Inhibition of Polymicrobial Biofilms of Candida albicans-Staphylococcus aureus/Streptococcus mutans by Fucoidan-Gold Nanoparticles.

The polymicrobial proliferation and development of complex biofilm morphologies by bacterial and fungal pathogens in the host are some of the key factors contributing to the failure of antimicrobial treatments. The polymicrobial interaction of Candida albicans and some bacterial species has been extensively studied in both in vitro and in vivo model systems. Alternative strategies for disrupting polymicrobial interaction and biofilm formation are constantly needed. Among several alternative strategies, the use of nanoparticles synthesized using a natural product in the treatment of microbial infection has been considered a promising approach. The current study aimed to synthesize gold nanoparticles (AuNPs) using a natural product, fucoidan, and to test their efficacy against mono and duo combinations of fungal (Candida albicans) and bacterial (Staphylococcus aureus/Streptococcus mutans) biofilms. Several methods were used to characterize and study Fu-AuNPs, including UV-vis absorption spectroscopy, FTIR, FE-TEM, EDS, DLS, zeta potential, and XRD. The concentration-dependent inhibition of early-stage biofilms and the eradication of mature biofilms of single species of C. albicans, S. aureus, and S. mutans have been observed. Early biofilms of a dual-species combination of C. albicans and S. aureus/S. mutans were also suppressed at an increasing concentration of Fu-AuNPs. Furthermore, Fu-AuNPs significantly eradicated the established mature biofilm of mixed species. The treatment method proposed in this study, which involves the use of marine-bioinspired nanoparticles, is a promising and biocompatible agent for preventing the growth of polymicrobial biofilms of bacterial and fungal pathogens.

Activation of Dendritic Cells Alters the Mechanism of MHC Class II Antigen Presentation to CD4 T Cells.

Both immature and mature dendritic cells (DCs) can process and present foreign Ags to CD4 T cells; however, the mechanism by which MHC class II (MHC-II) in mature DCs acquires antigenic peptides remains unknown. To address this, we have studied Ag processing and presentation of two distinct CD4 T cell epitopes of the influenza virus hemagglutinin coat protein by both immature and mature mouse DCs. We find that immature DCs almost exclusively use newly synthesized MHC-II targeted to DM+ late endosomes for presentation to influenza virus-specific CD4 T cells. By contrast, mature DCs exclusively use recycling MHC-II that traffics to both early and late endosomes for antigenic peptide binding. Rab11a knockdown partially inhibits recycling of MHC-II in mature DCs and selectively inhibits presentation of an influenza virus hemagglutinin CD4 T cell epitope generated in early endosomes. These studies highlight a "division of labor" in MHC-II peptide binding, in which immature DCs preferentially present Ags acquired in Rab11a- DM+ late endosomes, whereas mature DCs use recycling MHC-II to present antigenic peptides acquired in both Rab11a+ early endosomes and Rab11a- endosomes for CD4 T cell activation.

Lipopolysaccharide/TLR4 Stimulates IL-13 Production through a MyD88-BLT2-Linked Cascade in Mast Cells, Potentially Contributing to the Allergic Response.

In an experimental asthma model, the activation of TLR4 by bacterial LPS occasionally exacerbates allergic inflammation through the production of Th2 cytokines, and mast cells have been suggested to play a central role in this response. However, the detailed mechanism underlying how LPS/TLR4 stimulates the production of Th2 cytokines, especially IL-13, remains unclear in mast cells. In the current study, we observed that the expression levels of leukotriene B4 receptor-2 (BLT2) and the synthesis of its ligands were highly upregulated in LPS-stimulated bone marrow-derived mast cells and that BLT2 blockade with small interfering RNA or a pharmacological inhibitor completely abolished IL-13 production, suggesting a mediatory role of the BLT2 ligand-BLT2 axis in LPS/TLR4 signaling to IL-13 synthesis in mast cells. Moreover, we demonstrated that MyD88 lies upstream of the BLT2 ligand-BLT2 axis and that this MyD88-BLT2 cascade leads to the generation of reactive oxygen species through NADPH oxidase 1 and the subsequent activation of NF-κB, thereby mediating IL-13 synthesis. Interestingly, we observed that costimulation of LPS/TLR4 and IgE/FcεRI caused greatly enhanced IL-13 synthesis in mast cells, and blockading BLT2 abolished these effects. Similarly, in vivo, the IL-13 level was markedly enhanced by LPS administration in an OVA-induced asthma model, and injecting a BLT2 antagonist beforehand clearly attenuated this increase. Together, our findings suggest that a BLT2-linked cascade plays a pivotal role in LPS/TLR4 signaling for IL-13 synthesis in mast cells, thereby potentially exacerbating allergic response. Our findings may provide insight into the mechanisms underlying how bacterial infection worsens allergic inflammation under certain conditions.

