Direct 3D printing of triple-responsive nanocomposite hydrogel microneedles for controllable drug delivery.

Hydrogel microneedle patches have emerged as promising platforms for painless, minimally invasive, safe, and portable transdermal drug administration. However, the conventional mold-based fabrication processes and inherent single-functionality of such microneedles present significant hurdles to broader implementation. Herein, we have developed a novel approach utilizing a precursor solution of robust nanocomposite hydrogels to formulate photo-printable inks suitable for the direct 3D printing of high-precision, triple-responsive hydrogel microneedle patches through digital light processing (DLP) technology. The ink formulation comprises four functionally diverse monomers including 2-(dimethylamino)ethyl methacrylate, N-isopropylacrylamide, acrylic acid, and acrylamide, which were crosslinked by aluminum hydroxide nanoparticles (AH NPs) acting as both reinforcing agents and crosslinking centers. This results in the formation of a nanocomposite hydrogel characterized by exceptional mechanical strength, an essential attribute for the 3D printing of hydrogel microneeedle patches. Furthermore, this innovative 3D printing strategy facilitates facile customization of microneedle geometry and patch dimensions. As a proof-of-concept, we employed the fabricated hydrogel microneedles for transdermal delivery of bovine serum albumin (BSA). Importantly, these hydrogel microneedles displayed no cytotoxic effects and exhibited triple sensitivity to pH, temperature and glucose levels, thereby enabling more precise on-demand drug delivery. This study provides a universal method for the rapid fabrication of hydrogel microneedles with smart responsiveness for transdermal drug delivery applications.

The Role of JAK/STAT Signaling Pathway and Its Downstream Influencing Factors in the Treatment of Atherosclerosis.

Atherosclerosis is now widely considered to be a chronic inflammatory disease, with increasing evidence suggesting that lipid alone is not the main factor contributing to its development. Rather, atherosclerotic plaques contain a significant amount of inflammatory cells, characterized by the accumulation of monocytes and lymphocytes on the vessel wall. This suggests that inflammation may play a crucial role in the occurrence and progression of atherosclerosis. As research deepens, other pathological factors have also been found to influence the development of the disease. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a recently discovered target of inflammation that has gained attention in recent years. Numerous studies have provided evidence for the causal role of this pathway in atherosclerosis, and its downstream signaling factors play a significant role in this process. This brief review aims to explore the crucial role of the JAK/STAT pathway and its representative downstream signaling factors in the development of atherosclerosis. It provides a new theoretical basis for clinically affecting the development of atherosclerosis by interfering with the JAK/STAT signaling pathway.

Multi-material 3D printed eutectogel microneedle patches integrated with fast customization and tunable drug delivery.

Microneedle patches are emerging multifunctional platforms for transdermal diagnostics and drug delivery. However, it still remains challenging to develop smart microneedles integrated with customization, sensing, detection and drug delivery by 3D printing strategy. Here, we present an innovative but facile strategy to rationally design and fabricate multifunctional eutectogel microneedle (EMN) patches via multi-material 3D printing. Polymerizable deep eutectic solvents (PDES) were selected as printing inks for rapid one-step fabrication of 3D printing functional EMN patches due to fast photopolymerization rate and ultrahigh drug solubility. Moreover, stretchable EMN patches incorporating rigid needles and flexible backing layers were easily realized by changing PDES compositions of multi-material 3D printing. Meanwhile, we developed multifunctional smart multi-material EMN patches capable of performing wireless monitoring of body movements, painless colorimetric glucose detection, and controlled transdermal drug delivery. Thus, such multi-material EMN system could provide an effective platform for the painless diagnosis, detection, and therapy of a variety of diseases.

Biological Role and Related Natural Products of SIRT1 in Nonalcoholic Fatty Liver.

