveness of BAY1816032 with a PARP inhibitor (olaparib), platinum agent (cisplatin), and microtubule poison (paclitaxel) alone or in combination with radiotherapy using cytotoxicity and clonogenic survival assays. BUB1 inhibitor sensitized BRCA1/2 wild-type SUM159 and MDA-MB-231 cells to olaparib, cisplatin and paclitaxel synergistically (combination index; CI

Background: Non-alcoholic fatty liver disease (NAFLD) is manifested by hepatic steatosis, insulin resistance, hepatocyte death, and systemic inflammation. Obesity induces steatosis and chronic inflammation in the liver. However, the precise mechanism underlying hepatic steatosis in the setting of obesity remains unclear. Here we report studies that address this question. Methods: 14 weeks on high-fat diet (HFD) with high sucrose, C57BL/6 mice revealed a phenotype of liver steatosis. Transcriptional profiling analysis of the liver tissues was performed using RNA sequencing (RNA-seq). Results: Our RNA-seq data revealed 692 differentially expressed genes involved in processes of lipid metabolism, oxidative stress, immune responses, and cell proliferation. Notably, the gene encoding neutral sphingomyelinase SMPD3, was predominantly upregulated in the liver tissues of the mice displaying a phenotype of steatosis. Moreover, nSMase2 activity was elevated in these tissues of the liver. Pharmacological and genetic inhibition of nSMase2 prevented intracellular lipid accumulation and TNFα-induced inflammation in in-vitro HepG2-steatosis cellular model. Furthermore, nSMase2 inhibition ameliorates oxidative damage by rescuing PPARα and prevent cell death associated with high glucose/oleic acid-induced fat accumulation in HepG2 cells. Conclusions: Collectively, our findings highlight the prominent role of nSMase2 in hepatic steatosis which could serve as a potential therapeutic target for NAFLD and other hepatic steatosis-linked disorders.

Metformin is an oral antidiabetic agent with antimicrobial properties, excreted in an active and unmetabolized form. Like some non-antibiotic drugs, subinhibitory concentrations of metformin may contribute to the expression of microbial resistance in wild-type strains. This work aimed to evaluate the biofilm formation of Pseudomonas aeruginosa TGC04 exposed to 100 and 200 µg/mL of metformin, varying the Chemical Oxygen Demand (COD) and flow regime. Biofilms were quantified after 2 and 24 hours, observing reductions and increases in biofilm growth around 13 and 64%, respectively. The greatest biofilm growth occurred in cells exposed to 200 µg/mL of metformin. Both the flow regime and COD concentration were important for the development of the biofilm, whose cells were mostly weakly to moderately adhered. The study provides evidence that in polluted aquatic systems with turbulent regimes, the inhibitory concentration of metformin promoted the least disturbances to the biofilm.

Coagulase-Negative Staphylococci (CoNS) are commensal on human body surfaces and for years, they were not considered a cause of bloodstream infection and were often regardered as contamination. However, the association of CoNS with nosocomial infection is increasingly recognized. The insertion of cannulas and intravascular catheters represents the first source of CoNS entry into the bloodstream, causing bacteremia and sepsis. They owe their pathogenic power to their ability to produce biofilms on surfaces, such as medical devices. In this study, we evaluate the adhesive capacity of CoNS isolated from blood cultures by comparing spectrophotometric phenotypic assay with genotypic analysis based on the evidence of the ica operon. We retrospectively reviewed the database of CoNS isolated from blood cultures, that were considered to be responsible for 361 bloodstream infections. Among them, we selected 89 ones who had full records. Our data show that S. epidermidis was the predominant species isolated, and with greater adhesive capacities, especially those with the complete operon. Knowing the adhesive capabilities of a microorganism responsible for sepsis can be useful in implementing appropriate corrective and preventive measures, as conventional antibiotic therapy cannot effectively eradicate biofilms.

Introduction: Silver nanoparticles have been extensively investigated in dental and orthopedic materials. However, the impregnation of bone graft with silver nanoparticles has been poorly investigated. Objectives: The aim of this study was to evaluate the in vitro antibiofilm activity of a bovine bone impregnated with silver nanoparticles. Methods: Bone scaffolds from cancellous bovine femur were used for the tests and impregnated with silver nanoparticles (50nm) by physical adsorption. Silver nitrate minimal inhibitory and bactericidal concentration were performed Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Enterococcus faecalis, Acinetobacter baumannii, and Escherichia coli. Disc diffusion tests for silver nanoparticles susceptibility and quantification of biofilm production on plate and bone with sessile cell count were also performed. Results: All pathogens were susceptible to silver with low minimal inhibitory concentration (0.25 – 4 mg/L). The scaffold impregnated with silver nanoparticles presented a significant reduction in the biofilm cells for all microorganisms with a reduction of more than 3 logs in colony forming units count. Conclusion: Bone scaffolds impregnated with silver nanoparticles can significantly reduce biofilm, and it can be a strategical material to be used as an implant for different approaches.

The Mediterranean Sea is one of the most impacted basin in terms of microplastics pollution. Land-based activities are the major sources of plastic litter to the ocean, with harbors probably representing significant hotspots. In the framework of the SPlasH! project (Stop alle Plastiche in H2O, Interreg Marittimo project), microplastics were sampled in three north-western Mediterranean harbors during summer and winter. In this study, the areal concentrations of microplastics ranged from 5,576 to 379,965 items.km-2. A decreasing gradient was observed from the inner to the outer zones of the studied harbors, pointing out these enclosed systems as hotspots regarding microplastic pollution. During the summer, because of an enhancement of port activities, the areal concentrations of microplastics were higher than in winter. The investigation microplastics size classes distribution in the surface waters revealed that microplastic within a size range between 300 µm and 500 µm were depleted. During this study, we assessed trace metal partitioning (Pb, Fe, Cu, V, Cd and As) between the dissolved phase and biofilm, thus highlighting concentrations within the biofilm two and six orders higher than those in the dissolved phase. This result strongly suggest trace metal bioaccumulation within the biofilm. When trace metal concentrations are normalized over the corresponding surface of microplastics and microplastics, higher values were obtained for microplastics evidencing their enhanced capacities to bioaccumulate contaminants with respect to macroplastics.

Emergence of more virulent forms of human pathogenic bacteria with multi drug resistance is a serious global issue and requires alternative control strategies. The current study was focused to investigate the antibacterial and antibiofilm potential of ferulic acid grafted chitosan (CFA) against Listeria monocytogenes (LM), Pseudomonas aeruginosa (PA), and Staphylococcus aureus (SA). The present result showed that CFA at 64 µg/mL concentration exhibit bactericidal action against LM and SA (>4 log reduction) and bacteriostatic action against PA (<2 log CFU) within 24 h of incubation. Further studies based on propidium iodide uptake assay, measurement of material released from the cell, and electron microscopic analysis revealed that the bactericidal action of CFA was due to the altered membrane integrity and permeability. CFA dose-dependently inhibited biofilm formation (52-89% range), its metabolic activity (30.8-75.1% range) and eradicated mature biofilms, and reduced viability (71-82% range) of the test bacteria. Also, the swarming motility of LM was differentially affected at sub-MIC concentration of CFA. In the present study, the ability of CFA to kill and alter the virulence production in human pathogenic bacteria will insight a new scope for the application of these biomaterials in healthcare to effectively treat bacterial infections.