Polydopamine encapsulation of fluorescent nanodiamonds for biomedical applications.

Fluorescent nanodiamonds (FNDs) are promising bio-imaging probes compared with other fluorescent nanomaterials such as quantum dots, dye-doped nanoparticles, and metallic nanoclusters, due to their remarkable optical properties and excellent biocompatibility. Nevertheless, they are prone to aggregation in physiological salt solutions, and modifying their surface to conjugate biologically active agents remains challenging. Here, inspired by the adhesive protein of marine mussels, we demonstrate encapsulation of FNDs within a polydopamine (PDA) shell. These PDA surfaces are readily modified via Michael addition or Schiff base reactions with molecules presenting thiol or nitrogen derivatives. We describe modification of PDA shells by thiol terminated poly(ethylene glycol) (PEG-SH) molecules to enhance colloidal stability and biocompatibility of FNDs. We demonstrate their use as fluorescent probes for cell imaging; we find that PEGylated FNDs are taken up by HeLa cells and mouse bone marrow-derived dendritic cells and exhibit reduced nonspecific membrane adhesion. Furthermore, we demonstrate functionalization with biotin-PEG-SH and perform long-term high-resolution single-molecule fluorescence based tracking measurements of FNDs tethered via streptavidin to individual biotinylated DNA molecules. Our robust polydopamine encapsulation and functionalization strategy presents a facile route to develop FNDs as multifunctional labels, drug delivery vehicles, and targeting agents for biomedical applications.

Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells.

MHC class II (MHC-II)-dependent antigen presentation by antigen-presenting cells (APCs) is carefully controlled to achieve specificity of immune responses; the regulated assembly and degradation of antigenic peptide-MHC-II complexes (pMHC-II) is one aspect of such control. In this study, we have examined the role of ubiquitination in regulating pMHC-II biosynthesis, endocytosis, recycling, and turnover in APCs. By using APCs obtained from MHC-II ubiquitination mutant mice, we find that whereas ubiquitination does not affect pMHC-II formation in dendritic cells (DCs), it does promote the subsequent degradation of newly synthesized pMHC-II. Acute activation of DCs or B cells terminates expression of the MHC-II E3 ubiquitin ligase March-I and prevents pMHC-II ubiquitination. Most importantly, this change results in very efficient pMHC-II recycling from the surface of DCs and B cells, thereby preventing targeting of internalized pMHC-II to lysosomes for degradation. Biochemical and functional assays confirmed that pMHC-II turnover is suppressed in MHC-II ubiquitin mutant DCs or by acute activation of wild-type DCs. These studies demonstrate that acute APC activation blocks the ubiquitin-dependent turnover of pMHC-II by promoting efficient pMHC-II recycling and preventing lysosomal targeting of internalized pMHC-II, thereby enhancing pMHC-II stability for efficient antigen presentation to CD4 T cells.

Inadequacy of computed tomography for pre-operative planning of patellofemoral arthroplasty.

PURPOSE: To evaluate the accuracy of preoperative planning for patellofemoral arthroplasty (PFA) by comparing: (1) virtual implant positioning simulated on pre-operative images versus (2) real implant positioning from post-operative images. METHODS: The authors prospectively studied 15 patients that received a PFJ implant (Tornier, Montbonnot France). A pre-operative planning software was established to determine the size and position of the trochlear component. Pre-operative scans were used to perform virtual implantations by two different operators, which were then compared to the post-operative scans to calculate errors (ε) in implant positioning and intra-class correlation coefficients (ICC) for intra- and inter-observer repeatability. RESULTS: Analysis was performed for 13 patients, for whom agreement between virtual and real surgery was excellent for anteroposterior (AP) position (ICC = 0.84; ε max = 3.5 mm), fair for proximodistal (PD) position (ICC = 0.50; ε max = 9.5 mm), and poor for mediolateral (ML) position (ICC = 0.07; ε max = 9.0 mm). It was fair for flexum-recurvatum (FR) alignment (ICC = 0.53; ε max = 8.2°), poor for varus-valgus (VV) alignment (ICC = 0.34; ε max = 10.0°), and internal-external (IE) rotation (ICC = 0.34; ε max = 10.6°). CONCLUSIONS: Pre-operative planning was insufficiently accurate to follow intra-operatively, the greatest errors being angular alignment (VV and FR). The clinical relevance of these findings is that PFA is difficult to plan pre/operatively due to non-visibility of cartilage on CT scans and to trochlear dysplasia in most cases. LEVEL OF EVIDENCE: Prospective evaluation of operative tools on consecutive patients, Level III.

