Cell Permeation Research Articles

Self-Assembled Eutectogel with Cell Permeation and Multiple Anti-Inflammatory Abilities for Treating Chronic Periodontitis.

Eutectogels represent an attractive option for various industrial applications that use deep eutectic solvents (DESs) as effective liquid active ingredients and offer remarkable stability, cost-effectiveness, and environmental friendliness. However, the biological applications of these compounds are limited. DESs are highly structurally tunable and exhibit remarkable biofunctionality and biocompatibility, conferring substantial benefits in the treatment of diseases. In this study, choline-chloride and mannose are used to fabricate ChCl/M DES, followed by introduction of lysozyme fibers and gallic acid for self-assembly into injectable eutectogels through hydrogen bonding and hydrophilic/hydrophobic interaction interactions. The eutectogels demonstrate almost 100% bactericidal activities against three strains and significant immune-regulation. This is supported by a decrease in the proportion of CD86-expressing cells from 64.02% to 18.17% and an increase in CD206-expressing cells from 2.53% to 29.96% through flow cytometry experiments. The eutectogels effectively inhibit alveolar bone loss and alleviated local inflammation in a rat model of chronic periodontitis owing to the promotion of gallic acid in the cell membrane by the ChCl/M DES. Hence, self-assembled eutectogels exhibit the potential to enhance the efficacy if treatments/therapies against inflammatory diseases by facilitating bacterial control, reactive oxygen species scavenging, and the regulation of macrophages by promoting cell permeation of small-molecule drugs.

Quantifying skin permeation of a novel metformin lotion using modified hydrophilic interaction liquid chromatography.

Aim: This study aimed to quantify the permeation of metformin (Met) lotion through pig ear skin using high-performance liquid chromatography, specifically hydrophilic interaction liquid chromatography (HILIC), to separate Met from biological contaminants and effectively measure its permeation through skin similar to human skin.Materials & methods: A Franz cell permeation assay was used to assess the permeation kinetics of 6% Met lotion through pig ear skin. Samples were collected at various time points and prepared for high-performance liquid chromatography analysis by removing large biological contaminants. The permeated Met was quantified by monitoring its retention time (RT) at 9min using HILIC, with an acidic, polar mobile phase and a normal-phase column.Results: A distinct Met peak with a RT of approximately 9min was observed in the 6% Met lotion, which was absent in the permeation samples from the 0% Met lotion. This peak (RT 9min) was distinct from the 'biological-contaminants' peaks at RT 2-3min and increased linearly over time, reaching 36.8% of the total applied Met at 24h.Conclusion: These findings demonstrate that the HILIC method effectively separates Met from biological components in pig ear skin, allowing accurate quantification of Met despite the presence of skin lipids and proteins.

Exploiting the chemical diversity space of phosphopeptide binding to nasopharyngeal carcinoma PLK1 PBD domain with unnatural amino acid building blocks by using QSAR-based genetic optimization

ABSTRACT Human polo-like kinase 1 (PLK1) has been recognized as an attractive therapeutic target against nasopharyngeal carcinoma (NPC). The kinase contains a conserved polo-box domain (PBD) that exhibits a wide specificity across various substrates. Previously, we explored natural amino acid preference in PLK1 PBD-binding phosphopeptides. However, limited to the short sequence only natural amino acids cannot guarantee the sufficient exploitation of chemical and structural diversity of the phosphopeptides. Here, we described a genetic optimization (GO) strategy to systematically optimize a 104-sized 6-mer phosphopeptide array towards increasing affinity to PLK1 PBD domain by using 20 natural plus 34 unnatural amino acids as basic building blocks. A QSAR predictor was created to guide the GO optimization and then evaluated rigorously at molecular and cellular levels. Three unnatural phosphopeptides uPP8, uPP15 and uPP20 were designed as potent binders with K d = 0.18, 0.42 and 0.08 μM, respectively, in which the uPP20 also possessed a good anti-tumor activity against human NPC cells when fused with cell permeation sequence. In addition, we defined a relaxed 6-mer motif for the preferential PLK1 PBD-binding phosphosites, namely [Φ/П]-3-[ζ]-2-[ζ]-1-[pT/pS]0-[Φ/П]+1-[Φ]+2, where the symbols Φ, ζ and П represent hydrophobic, polar and aromatic amino acid types, respectively.