Topoisomerases, common targets for anti-tumor therapeutics, are crucial enzymes for DNA replication, transcription, and many other aspects of DNA metabolism. The potential anti-cancer effect of thiosemicarbazones (TSC) and metal-TSC complexes has been demonstrated by targeting several biological processes, including DNA metabolism. Human topoisomerases were discovered among the molecular targets for TSCs, and metal-chelated TSCs specifically displayed significant inhibition. The processes by which metal-TSCs or TSCs inhibit topoisomerases are still being studied. In this brief review, we summarize the TSCs and metal-TSCs that inhibit various types of human topoisomerases.

Streptococcus pneumoniae causes invasive infections such as otitis media, pneumonia and meningitis. It produces pneumolysin (Ply) toxin, which forms a pore to host cell membrane and has multiple functions in S. pneumoniae pathogenesis. The Ply C-terminal domain 4 mediates binding to membrane cholesterol and induces the formation of pores composed of up to 40 Ply monomers. Ply has a key role in the establishment of nasal colonization, pneumococcal transmission from host to host and pathogenicity. Altogether, 27 hydrolyzable tannins were tested for Ply inhibition in hemolysis assay and tannin-protein precipitation assay. Pentagalloylglucose (PGG) and gemin A showed nanomolar inhibitory activity. Ply oligomerization on the erythrocyte surface was inhibited with PGG. PGG also inhibited Ply cytotoxicity to A549 human lung epithelial cells. Molecular modelling of Ply interaction with PGG suggested that it binds to the pocket formed by domains 2, 3 and 4. In this study, we reveal the structural features of hydrolyzable tannins that are required for interaction with Ply. Monomeric hydrolysable tannins containing a sufficient number of polyvalent and flexible galloyl groups have highest inhibitory power to Ply cytotoxicity, and are followed by oligomers. Of the oligomers, macrocyclic and C-glycosidic structures were weaker in their inhibition than the glucopyranose-based oligomers. Accordingly, PGG-type monomers and certain oligomers might have therapeutic value in the targeting of S. pneumoniae infections.

For many years marine algae has been subject of numerous researches and as a source of natural products with antiviral activity, such as terpenes, alkaloids and sulphated polysaccharides. However, the anti-Zika virus (ZIKV) potential of algae has not been studied. In this study we evaluated extracts seven species of the three major classes of seaweeds (Phaeophyceae, Chlorophyceae and Rhodophyceae) against ZIKV. All seaweeds tested are native of the Brazilian coast, except for Kappaphycus alvarezii that can be cultivated. ZIKV a mosquito-borne flavivirus, has become a public health problem. In recent years there has been an increase in the number of cases and a strong association between ZIKV outbreak and the spread of cases of Guillain-Barré Syndrome and microcephaly. All seaweed extracts tested in this work inhibits ZIKV replication in a dose-dependent manner. Caulerpa racemosa, Kappaphycus alvarezii and Osmundaria obtusiloba extracts were able to inhibit viral replication at low concentrations with EC₅₀ values ranging from 1.38 to 1.98 µg/mL. We observed that O. obtusiloba presented a significant virucidal effect. Our results suggest that extracts of C. racemosa, K. alvarezii and O. obtusiloba presented very promising results, being excellent candidates for further studies, demonstrating that marine algae are an interesting source for the development of novel anti-ZIKV agents.

: Background: Pseudomonas aeruginosa is an opportunistic pathogen involved in number of hospital acquired infections such as catheter-associated urinary tract infections, bacteremia, septicemia, skin infections and ventilator-associated pneumoniae. Biofilm formation is an important trait implicated in chronic infections, such as cystic fibrosis and chromic pulmonary obstruction. Method: A total of 266 isolates were collected from the Armed Forces Institute of Pathology (AFIP). Antibiotic susceptibility was assessed by double disk synergy testing. ESBL and Modified Hodge testing was performed for phenotypic confirmation of carbapenemases. Molecular screening of the genes was done by PCR. Micro-dilution broth method was used to determine minimum inhibitory concentrations of antibiotics. Biofilm formation was done by micro-titer plate assay. Results: Overall, 20% of the P. aeruginosa isolates were extensively drug resistant (XDR-PA) and 25% were multi-drug-resistant (MDR-PA). Likewise, 43% of the isolates were ESBL producers and carbapenemase production was detected in 40% of the isolates. Molecular analysis confirmed occurrence of different resistant factors in ESBL positive isolates; 67% carried bla-TEM, 62% bla-CTXM-15, 41% bla-SHV, 34% bla-CTXM-14 and 33% bla-OXA-1. In addition, 68% of carbapenem-resistant isolates were positive for bla-NDM-1, 25% for bla-OXA-48 and 22% for bla-KPC-2. Biofilm formation was tested for 234 isolates, out of which 28% were strong biofilm formers. Moderate and weak biofilm formers were 46% and 23% respectively. Overall, ciprofloxacin, levofloxacin and cefepime showed inhibitory effects on P. aeruginosa biofilms. Antibiotics in combination showed strong synergistic effects (ciprofloxacin &amp; cefepime); while gentamicin and cefepime resulted into complete eradication of P. aeruginosa biofilm. Conclusion: We confirm strong synergistic effects of gentamicin and cefepime that completely eradicated P. aeruginosa biofilm. We further confirm inhibitory effects of ciprofloxacin, levofloxacin and cefepime on P. aeruginosa biofilms.

Biofilms are communities of microorganisms that can colonize biotic and abiotic surfaces playing a significant role in the persistence of bacterial infection and antibiotic resistance. About 65% and 80% of microbial and chronic infections are produced by biofilm formation. The increase in infections by multi-resistant bacteria draws attention to the discovery of new drugs based on natural inhibitory molecules. The inhibition of diguanylate cyclases (DGCs), the enzyme implicated in the synthesis of the second messenger, cyclic diguanylate (c-di-GMP), involved the biofilm formation, represents a potential method for preventing the biofilm development. It has been extensively studied using PleD protein as a model of DGC for in silico studies as virtual screening and as a model for in vitro studies in biofilms formation. In the present study 224205 molecules from natural products database, ZINC15 has been evaluated through molecular docking and molecular dynamic simulation, our result suggests trans-Aconitic acid (TAA) as a possible starting point for hit-to-lead methodologies to obtain new molecules capable of inhibiting the PleD protein and hence blocking the biofilm formation.

Staphylococcus aureus is a causative agent of nosocomial infections and its antibiotic-resistant strains are concerning. Solutions are being explored to improve the treatment of these infections, including repositioning drugs such as statins and using nanoparticles with antimicrobial properties. This study aimed to evaluate the antimicrobial effects of simvastatin (SIM) and biologically synthesized silver nanoparticles (bio-AgNPs) in isolate form and in combination by assays of minimum inhibitory concentration (MIC), an in vitro biofilm model, and the association of antimicrobials against clinical strains of S. aureus. Bio-AgNPs showed a 53.8 ± 1.23-nm mean diameter and standard deviation, a 0.23 polydispersity index, and a −25.66 ± 2.19-mV mean potential and standard deviation. Transmission electron microscopy confirmed the formation of nanoparticles and the presence of Ag0 and AgCl. S. aureus strains were sensitive to bio-AgNPs and SIM, showing 31.88-187.5 and 74.66-149.32 μM concentrations, respectively. Our association assay showed 2.0 fractional inhibitory concentration indices (i.e., indifferent for clinical strains) and 0.32 values for the standard ATCC 29213 strain (synergy). Our biofilm inhibition assays with isolated SIM and bio-AgNPs showed decreased biofilm formation from 4× to ⅛ MICs, showing no synergism in association. These findings evince that simvastatin and bio-AgNPs at subinhibitory concentrations can serve as antimicrobial agents against S. aureus biofilm.