Aberrant expression of plasma microRNA-33a in an atherosclerosis-risk group.

In order to investigate whether plasma microRNA-33a (miR-33a) can be a biomarker for the early detection of atherosclerosis and to reexamine the assumption that miR-33a represses the expression of ABCA1, we compared the expression levels of miR-33a and ATP-binding cassette A1 (ABCA1) using human plasma and supernatants of macrophage cultured media. We first separated ample number of plasma samples from left-over whole blood samples based on the criteria for normal or dyslipidemia, and stored them at -20 °C until use. Then we selected 18 plasma samples for each normal, athero-risk and treated group using a metabolic disease cohort in which candidate subjects have participated. For classifying into three groups, we primarily relied on the records of physicians' comments, prescriptions, treatment history, lipid profiles and test results from medical equipment aimed at the diagnosis for atherosclerosis or cardiovascular disease. After collecting the final 54 plasma samples, we analyzed and compared the expression levels of miR-33a and ABCA1 at the plasma levels. In the comparison of plasma levels of the three groups, the miR-33a expression level of athero-risk group was 5.01-fold higher than that of normal group. Meanwhile, in the culture of foam cells transfected with anti-miR-33a oligonucleotides, the miR-33a level significantly decreased, while ABCA1 level significantly increased. The results suggest that enhanced expression of miR-33a might induce cholesterol accumulation and aggravate inflammation in vessel walls by suppressing the expression of ABCA1 in macrophages. Thus, plasma miR-33a can be considered as a candidate biomarker of atherosclerosis.

Interleukin 10 (IL-10)-mediated Immunosuppression: MARCH-I INDUCTION REGULATES ANTIGEN PRESENTATION BY MACROPHAGES BUT NOT DENDRITIC CELLS.

Efficient immune responses require regulated antigen presentation to CD4 T cells. IL-10 inhibits the ability of dendritic cells (DCs) and macrophages to stimulate antigen-specific CD4 T cells; however, the mechanisms by which IL-10 suppresses antigen presentation remain poorly understood. We now report that IL-10 stimulates expression of the E3 ubiquitin ligase March-I in activated macrophages, thereby down-regulating MHC-II, CD86, and antigen presentation to CD4 T cells. By contrast, IL-10 does not stimulate March-I expression in DCs, does not suppress MHC-II or CD86 expression on either resting or activated DCs, and does not affect antigen presentation by activated DCs. IL-10 does, however, inhibit the process of DC activation itself, thereby reducing the efficiency of antigen presentation in a March-I-independent manner. Thus, IL-10 suppression of antigen presenting cell function in macrophages is March-I-dependent, whereas in DCs, suppression is March- I-independent.

Optimization of Protease Treatment Conditions for Chlorella pyrenoidosa Protein Extraction and Investigation of Its Potential as an Alternative Protein Source.

This study aimed to determine enzymes that effectively extract Chlorella pyrenoidosa proteins and optimize the processing conditions using response surface methods. Furthermore, the potential of enzymatically hydrolyzed C. pyrenoidosa protein extract (CPE) as a substitute protein source was investigated. The enzymatic hydrolysis conditions for protein extraction were optimized using single-factor analysis and a response surface methodology-Box-Behnken design. The R2 value of the optimized model was 0.9270, indicating the reliability of the model, and the optimal conditions were as follows: a hydrolysis temperature of 45.56 °C, pH 9.1, and a hydrolysis time of 49.85 min. The amino acid composition of CPE was compared to that of C. pyrenoidosa powder (CP), which was found to have a higher content of essential amino acids (EAA). The electrophoretic profiles of CP and CPE confirmed that CPE has a low molecular weight. Furthermore, CPE showed higher antioxidant activity and phenol content than CP, with ABTS and DPPH radical scavenging abilities of 69.40 ± 1.61% and 19.27 ± 3.16%, respectively. CPE had high EAA content, antioxidant activity, and phenol content, indicating its potential as an alternative protein source. Overall, in this study, we developed an innovative, ecofriendly, and gentle enzymatic hydrolysis strategy for the extraction and refinement of Chlorella proteins.