Non-alcoholic fatty liver disease(NAFLD) is an umbrella term for a range of diseases ranging from hepatic fat accumulation and steatosis to non-alcoholic steatohepatitis (NASH) in the absence of excessive alcohol consumption and other definite liver damage factors. The incidence of NAFLD has increased significantly in recent years and will continue to grow in the coming decades. NAFLD has become a huge health problem and economic burden. SIRT1 is a member of Sirtuins, a group of highly conserved histone deacetylases regulated by NAD+, and plays a vital role in regulating cholesterol and lipid metabolism, improving oxidative stress, inflammation, and insulin resistance through deacetylating some downstream transcription factors and thus improving NAFLD. Although there are no currently approved drugs for treating NAFLD and some unresolved limitations in developing SIRT1 activators, SIRT1 holds promise as a proper therapeutic target for NAFLD and other metabolic diseases. In recent years, natural products have played an increasingly important role in drug development due to their safety and efficacy. It has been discovered that some natural products may be able to prevent and treat NAFLD by targeting SIRT1 and its related pathways. This paper reviews the mechanism of SIRT1 in the improvement of NALFD and the natural products that regulate NAFLD through SIRT1 and its associated pathways, and discusses the potential of SIRT1 as a therapeutic target for treating NAFLD and the effectiveness of these related natural products as clinical drugs or dietary supplements. These works may provide some new ideas and directions for finding new therapeutic targets for NAFLD and the development of anti-NAFLD drugs with good pharmacodynamic properties.

[Diosgenin alleviates NAFLD induced by a high-fat diet in rats via mTOR/SREBP-1c/HSP60/MCAD/SCAD signaling pathway].

This study aims to observe the effects of diosgenin on the expression of mammalian target of rapamycin(mTOR), sterol regulatory element-binding protein-1c(SREBP-1c), heat shock protein 60(HSP60), medium-chain acyl-CoA dehydrogenase(MCAD), and short-chain acyl-CoA dehydrogenase(SCAD) in the liver tissue of the rat model of non-alcoholic fatty liver disease(NAFLD) and explore the mechanism of diosgenin in alleviating NAFLD. Forty male SD rats were randomized into five groups: a control group, a model group, low-(150 mg·kg~(-1)·d~(-1)) and high-dose(300 mg·kg~(-1)·d~(-1)) diosgenin groups, and a simvastatin(4 mg·kg~(-1)·d~(-1)) group. The rats in the control group were fed with a normal diet, while those in the other four groups were fed with a high-fat diet. After feeding for 8 weeks, the body weight of rats in the high-fat diet groups increased significantly. After that, the rats were administrated with the corresponding dose of diosgenin or simvastatin by gavage every day for 8 weeks. The levels of triglyceride(TG), total cholesterol(TC), alanine transaminase(ALT), and aspartate transaminase(AST) in the serum were determined by the biochemical method. The levels of TG and TC in the liver were measured by the enzyme method. Oil-red O staining was employed to detect the lipid accumulation, and hematoxylin-eosin(HE) staining to detect the pathological changes in the liver tissue. The mRNA and protein levels of mTOR, SREBP-1c, HSP60, MCAD, and SCAD in the liver tissue of rats were determined by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR) and Western blot, respectively. Compared with the control group, the model group showed increased body weight, food uptake, liver index, TG, TC, ALT, and AST levels in the serum, TG and TC levels in the liver, lipid deposition in the liver, obvious hepatic steatosis, up-regulated mRNA and protein expression levels of mTOR and SREBP-1c, and down-regulated mRNA and protein expression levels of HSP60, MCAD, and SCAD. Compared with the model group, the rats in each treatment group showed obviously decreased body weight, food uptake, liver index, TG, TC, ALT, and AST levels in the serum, TG and TC levels in the liver, lessened lipid deposition in the liver, ameliorated hepatic steatosis, down-regulated mRNA and protein le-vels of mTOR and SREBP-1c, and up-regulated mRNA and protein levels of HSP60, MCAD, and SCAD. The high-dose diosgenin outperformed the low-dose diosgenin and simvastatin. Diosgenin may prevent and treat NAFLD by inhibiting the expression of mTOR and SREBP-1c and promoting the expression of HSP60, MCAD, and SCAD to reduce lipid synthesis, improving mitochondrial function, and promoting fatty acid ß oxidation in the liver.

