Evaluating Drug Interactions between Ritonavir and Opioid Analgesics: Implications from Physiologically Based Pharmacokinetic Simulation.

Several commonly used opioid analgesics, such as fentanyl, sufentanil, alfentanil, and hydrocodone, are by report primarily metabolized by the CYP3A4 enzyme. The concurrent use of ritonavir, a potent CYP3A4 inhibitor, can lead to significant drug interactions. Using physiologically based pharmacokinetic (PBPK) modeling and simulation, this study examines the effects of different dosing regimens of ritonavir on the pharmacokinetics of these opioids. The findings reveal that co-administration of ritonavir significantly increases the exposure of fentanyl analogs, with over a 10-fold increase in the exposure of alfentanil and sufentanil when given with ritonavir. Conversely, the effect of ritonavir on fentanyl exposure is modest, likely due to additional metabolism pathways. Additionally, the study demonstrates that the steady-state exposure of hydrocodone and its active metabolite hydromorphone can be increased by up to 87% and 95%, respectively, with concurrent use of ritonavir. The extended-release formulation of hydrocodone is particularly affected. These insights from PBPK modeling provide valuable guidance for optimizing opioid dosing and minimizing the risk of toxicity when used in combination with ritonavir-containing prescriptions.

Overexpression of ETV2 in BMSCs promoted wound healing in cutaneous wound mice by triggering the differentiation of BMSCs into endothelial cells and modulating the transformation of M1 phenotype macrophages to M2 phenotype macrophages.

This study aimed to investigate the effects of E26-transformation-specific variant-2 (ETV2) overexpression on wound healing in a cutaneous wound (CW) model and clarify associated mechanisms. pLVX-ETV2 lentivirus expressing ETV2 was constructed and infected into BMSCs to generate ETV2-overexpressed BMSCs (BMSCs+pLVX+ETV2). The RT-PCR assay was applied to amplify ETV2, VE-cadherin, vWF, ARG-1, IL-6, iNOS, TGF-ß, IL-10, TNF-α. Western blot was used to determine expression of VE-cadherin and vWF. ETV2 induced differentiation of BMSCs into ECs by increasing CDH5/CD31, triggering tube-like structures, inducing Dil-Ac-LDL positive BMSCs. ETV2 overexpression increased the gene transcription and expression of VE-cadherin and vWF (P<0.01). Transcription of M1 phenotype specific iNOS gene was lower and transcription of M2 phenotype specific ARG-1 gene was higher in the RAW264.7+BMSCs+ETV2 group compared to the RAW264.7+BMSCs+pLVX group (P<0.01). ETV2 overexpression (RAW264.7+BMSCs+ETV2) downregulated IL-6 and TNF-α, and upregulated IL-10 and TGF-ß gene transcription compared to RAW264.7+BMSCs+pLVX group (P<0.01). ETV2-overexpressed BMSCs promoted wound healing in CW mice and triggered the migration of BMSCs to the wound region and macrophage activation. ETV2-overexpressed BMSCs promoted collagen fibers and blood vessel formation in the wound region of CW mice. In conclusion, this study revealed a novel biofunction of ETV2 molecule in the wound healing process. ETV2 overexpression in BMSCs promoted wound healing in CW mice by triggering BMSCs differentiation into endothelial cells and modulating the transformation of M1 pro-inflammatory and M2 anti-inflammatory macrophages in vitro and in vivo.

Alveoli-Mimetic Synergistic Liquid and Solid Thermal Conductive Interface as a Novel Strategy for Designing High-Performance Thermal Interface Materials.

Thermal interface materials (TIMs) are in desperate desire with the development of the modern electronic industry. An excellent TIM needs desired comprehensive properties including but not limited to high thermal conductivity, low Yong's modulus, lightweight, as well as low price. However, as is typically the case, those properties are naturally contradictory. To tackle such dilemmas, a strategy of construction high-performance TIM inspired by alveoli is proposed. The material design includes the self-alignment of graphite into 3D interconnected thermally conductive networks by polydimethylsiloxane beads (PBs) -the alveoli; and a small amount of liquid metal (LM) - capillary networks bridging the PBs and graphite network. Through the delicate structural regulation and the synergistic effect of the LM and solid graphite filler, superb thermal conductivity (9.98 ± 0.34 W m-1 K-1) can be achieved. The light emitting diode (LED) application and their performance in the central processing unit (CPU) heat dispersion manifest the TIM developed in the work has stable thermal conductivity for long-term applications. The thermally conductive, soft, and lightweight composites are believed to be high-performance silicone bases TIMs for advanced electronics.