Staphylococcus aureus is a major food-borne pathogen. The ability of S. aureus to produce biofilm is a significant virulence factor triggering its persistence in hostile environments. In this study, we screened a total of 420 different food samples and human hand swabs to detect S. aureus and to determine their biofilm formation ability. Samples analyzed were meat, milk, egg, fish, fast foods, and hand swabs. S. aureus were detected by culturing, staining, biochemical, and PCR. Biofilm formation ability was determined by Congo Red Agar (CRA) plate and Crystal Violet Microtiter Plate (CVMP) tests. The icaA, icaB, icaC, icaD, and bap genes involved in the synthesis of bio-film-forming intracellular adhesion compounds were detected by PCR. About 23.81% (100/420; 95% CI: 14.17-29.98%) samples harbored S. aureus as revealed by detection of the nuc gene. CRA plate revealed 20% of S. aureus isolates as strong biofilm producers, while 69% and 11% as in-termediate and non-biofilm producers, respectively. By the CVMP staining method, 20%, 77%, and 3% of the isolates were found strong, intermediate, and non-biofilm producers. Furthermore, 21% of S. aureus isolates carried at least one biofilm-forming gene, where icaA, icaB, icaC, icaD, and bap genes were detected in 15%, 20%, 7%, 20%, and 10% of the S. aureus isolates, respectively. Bivariate analysis showed high significant correlations (p<0.001) between any of the two adhesion genes of S. aureus isolates. To the best of our knowledge, this is the first study in Bangladesh describing the detection of biofilm-forming S. aureus from foods and hand swabs with molecular-based evidence. Our findings suggest that food samples should be deemed a potential reservoir of biofilm-forming S. aureus that indicates a potential public health significance.

Application of toxic antibacterial agents is considered necessary to control prevalent fresh water microorganisms in evaporative cooling water systems, but these agents can adversely affect the environment and human health. Alternatively, natural antibacterial water chemistry has been applied in industrial cooling water systems for over 10 years with excellent results. The tower water chemistry method concentrates natural salts in highly-softened water to produce elevated pH and dissolved solids, with low calcium and magnesium. This practice conserves water while generating only a small volume of non-toxic natural salt concentrate for cost efficient separation and disposal if required. This review presents a novel perspective of natural antimicrobial chemistry for inhibiting parasitic microbiome functional relationships within the bio-triad of Legionella outbreaks, "Trojan Protozoans" and biofilms. The review further examines practical application and function of polyvalent metal ions in the inhibition of biofilms. Reducing global dependence on toxic antibacterial agents discharged to the environment is an emerging concern due to their impact on the natural microbiome, plants, animals and humans. Discharge of antibacterial agents also contributes to development of pathogen resistance. Use of natural antibacterial chemistry can play a key role in managing the cooling water environment in a more ecologically sustainable manner.

The integrated stress response is a signaling network comprised of four branches, each of which senses different cellular stressors, converging on the phosphorylation of eIF2α to depress global translation and initiate recovery. One of these branches is composed of GCN2, which senses cellular amino acid insufficiency and participates in the maintenance of amino acid homeostasis. Previous studies have shown that GCN2 is a viable cancer target when amino acid stress is provoked by inhibiting an additional target. In this light, we screened a combination of drugs to identify biologically active compounds which synergize with the GCN2 inhibitor TAP20. First, a panel of 25 compounds was assayed in six cancer cell lines for drug sensitivity. Each compound was then combined with TAP20 at concentrations below their IC50, and the impact on cell growth was assessed. Selected strongly synergistic combinations were further characterised using synergy analyses and matrix-dependent invasion assays. Inhibitors of proteostasis, of the MEK-ERK pathway and pan-CDK inhibitors flavopiridol and seliciclib were found to potently synergize with TAP20 in two of the tested cell lines. Among their common CDK targets is CDK7, which was selectively targeted with THZ-1 and found to synergize with TAP20. Finally, these combinations were found to be partially synergistic when assessed using matrix-dependent invasion assays. However, we found that TAP20 alone was sufficient to restrict invasion at concentrations well below its growth-inhibitory IC50. We conclude that GCN2 can be targeted for treating cancers by polytherapy or even monotherapy.

BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Targeting BRAF and its effector mitogen-activated protein kinase kinase 1/2 (MEK1/2) is now a key therapeutic strategy for BRAF-mutant tumors, and therapies based on dual BRAF/MEK inhibition showed significant efficacy in a broad spectrum of BRAF tumors. Nonetheless, BRAF/MEK inhibition therapy is not always effective for BRAF tumor suppression, and significant challenges remain to improve its clinical outcomes. First, certain BRAF tumors have an intrinsic ability to rapidly adapt to the presence of BRAF and MEK1/2 inhibitors by bypassing drug effects via rewired signaling, metabolic, and regulatory networks. Second, almost all tumors initially responsive to BRAF and MEK1/2 inhibitors eventually acquire therapy resistance via an additional genetic or epigenetic alteration(s). Overcoming these challenges requires identifying the molecular mechanism underlying tumor cell resistance to BRAF and MEK inhibitors and analyzing their specificity in different BRAF tumors. This review aims to update this information.

Several preclinical and clinical reports have demonstrated that levels of circulating high mobility group box 1 protein (HMGB1) are increased early after trauma and are associated with systemic inflammation and clinical outcomes. However, the mechanisms of the interaction between HMGB1 and inflammatory mediators that lead to the development of remote organ damage after trauma remain obscure. HMGB1 and inflammatory mediators were analyzed in plasma from 54 combat casualties, collected on admission to a military hospital in Iraq, and at 8 and 24 hours after admission. Forty-five (83%) of these patients had traumatic brain injury (TBI). Nine healthy volunteers were enrolled as controls. HMGB1 plasma levels were significantly increased in the first 8 hours after admission, and were found to be associated with systemic inflammatory responses, injury severity score, and presence of TBI. These data provided the rationale for designing experiments in rats subjected to blast injury and hemorrhage, to explore the effect of HMGB1 inhibition by CX-01. Animals were cannulated, then recovered for 5-7 days before blast injury in a shock tube and volume-controlled hemorrhage. Blast injury and hemorrhage induced an early increase in HMGB1 plasma levels that coincided with severity of tissue damage and mortality. CX-01 inhibited systemic HMGB1 release, decreased local and systemic inflammatory responses, significantly reduced tissue and organ damage, and tended to increase survival. These data suggest that CX-01 has potential as an adjuvant treatment for traumatic hemorrhage.