Transparent, Mechanically Robust, Adhesive, Temperature-Tolerant, and 3D Printable Nanocomposite Ionogels for Flexible Sensors.

Ionogels are emerging as soft materials for flexible strain sensors. However, the integration of multiple functionalities into a single ionogel for diverse applications in complex scenarios remains a challenge. In this study, we present a multifunctional nanocomposite ionogel that combines high strength, transparency, stretchability, temperature tolerance, adhesiveness, and 3D printing capabilities. The ionogels are fabricated through a one-step photopolymerization process involving acrylic acid and 2-acrylamide-2-methylpropanesulfonic acid in an ionic liquid, with Al(OH)3 nanoparticles serving as cross-linkers. The resulting ionogels exhibit robust noncovalent interactions, including ionic coordination, hydrogen bonding, and ionic dipole interactions, providing exceptional mechanical strength, conductivity, and wide temperature tolerance while ensuring strong adhesion to various substrates. Wearable strain sensors based on these ionogels can accurately detect and differentiate a range of movements, from large body motions such as bending limbs to subtle distinctions such as writing different letters. Additionally, the pregel solution can serve as printing ink for the rapid and efficient mass production of 3D printed high-precision microcircuits. Impressively, the nanocomposite ionogels exhibit a high latent heat value of 240 J g-1 at a melting temperature of -65 °C, suggesting significant potential for cold energy storage in ultralow-temperature cold-chain transportation systems. Thus, these outstanding features of the ionogels offer a promising strategy for advancing wearable electronics and cold energy storage systems.

Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and has no approved treatment. The hepatic farnesoid X receptor (FXR) is one of the most promising therapeutic targets for NAFLD. Diosgenin (DG), a natural compound extracted from Chinese herbal medicine, is very effective in preventing metabolic diseases. Our research aims to determine the effects and molecular mechanisms of DG on NAFLD in vivo and in vitro. The effect of DG on hepatic steatosis was evaluated in Sprague‒Dawley (SD) rats induced by a high-fat diet (HFD) and in HepG2 cells exposed to free fatty acids (FFAs, sodium oleate:sodium palmitate = 2:1). DG treatment efficiently managed hepatic lipid deposition in vivo and in vitro. Mechanistically, DG upregulated the expression of FXR and small heterodimer partner (SHP) and downregulated the expression of genes involved in hepatic de novo lipogenesis (DNL), including sterol regulatory element-binding protein 1C (SREBP1C), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FASN). Moreover, DG promoted the expression of peroxisome proliferator-activated receptor alpha (PPARα), which is related to fatty acid oxidation. In addition, DG inhibited the expression of the CD36 molecule (CD36) related to fatty acid uptake. However, hepatic FXR silencing weakened the regulatory effects of DG on these genes. Collectively, our data show that DG has a good effect on alleviating nonalcoholic hepatic steatosis via the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway. DG promises to be a novel candidate FXR activator that can be utilized to treat NAFLD.

Anatomical Imaging Study on Uneven Settlement of the Proximal Tibia.

