Understanding intercalative modulation of G-rich sequence folding: solution structure of a TINA-conjugated antiparallel DNA triplex.

We present here the high-resolution structure of an antiparallel DNA triplex in which a monomer of para-twisted intercalating nucleic acid (para-TINA: (R)-1-O-[4-(1-pyrenylethynyl)phenylmethyl]glycerol) is covalently inserted as a bulge in the third strand of the triplex. TINA is a potent modulator of the hybridization properties of DNA sequences with extremely useful properties when conjugated in G-rich oligonucleotides. The insertion of para-TINA between two guanines of the triplex imparts a high thermal stabilization (ΔTM = 9ºC) to the structure and enhances the quality of NMR spectra by increasing the chemical shift dispersion of proton signals near the TINA location. The structural determination reveals that TINA intercalates between two consecutive triads, causing only local distortions in the structure. The two aromatic moieties of TINA are nearly coplanar, with the phenyl ring intercalating between the flanking guanine bases in the sequence, and the pyrene moiety situated between the Watson-Crick base pair of the two first strands. The precise position of TINA within the triplex structure reveals key TINA-DNA interactions, which explains the high stabilization observed and will aid in the design of new and more efficient binders to DNA.

Comparative Analysis of PEG-Free and PEG-Based Self-Emulsifying Drug Delivery Systems for Enhanced Oral Bioavailability of Therapeutic (Poly) Peptides.

This study aims to compare the potential of Polyethylene glycol (PEG-free and PEG-based self-emulsifying drug delivery systems (SEDDS) for the oral administration of insulin glargine (IG). Hydrophobic ion pairs (HIPs) of IG are formed using various counterions. HIPs are assessed for log P octanol/water and dissociation behavior. They are incorporated into SEDDS based on polyglycerol (PG) and zwitterionic surfactant (ZW) using response surface methodology and compared to conventional PEG-SEDDS in size, stability, and log D SEDDS/release medium. Oral IG bioavailability in PG/ZW-SEDDS and PEG-SEDDS is evaluated in rats. Among the various counterions studied, IG-BIS (bis(isotridecyl)sulfosuccinate) HIPs demonstrated the highest log P and an improved dissociation profile. PG/ZW-SEDDS and PEG-SEDDS have similar ≈40 nm sizes and are stable over 24 h. Both formulations have log D > 4 in water and >2 in 50 mM phosphate buffer pH 6.8. PG/ZW-SEDDS yielded an oral bioavailability of 2.13 ± 0.66% for IG, while the employment of PEG-SEDDS resulted in an oral bioavailability of 1.15 ± 0.35%. This study highlights the prospective utilization of PEG-free SEDDS involving the concurrent application of PG and ZW surfactants, an alternative to conventional PEG surfactants, for improved oral therapeutic (poly) peptide delivery.

Lysosomal diacylglycerol pyrophosphate phosphatase is not essential in Trypanosoma brucei.

Mg2+-independent phosphatidic acid phosphatase (PAP2), diacylglycerol pyrophosphate phosphatase 1 (Dpp1) is a membrane-associated enzyme in Saccharomyces cerevisiae. The enzyme is responsible for inducing the breakdown of ß-phosphate from diacylglycerol pyrophosphate (DGPP) into phosphatidate (PA) and then removes the phosphate from PA to give diacylglycerol (DAG). In this study through RNAi suppression, we have demonstrated that Trypanosoma brucei diacylglycerol pyrophosphate phosphatase 1 (TbDpp1) procyclic form production is not required for parasite survival in culture. The steady-state levels of triacylglycerol (TAG), the number of lipid droplets, and the PA content are all maintained constant through the inducible down-regulation of TbDpp1. Furthermore, the localization of C-terminally tagged variants of TbDpp1 in the lysosome was demonstrated by immunofluorescence microscopy.

Jasmonates and Ethylene Shape Floridoside Synthesis during Carposporogenesis in the Red Seaweed Grateloupia imbricata.