Computational design and experimental confirmation of a disulfide-stapled YAP helixα1-trap derived from TEAD4 helical hairpin to selectively capture YAP α1-helix with potent antitumor activity.

Human Hippo signaling pathway is an evolutionarily conserved regulator network that controls organ development and has been implicated in various cancers. Transcriptional enhanced associate domain-4 (TEAD4) is the final nuclear effector of Hippo pathway, which is activated by Yes-associated protein (YAP) through binding to two separated YAP regions of α1-helix and Ω-loop. Previous efforts have all been addressed on deriving peptide inhibitors from the YAP to target TEAD4. Instead, we herein attempted to rationally design a so-called 'YAP helixα1-trap' based on the TEAD4 to target YAP by using dynamics simulation and energetics analysis as well as experimental assays at molecular and cellular levels. The trap represents a native double-stranded helical hairpin covering a specific YAP-binding site on TEAD4 surface, which is expected to form a three-helix bundle with the α1-helical region of YAP, thus competitively disrupting TEAD4-YAP interaction. The hairpin was further stapled by a disulfide bridge across its two helical arms. Circular dichroism characterized that the stapling can effectively constrain the trap into a native-like structured conformation in free state, thus largely minimizing the entropy penalty upon its binding to YAP. Affinity assays revealed that the stapling can considerably improve the trap binding potency to YAP α1-helix by up to 8.5-fold at molecular level, which also exhibited a good tumor-suppressing effect at cellular level if fused with TAT cell permeation sequence. In this respect, it is considered that the YAP helixα1-trap-mediated blockade of Hippo pathway may be a new and promising therapeutic strategy against cancers.

BAR502/fibrate conjugates: synthesis, biological evaluation and metabolic profile.

BAR502, a bile acid analogue, is active as dual FXR/GPBAR1 agonist and represents a promising lead for the treatment of cholestasis and NASH. In this paper we report the synthesis and the biological evaluation of a library of hybrid compounds prepared by combining, through high-yield condensation reaction, some fibrates with BAR502.The activity of the new conjugates was evaluated towards FXR, GPBAR1 and PPARα receptors, employing transactivation or cofactor recruitment assays. Compound 1 resulted as the most promising of the series and was subjected to further pharmacological investigation, together with stability evaluation and cell permeation assessment. We have proved by LCMS analysis that compound 1 is hydrolyzed in mice releasing clofibric acid and BAR505, the oxidized metabolite of BAR502, endowed with retained dual FXR/GPBAR1 activity.

Development and characterization of ferulic acid-loaded chitosan nanoparticle embedded- hydrogel for diabetic wound delivery

Diabetic wounds present a significant global health challenge exacerbated by chronic hyperglycemia-induced oxidative stress, impeding the natural healing process. Despite various treatment strategies, diabetic foot ulceration lacks standardized therapy. Ferulic acid (FA), known for its potent antidiabetic and antioxidant properties, holds promise for diabetic wound management. However, oral administration of FA faces limitations due to rapid oxidation, stability issues, and low bioavailability. The topical application of FA-loaded chitosan nanoparticles (FA-CSNPs) has emerged as a promising approach to overcome these challenges. Here, we report the development of a sustained-release formulation of FA-CSNPs within a hydrogel matrix composed of Chitosan and gelatin. The FA-CSNPs were synthesized using the ionic gelation method andoptimized through a Central Composite Design (CCD) approach. Characterization of the optimized nanoparticles revealed spherical morphology, a particle size of 56.9 ± 2.5 nm, and an impressive entrapment efficiency of 90.3 ± 2.4 %. Subsequently, an FA-CSNPs-loaded hydrogel was formulated, incorporating chitosan as a gelling agent, gelatin to enhance mechanical properties and cell permeation, and glutaraldehyde as a cross-linker. Comprehensive characterization of the hydrogel included pH, moisture loss, porosity, swelling index, rheology, water vapor transmission rate (WVTR), SEM, TEM, invitro drug release studies, antioxidant activity, antibacterial efficacy, cell cytotoxicity, cell migration studies on L929 fibroblast cell line, and stability studies. The stability study demonstrated negligible variations in particle size, zeta potential, and entrapment efficiency over 60 days, ensuring the stable nature of nanoparticles and hydrogel. This innovative delivery approach embedded within a hydrogel matrix holds significant promise for enhancing the therapeutic efficacy of FA-CSNPs-hydrogel in diabetic wound healing applications.