Explore novel molecular mechanisms of FNDC5 in ischemia-reperfusion (I/R) injury by analyzing transcriptome changes in mouse model of skeletal muscle I/R injury with FNDC5 knockout.

BACKGROUND: Irisin, a myokine derived from proteolytic cleavage of the fibronectin type III domain-containing protein 5 (FNDC5) protein, is crucial in protecting tissues and organs from ischemia-reperfusion (I/R) injury. However, the underlying mechanism of its action remains elusive. In this study, we investigated the expression patterns of genes associated with FNDC5 knockout to gain insights into its molecular functions. METHODS: We employed a mouse model of skeletal muscle I/R injury with FNDC5 knockout to examine the transcriptional profiles using RNA sequencing. Differentially expressed genes (DEGs) were identified and subjected to further analyses, including gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein-protein interaction (PPI) network analysis, and miRNA-transcription factor network analysis. The bioinformatics findings were validated using qRT-PCR and Western blotting. RESULTS: Comparative analysis of skeletal muscle transcriptomes between wild-type (WT; C57BL/6), WT-I/R, FNDC5 knockout (KO), and KO-I/R mice highlighted the significance of FNDC5 in both physiological conditions and I/R injury. Through PPI network analysis, we identified seven key genes (Col6a2, Acta2, Col4a5, Fap, Enpep, Mmp11, and Fosl1), which facilitated the construction of a TF-hub genes-miRNA regulatory network. Additionally, our results suggested that the PI3K-Akt pathway is predominantly involved in FNDC5 deletion-mediated I/R injury in skeletal muscle. Animal studies revealed reduced FNDC5 expression in skeletal muscle following I/R injury, and the gastrocnemius muscle with FNDC5 knockout exhibited larger infarct size and more severe tissue damage after I/R. Moreover, Western blot analysis confirmed the upregulation of Col6a2, Enpep, and Mmp11 protein levels following I/R, particularly in the KO-I/R group. Furthermore, FNDC5 deletion inhibited the PI3K-Akt signaling pathway. CONCLUSION: This study demonstrates that FNDC5 deletion exacerbates skeletal muscle I/R injury, potentially involving the upregulation of Col6a2, Enpep, and Mmp11. Additionally, the findings suggest the involvement of the PI3K-Akt pathway in FNDC5 deletion-mediated skeletal muscle I/R injury, providing novel insights into the molecular mechanisms underlying FNDC5's role in this pathological process.

Physiologically Based Pharmacokinetic Modeling in Neonates: Current Status and Future Perspectives.

Rational drug use in special populations is a clinical problem that doctors and pharma-cists must consider seriously. Neonates are the most physiologically immature and vulnerable to drug dosing. There is a pronounced difference in the anatomical and physiological profiles be-tween neonates and older people, affecting the absorption, distribution, metabolism, and excretion of drugs in vivo, ultimately leading to changes in drug concentration. Thus, dose adjustments in neonates are necessary to achieve adequate therapeutic concentrations and avoid drug toxicity. Over the past few decades, modeling and simulation techniques, especially physiologically based pharmacokinetic (PBPK) modeling, have been increasingly used in pediatric drug development and clinical therapy. This rigorously designed and verified model can effectively compensate for the deficiencies of clinical trials in neonates, provide a valuable reference for clinical research design, and even replace some clinical trials to predict drug plasma concentrations in newborns. This review introduces previous findings regarding age-dependent physiological changes and pathological factors affecting neonatal pharmacokinetics, along with their research means. The application of PBPK modeling in neonatal pharmacokinetic studies of various medications is also reviewed. Based on this, we propose future perspectives on neonatal PBPK modeling and hope for its broader application.

Screening diagnostic markers of osteoporosis based on ferroptosis of osteoblast and osteoclast.