Fucoidan is a brown algae-derived polysaccharide having several biomedical applications. This study simultaneously compares the anticancer activities of crude fucoidans from Fucus vesiculosus and Sargassum filipendula, and effects of low (LMW, 10-50kDa), medium (MMW, 50-100kDa) and high (HMW, >100kDa) molecular weight fractions of S. filipendula fucoidan against osteosarcoma cells. Glucose, fucose and acid levels were lower and sulphation was higher in F. vesiculosus crude fucoidan compared to S. filipendula crude fucoidan. MMW had highest the levels of sugars, acids and sulphation among molecular weight fractions. There was a dose dependent drop in focal adhesion formation and proliferation of cells for all fucoidan-types, but F. vesiculosus fucoidan and HMW had the strongest effects. G1-phase arrest was induced by F. vesiculosus fucoidan, MMW and HMW, however F. vesiculosus fucoidan treatment also caused accumulation in sub G1-phase. Mitochondrial damage occurred for all fucoidan-types, however F. vesiculosus fucoidan led to mitochondrial fragmentation. Annexin V/PI, TUNEL and cytochrome c staining confirmed stress induced apoptosis-like cell death for F. vesiculosus fucoidan but features of stress-induced necrosis-like cell death for S. filipendula fucoidans. There was also variation in penetrability of different fucoidans inside the cell. These differences in anti-cancer activity of fucoidans are applicable for osteosarcoma treatment.

Inositol is a natural carbocyclic sugar that plays an essential role in regulating the vital cellular functions of plants and animals. Current research has explored methyl derivatives of inositol, reporting on their various biological activities, including antitumor, anti-inflammatory, and anti-osteoporosis activities. Our previous study demonstrated that L-quebrachitol, a methyl derivative of inositol, enhances osteoblastogenesis and bone formation; however, its effect on osteoclastogenesis remains unclear. Consequently, we aimed to investigate the effect of L-quebrachitol on the receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis in pre-osteoclastic RAW 264.7 cells. The results revealed that L-quebrachitol suppressed RANK-mediated signalling, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Fos proto-oncogene (cFOS) pathways, at both gene and protein levels. Moreover, the critical transcription factor for osteoclastogenesis, nuclear factor of activated T cells c1 (NFATc1), was downregulated. Inhibition of osteoclast-associated marker genes encoding proteolytic enzymes, such as tartrate-resistant acid phosphatase (TRAP), matrix metallopeptidase 9 (MMP-9), and cathepsin K, led to reduced formation of TRAP-positive multinucleated cells and resorption pits. These findings demonstrate the dose-dependent inhibitory effect of L-quebrachitol on osteoclastogenesis through the modulation of receptor activator of nuclear factor κB (RANK)-mediated signalling pathways. However, further exploration of L-quebrachitol's potential as a therapeutic approach for osteoporosis is warranted.

: Since the COVID-19 pandemic, people have become aware that materials (products) can transmit infection and have begun to focus on questions such as how bacteria and germs, the sources of in-fection, maintain their infectivity on material surfaces, and the extent to which materials can or cannot prevent this. and to what extent materials can and cannot prevent it. The SIAA, a non-profit organization of many Japanese companies, had created an entirely separate interna-tional standard for materials' antibacterial, antiviral, and antibiofilm properties (products). The authors have studied the academic basis for the operation of the standards and were deeply in-volved as researchers in establishing one of the standards. This paper describes the interna-tional standards and some representative examples of the authors' actual use of these standards and explains the current status and future problems.

In Argentina there are urban areas of intensive cultivation around most of the big cities, where the soils may be unsuitable for some of the horticultural species and the use of chemical fertilizers is common. Bioinoculants based on plant growth promoting rhizobacteria (PGPR) could be an al-ternative for crop improvement, without affecting the environment. These formulations are gen-erally liquid, and their main disadvantage is the low viability of microorganisms. The objectives of this work were to evaluate a different inoculation method, the application of the biofilm pro-duced by Bacillus subtilis as a growth promoter on seeds of three varieties of Lactuca sativa. Biofilm was obtained under static culture conditions, the liquid (planktonic) inoculum was produced at 150 rpm. The major effects were observed with Bacillus subtilis subsp. spizizenii, that showed an-tifungal activity against phytopathogens, synthesize plant growth regulators (IAA, cytokinin and ABA) and solubilize phosphates. The best results were obtained with the Grand Rapid variety inoculated with biofilm, its positive effect was throughout the plant development until the har-vest time, when the bacterium was recovered from the interior of the roots. The biofilm of B. sub-tilis subsp. spizizenii would be an innovative and promising seed inoculant for horticultural spe-cies.

Prevalence of antimicrobial-resistant bacteria has become a major challenge worldwide. Methicillin-resistant Staphylococcus aureus (MRSA)—a leading cause of infections—forms biofilms on polymeric medical devices and implants, increasing their resistance to antibiotics. Antibiotic administration before biofilm formation is crucial. Raman spectroscopy was used to assess MRSA biofilm development on solid culture media from 0 to 48 h. Biofilm formation was monitored by measuring DNA/RNA-associated Raman peaks and protein/lipid-associated peaks. The search for an antimicrobial agent against MRSA biofilm revealed that Eugenol was a promising candidate as it showed significant potential for breaking down the biofilm. Eugenol was applied at different times to test the optimal time for inhibiting MRSA biofilms, and the Raman spectrum showed that the first 5 h of biofilm formation was the most antibiotic-sensitive time. This study investigated the performance of Raman spectroscopy coupled with Principal Component Analysis (PCA) to identify planktonic bacteria from biofilm conglomerates. Raman analysis, microscopic observation, and quantification of the biofilm growth curve indicated early adhesion from 5 to 10 h of incubation time. Therefore, Raman spectroscopy can help in monitoring biofilm formation on a solid culture medium and performing rapid antibiofilm assessments with new antibiotics during the early stages of the procedure.

Clinical evidence has shown that bacterial infections are more difficult to eradicate when form-ing a biofilm aggregate than when are produced by bacteria in planktonic form. Therefore, com-pounds that inhibit biofilm formation could be used against severe infections. It has been re-ported that bromo 2-(5H) furanones inhibited biofilm formation by their anti-quorum sensing properties. To determine if the 2-(5H) furanone moiety is essential to induce inhibition of biofilm formation, we evaluated ten halogen 2-(5H) furanones derivates previously synthesized. Besides evaluating the inhibition of biofilm formation, we assessed pyocyanin production, swarming motility, and transcription of essential QS genes: rsaL, rhlA, pqsA and phz1 genes. Our results showed that although three bromo-furan-2(5H)-one-type derivatives (A1-A3) and two bromo-4-(phenylamino)-furan-2(5H)-one-type compounds (B2 and B6) inhibited the biofilm formation in both P. aeruginosa PA14 (reference) and PA64 (drug-resistant) strains only the furanones A1-A3 were efficient to inhibit QSS.

Psoriasis is a common chronic immune-mediated disease with many comorbidities and impacts on quality of life. Among the treatment options for psoriasis, phosphodiesterase-4 (PDE4) inhibi-tors are emerging with expanding options. PDE4 inhibitors play a pivotal role in the inflamma-tory cascade by degrading cyclic adenosine monophosphate (cAMP), contributing to pro-inflammatory mediator production. Apremilast, an oral PDE4 inhibitor, is an approved class for psoriasis. While effective, its adverse effects can limit its utility. Roflumilast, a topical PDE4 inhibitor, was recently also approved for psoriasis and shows promise in clinical trials. Crisaborole, approved for atopic dermatitis, has also been studied in psoriasis. This updated re-view summarizes evidence from randomized clinical trials regarding the efficacy and safety of PDE4 inhibitors in psoriasis treatment. By highlighting their potential benefits and limitations, this review provides valuable insights for clinicians and researchers aiming to optimize psoriasis therapy.