Floridoside is a galactosyl-glycerol compound that acts to supply UDP-galactose and functions as an organic osmolyte in response to salinity in Rhodophyta. Significantly, the UDP-galactose pool is shared for sulfated cell wall galactan synthesis, and, in turn, affected by thallus development alongside carposporogenesis induced by volatile growth regulators, such as ethylene and methyl jasmonate, in the red seaweed Grateloupia imbricata. In this study, we monitored changes in the floridoside reservoir through gene expression controlling both the galactose pool and glyceride pool under different reproductive stages of G. imbricata and we considered changing salinity conditions. Floridoside synthesis was followed by expression analysis of galactose-1-phosphate uridyltransferase (GALT) as UDP-galactose is obtained from UDP-glucose and glucose-1P, and through α-galactosidase gene expression as degradation of floridoside occurs through the cleavage of galactosyl residues. Meanwhile, glycerol 3-phosphate is connected with the galactoglyceride biosynthetic pathway by glycerol 3-phosphate dehydrogenase (G3PD), monogalactosyl diacylglyceride synthase (MGDGS), and digalactosyl diacylglyceride synthase (DGDGS). The results of our study confirm that low GALT transcripts are correlated with thalli softness to locate reproductive structures, as well as constricting the synthesis of UDP-hexoses for galactan backbone synthesis in the presence of two volatile regulators and methionine. Meanwhile, α-galactosidase modulates expression according to cystocarp maturation, and we found high transcripts in late development stages, as occurred in the presence of methyljasmonate, compared to early stages in ethylene. Regarding the acylglyceride pool, the upregulation of G3PD, MGDGS, and DGDGS gene expression in G. imbricata treated with MEJA supports lipid remodeling, as high levels of transcripts for MGDGS and DGDGS provide membrane stability during late development stages of cystocarps. Similar behavior is assumed in three naturally collected thalli development stages-namely, fertile, fertilized, and fertile-under 65 psu salinity conditions. Low transcripts for α-galactosidase and high for G3PD are reported in infertile and fertilized thalli, which is the opposite to high transcripts for α-galactosidase and low for G3PD encountered in fertile thalli within visible cystocarps compared to each of their corresponding stages in 35 psu. No significant changes are reported for MGDGS and DGDGS. It is concluded that cystocarp and thallus development stages affect galactose and glycerides pools with interwoven effects on cell wall polysaccharides.

Fluconazole-Loaded Ibuprofen In Situ Gel-Based Oral Spray for Oropharyngeal Candidiasis Treatment.

Oral candidiasis is a fungal infection affecting the oral mucous membrane, and this research specifically addresses on a localized treatment through fluconazole-loaded ibuprofen in situ gel-based oral spray. The low solubility of ibuprofen is advantageous for forming a gel when exposed to an aqueous phase. The 1% w/w fluconazole-loaded in situ gel oral sprays were developed utilizing various concentrations of ibuprofen in N-methyl pyrrolidone. The prepared solutions underwent evaluation for viscosity, surface tension, contact angle, water tolerance, gel formation, interface interaction, drug permeation, and antimicrobial studies. The higher amount of ibuprofen reduced the surface tension and retarded solvent exchange. The use of 50% ibuprofen as a gelling agent demonstrated prolonged drug permeation for up to 24 h. The incorporation of Cremophor EL in the formulations resulted in increased drug permeation and exhibited effective inhibition against Candida albicans, Candida krusei, Candida lusitaniae, and Candida tropicalis. While the Cremophor EL-loaded formulation did not exhibit enhanced antifungal effects on agar media, its ability to facilitate the permeation of fluconazole and ibuprofen suggested potential efficacy in countering Candida invasion in the oral mucosa. Moreover, these formulations demonstrated significant thermal inhibition of protein denaturation in egg albumin, indicating anti-inflammatory properties. Consequently, the fluconazole-loaded ibuprofen in situ gel-based oral spray presents itself as a promising dosage form for oropharyngeal candidiasis treatment.

[Treatment of ornithine transcarbamylase deficiency in a child with glyceryl phenylbutyrate]. / è‹¯ä¸é ¸ç”˜æ²¹é ¯æ²»ç–—å„¿ç«¥é¸Ÿæ°¨é ¸æ°¨ç”²é °åŸºè½¬ç§»é ¶ç¼ºä¹ç—‡1例.