BACKGROUND: Osteoporosis is a negative balance of bone metabolism caused by the lower bone formation of osteoblasts than the bone absorption of osteoclasts. Ferroptosis plays an important role in osteoporosis, but its effects on osteoblasts and osteoclasts are still unclear. METHODS: First, we compared the osteogenic differentiation potential of MSCs and osteoclast differentiation potential of monocytes between osteoporosis mice and control. Then, we obtained gene expression profiles of MSCs and monocytes, and screened differentially expressed genes for enrichment analysis. Next, we cluster the patients with osteoporosis according to genes related to osteogenesis inhibition and osteoclast promotion. Finally, according to the expression of different subtypes of ferroptosis genes, diagnostic markers were screened and verified. RESULTS: The osteogenic differentiation ability of MSCs in osteoporosis mice was decreased, while the osteoclast differentiation ability of monocytes was enhanced. The DEGs of MSCs are enriched in iron ion, oxygen binding and cytokine activity, while the DEGs of monocytes are enriched in iron ion transmembrane transport and ferroptosis. Compared with the osteogenic inhibition subtype, the osteoclast promoting subtype has a higher correlation with ferroptosis, and its functions are enriched in fatty acids, reactive oxygen species metabolism and oxidoreductase activity of metal ions. SLC40A1 may be the hub gene of ferroptosis in osteoporosis by promoting osteoclast differentiation. CONCLUSION: Ferroptosis may inhibit bone formation and promote bone absorption through oxidative stress, thus leading to osteoporosis. The study of ferroptosis on osteoblasts and osteoclasts provides a new idea for the diagnosis and treatment of osteoporosis.

Exploring Lipoic Acid-Mediated Dynamic Bottlebrush Elastomers as a New Platform for the Design of High-Performance Thermally Conductive Materials.

The development of high-performance thermally conductive interface materials is the key to unlocking the serious bottleneck of modern microelectronic technology through enhanced heat dispersion. Existing methods that utilize silicone composites rely either on loading large doses of randomly distributed thermal conductive fillers or on filling prealigned thermal conductive scaffolds with liquid silicone precursors. Both approaches suffer from several limitations in terms of physical traits and processability. We describe an alternative approach in which malleable silicone matrices, based on the dynamic cyclic disulfide nature cross-linker (α-lipoic acid), are readily prepared using ring-opening polymerization. The mechanical properties of the resultant dynamic silicone matrix are readily tunable. Stress-dependent depolymerization of the disulfide network demonstrates the ability to reprocess the silicone elastomer matrix, which allows for the fabrication of highly efficient thermal conductive composites with a 3D interconnecting, thermally conductive network (3D-graphite/MxBy composites) via in situ methods. Applications of the composites as thermal dispersion interface materials are demonstrated by LEDs and CPUs, suggesting great potential in advanced electronics.

Optimal insertion positions of anterior-posterior orientation sacroiliac screw.

PURPOSE: To explore the optimal insertion positions of anterior-posterior orientation sacroiliac screw (AP-SIS). METHODS: Pelvic CT data of 80 healthy adults were employed to measure the anatomical parameters including the insertable ranges of S1 and S2, the length, width and height of the channel with three different horizontal and vertical anterior insertion points starting from the ilium-acetabular recess. To compare pelvic stability by replicating a type C Tile lesions, fifteen synthetic pelvises were fixed with an anterior plate and a posterior AP-SIS employing different anterior insertion points, the whole specimen displacements and shifts in the sacroiliac gap under a cyclic vertical load of 300 N in a biomechanical machine recorded. RESULTS: The posterior and anterior insertable ranges averaged 17.9 × 8.5mm2 and 47.1 × 21.2 mm2, respectively. The channel lengths for three horizontal anterior insertion points gradually decreased from front to back with significant difference (p < 0.05), whereas the width and height for three horizontal anterior insertion points and the parameters for the three vertical anterior insertion points were similar (p > 0.05). The displacements and shifts for three horizontal insertion points gradually increased from front to back (p < 0.05) whereas the measurements involving the three vertical insertion points were similar (p > 0.05). CONCLUSION: The posterior insertable range is small, where the center between adjacent nerve roots (foramens) is the optimal posterior insertion point. The anterior insertable range is large, where the iliac-acetabular recess is the optimal anterior insertion point for S1 and S2, providing the longest channel and best stability.