OBJECTIVE: Uneven settlement of the proximal tibia significantly contributes to the onset and progression of medial compartment knee OA; however, the specific location and variations of proximal tibial deformity remain unclear. Therefore, this study aimed to explore the effects of the anatomic morphology of different tibial regions on proximal tibial vara and proximal tibial microstructural changes with age in both sexes to reveal the pattern of uneven settlement of the proximal tibia. METHODS: In this retrospective study, we reviewed the radiographs of 414 patients (789 legs) between May and September 2021. The medial proximal tibial angle (MPTA) and four anatomic angles of the tibia (i.e., the tibial plateau-epiphyseal line [PT-EL] angle, epiphyseal line-tibial platform [EL-PF] angle, epiphyseal axis inclination angle [EAIA], and subepiphyseal axis inclination angle [SAIA]) were measured. The effect of each angle on MPTA and their changes with age in both sexes were investigated using Pearson's correlation coefficient and multiple linear regression. RESULTS: In females, PT-EL angle, EL-PF angle, and SAIA negatively correlated with MPTA (r = -0.325, -0.246, and -0.502; p < 0.05), and EAIA positively correlated with MPTA (r = 0.099, p < 0.05). Regression analysis showed that the correlations between MPTA and PT-EL angle, EL-PF angle, and SAIA were significant (ß = -1.003, -0.013, and -0.971; adjusted R2  = 0.979). Furthermore, MPTA negatively correlated with age (r = -0.202, p < 0.05); PT-EL angle and EAIA positively correlated with age (r = 0.237 and 0.142, p < 0.05). Regression analysis showed that only the correlation between PT-EL angle and age was significant (ß = 5.635, p < 0.05). In males, PT-EL angle, EL-PF angle, and SAIA negatively correlated with MPTA (r = -0.270, -0.267, and -0.533; p < 0.05), and EAIA positively correlated with MPTA (r = 0.135, p < 0.05). Regression analysis showed that the correlations between MPTA and PT-EL angle, EL-PF angle, and SAIA were significant (ß = -0.992, -0.017, and -0.958; adjusted R2  = 0.970). However, there was no significant correlation between age and any of the measured angles (p > 0.05). CONCLUSIONS: Proximal tibial vara is affected by the anatomic morphology of the epiphyseal and subepiphyseal regions. In females, the uneven settlement of the epiphysis progresses with age and may be responsible for dynamic varus deformity of the proximal tibia.

Association between gastroesophageal reflux disease and stroke: a bidirectional Mendelian randomization study.

Objective: Some previous studies have suggested a potential link between stroke and gastroesophageal reflux disease (GERD). We used a two-sample bidirectional Mendelian randomization (MR) method to explore the causal relationship between stroke and GERD. Design: Summary-level data derived from the published genome-wide association studies (GWAS) were employed for analyses. Single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for stroke (n = 446,696) and its common subtypes ischemic stroke (IS) (n = 440,328), large vessel stroke (LVS) (n = 410,484), small vessel stroke (SVS) (n = 198,048), and cardioembolic stroke (CES) (n = 413,304) were obtained from the MEGASTROKE consortium. The data on intracerebral hemorrhage (ICH) (n = 721,135) come from the UK Biobank. Instrumental variables (IVs) for lacunar stroke (LS) (n = 474,348) and GERD (n = 602,604) were screened from publicly available genetic summary data. The inverse variance weighted (IVW) method was used as the main MR method. Pleiotropy was detected by the MR-Egger intercept test, MR pleiotropy residual sum and outlier, and leave-one-out analysis. Cochran Q statistics were used as supplements to detect pleiotropy. Results: We found that GERD can causally increase the risk of stroke [IVW odds ratio (OR): 1.22, 95% confidence interval (CI): 1.13-1.32, p = 1.16 × 10-6] and its common subtypes IS (OR: 1.19, 95% CI: 1.10-1.30, p = 3.22 × 10-5), LVS (OR: 1.49, 95% CI: 1.21-1.84, p = 1.47 × 10-4), and LS (OR: 1.20, 95% CI: 1.001-1.44, p = 0.048). Several important risk factors for stroke have also been implicated in the above causal relationship, including type 2 diabetes, sleep apnea syndrome, high body mass index, high waist-to-hip ratio, and elevated serum triglyceride levels. In reverse MR analysis, we found that overall stroke (OR: 1.09, 95% CI: 1.004-1.19, p = 0.039) and IS (OR: 1.10, 95% CI: 1.03-1.17, p = 0.007) have the causal potential to enhance GERD risk. Conclusion: This MR study provides evidence supporting a causal relationship between GERD and stroke and some of its common subtypes. We need to further explore the interconnected mechanisms between these two common diseases to better prevent and treat them.

A low-dose therapy of fibrinogen supplement during perioperative period of total knee arthroplasty in an asymptomatic man with congenital dysfibrinogenemia: A case report.