Ganoderma lucidum Polysaccharides Ameliorate Acetaminophen-Induced Acute Liver Injury by Inhibiting Oxidative Stress and Apoptosis along the Nrf2 Pathway.

The excessive employment of acetaminophen (APAP) is capable of generating oxidative stress and apoptosis, which ultimately result in acute liver injury (ALI). Ganoderma lucidum polysaccharides (GLPs) exhibit hepatoprotective activity, yet the protective impact and potential mechanism of GLPs in relation to APAP-induced ALI remain ambiguous. The intention of this research was to scrutinize the effect of GLPs on APAP-induced ALI and to shed light on their potential mechanism. The results demonstrated that GLPs were capable of notably alleviating the oxidative stress triggered by APAP, as shown through a significant drop in the liver index, the activities of serum ALT and AST, and the amounts of ROS and MDA in liver tissue, along with an increase in the levels of SOD, GSH, and GSH-Px. Within these, the hepatoprotective activity at the high dose was the most conspicuous, and its therapeutic efficacy surpassed that of the positive drug (bifendate). The results of histopathological staining (HE) and apoptosis staining (TUNEL) indicated that GLPs could remarkably inhibit the necrosis of hepatocytes, the permeation of inflammatory cells, and the occurrence of apoptosis induced by APAP. Moreover, Western blot analysis manifested that GLPs enhanced the manifestation of Nrf2 and its subsequent HO-1, GCLC, and NQO1 proteins within the Nrf2 pathway. The results of qPCR also indicated that GLPs augmented the expression of antioxidant genes Nrf2, HO-1, GCLC, and NQO1. The results reveal that GLPs are able to set off the Nrf2 signaling path and attenuate ALI-related oxidative stress and apoptosis, which is a potential natural medicine for the therapy of APAP-induced liver injury.

Self-assembly mucoadhesive beads of κ-carrageenan/sericin for indomethacin oral extended release

Oral drug administration, especially when composed of mucoadhesive delivery systems, has been a research trend due to increased residence time and contact with the mucosa, potentially increasing drug bioavailability and stability. In this context, this study aimed to develop self-assembly mucoadhesive beads composed of blends of κ-carrageenan and sericin (κ-Car/Ser) loaded with the anti-inflammatory drug indomethacin (IND). We investigated the swelling, adhesion behaviour, and mechanical/physical properties of the beads, assessing their effects on cell viability, safety and permeation characteristics in both 2D and triple-culture model. The swelling ratio of the beads indicated pH-responsiveness, with maximum water absorption at pH 6.8, and strong mucoadhesion, increasing primarily with higher polymer concentrations. The beads exhibited thermal stability and no chemical interaction with IND, showing improved mechanical properties. Furthermore, the beads remained stable during accelerated and long-term storage studies. The beads were found to be biocompatible, and IND encapsulation improved cell viability (>70 % in both models, 79 % in VN) and modified IND permeation through the models (6.3 % for F5 formulation (κ-Car 0.90 % w/v | Ser 1.2 % w/v| IND 3.0 g); 10.9 % for free IND, p < 0.05). Accordingly, κ-Car/Ser/IND beads were demonstrated to be a promising IND drug carrier to improve oral administration while mitigating the side effects of non-steroidal anti-inflammatories.

Increasing the bioavailability of curcumin using a green supercritical fluid technology-assisted approach based on simultaneous starch aerogel formation-curcumin impregnation

A green approach based on simultaneous starch aerogel formation-curcumin impregnation via supercritical fluid technology was used to increase the bioavailability of curcumin. The loading amounts of curcumin were 16.4, 21.4, and 24.9 mg/g of aerogel for the 25% Amyl-loaded, 55% Amyl-loaded, and 72% Amyl-loaded samples, respectively. Curcumin-loaded aerogels showed the eventual distribution of curcumin in the hydrophobic area of the internal structure of the aerogels. In vitro gastrointestinal release profiles demonstrated the enhanced curcumin release from the curcumin-loaded aerogel formulations produced by the SC-CO2 technology over free curcumin. After intestinal digestion, the percentage of released curcumin from 25% Amyl-loaded, 55% Amyl-loaded, and 72% Amyl-loaded was 7.2, 12.1, and 12.1%, respectively, while the release of native curcumin was only 0.5%. Caco-2 cell permeation studies revealed superior bioavailability of curcumin from the curcumin-loaded aerogels. Curcumin-loaded aerogels exhibited improved storage stability than free curcumin.