This study investigated the effects of silibinin, derived from milk thistle (Silybum marianum), on lipopolysaccharide (LPS)-induced morphological changes in mouse macrophages. Silibinin was treated at various doses and time points to assess its effects on macrophage activation including morphological changes and phagocytosis. Silibinin effectively inhibited LPS-induced pseudopodia formation and size increase, while unstimulated cells remained round. Silibinin's impact on phagocytosis was dose- and time-dependent, showing a decrease. We explored its mechanism of action on kinases using a MAPK array. Among the three MAPK family members tested, silibinin had a limited effect on JNK and p38 but significantly inhibited ERK1/2 and related RSK1/2. Silibinin also inhibited MKK6, AKT3, MSK2, p70S6K, and GSK-3β. These findings highlight silibinin's potent inhibitory effects on phagocytosis and morphological changes in macrophages. We suggest its potential as an anti-inflammatory agent due to its ability to target key inflammatory pathways involving ERK1/2 and related kinases. Overall, this study demonstrates the promising therapeutic properties of silibinin in modulating macrophage function and inflammation.

Aims: Adolescence is a critical period because the brain is involved in the process of maturation that entails cognitive functions. On the way of maturation, an individual’s inhibitory control undergoes many changes and becomes vulnerable to different thrill-seeking like smoking, drinking, and so on. Smoking is highly prevalent among teenagers that are trying to take control of their behaviors in order to join society. They experience antisocial behavior too which is a trait that can lead adolescents to addiction. This trait is an inevitable part of psychopathy. Inhibitory deficits and psychopathy have been widely reported in addiction studies. The current study tried to investigate the relationship between psychopathic traits and behavioral inhibition between male smokers and non-smoker teenage students.Materials & Methods: Statistical sample of this research is 62 teenage students aged 17 years that are divided into smoker and non-smoker groups. The participants have been chosen through random sampling from the population of 10 high schools. The data have been gathered in Kordkoy and Gorgan in Golestan province. Behavioral bias has been measured by Go/NoGo task and psychopathic traits through youth psychopathic traits inventory. Also, the short form of Wechsler Adult Intelligence Scale test has been executed and used as a control variable.Findings: A meaningful difference has been found between the performance of smoker and non-smoker groups in Go/No Go task and psychopathic traits that are smokers performed weaker in comparison with non-smokers and psychopathic traits of smokers were meaningfully higher than non-smokers. On the other hand, there was no significant difference between these two groups in their Wechsler Adult Intelligence Scale scores.Conclusion: The results have shown that smokers have higher psychopathic traits and lower behavioral inhibition when compared with their non-smoker peers. According to the results of current research, smoking can decline the cognitive functions.

Quorum sensing (QS), a well-established phenomenon in microorganisms, involves the communication between cells through chemical signals, which is dependent on cell density. Extensive research has been conducted on this microbial ability, encompassing the early stages of understanding QS to the latest advancements in the identification and characterization of its mechanisms. This minireview comprehensively examines the role of QS in various aspects, including biofilm formation, virulence in pathogenic bacteria such as Helicobacter pylori and Pseudomonas sp., as well as its influence on biogeochemical cycling in deep-sea environments. Furthermore, future progress in the field will be achieved by combining state-of-the-art methods for observing QS in the deep sea with a deeper understanding of the underlying processes, which will facilitate the engineering of microorganisms for improved degradation of persistent environmental pollutants and other biotechnological applications.

Antibiotic resistance represents a significant threat to the modern healthcare provision. The ESKAPEE pathogens, in particular, have proven to be especially challenging to treat, due to their intrinsic and acquired ability to rapidly develop resistance mechanisms in response to environmental threats. The development of biofilm has been characterised as an essential contributing factor towards antimicrobial-resistance and tolerance. Several studies have implicated the involvement of efflux pumps in antibiotic resistance, both directly, via drug extrusion and indirectly, through the formation of biofilm. As a result, the underlying mechanism of these pumps has attracted considerable interest due to the potential of targeting these protein structures and developing novel adjunct therapies. Subsequent investigations have revealed the ability of efflux pump-inhibitors (EPIs) to block drug-extrusion and disrupt biofilm formation, thereby, potentiating antibiotics and reversing resistance of pathogen towards them. This review will discuss the potential of EPIs as a possible solution to antimicrobial resistance, examining different challenges to the design of these compounds, with an emphasis on Gram-negative ESKAPEE pathogens.

This study focused on the investigation of myeloperoxidase through a Molecular Docking approach with various natural compounds to identify potential substances for cardiovascular research. Recent research has linked elevated myeloperoxidase levels to the severity of coronary artery disease. The results of the docking analysis revealed Polydatin, Daidzin, Astringin, Ginkgetin, and Amentoflavone as promising compounds with excellent binding capacity. To complement this, toxicity prediction studies were conducted using pkCSM. Overall, all four investigated molecules (Amentoflavone, Daidzin, Ginkgetin, and Astringin) were found to be non-toxic, exhibiting high maximum tolerated doses (human) and favorable values for Oral Rat Acute Toxicity and Oral Rat Chronic Toxicity. Moreover, they showed non-AMES toxicity and non-hepatotoxicity. Astringin, in particular, stood out with the highest positive effects, including a high maximum tolerated dose (human) and favorable values for Oral Rat Chronic Toxicity, along with dual inhibition of hERG II and hERG I. These findings suggest the potential utility of these compounds in cardiovascular research with minimized unwanted effects.

Zika virus (ZIKV) is a mosquito-born flavivirus which human infection became relevant dur-ing recent outbreaks in Latin America, due to its unrecognized association with fetal neurologi-cal disorders. Currently there are no approved effective antivirals or vaccines for treatment or prevention of ZIKV infections. Amantadine and rimantadine are approved antivirals used against susceptible influenza A virus infections, that have been shown to have antiviral activity against other viruses, such as dengue virus (DENV). Here, we report the in vitro effectiveness of both amantadine and rimantadine hydrochlorides against ZIKV replication, resulting in a dose-dependent reduction in viral titers of a ZIKV clinical isolate and two different ZIKV refer-ence strains. Additionally, we demonstrate similar in vitro antiviral activity of these drugs against DENV-1 and yellow fever virus (YFV), although at higher drug concentrations for the later. ZIKV replication was inhibited at drug concentrations well below cytotoxic levels of both compounds, as denoted by the high selectivity indexes obtained with the tested strains. Further work is absolutely needed to determine a potential clinical use of these antivirals against ZIKV infections, but our results suggest the existence of a highly conserved mechanism across fla-vivirus, susceptible to be blocked by modified more specific adamantane compounds.