Strategies for controlling polymicrobial biofilms: a focus on antibiofilm agents.

Polymicrobial biofilms are among the leading causes of antimicrobial treatment failure. In these biofilms, bacterial and fungal pathogens interact synergistically at the interspecies, intraspecies, and interkingdom levels. Consequently, combating polymicrobial biofilms is substantially more difficult compared to single-species biofilms due to their distinct properties and the resulting potential variation in antimicrobial drug efficiency. In recent years, there has been an increased focus on developing alternative strategies for controlling polymicrobial biofilms formed by bacterial and fungal pathogens. Current approaches for controlling polymicrobial biofilms include monotherapy (using either natural or synthetic compounds), combination treatments, and nanomaterials. Here, a comprehensive review of different types of polymicrobial interactions between pathogenic bacterial species or bacteria and fungi is provided along with a discussion of their relevance. The mechanisms of action of individual compounds, combination treatments, and nanomaterials against polymicrobial biofilms are thoroughly explored. This review provides various future perspectives that can advance the strategies used to control polymicrobial biofilms and their likely modes of action. Since the majority of research on combating polymicrobial biofilms has been conducted in vitro, it would be an essential step in performing in vivo tests to determine the clinical effectiveness of different treatments against polymicrobial biofilms.

Bacterial extracellular vesicles: Modulation of biofilm and virulence properties.

Microbial pathogens cause persistent infections by forming biofilms and producing numerous virulence factors. Bacterial extracellular vesicles (BEVs) are nanostructures produced by various bacterial species vital for molecular transport. BEVs include various components, including lipids (glycolipids, LPS, and phospholipids), nucleic acids (genomic DNA, plasmids, and short RNA), proteins (membrane proteins, enzymes, and toxins), and quorum-sensing signaling molecules. BEVs play a major role in forming extracellular polymeric substances (EPS) in biofilms by transporting EPS components such as extracellular polysaccharides, proteins, and extracellular DNA. BEVs have been observed to carry various secretory virulence factors. Thus, BEVs play critical roles in cell-to-cell communication, biofilm formation, virulence, disease progression, and resistance to antimicrobial treatment. In contrast, BEVs have been shown to impede early-stage biofilm formation, disseminate mature biofilms, and reduce virulence. This review summarizes the current status in the literature regarding the composition and role of BEVs in microbial infections. Furthermore, the dual functions of BEVs in eliciting and suppressing biofilm formation and virulence in various microbial pathogens are thoroughly discussed. This review is expected to improve our understanding of the use of BEVs in determining the mechanism of biofilm development in pathogenic bacteria and in developing drugs to inhibit biofilm formation by microbial pathogens. STATEMENT OF SIGNIFICANCE: Bacterial extracellular vesicles (BEVs) are nanostructures formed by membrane blebbing and explosive cell lysis. It is essential for transporting lipids, nucleic acids, proteins, and quorum-sensing signaling molecules. BEVs play an important role in the formation of the biofilm's extracellular polymeric substances (EPS) by transporting its components, such as extracellular polysaccharides, proteins, and extracellular DNA. Furthermore, BEVs shield genetic material from nucleases and thermodegradation by packaging it during horizontal gene transfer, contributing to the transmission of bacterial adaptation determinants like antibiotic resistance. Thus, BEVs play a critical role in cell-to-cell communication, biofilm formation, virulence enhancement, disease progression, and drug resistance. In contrast, BEVs have been shown to prevent early-stage biofilm, disperse mature biofilm, and reduce virulence characteristics.

Marine-derived bioactive materials as antibiofilm and antivirulence agents.