Glyceryl phenylbutyrate (GPB) serves as a long-term management medication for Ornithine transcarbamylase deficiency (OTCD), effectively controlling hyperammonemia, but there is a lack of experience in using this medicine in China. This article retrospectively analyzes the case of a child diagnosed with OTCD at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, including a review of related literature. After diagnosis, the patient was treated with GPB, followed by efficacy follow-up and pharmacological monitoring. The 6-year and 6-month-old male patient exhibited poor speech development, disobedience, temper tantrums, and aggressive behavior. Blood ammonia levels peaked at 327 µmol/L; urine organic acid analysis indicated elevated uracil levels; cranial MRI showed extensive abnormal signals in both cerebral hemispheres. Genetic testing revealed de novo mutation in the OTC gene (c.241T>C, p.S81P). Blood ammonia levels were approximately 43, 80, and 56 µmol/L at 1, 2, and 3 months after starting GPB treatment, respectively. During treatment, blood ammonia was well-controlled without drug-related adverse effects. The patient showed improvement in developmental delays, obedience, temperament, and absence of aggressive behavior.

Biodegradable poly(ethylene glycol-glycerol-itaconate-sebacate) copolyester elastomer with significantly reinforced mechanical properties by in-situ construction of bacterial cellulose interpenetrating network.

To address the concern that biodegradable elastomers are environmental-friendly but usually associated with poor properties for practical utilization, we report a star-crosslinked poly(ethylene glycol-glycerol-itaconate-sebacate) (PEGIS) elastomer synthesized by esterification, polycondensation and UV curing, and reinforced by bacterial cellulose (BC). The interpenetrating network of primary BC backbone and vulcanized elastomer is achieved by the "in-situ secondary network construction" strategy. With the well dispersion of BC without agglomeration, the mechanical properties of PEGIS are significantly enhanced in tensile strength, Young's modulus and elongation at break. The reinforcement strategy is demonstrated to be efficient and offers a route to the development of biodegradable elastomers for a variety of applications in the future.

Plasma metabolomic profile in orthostatic intolerance children with high levels of plasma homocysteine.

BACKGROUND: Orthostatic intolerance, which includes vasovagal syncope and postural orthostatic tachycardia syndrome, is common in children and adolescents. Elevated plasma homocysteine levels might participate in the pathogenesis of orthostatic intolerance. This study was designed to analyze the plasma metabolomic profile in orthostatic intolerance children with high levels of plasma homocysteine. METHODS: Plasma samples from 34 orthostatic intolerance children with a plasma homocysteine concentration > 9 µmol/L and 10 healthy children were subjected to ultra-high-pressure liquid chromatography and quadrupole-time-of-flight mass spectrometry analysis. RESULTS: A total of 875 metabolites were identified, 105 of which were significantly differential metabolites. Choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, 1-(1Z-octadecenyl)-2-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphocholine, histidine, isocitric acid, and DL-glutamic acid and its downstream metabolites were upregulated, whereas 1-palmitoyl-sn-glycero-3-phosphocholine, 1-stearoyl-sn-glycerol 3-phosphocholine, sphingomyelin (d18:1/18:0), betaine aldehyde, hydroxyproline, and gamma-aminobutyric acid were downregulated in the orthostatic intolerance group compared with the control group. All these metabolites were related to choline and glutamate. Heatmap analysis demonstrated a common metabolic pattern of higher choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and DL-glutamic acid, and lower sphingomyelin (d18:1/18:0), 1-stearoyl-sn-glycerol 3-phosphocholine, and 1-palmitoyl-sn-glycero-3-phosphocholine in patients with certain notable metabolic changes (the special group) than in the other patients (the common group). The maximum upright heart rate, the change in heart rate from the supine to the upright position, and the rate of change in heart rate from the supine to the upright position of vasovagal syncope patients were significantly higher in the special group than in the common group (P < 0.05). Choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and DL-glutamic acid were positively correlated with the rate of change in heart rate from the supine to the upright position in vasovagal syncope patients (P < 0.05). CONCLUSIONS: The levels of choline-related metabolites and glutamate-related metabolites changed significantly in orthostatic intolerance children with high levels of plasma homocysteine, and these changes were associated with the severity of illness. These results provided new light on the pathogenesis of orthostatic intolerance.

Polyglycerol polyricinoleate and lecithin stabilized water in oil nanoemulsions for sugaring Beijing roast duck: Preparation, stability mechanisms and color improvement.

Traditional Beijing roast duck often suffers from uneven color and high sugar content after roasting. Water-in-oil (W/O) nanoemulsion is a promising alternative to replace high concentration of sugar solution used in sugaring process according to similarity-intermiscibility theory. Herein, 3% of xylose was embedded in the aqueous phase of W/O emulsion to replace 15% maltose solution. W/O emulsions with different ratios of lecithin (LEC) and polyglycerol polyricinoleate (PGPR) were constructed by high-speed homogenization and high-pressure homogenization. Distribution and penetration extent of solutions and emulsions through the duck skin, as well as the color uniformity of Beijing roast duck were analyzed. Emulsions with LEC:PGPR ratios of 1:3 and 2:2 had better stability. Stable interfacial film and spatial structure were important factors influencing emulsion stabilization. The stable W/O emulsions could more uniformly distribute onto the surface of duck skin and longitudinally penetrate through the skin than solutions.