Background: The SARS-CoV-2 virus is a new highly pathogen virus that can suppress cell immune response (Poly ADPR process, and interferon releasing in infected cell) by viral macrodomain and create fatal pneumonia. Cytokine storm phenomenon which can create consequence of SARS COV-2 by increase of the performance of human TRPM2, is a dangerous condition for human and its body organ such as kidney, heart, and liver. it seems like prevention of beginning of these events is necessary. Material and methods: in this study drug and drug like database was used for inhibition of the viral macrodomain and human TRPM2 that can initiate of the viral cell cycle infection and human cytokine storm respectively. Ligand base drug designed, pharmacophore modeling, docking and molecular dynamic simulation was performed Results: among up to billion compounds, 20 compounds were screened by infinisee program. Then 7 compounds were selected by pharmacophore modeling. between 7 compounds, 5 compound was removed because of high similarity to ADPR and possibility of toxic effect for human RNA and DNA polymerase. One compound was losartan and selected for docking and molecular dynamic simulation. Conclusion: losartan earned a proper dock score and binding affinity to create the complexes with TRPM2 and macrodomain. Molecular dynamic simulation has shown losartan had an adequate binding free energy for human trpm2 and viral macrodomain. The inhibitory effect of losartan on these protein has shown and it could interfere in several points (PARP, PARG- macrodomain and TRPM2) and decreases oxidative stress, apoptosis, cytokine storm in COVID-19.

Background: Mycobacterium avium complex includes the commonest nontuberculous mycobacteria associated with human infections. These infections have been associated with the production of biofilms in many cases, but there are only a few studies about biofilms produced by the species included in this group. Methods: Three collection strains (M. avium ATCC25291, M. intracellulare ATCC13950, and M. chimaera DSM756), three clinically significant strains (647, 657, and 655), and three clinically nonsignificant ones (717, 505, and 575) of each species were included. The clinical significance of the clinical isolates was established according to the internationally accepted criteria. Biofilm ultrastructure was studied by Confocal-Laser Scanning Microscopy using Backlight Live dead and Red Nile stains. Viability, covered surface, height and relative autofluorescence were measured in several images/strain. The effect of clarithromycin was studied the technique described by Muñoz-Egea et al with modifications regarding incubation time. The study included clarithromycin in the culture medium at a concentration achievable in the lungs (11.3 mg/L), using one row of wells as the control without antibiotic. Bacterial viability inside the biofilm is expressed as a percentage of viable cells. The differences between the different parameters of biofilm ultrastructure were analysed using Kruskal-Wallis test. The correlation between bacterial viability in the biofilm and treatment time was evaluated using Spearman's rank correlation coefficient (ρ). Results: The strains showed differences between them with all the studied parameters, but neither a species-specific pattern nor a clinical significance-specific patter were detected. For the effect of clarithromycin, the viability of the bacteria contained in the biofilm was inversely proportional to the exposure time of the biofilm (ρ > -0.3; p-value < 0.05), excluding two M. chimaera strains (M. chimaera DSM756 and 575), which showed a weak positive correlation with treatment time (0.2 < ρ < 0.39; p-value < 0.05). Curiously, despite a clarithromycin treatment of 216 hours, the percentage of biofilm viability of the strains evaluated here was not less than 40% at best (M. avium 717). Conclusions: All the M. avium complex studied strains are able to form biofilm in vitro, but ultrastructural characteristics between them suggest that these are strain-specific characteristics unrelated with neither with the species nor with the clinical significance. The clarithromycin effect on MAC species is biofilm age/time of treatment-dependent and appears to be strain-specific while being independent of the clinical significance of the strain.

The biofilm is a conglomerate of cells surrounded by an extracellular matrix, which contributes to the persistence of infections. The difficulty in removing the biofilm drives the research for new therapeutic options. In this work, the effect of terpenes (-)-trans-Caryophyllene, (S)-cis-Verbenol, (S)-(-)-Limonene, (R)-(+)-Limonene, and linalool was evaluated, individually and in combinations on bacterial growth, by assay with resazurin; the formation of biofilm, by assay with violet crystal; and the expression of associated genes, by real-time PCR, in two clinical isolates of S. aureus, ST30-t019 and ST5-t311, responsible for more than 90% of pediatric infections by this pathogen in Paraguay. All combinations of terpenes can inhibit biofilm formation in more than 50% without affecting bacterial growth. The most effective combination was (-)-trans-Caryophyllene and linalool at a 500 μg/mL concentration for each, with an inhibition percentage of 88%. This combination decreased the expression levels of the sdrD, spa, agr, and hld genes associated with the initial cell adhesion stage and quorum sensing. At the same time, it increased the expression levels of the cap5B and cap5C genes related to the production of capsular polysaccharides. The combinations of compounds tested are promising alternatives to inhibit biofilm formation in S. aureus.

Chromobacterium species are common in tropical and subtropical zones in environmental water samples and believed to «tropical» species. Here we describe an environmental case of resident Chromobacterium vaccinii in biofilms associated with Carex spp. roots in Moscow region, Russia (warm-summer humid continental climate zone). We performed broad characterization of individual properties as well as surrounding context for better understanding the premise of C. vaccinii survival during winter season. Genome properties of isolated strains propose some insights into adaptation to habit and biofilm mode of life, including social cheaters carrying ΔluxR mutation. Isolated C. vaccinii differs with previously described strains in some biochemical properties and some basic characteristics like fatty acid composition as well as unique genome features. Despite potential to modulate membrane fluidity and presence of several genes responsible for cold shock response, isolated C. vaccinii didn`t survive during exposure to 4 °C, while in initial complex biofilm it was able to survive for months in vitro at 4 °C. Surrounding bacterial community within the same biofilm with C. vaccinii represented a series of psychrophilic bacterial species which may share resistance to low temperatures with other species within biofilm and provide C. vaccinii opportunity to survive during cold winter season.

Traditional aquaculture systems appear to be confronted with the high total ammonia nitrogen (TAN) produced during production, which can be harmful to aquatic life. As the demand for global fish production continues to increase, farmers should adopt Recirculating Aquaculture Systems (RAS) to improve production. The biofilter plays a vital role in ammonia removal. However, the drawback of the biofilter operation is needed an automatic and controlled system with a water quality monitoring system to guarantee optimal performance. RAS utilize a monitoring and control system to maintain the water quality and control the biofilm growth in the biofilter to reduce the ammonia. Therefore, this study focuses on developing a water quality monitoring and control system to achieve optimum biofilm performance. From 35 days of the experiment, the water quality was controlled at a level save for the aquatic environment, such as dissolved oxygen, pH, temperature, and TDS. Thus, the highest TAN removal efficiency is 50% when biofilm thickness reaches 119.88 µm.

There was no significant difference in bacterial adhesion between the 3 bone graft types tested, regardless of the bacterial strain used (p &gt; 0.22). After 72 hours of culture, there was no significant difference between the Fresh and Frozen bone groups, while the number of CFU in the Decellularised group was significantly lower (p &lt; 0.01), averaging -0.72 +/- 0.08 lg, -0.20 +/- 0.01 lg and -0.78 +/- 0.48 lg with S. epidermidis, S. aureus and E. coli respectively. Absolute values differences are low, and considering fresh bone (equivalent to autograft) as the gold standard due to its low infection rates in clinical studies, we can conclude that adhesion and biolfilm development characteristics are similar between Fresh, Frozen and Decellularised bone grafts..