Ratiometric peptide-based fluorescent probe with large Stokes shift for detection of Hg2+ and S2− and its applications in cells imaging and smartphone-assisted recognition

In this work, a new ratiometric fluorescent probe DKA was synthesized based on the double sides of lysine backbone conjugated with alanine and dansyl groups. DKA exhibited fluorescence ratiometric response for Hg2+ with high sensitivity (13.4 nM), specific selectivity (only Hg2+), strong anti-interference ability (no interference), fast recognition (within 60 s) and wide pH range (5–10). The stoichiometry of binding of DKA and Hg2+ was determined to be 1:1 via Job’s plot, ESI-HRMS and 1HNMR titration analysis. Subsequently, the in situ formation of DKA-Hg2+ complex was used for highly selective detection of S2− as a novel fluorescence “on–off” probe, and the lowest detection limit for S2− was 12.9 nM. In addition, DKA possessed excellent cells permeation and low toxicity, and fluorescence imaging of Hg2+ and S2− was performed in living Hacat cells. Most importantly, the digital imaging using a smartphone color recognition APP indicated that DKA could semi-quantitatively and visually detected Hg2+ and S2− without expensive equipment.

Nitrocellulose for Prolonged Permeation of Levofloxacin HCl-Salicylic Acid In Situ Gel.

Currently, the application of solvent exchange-induced in situ gel is underway for drug delivery to the body target site. Nitrocellulose was attempted in this research as the matrix-forming agent in solvent exchange-induced in situ gel for acne and periodontitis treatments. The gel incorporated a combination of 1% w/w levofloxacin HCl and 2% w/w salicylic acid as the active compounds. In order to facilitate formulation development, the study explored the matrix-forming behavior of different concentrations of nitrocellulose in N-methyl pyrrolidone (NMP). Consequently, their physicochemical properties and matrix-forming behavior, as well as antimicrobial and anti-inflammatory activities, were evaluated using the agar cup diffusion method and thermal inhibition of protein denaturation in the egg albumin technique, respectively. All prepared formulations presented as clear solutions with Newtonian flow. Their contact angles on agarose gel were higher than on a glass slide due to matrix formation upon exposure to the aqueous phase of agarose, with an angle of less than 60° indicating good spreadability. Nitrocellulose concentrations exceeding 20% initiated stable opaque matrix formation upon contact with phosphate buffer pH 6.8. The high hardness and remaining force of the transformed gel indicated their robustness after solvent exchange. Fluorescence tracking using sodium fluorescein and Nile red confirmed the retardation of NMP and water diffusion by the nitrocellulose matrix. From the Franz cell permeation study, these drugs could permeate through neonate porcine skin and tissue of porcine buccal from the nitrocellulose in situ forming gel. Their accumulation in these tissues might enable the inhibition of the invading bacterial pathogens. The developed in situ gels effectively inhibited Staphylococcus aureus, Staphylococcus epidermidis, Propionibacterium acnes, and Porphyromonas gingivalis. Furthermore, the formulations demonstrated an anti-inflammatory effect. The low viscosity of LvSa25Nc makes it appropriate for injectable treatments targeting periodontitis, while the higher viscosity of LvSa40Nc renders it appropriate for topical applications in acne treatment. Therefore, the nitrocellulose in situ gel loaded with combined levofloxacin HCl and salicylic acid emerges as a promising dosage form for treating acne and periodontitis.

Harnessing HetHydrogel: A Universal Platform to Dropletize Single-Cell Multiomics.