Microbial infections are major human health issues, and, recently, the mortality rate owing to bacterial and fungal infections has been increasing. In addition to intrinsic and extrinsic antimicrobial resistance mechanisms, biofilm formation is a key adaptive resistance mechanism. Several bioactive compounds from marine organisms have been identified for use in biofilm therapy owing to their structural complexity, biocompatibility, and economic viability. In this review, we discuss recent trends in the application of marine natural compounds, marine-bioinspired nanomaterials, and marine polymer conjugates as possible therapeutic agents for controlling biofilms and virulence factors. We also comprehensively discuss the mechanisms underlying biofilm formation and inhibition of virulence factors by marine-derived materials and propose possible applications of novel and effective antibiofilm and antivirulence agents.

Poly(vinyl alcohol)/chitosan hydrogel incorporating chitooligosaccharide-gentisic acid conjugate with antioxidant and antibacterial properties as a potential wound dressing.

The design and development of wound dressing with antioxidant and antibacterial properties to accelerate wound healing remain challenging. In this study, we synthesize a chitooligosaccharide-gentisic acid (COS-GSA) conjugate using the free-radical grafting method, and fabricate a poly(vinyl alcohol) (PVA)/chitosan (CH)/COS-GSA (PVA/CH/CG) hydrogel using a freeze-thaw method. We characterize the synthesized COS-GSA conjugates using through polyphenol assay, absorbance, and 1H NMR spectroscopy and evaluate their antioxidant properties. The COS-GSA conjugates are successfully synthesized and exhibit better antioxidant properties than pristine COSs. Subsequently, the fabricated hydrogel is characterized based on its morphological analysis, rheological properties, water contact angle, swelling, degradation, water retention properties, and COS-GSA release profiles. Finally, the biocompatibility of the fabricated hydrogel is evaluated on HDF and HaCaT cells through indirect and direct cytotoxicity. The PVA/CH/CG hydrogel exhibited significantly higher antioxidant properties (DPPH, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and hydrogen peroxide (H2O2) scavenging activities) and antibacterial activities (Staphylococcus aureus and Pseudomonas aeruginosa) compared to other fabricated hydrogels such as PVA, PVA/CH, and PVA/CH/COS (PVA/CH/C). These results provide evidence that PVA/CH/CG hydrogels with antioxidant, antibacterial, and non-cytotoxic properties have great potential for wound-dressing applications.

Increased SCF/c-kit by hypoxia promotes autophagy of human placental chorionic plate-derived mesenchymal stem cells via regulating the phosphorylation of mTOR.

Hypoxia triggers physiological and pathological cellular processes, including proliferation, differentiation, and death, in several cell types. Mesenchymal stem cells (MSCs) derived from various tissues have self-renewal activity and can differentiate towards multiple lineages. Recently, it has been reported that hypoxic conditions tip the balance between survival and death by hypoxia-induced autophagy, although the underlying mechanism is not clear. The objectives of this study are to compare the effect of hypoxia on the self-renewal of bone marrow-derived mesenchymal stem cells (BM-MSCs) and placental chorionic plate-derived mesenchymal stem cells (CP-MSCs) and to investigate the regulatory mechanisms of self-renewal in each MSC type during hypoxia. The expression of self-renewal markers (e.g., Oct4, Nanog, Sox2) was assessed in both cell lines. PI3K and stem cell factor (SCF) expression gradually increased in CP-MSCs but were markedly downregulated in BM-MSCs by hypoxia. The phosphorylation of ERK and mTOR was augmented by hypoxia in CP-MSCs compared to control. Also, the expression of LC3 II, a component of the autophagosome and the hoof-shaped autophagosome was detected more rapidly in CP-MSCs than in BM-MSCs under hypoxia. Hypoxia induced the expression of SCF in CP-MSCs and increased SCF/c-kit pathway promotes the self-renewal activities of CP-MSCs via an autocrine/paracrine mechanism that balances cell survival and cell death events by autophagy. These activities occur to a greater extent in CP-MSCs than in BM-MSCs through regulating the phosphorylation of mTOR. These findings will provide useful guidelines for better understanding the function of SCF/c-kit in the self-renewal and autophagy-regulated mechanisms that promote of MSC survival.

Comparison of in vitro hepatogenic differentiation potential between various placenta-derived stem cells and other adult stem cells as an alternative source of functional hepatocytes.