(1) Background: Formation of biofilms on food-contact surfaces by Shiga-toxigenic Escherichia coli (STEC) can pose a significant challenge to the food industry, making conventional control-methods insufficient. Targeted use of bacteriophages to disrupt these biofilms could reduce this problem. Previously isolated and characterized bacteriophages (n=52) were evaluated against STEC biofilms in-vitro and on food-contact surfaces. (2) Methods: Phage-treatments (9 logs PFU/ml), in phosphate-buffered-saline, were used individually or as cocktails. Biofilms of STEC (O157, O26, O45, O103, O111, O121, and O145) were formed in 96-well micro-titer plates (7 logs CFU/ml; 24 h) or on stainless-steel (SS) and high-density-polyethylene (HDPE) coupons (9 logs CFU/cm2; 7 h), followed by phage-treatment. Biofilm-disruption was measured in-vitro at 0, 3, and 6 h as a change in optical-density (A595). Coupons were treated with STEC-serotype-specific phage-cocktails or a 21-phage cocktail (3 phages/serotype) for 0, 3, 6 and 16 h and surviving STEC populations enumerated. (3) Results: Of the 52 pages, 77% showed STEC-biofilm disruption in-vitro. Serotype-specific phage-treatments reduced pathogen population within the biofilms by 1.9-4.1 and 2.3-5.6 logs CFU/cm2, while the 21-pahge cocktail reduced it by 4.0 and 4.8 logs CFU/cm2 on SS and HDPE, respectively. (4) Conclusions: Bacteriophages can be used to reduce STEC and their biofilms.

Antifungal agents are not always efficient in resolving vulvovaginal candidiasis (VVC), a common genital infection caused by overgrowth of Candida spp., including Candida albicans, or preventing recurrent infections. Although lactobacilli (which are dominant microorganisms constituting healthy human vaginal microbiota) are important barriers against VVC, the Lactobacillus metabolite concentration needed to suppress VVC is unknown. Therefore, we quantitatively evaluated Lactobacillus metabolite concentrations to determine their effect on Candida spp., including 27 vaginal strains of Lactobacillus crispatus, Lactobacillus jensenii, Lactobacillus gasseri, Lacticaseibacillus rhamnosus, and Limosilactobacillus vaginalis, with inhibitory abilities against biofilms of Candida clinical isolates. Lactobacillus culture supernatants suppressed viable bacteria by approximately 24%-92% relative to preformed Candida biofilms, but their suppression differed between strains, not species. Lactate production was necessary to suppress preformed biofilms and hyphal elongation of C. albicans, whereas hydrogen peroxide was not always essential. Both lactic acid and hydrogen peroxide were required to suppress Candida planktonic cell growth. Lactobacillus strains that significantly inhibited biofilm formation in culture supernatant also inhibited Candida adhesion to epithelial cells in an actual live bacterial adhesion competition test. Healthy human microflora and their metabolites may play important roles in the development of new antifungal agent against VVC caused by C. albicans.

(1) Background: Bacterial reinfection and root fracture are the main culprits related to root canal treatment failure. This study aimed to assess the utility of quercetin solution as an adjunctive endodontic irrigant that strengthen root canal dentin with commitment anti-biofilm activity and bio-safety. (2) Methods: Based on a noninvasive dentin infection model, dentin tubules infected with Enterococcus faecalis (E. faecalis) were irrigated with sterile water (control group), and 0, 1, 2, 4 wt% quercetin-containing ethanol solutions. The live and dead bacteria proportions within E. fae-calis biofilms were analyzed using confocal laser scanning microscopy (CLSM). Elastic modulus and hydroxyproline release and X-ray photoelectron spectroscopy (XPS) characterization was tested on irrigant-treated demineralized dentin to evaluate irrigants’ biostability. The cytotoxicity of irrigants was tested by CCK-8 assay. (3) Results: Quercetin increased the proportion of dead bacteria volumes within E. faecalis, and improved the flexural strength of dentin collagen com-pared to control group. The XPS characterization revealed an increase in C-O peak area under both C1s and O1s narrow-scan spectra. The CCK-8 assay confirmed no cytotoxicity of quercetin solutions. (4) Conclusions: Quercetin exhibited anti-biofilm activity, collagen-stabilizing effect as well as cytocompatibility, supporting quercetin as a potential candidate for endodontic irrigant.

Indwelling urinary catheters are common in healthcare settings and can lead to catheter-associated urinary tract infection (CAUTI). Long-term catheterization causes polymicrobial colonization of the catheter and urine, for which the clinical significance is poorly understood. Through prospective assessment of catheter urine colonization, we identified Enterococcus faecalis and Proteus mirabilis as the most prevalent and persistent co-colonizers. Clinical isolates of both species successfully co-colonized in a murine model of CAUTI, and they were observed to co-localize on catheter biofilms during infection. We further demonstrate that P. mirabilis preferentially adheres to E. faecalis during biofilm formation, and that contact-dependent interactions between E. faecalis and P. mirabilis facilitate establishment of a robust biofilm architecture that enhances antimicrobial resistance for both species. E. faecalis may therefore act as a pioneer species on urinary catheters, establishing an ideal surface for persistent colonization by more traditional pathogens such as P. mirabilis.

Leukemia encompasses diverse blood cancers marked by the unchecked growth and developmental blockage of myeloid or lymphoid precursor cells within the bone marrow and the bloodstream. Treatment traditionally involves intensive chemotherapy or hematopoietic stem cell transplantation, albeit these approaches often yield severe side effects and encounter resistance from leukemia cells. Hence, the quest for novel therapies targeting leukemic cells selectively is paramount to enhancing leukemia outcomes. Exploring natural products is a promising avenue for pursuing effective chemotherapy and preventive measures against leukemia. These compounds serve as a crucial wellspring for drug development and offer a source of biologically active elements for potential therapeutic interventions in leukemia. The enzyme telomerase plays a vital role in stabilizing chromosomes by adding DNA sections to the end of chromosomes during the mitotic cycle. Notably, hTERT mRNA expression strongly correlates with telomerase activity, making it a potential target for therapeutic intervention without adverse systemic effects. Telomerase inhibition is a promising target in cancer therapy, especially in combination with natural ingredients, demonstrating less cytotoxicity than chemotherapies.

HIV-1 Tat protein interacts with TAR RNA and recruits CDK9/cyclin T1 and other host factors to induce HIV-1 transcription. Thus Tat-TAR RNA interaction, which is unique for HIV-1, represents an attractive target for anti-HIV-1 therapeutics. To target Tat-TAR RNA interaction, we used a crystal structure of TAR RNA with acetylpromazine bound to the bulge of TAR RNA, to dock compounds from Enamine database containing 1.6 million individual compounds. Docking identified 173 compounds that were analyzed for the inhibition of HIV-1 infection. Top ten inhibitory compounds with IC50 ≤ 6 µM were selected and the three least toxic compounds, T6780107 (IC50=2.97 μM), T0516-4834 (IC50=0.2 μM) and T5628834 (IC50=3.46 μM), were further tested for HIV-1 transcription inhibition. Only T0516-4834 compound showed selective inhibition of Tat-induced HIV-1 transcription, whereas T6780107 compound inhibited equally basal and Tat-induced transcription and T5628834 compound only inhibited basal HIV-1 transcription. The T0516-4834 compound also showed strongest inhibition of HIV-1 gag RNA expression and p24 production in CEM T cells infected with HIV-1 IIIB. Of the three compounds, only the T0516-4834 compound disrupted Tat-TAR RNA interaction indicating that it might target TAR RNA. Also, of the three tested compounds, T5628834 but not T6780107 or T0516-4834 disrupted Tat-CDK9/cyclin T1 interaction. Taken together, our study identified novel compound T0516-4834 that disrupted Tat-TAR RNA interaction and inhibited Tat-induced transcription and HIV-1 infection suggesting that this compound might serve as a new lead for anti-HIV-1 therapeutics.