Development of a GC-FID method for quantitative characterisation of polyglycerols in polyglycerol polyricinoleate (PGPR) present in a lipid matrix.

PGPR is an emulsifier (E476) widely used in the food industry. In this study, a gas chromatography-flame ionisation detection (GC-FID) method was developed for the quantitative characterisation of the polyglycerol composition of PGPR. The method was validated to analyse quantitatively the polyglycerol species in neat PGPR products and in PGPR samples present in a lipid matrix. This method consists of saponification, acidification and petroleum ether extraction to remove interfering fatty acids, neutralisation, silylation and finally GC-FID analysis. Phenyl ß-D-glucopyranoside was used as internal standard as sorbitol proved unsuitable due to its susceptibility to interference from Na/K chloride during silylation. The response factors of glycerol and diglycerol towards phenyl ß-D-glucopyranoside were determined using pure standards, while response factors of polyglycerols with a degree of polymerisation of at least 3 could be reliably estimated according to an effective carbon number (ECN) approach. The validity of the method applied to PGPR samples was further supported on the basis of a mass balance considering the experimentally determined polyglycerol and fatty acid content. Moreover, recoveries of di-, tri-, tetra- and pentaglycerol were more than 95% for various PGPR samples added to two different lipid matrices at 2 wt% and 5 wt% concentrations. Furthermore, the method proved to be very repeatable (with relative standard deviation values below 2.2%). On the other hand, the inevitable presence of glycerol in the lipid samples caused fouling of the detector and column overloading, requiring frequent cleaning of the detector and trimming off part of the column.

Toxicity of organic solvents and surfactants to the sea urchin embryos.

A comparative toxicity of widely applied organic solvents (methanol, ethanol, n-propanol, i-propanol, n-butanol, 2-butanol, i-butanol, t-butanol, 3-methoxy-3-methylbutanol-1 (MMB), ethylene glycol, diethylene glycol, 2-methoxyethanol, 2-ethoxyethanol, glycerol, ethyl acetate, acetonitrile, benzene, dioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, 2-pyrrolidone, and N-methyl-2-pyrrolidone) and surfactants (PEG 300, PEG 6000, Tween 20, Tween 80, miramistin, and Cremophor EL) was studied using a sea urchin embryo model. Sea urchin embryo morphological alterations caused by the tested chemicals were described. The tested molecules affected P. lividus embryo development in a concentration-dependent manner. The observed phenotypic anomalies ranged from developmental delay and retardation of plutei growth to formation of aberrant blastules and gastrules, cleavage alteration/arrest, and embryo mortality. Discernible morphological defects were found after embryo exposure with common pharmaceutical ingredients, such as glycerol, Tween 80, and Cremophor EL. In general, solvents were less toxic than surfactants. PEG 6000 PEG 300, DMSO, ethanol, and methanol were identified as the most tolerable compounds with minimum effective concentration (MEC) values of 3.0-7.92 mg/mL. Previously reported MEC value of Pluronic F127 (4.0 mg/mL) fell within the same concentration range. Toxic effects of methanol, ethanol, DMSO, 2-methoxyethanol, 2-ethoxyethanol, Tween 20, and Tween 80 on P. lividus embryos correlated well with their toxicity obtained using other cell and animal models. The sea urchin embryos could be considered as an appropriate test system for toxicity assessment of solvents and surfactants for their further application as solubilizers of hydrophobic molecules in conventional in vitro cell-based assays and in vivo mammalian models. Nevertheless, to avoid adverse effect of a solubilizing agent in ecotoxicological and biological experiments, the preliminary assessment of its toxicity on a chosen test model would be beneficial.

An Encapsulation-Free and Hierarchical Porous Triboelectric Scaffold with Dynamic Hydrophilicity for Efficient Cartilage Regeneration.