A universal platform is developed for dropletizing single cell plate-based multiomic assays, consisting of three main pillars: a miniaturized open Heterogeneous Hydrogel reactor (abbreviated HetHydrogel) for multi-step biochemistry, its tunable permeability that allows Tn5 tagmentation, and single cell droplet barcoding. Through optimizing the HetHydrogel manufacturing procedure, the chemical composition, and cell permeation conditions, simultaneous high-throughput mitochondrial DNA genotyping and chromatin profiling at the single-cell level are demonstrated using a mixed-species experiment. This platform offers a powerful way to investigate the genotype-phenotype relationships of various mtDNA mutations in biological processes. The HetHydrogel platform is believed to have the potential to democratize droplet technologies, upgrading a whole range of plate-based single cell assays to high throughput format.

Bisubstrate Uridine‐Mimetic‐Peptide Conjugates as O‐GlcNAc Transferase (OGT) Inhibitors

AbstractO‐linked β‐N‐acetylglucosamine transferase (OGT) is the pivotal mammalian enzyme that serves as a nutrient sensor, linking metabolic status to diverse cellular signalling pathways by catalyzing N‐acetylglucosamine transfer to various proteins and detects fluctuations in UDP‐GlcNAc concentrations. Increased UDP‐GlcNAc levels induce O‐GlcNAcylation of proteins, influencing the stability and localization of biomolecules, including transcription factors, kinases, phosphatases, tumour suppressors, and histone‐modifying proteins. Dysregulation and excessive OGT expression can adversely impact cellular processes. The lack of potent and selective inhibitors for OGT has impeded the progress in understanding the enzyme and its molecular mechanisms. This research article details the successful development and synthesis of a series of bisubstrate analogue inhibitors, specifically focusing on inhibiting the O‐GlcNAc transferase (OGT) enzyme. Compound 29 emerged as a promising inhibitor, demonstrating an IC50 value of 134.40 μM in in‐vitro assays. The study emphasizes the crucial role of the acceptor substrate analogue in bisubstrate inhibitor design, highlighting its equal importance alongside the donor substrate analogue. While donor substrate mimetics alone exhibited limited inhibition, their conjugation with appropriate peptides significantly enhanced the overall potency of the final bisubstrate inhibitor. Particularly, peptide derivatives proved superior as acceptor substrate analogues compared to normal substrate peptides. Preliminary data suggest the potential of uridine‐mimetics, like Q6S and Q4 C, following scaffold structure refinement. In‐silico predictions propose that replacing pyrophosphate with a flexible linker substantially improves physicochemical properties relevant to cell permeation. This comprehensive investigation offers valuable insights into designing and optimizing bisubstrate analogue inhibitors for OGT, revealing potential avenues for further refinement and development.

Vancomycin-Polyguanidino Dendrimer Conjugates Inhibit Growth of Antibiotic-Resistant Gram-Positive and Gram-Negative Bacteria and Eradicate Biofilm-Associated S.aureus.

The global challenge of antibiotic resistance necessitates the introduction of more effective antibiotics. Here we report a potentially general design strategy, exemplified with vancomycin, that improves and expands antibiotic performance. Vancomycin is one of the most important antibiotics in use today for the treatment of Gram-positive infections. However, it fails to eradicate difficult-to-treat biofilm populations. Vancomycin is also ineffective in killing Gram-negative bacteria due to its inability to breach the outer membrane. Inspired by our seminal studies on cell penetrating guanidinium-rich transporters (e.g., octaarginine), we recently introduced vancomycin conjugates that effectively eradicate Gram-positive biofilm bacteria, persister cells and vancomycin-resistant enterococci (with V-r8, vancomycin-octaarginine), and Gram-negative pathogens (with V-R, vancomycin-arginine). Having shown previously that the spatial array (linear versus dendrimeric) of multiple guanidinium groups affects cell permeation, we report here for the first time vancomycin conjugates with dendrimerically displayed guanidinium groups that exhibit superior efficacy and breadth, presenting the best activity of V-r8 and V-R in single broad-spectrum compounds active against ESKAPE pathogens. Mode-of-action studies reveal cell-surface activity and enhanced vancomycin-like killing. The vancomycin-polyguanidino dendrimer conjugates exhibit no acute mammalian cell toxicity or hemolytic activity. Our study introduces a new class of broad-spectrum vancomycin derivatives and a general strategy to improve or expand antibiotic performance through combined mode-of-action and function-oriented design studies.