Treatment of inferior pole patella fracture using Krackow suturing combined with the suture bridge technique.

PURPOSE: To evaluate the feasibility and clinical effect of Krackow suturing combined with the suture bridge technique for the treatment of acute inferior pole patella fracture. METHODS: In this study, 18 patients with acute inferior pole patella fracture who received treatment using Krackow suturing combined with the suture bridge technique between January 2019 and March 2020 were retrospectively reviewed. There were 10 men and 8 women, with an average age of 50.1 years (range 24-69 years). X-ray examinations were performed to assess fracture healing and the Insall-Salvati index. The clinical effect was measured by the range of motion of the knee joint and the Böstman scale. RESULTS: Patients were followed up for 13-26 months, with an average follow-up period of 19.6 months. X-ray indicated that fracture union had occurred in all patients by 10.1 weeks after surgery on average (range 8-14 weeks). The mean Insall-Salvati index immediately after surgery and at the final follow-up was 0.98 ± 0.07 and 0.90 ± 0.22, respectively (P > 0.05). At the last follow-up, the mean flexion and extension ranges for the knee joint were 135.8° ± 8.8° and - 2.8° ± 3.9°, respectively, and the mean Böstman scale was 28.9 ± 1.1 points. Functional recovery was excellent in 17 patients and good in one patient, resulting in an overall good/excellent recovery rate of 100%. CONCLUSIONS: Our results indicated that Krackow suturing combined with the suture bridge technique can achieve stable fracture fixation, provides good clinical outcomes in the treatment of acute inferior pole patella fracture, and is worthy of clinical application.

Delicate and Independent Manipulation of Dynamic Fluorescence Behavior of Polymer Nanoparticles Based on a Core-Shell Strategy.

Fluorescent polymer nanomaterials with dynamic fluorescence properties hold great potential in many advanced applications, including but not limited to information encryption, adaptive camouflage, and biosensors. The key to improving the application value of materials is to establish an accurate control strategy for dynamic fluorescence behavior. Herein, we develop a core-shell engineering strategy to precisely and independently manipulate the dynamic fluorescence behavior through the shell polymeric matrix. The core-shell fluorescent polymer nanoparticles (CS-FPNPs) are constructed through a sequential process of miniemulsion polymerization and seeded emulsion polymerization. Taking advantage of the core-shell structure, the rigid core matrix ensures the strong initial emission of AIE units, while the photoisomerization behavior of spiropyrane (SP) units is delicately and independently regulated by the rigidness of the shell matrix. Thereby, CS-FPNPs exhibit bright time-dependent reversible dynamic fluorescence behavior under alternating UV/vis irradiation. Benefited from the excellent processability and film formation ability, we have successfully applied CS-FPNPs to dynamic decorative painting, warning labels, and dynamic QR code security. Impressively, the fluorescence manipulation strategy based on core-shell engineering allows the independent regulation of specific luminescent units in complicated emission systems to accurately embody designed emission behavior.

In situ synthesis of TiO2/NC on cotton fibers with antibacterial properties and recyclable photocatalytic degradation of dyes.

A cotton fabric/titanium dioxide-nanocellulose (TiO2-Cot.) flexible and recyclable composite material with highly photocatalytic degradation of dyes and antibacterial properties was synthesized. During the preparation process, nano-TiO2 particles were synthesized through an in situ strategy and grown on cotton fiber, and were wrapped with cellulose nanocrystals (NC). The prepared TiO2-Cot. was characterized by field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). The SEM and EDS results showed that nano-TiO2 particles were evenly distributed on the fiber surface. The prepared TiO2@Cot. has excellent photocatalytic efficiency of 95.68% for MB and 92.77% for AR under weak ultraviolet irradiation over 6 h. At the same time, it has excellent antibacterial activity against S. aureus and E. coli. The stability and reusability of the materials were also investigated.

Preparation of quaternized chitosan/Ag composite nanogels in inverse miniemulsions for durable and antimicrobial cotton fabrics.