Tissue engineering and electrotherapy are two promising methods to promote tissue repair. However, their integration remains an underexplored area, because their requirements on devices are usually distinct. Triboelectric nanogenerators (TENGs) have shown great potential to develop self-powered devices. However, due to their susceptibility to moisture, TENGs have to be encapsulated in vivo. Therefore, existing TENGs cannot be employed as tissue engineering scaffolds, which require direct interaction with surrounding cells. Here, the concept of triboelectric scaffolds (TESs) is proposed. Poly(glycerol sebacate), a biodegradable and relatively hydrophobic elastomer, is selected as the matrix of TESs. Each hydrophobic micropore in multi-hierarchical porous TESs efficiently serves as a moisture-resistant working unit of TENGs. Integration of tons of micropores ensures the electrotherapy ability of TESs in vivo without encapsulation. Originally hydrophobic TESs are degraded by surface erosion and transformed into hydrophilic surfaces, facilitating their role as tissue engineering scaffolds. Notably, TESs seeded with chondrocytes obtain dense and large matured cartilages after subcutaneous implantation in nude mice. Importantly, rabbits with osteochondral defects receiving TES implantation show favorable hyaline cartilage regeneration and complete cartilage healing. This work provides a promising electronic biomedical device and will inspire a series of new in vivo applications.

Exploring novel type of lipid-bases drug delivery systems that contain one lipid and one water-soluble surfactant only.

None of transitional lipid-based drug delivery systems (LBDDS) includes compositions containing one lipid and one water-soluble surfactant that form stable microemulsions. The conversion of liquid LBDDS to solid LBDDS has been limited by low drug loading. Previously, we have developed drug solid microemulsions containing one lipid and TPGS (a water-soluble surfactant) that achieved high drug loading and remarkably increased oral bioavailability. This study aimed to test if binary lipid systems (BLS), composed of one lipid and one water-soluble surfactant that form stable self-emulsifying microemulsions, is not an exclusive but widely applicable type of LBDDS for other lipids and surfactants and evaluate the influences of chemical structures of lipids and surfactants on microemulsions and solid microemulsions. We systemically identified new BLS by using a library of lipids and surfactants. Propylene glycol diesters and glycerol triesters were favorable for forming stable microemulsions with Tween 80, Cremophor EL, or TPGS. To the best of our knowledge, this is the first report exploring and confirming that the BLS is a new addition to traditional LBDDS, provides a promising option for researchers, and has the potential to increase drug loading to facilitate the development of solid microemulsions.

Wireless electrostimulation for cancer treatment: An integrated nanoparticle/coaxial fiber mesh platform.

Cancer, namely breast and prostate cancers, is the leading cause of death in many developed countries. Controlled drug delivery systems are key for the development of new cancer treatment strategies, to improve the effectiveness of chemotherapy and tackle off-target effects. In here, we developed a biomaterials-based wireless electrostimulation system with the potential for controlled and on-demand release of anti-cancer drugs. The system is composed of curcumin-loaded poly(3,4-ethylenedioxythiophene) nanoparticles (CUR/PEDOT NPs), encapsulated inside coaxial poly(glycerol sebacate)/poly(caprolactone) (PGS/PCL) electrospun fibers. First, we show that the PGS/PCL nanofibers are biodegradable, which allows the delivery of NPs closer to the tumoral region, and have good mechanical properties, allowing the prolonged storage of the PEDOT NPs before their gradual release. Next, we demonstrate PEDOT/CUR nanoparticles can release CUR on-demand (65 % of release after applying a potential of -1.5 V for 180 s). Finally, a wireless electrostimulation platform using this NP/fiber system was set up to promote in vitro human prostate cancer cell death. We found a decrease of 67 % decrease in cancer cell viability. Overall, our results show the developed NP/fiber system has the potential to effectively deliver CUR in a highly controlled way to breast and prostate cancer in vitro models. We also show the potential of using wireless electrostimulation of drug-loaded NPs for cancer treatment, while using safe voltages for the human body. We believe our work is a stepping stone for the design and development of biomaterial-based future smarter and more effective delivery systems for anti-cancer therapy.

Comparative study of iodine-doped and undoped pyrrole grafting with plasma on poly (glycerol sebacate) scaffolds and its human dental pulp stem cells compatibility.