Mesenchymal stem cells (MSCs) are powerful sources for cell therapy in regenerative medicine. The capability to obtain effective stem cell-derived hepatocytes would improve cell therapy for liver diseases. Recently, various placenta-derived stem cells (PDSCs) depending on the localization of placenta have been suggested as alternative sources of stem cells are similar to bone marrow-derived MSC (BM-MSCs) and adipose-derived MSC (AD-MSCs). However, comparative studies for the potentials of the hepatogenic differentiation among various MSCs largely lacking. Therefore, we investigated to compare the potentials for hepatogenic differentiation of PDSCs with BM-MSCs, AD-MSCs, and UCB-MSCs. Several MSCs were isolated from human term placenta, adipose tissue, and umbilical cord blood and characterized isolated MSCs and BM-MSCs was performed by quantitative reverse transcription-PCR (RT-PCR) and special stains after mesodermal differentiation. The hepatogenic potential of PDSCs was compared with AD-MSCs, UCB-MSCs, and BM-MSCs using RT-PCR, PAS stain, ICG up-take assays, albumin expression, urea production, and cytokine assays. MSCs isolated from different tissues all presented similar characteristics of MSCs. However, the proliferative potential of PDSCs and the expression of hepatogenic markers in differentiated PDSCs were higher than other MSCs. Interestingly, the expression of hepatocyte growth factor (HGF) increased in PDSCs after hepatogenic differentiation. Interestingly, stem cell factor (SCF) expression in chorionic plate-derived MSCs, one of the PDSCs, was significantly higher than in the other PDSCs. Taken together, the results of the present study suggest that MSCs isolated from various adult tissues can be induced to undergo hepatogenic differentiation in vitro, and that PDSCs may have the greatest potential for hepatogenic differentiation and proliferation. Therefore, PDSCs could be used as a stem cell source for cell therapy in liver diseases.

Inhibition of Biofilm and Virulence Properties of Pathogenic Bacteria by Silver and Gold Nanoparticles Synthesized from Lactiplantibacillus sp. Strain C1.

The emergence of antibiotic resistance in microbial pathogens necessitates the development of alternative ways to combat the infections that arise. The current study used nanotechnology as an alternate technique to control virulence characteristics and biofilm development in Pseudomonas aeruginosa and Staphylococcus aureus. Furthermore, based on the acceptance and biocompatibility of the probiotic bacteria, we chose a lactic acid bacteria (LAB) for synthesizing two types of metallic nanoparticles (NPs) in this study. Using molecular techniques, the LAB strain C1 was isolated from Kimchi food samples and identified as Lactiplantibacillus sp. strain C1. The prepared supernatant from strain C1 was used to produce gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs). C1-AuNPs and C1-AgNPs were characterized physiochemically using a variety of instruments. C1-AuNPs and C1-AgNPs had spherical shapes and sizes of 100.54 ± 14.07 nm (AuNPs) and 129.51 ± 12.31 nm (AgNPs), respectively. C1-AuNPs and C1-AgNPs were discovered to have high zeta potentials of -23.29 ± 1.17 and -30.57 ± 0.29 mV, respectively. These nanoparticles have antibacterial properties against several bacterial pathogens. C1-AuNPs and C1-AgNPs significantly inhibited the initial stage biofilm formation and effectively eradicated established mature biofilms of P. aeruginosa and S. aureus. Furthermore, when P. aeruginosa was treated with sub-MIC levels of C1-AuNPs and C1-AgNPs, their different virulence features were significantly reduced. Both NPs greatly inhibited the hemolytic activity of S. aureus. The inhibition of P. aeruginosa and S. aureus biofilms and virulence features by C1-AuNPs and C1-AgNPs can be regarded as viable therapeutic strategies for preventing infections caused by these bacteria.

Synthesis and evaluation of tirbanibulin derivatives: a detailed exploration of the structure-activity relationship for anticancer activity.

Tirbanibulin, an FDA-approved microtubule-targeting agent (MTA) introduced in 2020, represents a pioneering treatment for precancerous actinic keratosis. Despite its failure to gain approval as an anticancer agent due to insufficient efficacy, there remains potential value in extending its application into malignancy treatment through tirbanibulin-based derivatives. Tirbanibulin possesses a distinctive dual mechanism of action involving microtubule and Src inhibition, distinguishing it from other MTAs. In spite of its unique profile, exploration of tirbanibulin's structure-activity relationship (SAR) and the development of its derivatives are significantly limited in the current literature. This study addresses this gap by synthesizing various tirbanibulin derivatives and exploring their SAR through modifications in the core amide motif and the eastern benzylamine part. Our results underscore the critical role of the pyridinyl acetamide core structure for optimal cellular potency, with favorable tolerance observed for modifications at the para position of the benzylamine moiety. Particularly noteworthy is the analogue modified with p-fluorine benzylamine, which exhibited favorable in vivo PK profiles. These findings provide crucial insights into the potential advancement of tirbanibulin-based compounds as promising anticancer agents.