It is an urgent task to exploit effective antimicrobial agents due to the rise of drug-resistant pathogens. Herein, antimicrobial quaternized chitosan/Ag composite nanogels (QCS/Ag CNGs) with tunable properties were fabricated through inverse miniemulsion technique with a high encapsulation efficiency of NH2-Ag nanoparticles (NPs). The QCS/Ag CNGs possess superior broad-spectrum antimicrobial activity and low biotoxicity, via synergistic sterilization of Ag NPs and QCS. Furthermore, the NH2-Ag NPs were chemically linked to the QCS matrix through Schiff base reactions, and the QCS/Ag CNGs have reactive groups, making it possible to obtain durable antibacterial cotton fabrics. Thus, QCS/Ag CNGs modified cotton fabrics exhibited laundering durability of antimicrobial effect after 100 washing cycles without sacrificing other inherent properties of cotton fabrics. Our study provides a facile and controllable method to construct polymer/inorganic CNGs to address the urgent need for antibacterial agents/fabrics.

Dynamic Photochromic Polymer Nanoparticles Based on Matrix-Dependent Förster Resonance Energy Transfer and Aggregation-Induced Emission Properties.

Dynamic color-tunable fluorescent materials are sought-after materials in many applications. Here, we report a polymeric matrix-regulated fluorescence strategy via synergistically modulating aggregation-induced emission (AIE) properties and the Förster resonance energy transfer (FRET) process, which leads to tunable dynamic variation of color and photoluminescence (PL) intensity of fluorescent polymeric nanoparticles (FRET-PNPs) driven by photoirradiation. The FRET-PNPs were prepared via a facile one-pot miniemulsion copolymerization with the tetraphenyletheyl (TPE) and spiropyran (SP) units chemically bonded to the polymer matrix. The FRET-PNPs exhibited dynamic variation of fluorescence properties (colors and PL intensity) under photoirradiation on the timescale of minutes. The variation of the polymer matrix composition could deliberately influence the AIE property of TPE units and the isomerization process of SP to merocyanine units, which further affect the FRET efficiency of FRET-PNPs and, eventually, lead to versatile dynamic fluorescence variation. The dynamic fluorescence property as well as the excellent processability and film formation ability of FRET-PNPs allowed for diverse applications, such as warning labels, dynamic decorative painting, and multiple information encryption. Without sophisticated molecular design or tedious preparation processes, a new perspective for the design, fabrication, and performance optimization of fluorescent nanomaterials for innovative applications was proposed.

LINC00459 sponging miR-218 to elevate DKK3 inhibits proliferation and invasion in melanoma.

The lncRNA biomarkers in melanoma remain to be further explored. The lncRNAs with different expression levels in melanoma tissue were identified by microarray analysis. To investigate the biological functions of target lncRNA, several in-vivo and in-vitro studies were performed. Potential mechanisms of competitive endogenous RNAs (ceRNAs) were predicted by using bioinformatics analysis and explored by western blot assay, fluorescence in situ hybridization assay, real-time quantitative PCR (RT-qPCR) array, RNA pull-down analysis, AGO2-RIP assay, and dual-luciferase reporter assay. The results demonstrated decreased LINC00459 in melanoma cell lines and tissues. According to the in-vitro and in-vivo experiments, up-regulated LINC00459 had inhibitory effect on cell proliferation and invasion. Bioinformatics analyses suggested that miR-218 could be a direct target of LINC00459. In addition, miR-218 was proved to be able to directly target the dickkopf-related protein 3 (DKK3) gene. In conclusion, our analysis suggested that the LINC00459 could sponge miR-218 and increase the expression of DKK3 gene, thus inhibiting the invasion and proliferation of melanoma cells, which indicated that the LINC00459 could be an effective biomarker for melanoma and its potential as the therapeutic target.

Controllable synthesis of raspberry-like PS-SiO2 nanocomposite particles via Pickering emulsion polymerization.

This paper presents a simple and controllable method for the synthesis of monodisperse nanometer-sized organic-inorganic raspberry-like polystyrene (PS)-SiO2 nanocomposite particles (NCPs) via Pickering emulsion polymerization, by simply using a silane coupling agent, 3-(trimethoxysilyl)propyl methacrylate (MPS), as an auxiliary monomer and controlling its hydrolysis/condensation processes and amount. In this method, when MPS was stirred in acidic water with styrene (St) for a period of time, and then a basic silica solution added, raspberry-like PS-SiO2 NCPs were directly obtained after the polymerization. The whole process needs neither surface treatment for the silica particles nor additional surfactants or stabilizers. We propose that a silica-stabilized Pickering emulsion is formed through Si-OH reaction between the hydrolysis/condensation products of MPS distributed on the St droplets surface and the silica particles.