This study addresses the morphological and chemical characterization of PGS scaffolds after (6, 12, 18, 24, and 30 min) residence in undoped pyrrole plasma (PGS-PPy) and the evaluation of cell viability with human dental pulp stem cells (hDPSCs). The results were compared with a previous study that used iodine-doped pyrrole (PGS-PPy/I). Analyses through SEM and AFM revealed alterations in the topography and quantity of deposited PPy particles. FTIR spectra of PGS-PPy scaffolds confirmed the presence of characteristic absorption peaks of PPy, with higher intensities observed in the nitrile and -C≡C- groups compared to PGS-PPy/I scaffolds, while raman spectra indicated a lower presence of polaron N+ groups. On the other hand, PGS scaffolds modified with PPy exhibited lower cytotoxicity compared to PGS-PPy/I scaffolds, as evidenced by the Live/Dead assay. Furthermore, the PGS-PPy scaffolds at 6 and 12 min, and particularly the PGS-PPy/I scaffold at 6 min, showed the best results in terms of cell viability by the fifth day of culture. The findings of this study suggest that undoped pyrrole plasma modification for short durations could also be a viable option to enhance the interaction with hDPSCs, especially when the treatment times range between 6 min and 12 min.

Tropoelastin modulates systemic and local tissue responses to enhance wound healing.

Wound healing is facilitated by biomaterials-based grafts and substantially impacted by orchestrated inflammatory responses that are essential to the normal repair process. Tropoelastin (TE) based materials are known to shorten the period for wound repair but the mechanism of anti-inflammatory performance is not known. To explore this, we compared the performance of the gold standard Integra Dermal Regeneration Template (Integra), polyglycerol sebacate (PGS), and TE blended with PGS, in a murine full-thickness cutaneous wound healing study. Systemically, blending with TE favorably increased the F4/80+ macrophage population by day 7 in the spleen and contemporaneously induced elevated plasma levels of anti-inflammatory IL-10. In contrast, the PGS graft without TE prompted prolonged inflammation, as evidenced by splenomegaly and greater splenic granulocyte and monocyte fractions at day 14. Locally, the inclusion of TE in the graft led to increased anti-inflammatory M2 macrophages and CD4+T cells at the wound site, and a rise in Foxp3+ regulatory T cells in the wound bed by day 7. We conclude that the TE-incorporated skin graft delivers a pro-healing environment by modulating systemic and local tissue responses. STATEMENT OF SIGNIFICANCE: Tropoelastin (TE) has shown significant benefits in promoting the repair and regeneration of damaged human tissues. In this study, we show that TE promotes an anti-inflammatory environment that facilitates cutaneous wound healing. In a mouse model, we find that inserting a TE-containing material into a full-thickness wound results in defined, pro-healing local and systemic tissue responses. These findings advance our understanding of TE's restorative value in tissue engineering and regenerative medicine, and pave the way for clinical applications.

Low drug load, high retention mometasone furoate cream with polyglyceryl - 3 oleate as a chemical enhancer: Formulation development, in vivo and in vitro evaluation and molecular mechanisms.

The study aimed to create a low loading, high retention, easier to apply O/W mometasone furoate (MF) cream using a chemical enhancer (CE) approach to provide more options for patients with atopic dermatitis (AD) and to investigate molecular mechanisms of its increased release and retention. A Box-Behnken design determined the optimal formulation based on stability and in vitro skin retention. Evaluations included appearance, rheological properties, irritation, in vivo tissue distribution and pharmacodynamics. Molecular mechanisms of enhanced release were studied using high-speed centrifugation, molecular dynamics and rheology. The interaction between the CE, MF and skin was studied by tape stripping, CLSM, ATR-FTIR and SAXS. The formulation was optimized to contain 0.05% MF and used 10% polyglyceryl-3 oleate (POCC) as the CE. There was no significant difference from Elocon® cream in in vivo retention and pharmacodynamics but increased in vivo retention by 3.14-fold and in vitro release by 1.77-fold compared to the basic formulation. POCC reduced oil phase cohesive energy density, enhancing drug mobility and release. It disrupted skin lipid phases, aiding drug entry and formed hydrogen bonds, prolonging retention. This study highlights POCC as a CE in the cream, offering insights for semi-solid formulation development.

Enhanced wound regeneration by PGS/PLA fiber dressing containing platelet-rich plasma: an in vitro study.