RATIONALE: Congenital dysfibrinogenemia (CD) is a rare coagulation system disease that is often treated without unified management. Individualized treatment thereof presents clinicians with great challenges. PATIENT CONCERNS: A patient who was about to undergo total knee arthroplasty was found to have CD. DIAGNOSES: Coagulation screening revealed low fibrinogen, prolonged thrombin time, minor prolonged prothrombin time, and normal activated partial thromboplastin time were detected during admission, but no abnormal personal and family history findings were observed. Therefore, CD and hypofibrinogenemia were suspected. The gene sequencing confirmed the diagnosis of CD. INTERVENTIONS: The patient received plenty and low level of fibrinogen concentrate during 2 perioperative periods, respectively. OUTCOMES: Successful clinical outcomes were obtained using different treatment strategies. LESSONS: In contrast to prior case reports, this case illustrates the feasibility of low dosing of fibrinogen supplements within an asymptomatic patient in a selective operation. Changes in the level of fibrinogen and fibrin degradation product are of great importance for individualized treatment after supplementation.

Bonding analysis of the donor-acceptor sandwiches CpE-MCp (E = B, Al, Ga; M = Li, Na, K; Cp = η5-C5H5).

The nature of E-M bonds in CpE-MCp (E = B, Al, Ga; M = Li, Na, K; Cp = η (5)-C5H5) donor-acceptor sandwiches was studied using the atoms in molecules (AIM) theory, electron localization function (ELF), energy decomposition analysis (EDA), and natural bond orbital analysis (NBO) methods. Both topological and orbital analysis show that the E atom determines the bond strength of the E-M bonds, while the M atom has little influence on it. E-M bond strength decreases in the order E = B, Al, and Ga. The EDA analysis shows that the electrostatic character decreases following the sequence E = B > Al > Ga. Not only the s orbital, but also the p orbital of the E/M atom participates in formation of the E-M bond. The interactions of E and M with Cp are different. The M-Cp interaction is purely electrostatic while the E-Cp interaction has a partly covalent character.

Enhancing effects of hydrogen/halogen bonds on σ-hole interactions involving ylide.

Cooperativity between the H/Cl···C bonds of XH/XCl···CH2PH3 and the P···N interaction of CH2PH3···NH3 in XH/XCl···CH2PH3···NH3 (X = F, N3, CN, CCCN, CCF) was investigated by performing second-order Møller-Plesset perturbation theory (MP2) calculations and quantum theory of atoms in molecules (QTAIM) studies. The formation of a hydrogen/halogen bond greatly extends the scope and increases the most positive electrostatic potential of the σ-hole on the outer surface of the phosphorus atom. This increases the P···N interaction energy, the electron density at the P···N bond critical point, the electrostatic character of the P···N interaction, and it decreases the P···N interaction distance. The net result is that the formation of a hydrogen/halogen bond enhances the P···N interaction, and vice versa. However, the P···N interaction is enhanced by the presence of the hydrogen or halogen bond to a much greater degree than the hydrogen or halogen bond is enhanced by the P···N interaction.

In vitro evaluation of 45S5 Bioglass®-derived glass-ceramic scaffolds coated with carbon nanotubes.

Highly porous (> 90% porosity) 45S5 Bioglass®-derived glass-ceramic scaffolds were fabricated by foam replication method, and coated with carbon nanotubes (CNT) (coating thickness: 1 µm) using electrophoretic deposition (EPD). In vitro cell culture using mesenchymal stem cells (MSCs) was carried out on both scaffold systems (with and without CNT coating) over a 4-week period. By using AlamarBlue™, BSA and alkaline phosphatase assays; the cell viability and differentiation were measured quantitatively measured and compared between the two scaffold types. The results showed that both scaffold systems are biocompatible with MSCs and they can support the cellular activity. No cytotoxic effects of CNT were observed under the conditions of the present experiments. Although a lower initial cell viability on the CNT-coated scaffolds was observed, no significant differences were found after 4 weeks of culture compared with the uncoated scaffolds. This work therefore shows that there is in principle no significant improvement of cellular responses by creating a CNT-coating on this type of highly bioactive scaffolds. However, the electrical conductivity introduced by the coating might have the potential to increase cell viability and differentiation when cell culture is carried out under the effect of electrical stimulation.

Controlled delivery of gentamicin using poly(3-hydroxybutyrate) microspheres.