Inverse Pickering Emulsions with Droplet Sizes below 500 nm.

Inverse Pickering emulsions with droplet diameters between 180 and 450 nm, a narrow droplet size distribution, and an outstanding stability were prepared using a miniemulsion technique. Commercially available hydrophilic silica nanoparticles were used to stabilize the emulsions. They were hydrophobized in situ by the adsorption of various neutral polymeric surfactants. The influence of different parameters, such as kind and amount of surfactant as hydrophobizing agent, size and charge of the silica particles, and amount of water in the dispersed phase, as well as the kind of osmotic agent (sodium chloride and phosphate-buffered saline), on the emulsion characteristics was investigated. The systems were characterized by dynamic light scattering, transmission electron microscopy, cryo-scanning electron microscopy (cryo-SEM), thermogravimetric analysis, and semiquantitative attenuated total reflection infrared spectroscopy. Cryo-SEM shows that some silica particles are obviously rendered hydrophilic and form a three-dimensional network inside the droplets.

Superparamagnetic Fe3O4/Poly(N-isopropyl acrylamide) Nanocomposites Synthesized in Inverse Miniemulsions: Magnetic and Particle Properties.

In the present study, superparamagnetic Fe3O4/poly(N-isopropyl acrylamide) nanocomposites were synthesized by one-step inverse miniemulsion copolymerization of N-isopropyl acrylamide and N,N'-methylene diacrylamide. The loading of Fe3O4 nanoparticles in the nanocomposites was 27 wt%, and the saturation moment of the nanocomposites was 12.4 emu x g(-1). Fe3O4 nanoparticles were prepared through a coprecipitation method. The amount of stabilizer (poly(acrylic acid)) significantly influenced the size and size distribution of the Fe3O4 nanoparticles, and, therefore, their magnetic properties. Superparamagnetism of the Fe3O4 nanoparticles was preserved in the nanocomposites. The effects of synthetic parameters on the particle properties, namely surfactant loading, concentration of ferrofluid, type of lipophobe and initiator, and amount of cross-linker were investigated. Nanocomposites of Fe3O4/poly(N-isopropyl acrylamide) displayed a guava-like morphology, which they could retain after being redispersed in polar solvents.

Preparation of Janus Pd/SiO2 nanocomposite particles in inverse miniemulsions.

Janus Pd/SiO2 nanocomposite particles (NCPs) were successfully synthesized through a combination of the sol-gel process of tetramethoxysilane in inverse miniemulsions and in situ reduction of Pd salts via a gas diffusion process of hydrazine. The formation of Pd nanoparticles (NPs) was verified by X-ray diffraction. The Janus morphology of the Pd/SiO2 NCPs was confirmed by microscopic observation. The Pd/SiO2 NCPs displayed a mesoporous structure. The content of Pd NPs in the NCPs could be conveniently adjusted by the K2PdCl4 loading. A formation mechanism of the Janus Pd/SiO2 NCPs was proposed. The mesoporous Janus Pd/SiO2 NCPs show good catalytic activity toward the reduction of p-nitrophenol with NaBH4.

Preparation of visible-light nano-photocatalysts through decoration of TiO2 by silver nanoparticles in inverse miniemulsions.

Ag/TiO2 nanocomposites were prepared through combination of a sol-gel process of a titanium precursor in inverse miniemulsions and in situ reduction of silver ions in the "nanoreactors". The morphological investigation shows that Ag nanoparticles are mainly located on the surface of TiO2 nano-supports because of the fast reduction rate of Ag ions by hydrazine. Ag/TiO2 nanocomposites with amorphous or anatase TiO2 phase displayed high visible-light catalytic activity for degradation of Rhodamine B. The photoactivity of Ag/anatase TiO2 nanocomposites could be influenced by the Ag content that could be conveniently tuned by the loading of silver salts. The influence of the loading of silver salts on the particle properties of the Ag/TiO2 nanocomposites was investigated systematically.