Novel wound dressings with therapeutic effects are being continually designed to improve the wound healing process. In this study, the structural, chemical, physical, and biological properties of an electrospun poly glycerol sebacate/poly lactide acid/platelet-rich plasma (PGS/PLA-PRP) nanofibers were evaluated to determine its impacts on in vitro wound healing. Results revealed desirable cell viability in the Fibroblast (L929) and macrophage (RAW-264.7) cell lines as well as human umbilical vein endothelial cells (HUVEC). Cell migration was evident in the scratch assay (L929 cell line) so that it promoted scratch contraction to accelerate in vitro wound healing. Moreover, addition of PRP to the fiber structure led to enhanced collagen deposition (~ 2 times) in comparison with PGS/PLA scaffolds. While by addition PRP to PGS/PLA fibers not only decreased the expression levels of pro-inflammatory cytokines (IL-6 and TNF-α) in RAW-264.7 cells but also led to significantly increased levels of cytokine (IL-10) and the growth factor (TGF-ß), which are related to the anti-inflammatory phase (M2 phenotype). Finally, PGS/PLA-PRP was found to induce a significant level of angiogenesis by forming branching points, loops, and tubes. Based on the results obtained, the PGS/PLA-PRP dressing developed might be a promising evolution in skin tissue engineering ensuring improved wound healing and tissue regeneration.

A bioenergetically-active ploy (glycerol sebacate)-based multiblock hydrogel improved diabetic wound healing through revitalizing mitochondrial metabolism.

Diabetic wounds impose significant burdens on patients' quality of life and healthcare resources due to impaired healing potential. Factors like hyperglycemia, oxidative stress, impaired angiogenesis and excessive inflammation contribute to the delayed healing trajectory. Mounting evidence indicates a close association between impaired mitochondrial function and diabetic complications, including chronic wounds. Mitochondria are critical for providing energy essential to wound healing processes. However, mitochondrial dysfunction exacerbates other pathological factors, creating detrimental cycles that hinder healing. This study conducted correlation analysis using clinical specimens, revealing a positive correlation between mitochondrial dysfunction and oxidative stress, inflammatory response and impaired angiogenesis in diabetic wounds. Restoring mitochondrial function becomes imperative for developing targeted therapies. Herein, we synthesized a biodegradable poly (glycerol sebacate)-based multiblock hydrogel, named poly (glycerol sebacate)-co-poly (ethylene glycol)-co-poly (propylene glycol) (PEPGS), which can be degraded in vivo to release glycerol, a crucial component in cellular metabolism, including mitochondrial respiration. We demonstrate the potential of PEPGS-based hydrogels to improve outcomes in diabetic wound healing by revitalizing mitochondrial metabolism. Furthermore, we investigate the underlying mechanism through proteomics analysis, unravelling the regulation of ATP and nicotinamide adenine dinucleotide metabolic processes, biosynthetic process and generation during mitochondrial metabolism. These findings highlight the therapeutic potential of PEPGS-based hydrogels as advanced wound dressings for diabetic wound healing.

Injectable Nanocomposite Hydrogels Improve Intraperitoneal Co-delivery of Chemotherapeutics and Immune Checkpoint Inhibitors for Enhanced Peritoneal Metastasis Therapy.

Intraperitoneal co-delivery of chemotherapeutic drugs (CDs) and immune checkpoint inhibitors (ICIs) brings hope to improve treatment outcomes in patients with peritoneal metastasis from ovarian cancer (OC). However, current intraperitoneal drug delivery systems face issues such as rapid drug clearance from lymphatic drainage, heterogeneous drug distribution, and uncontrolled release of therapeutic agents into the peritoneal cavity. Herein, we developed an injectable nanohydrogel by combining carboxymethyl chitosan (CMCS) with bioadhesive nanoparticles (BNPs) based on polylactic acid-hyperbranched polyglycerol. This system enables the codelivery of CD and ICI into the intraperitoneal space to extend drug retention. The nanohydrogel is formed by cross-linking of aldehyde groups on BNPs with amine groups on CMCS via reversible Schiff base bonds, with CD and ICI loaded separately into BNPs and CMCS network. BNP/CMCS nanohydrogel maintained the activity of the biomolecules and released drugs in a sustained manner over a 7 day period. The adhesive property, through the formation of Schiff bases with peritoneal tissues, confers BNPs with an extended residence time in the peritoneal cavity after being released from the nanohydrogel. In a mouse model, BNP/CMCS nanohydrogel loaded with paclitaxel (PTX) and anti-PD-1 antibodies (αPD-1) significantly suppressed peritoneal metastasis of OC compared to all other tested groups. In addition, no systemic toxicity of nanohydrogel-loaded PTX and αPD-1 was observed during the treatment, which supports potential translational applications of this delivery system.