Recent studies suggest that the developmental curves in adolescence, related to the development of executive functions, could be fitted to a non-linear trajectory of development with progressions and retrogressions. Therefore, the present study proposes to analyze the pattern of development in Perceptual Inhibition (PI), considering all stages of adolescence (early, middle, and late) in intervals of one year. To this aim, we worked with a sample of 275 participants between 10 and 25 years, who performed a joint visual and search task (to measure PI). We have fitted exGaussian functions to the probability distributions of the mean response time across the sample and performed a covariance analysis (ANCOVA). The results showed that the 10- to 13-year-old groups performed similarly in the task and differ from the 14- to 19-year-old participants. We found significant differences between the older group and all the rest of the groups. We discuss the important changes that can be observed in relation to the nonlinear trajectory of development that would show the PI during adolescence.

CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis thereby supports tumor survival in OSCC. Immunohistochemistry on human clinical specimens revealed that CXCR4 and a tumor vasculature marker CD34 were co-distributed in tumor vessels in human OSCC specimens. To ask the effects of CXCR4 inhibition, we treated the OSCC-xenografted mice with AMD3100, so-called plerixafor, an antagonist of CXCR4. Notably, we found a unique pathophysiological structure defined as Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) induced by the CXCR4 antagonism. Treatment with AMD3100 increased necrotic area with the induction of hypoxia-inducible factor-1α in the xenografted tumors, suggesting that AMD3100-induced TAITN was involved in hypoxia and ischemia. Taken together, we demonstrated that CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment.

Inflammation is a vital aspect of the body's immune response, appearing either as an acute reaction that swiftly develops (e.g., after injury or during an infection) or as a chronic condition that persists over a prolonged period, often linked with autoimmune disorders or cancer. This study introduces potential TNF-alpha inhibitors investigated by Molecular Docking investigation. They are Dactolisib with a binding energy of -10.1 kcal/mol, Nilotinib with -9.6 kcal/mol, Eltrombopag with -9.7 kcal/mol, Radotinib with -9.6 kcal/mol, and Nilotinib again with -9.7 kcal/mol. Additionally, Hypericin exhibited a notable binding energy of -9.9 kcal/mol, suggesting its potential as a natural TNF-alpha inhibitor. While these computational results are preliminary, they provide a foundation for further biological studies to confirm their efficacy. The significance of these findings extends to the scientific community, offering potential applications in the field of inflammatory diseases.

The impacts of spice (sumac, cumin, black pepper, and red pepper) extract on Gram-positive (S. aureus and E. faecalis) and Gram-negative (K. pneumonia, P. aureginosa, C. jejuni, A. hydrophila, S. Paratyphi A, and Y. enterocolitica) food-borne pathogen bacterial strains (FBP) for their antibacterial activity and accumulation of ammonia (AMN), trimethylamine (TMA), and biogenic amines (BAs) in tyrosine decarboxylase broth (TDB) were investigated. Sumac extract exhibited the highest an-tibacterial potential against all FBP followed by cumin and peppers. Ammonia (AMN) production (844.24-543 mg/L) was strongly inhibited by sumac extract (55.10 mg/L), whilst suppression of trimethylamine (TMA) production (53.66-3.21 mg/L) was observed by sumac (1.28 mg/L), followed by red pepper (0.91 mg/L) extract. Cumin extracts stimulated the production of cadaverine, spermidine, tryptamine, and 2-phenylethylamine. Furthermore, sumac extracts inhibited hista-mine and tyramine production in the majority of FBP. This research suggests the application of sumac extracts as natural preservatives for inhibiting the growth of FBP and inhibiting the pro-duction of AMN, TMA, and BAs.

Cardiac hypertrophy is an adaptive response to various pathological insults including hypertension. However, sustained hypertrophy can cause impaired calcium regulation, cardiac dysfunction, and remodeling, accompanied by cardiac fibrosis. Our previous study identified miR-25 as a regulator of SERCA2a, and that inhibition of miR-25 improved cardiac function and reduced fibrosis by restoring SERCA2a expression in a murine heart failure model. However, the precise mechanism underlying the reduction of fibrosis by miR-25 inhibition remains unclear. Therefore, we postulate that miR-25 may have additional targets that contribute to regulating cardiac fibrosis. Using in silico analysis, Krüppel-like factor 4 (KLF4) was identified as an additional target of miR-25. Further experiments confirmed that KLF4 was directly targeted by miR-25 and that its expression was reduced by long-term treatment with Angiotensin II, a major hypertrophic inducer. Subsequently, treatment with a miR-25 inhibitor alleviated the cardiac dysfunction, fibrosis, and inflammation induced by Angiotensin II. These findings indicate that inhibiting miR-25 not only enhances calcium cycling and cardiac function via SERCA2a restoration but also reduces fibrosis by restoring KLF4 expression. Therefore, targeting miR-25 may be a promising therapeutic strategy for treating hypertensive heart diseases.

Cadmium (Cd) contamination in rice grains is posing a significant threat to global food security. To restrict the transport of Cd in the soil-rice system, an efficient way is to use the ionomics strate-gy. Since calcium (Ca) and Cd have similar ionic radii, their uptake and translocation may be linked in multiple aspects in rice. However, the underlying antagonistic mechanisms are still not fully understood. Therefore, we first summarized the current knowledge on the physiological and molecular footprints of Cd translocation in plants and then explored the potential antagonistic points between Ca and Cd in rice, including exchange adsorption on roots, plant cell wall compo-sition, co-transporter gene expression, and transpiration inhibition. This review provides sugges-tions for the Ca/Cd interacting study in rice and introduces the ionomics research to better control the accumulation of Cd in plants.

Even after debridement and chemical root canal preparation, multispecies bacterial biofilms can still be found in root canals and dentinal tubules. This demonstrates the necessity of using suitable antibacterial endodontic sealers. Due to their well-known biological qualities, calcium silicate based root canal sealers or “bioceramic’ sealers have recently been launched and can be successful in endodontic procedures. This study's objective was to compare the impact of CerasealR, Total Fill BC SealerR, Bio-C SealerR, AH Plus BioceramicR, K-biocerR and SealiteR on the elimination of a multispecies’ endodontic biofilm at 3, 7 and 14 days. Enterococcus faecalis, Pseudomonas Aeruginosa, Candida Albicans and Proteus Mirabilis were cultured on specific agars and later grown in Brain Heart Infusion broth on hydroxyapatite discs pretreated with collagen type 1 and incubated for 18 days. The resulting biofilm was then placed on a 10mm round shaped blotting paper set on a metallic net in a 6cm petri dish with an orthodontic bend filled with the calcium silicate based root canal sealer in direct contact with the biofilm. In all tested groups, the total bacterial count has significantly decreased between day 3 and day 14 (P<0.05) with no statistically significant differences among the different sealers’ groups at all time points. Sealite group was capable of decreasing the Candida Albicans count significantly between day 3 and day 14 (P<0.05) in comparison with the bioceramic groups. All sealers had antibacterial activity against the multispecies biofilm between day 3 and day 14.