Controlling biofilm and virulence properties of Gram-positive bacteria by targeting wall teichoic acid and lipoteichoic acid.

Wall teichoic acid (WTA) and lipoteichoic acid (LTA) are structural components of Gram-positive bacteria's peptidoglycan and cell membrane, which are mostly anionic glycopolymers. WTA confers numerous physiological, virulence, and pathogenic features to bacterial pathogens. It controls cell shape, cell division, and the localisation of autolytic enzymes and ion homeostasis. In the context of virulence and pathogenicity, it aids bacterial cell attachment and colonisation and protects against the host defence system and antibiotics. Having such a broad function in pathogenic bacteria's lifecycle, WTA/LTA become one of the potential targets for antibacterial agents to reduce bacterial infection in the host. The number of reports for targeting the WTA/LTA pathway has risen, mostly by focusing on three distinct targets: antivirulence targets, ß-lactam potentiator targets, and essential targets. The current review looked at the role of WTA/LTA in biofilm development and virulence in a range of Gram-positive pathogenic bacteria. Furthermore, alternate strategies, such as the application of natural and synthetic compounds that target the WTA/LTA pathway, have been thoroughly discussed. Moreover, the application of nanomaterials and a combination of drugs have also been discussed as a viable method for targeting the WTA/LTA in numerous Gram-positive bacteria. In addition, a future perspective for controlling bacterial infection by targeting the WTA/LTA is proposed.

Mesoporous Polydopamine-Encapsulated Fluorescent Nanodiamonds: A Versatile Platform for Biomedical Applications.

Fluorescent nanodiamonds (FNDs) are versatile nanomaterials with promising properties. However, efficient functionalization of FNDs for biomedical applications remains challenging. In this study, we demonstrate mesoporous polydopamine (mPDA) encapsulation of FNDs. The mPDA shell is generated by sequential formation of micelles via self-assembly of Pluronic F127 (F127) with 1,3,5-trimethyl benzene (TMB) and composite micelles via oxidation and self-polymerization of dopamine hydrochloride (DA). The surface of the mPDA shell can be readily functionalized with thiol-terminated methoxy polyethylene glycol (mPEG-SH), hyperbranched polyglycerol (HPG), and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). The PEGylated FND@mPDA particles are efficiently taken up by, and employed as a fluorescent imaging probe for, HeLa cells. HPG-functionalized FND@mPDA is conjugated with an amino-terminated oligonucleotide to detect microRNA via hybridization. Finally, the increased surface area of the mPDA shell permits efficient loading of doxorubicin hydrochloride. Further modification with TPGS increases drug delivery efficiency, resulting in high toxicity to cancer cells.

Integrative Analyses Reveal the Anticancer Mechanisms and Sensitivity Markers of the Next-Generation Hypomethylating Agent NTX-301.

Epigenetic dysregulation characterized by aberrant DNA hypermethylation is a hallmark of cancer, and it can be targeted by hypomethylating agents (HMAs). Recently, we described the superior therapeutic efficacy of a novel HMA, namely, NTX-301, when used as a monotherapy and in combination with venetoclax in the treatment of acute myeloid leukemia. Following a previous study, we further explored the therapeutic properties of NTX-301 based on experimental investigations and integrative data analyses. Comprehensive sensitivity profiling revealed that NTX-301 primarily exerted anticancer effects against blood cancers and exhibited improved potency against a wide range of solid cancers. Subsequent assays showed that the superior efficacy of NTX-301 depended on its strong effects on cell cycle arrest, apoptosis, and differentiation. Due to its superior efficacy, low doses of NTX-301 achieved sufficiently substantial tumor regression in vivo. Multiomics analyses revealed the mechanisms of action (MoAs) of NTX-301 and linked these MoAs to markers of sensitivity to NTX-301 and to the demethylation activity of NTX-301 with high concordance. In conclusion, our findings provide a rationale for currently ongoing clinical trials of NTX-301 and will help guide the development of novel therapeutic options for cancer patients.