Poly(3-hydroxybutyrate), P(3HB), produced from Bacillus cereus SPV using a simple glucose feeding strategy was used to fabricate P(3HB) microspheres using a solid-in-oil-water (s/o/w) technique. For this study, several parameters such as polymer concentration, surfactant and stirring rates were varied in order to determine their effect on microsphere characteristics. The average size of the microspheres was in the range of 2 µm to 1.54 µm with specific surface areas varying between 9.60 m(2)/g and 6.05 m(2)/g. Low stirring speed of 300 rpm produced slightly larger microspheres when compared to the smaller microspheres produced when the stirring velocity was increased to 800 rpm. The surface morphology of the microspheres after solvent evaporation appeared smooth when observed under SEM. Gentamicin was encapsulated within these P(3HB) microspheres and the release kinetics from the microspheres exhibiting the highest encapsulation efficiency, which was 48%, was investigated. The in vitro release of gentamicin was bimodal, an initial burst release was observed followed by a diffusion mediated sustained release. Biodegradable P(3HB) microspheres developed in this research has shown high potential to be used in various biomedical applications.

Multi-functional P(3HB) microsphere/45S5 Bioglass-based composite scaffolds for bone tissue engineering.

Novel multi-functional P(3HB) microsphere/45S5 Bioglass-based composite scaffolds exhibiting potential for drug delivery were developed for bone tissue engineering. 45S5 Bioglass-based glass-ceramic scaffolds of high interconnected porosity produced using the foam-replication technique were coated with biodegradable microspheres (size<2 microm) made from poly(3-hydroxybutyrate), P(3HB), produced using Bacillus cereus SPV. A solid-in-oil-in-water emulsion solvent extraction/evaporation technique was used to produce these P(3HB) microspheres. A simple slurry-dipping method, using a 1 wt.% suspension of P(3HB) microspheres in water, dispersed by an ultrasonic bath, was used to coat the scaffold, producing a uniform microsphere coating throughout the three-dimensional scaffold structure. Compressive strength tests confirmed that the microsphere coating slightly enhanced the scaffold mechanical strength. It was also confirmed that the microsphere coating did not inhibit the bioactivity of the scaffold when immersed in simulated body fluid (SBF) for up to 4 weeks. The hydroxyapatite (HA) growth rate on P(3HB) microsphere-coated 45S5 Bioglass composite scaffolds was very similar to that on the uncoated control sample, qualitatively indicating similar bioactivity. However, the surface topography of the HA surface layer was affected as shown by results obtained from white light interferometry. The roughness of the surface was much higher for the P(3HB) microsphere-coated scaffolds than for the uncoated samples, after 7 days in SBF. This feature would facilitate cell attachment and proliferation. Finally, gentamycin was successfully encapsulated into the P(3HB) microspheres to demonstrate the drug delivery capability of the scaffolds. Gentamycin release kinetics was determined using liquid chromatography-mass spectrometry. The release of the drug from the coated composite scaffolds was slow and controlled when compared to the observed fast and relatively uncontrolled drug release from the bone scaffold (without microsphere coating). Thus, this unique multifunctional bioactive composite scaffold has the potential to enhance cell attachment and to provide controlled delivery of relevant drugs for bone tissue engineering.

Bioglass-based scaffolds with carbon nanotube coating for bone tissue engineering.

Highly porous 45S5 Bioglass-based foam scaffolds were coated with multi-walled carbon nanotubes (CNT) by electrophoretic deposition (EPD) technique. By placing the scaffolds in between the two electrodes of the EPD cell, a CNT coating of up to 1 mum thickness was achieved on the surface throughout the whole three dimensional (3D) matrix. A 0.5 wt% CNT aqueous suspension was used and EPD was carried out at 2.8 V for 10 mins. The compression strength of this CNT/Bioglass composite was measured to be 0.70 MPa. Moreover the increased electrical conductivity of the composite with CNT coating was confirmed. The scaffolds have the potential for applications in bone tissue engineering due to the high bioactivity, nano-roughness in 3D and electrical conductivity provided by the addition of CNT.