Innovative Photodynamic Strategies for Antimicrobial Treatments: Biosafety and Effectiveness in a Cnidarian Model

Thiophene-based materials (TMs) have emerged as promising candidates in the field of photodynamic therapy (PDT) as photosensitizers agents owing to their remarkable electron transport properties, which facilitate efficient energy transfer processes crucial for PDT. In detail, TMs exhibit favourable optical characteristics, making them suitable candidates for the absorption and conversion of light energy into reactive oxygen species (ROS), thereby inducing cytotoxic effects in targeted cells. Recent studies have explored natural carriers, including proteins and phages, for enhanced cell uptake and permeation of photosensitizers, thereby enabling the induction of apoptosis across various cell lines. Despite the remarkable potential of this approach for PDT purposes, clinical translation necessitates in vivo models to validate these innovative tools. Here, we investigated the nanosafety and in vivo efficacy of these phototheranostic agents using the tissue-like animal model Hydra vulgaris. The transparency, softness, structural simplicity, and ethical neutrality of Hydra collectively render it an exemplary model for such inquiries. These features facilitate rapid screening of cytotoxicity and the effectiveness for photodinamic purposes.

Antimicrobial potential of quaternary phosphonium salt compounds: a review.

Given that mitochondrial dysregulation is a biomarker of many cancers, cationic quaternary phosphonium salt (QPS) conjugation is a widely utilized strategy for anticancer drug design. QPS-conjugated compounds exhibit greater cell permeation and accumulation in negatively charged mitochondria, and thus, show enhanced activity. Phylogenetic similarities between mitochondria and bacteria have provided a rationale for exploring the antibacterial properties of mitochondria-targeted compounds. Additionally, due to the importance of mitochondria in the survival of pathogenic microbes, including fungi and parasites, this strategy can be extended to these organisms as well. This review examines recent literature on the antimicrobial activities of various QPS-conjugated compounds and provides future directions for exploring the medicinal chemistry of these compounds.

Functional Peptide-Modified Liposomes for siRNA Delivery to Rat Retinal Pigment Epithelium Cells: Effect of Peptide Sequences.

Most retinal diseases involve the degeneration of choroidal retinal pigment epithelial (RPE) cells. Because of a blood-retina barrier (tight junction formation), RPE cells restrict the entry of hydrophilic macromolecules (e.g., small interfering RNA (siRNA)) through blood stream and eye drops. A cytoplasm-responsive stearylated (STR) peptide, STR-CH2R4H2C (CH2R4) enables stable siRNA complexation, cell permeation, and intracellular dynamics control. We previously demonstrated how CH2R4-modified liposomes promoted siRNA efficacy. We investigated the influence of amino acid sequences of functional peptides on cellular uptake pathways, siRNA transfection efficacy, and the permeation of peptide-modified liposomes in rat RPE-J cells. Four STR-peptides, consisting of arginine (R), cysteine (C), histidine (H), lysine (K) or serine (S), were designed based on CH2R4. We prepared siRNA-loaded, peptide-modified cationic liposomes (CH2R4-, CH2K4-, CH2S4-, SH2R4-, and SH2S4-lipoplexes). CH2R4-, CH2K4-, and SH2R4-lipoplexes induced cellular uptake by macropinocytosis by activating cytoskeletal F-actin, possibly due to cationic amino acids (arginine, lysine). SH2R4-lipoplexes were trapped in endosomes, whereas CH2R4- and CH2K4-lipoplexes enhanced endosomal siRNA release suggesting cysteine contributes to endosomal escape. Although cationic liposome-based, CH2S4- and SH2S4-lipoplexes (not including arginine and lysine) showed lower siRNA transfection efficiency. This difference may be because siRNAs were retained on both peptide moieties and cationic liposomes in CH2R4-, CH2K4- and SH2R4-lipoplexes, whereas in CH2S4- and SH2S4-lipoplexes, siRNAs were loaded to the cationic liposomes, but not on peptides. In three-dimensional spheroids, CH2R4- and CH2K4-modified liposomes promoted permeation through tight junctions. Thus, cationic amino acids and cysteine within peptide sequences of CH2R4 could be effective for siRNA delivery to the retina using functional peptide-modified liposomes.

Optimize the pore size-pore distribution-pore geometry-porosity of 3D-printed porous tantalum to obtain optimal critical bone defect repair capability

The treatment and reconstruction of large or critical size bone defects is a challenging clinical problem. Additive manufacturing breaks the technical difficulties of preparing complex conformation and anatomically matched personalized porous tantalum implants, but the ideal pore structure for 3D-printed porous tantalum in critical bone defect repair applications remains unclear. Guiding appropriate bone tissue regeneration by regulating proper pore size-pore distribution-pore geometry-porosity is a challenge for its fabrication and application. We fabricated porous tantalum (PTa) scaffolds with six different combinations of pore structures using powder bed laser melting (L-PBF) technology. In vitro biological experiments were conducted to systematically investigate the effects of pore structure characteristics on osteoblast behaviors, showing that the bionic trabecular structure with both large and small poress facilitated cell permeation, proliferation and differentiation compared to the cubic structure with uniform pore sizes. The osteogenesis of PTa with different porosity of trabecular structures was further investigated by a rabbit condyle critical bone defect model. Synthetically, T70% up-regulated the expression of osteogenesis-related genes (ALP, COLI, OCN, RUNX-2) and showed the highest bone ingrowth area and bone contact rate in vivo after 16 weeks, with the best potential for critical bone defect repair. Our results suggested that the bionic trabecular structure with a pore size distribution of 200–1200 μm, an average pore size of 700 μm, and a porosity of 70 % is the best choice for repairing critical bone defects, which is expected to guide the clinical application of clinical 3D-printed PTa scaffolds.

An Overview of Cefiderocol's Therapeutic Potential and Underlying Resistance Mechanisms.

Antimicrobial resistance continues to increase globally and treatment of difficult-to-treat (DTT) infections, mostly associated with carbapenem-resistant (CR) Pseudomonas aeruginosa, CR Acinetobacter baumannii, and CR- and third-generation-cephalosporins-resistant Enterobacterales remains a challenge for the clinician. The recent approval of cefiderocol has broaden the armamentarium for the treatment of patients with DTT infections. Cefiderocol is a siderophore cephalosporin that has shown excellent antibacterial activity, in part due to its innovative way of cell permeation. It is relatively stable compared to most commonly found carbapenamases. However, some resistant mechanisms to cefiderocol have already been identified and reduced susceptibility has developed during patient treatment, highlighting that the clinical use of cefiderocol must be rational. In this review, we summarize the current available treatments against the former resistant bacteria, and we revise and discuss the mechanism of action of cefiderocol, underlying the biological function of siderophores, the therapeutic potential of cefiderocol, and the mechanisms of resistance reported so far.

Development, characterization and Caco-2 cells absorption of curcumin solid dispersion for oral administration

Curcumin is an active dietary compound. However, its low solubility and rapid metabolism limit its absorption in the gastrointestinal (GI) tract and reduces its systemic bioavailability. To overcome these drawbacks, curcumin solid dispersion (CSD) was developed employing polyvinylpyrrolidone (PVP) as a carrier without and with soybean phospholipids (SP) as a co-carrier and prepared using a melting solvent method. The influence PVP and SP on physicochemical properties and in vitro permeability of CSD was investigated. Curcumin in all developed CSD demonstrated amorphous state as confirmed by X-ray diffraction. Spherical particles of ∼140 nm and ∼190 nm were obtained when CSD without and with SP was diluted with water. Consequently, CSD without and with SP possessed significantly greater curcumin water solubility of ∼4200-fold and ∼6500-fold, respectively, as compared to free curcumin, which leading to enhanced curcumin absorption across Caco-2 cell. The dissolution studies, both in 0.1 N HCl and phosphate buffer pH6.8, of CSD showed that curcumin was quickly and completely dissolved within 5 min. Caco-2 cell permeation studies revealed that CSD with SP presented a lag time with slightly lower curcumin absorption than CSD without SP. Moreover, the physical and chemical stability of CSD was found to be stable for up to 6 months at 4 °C and room temperature. From these findings, CSD could be beneficial for enhancing the oral absorption profiles of curcumin.