Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships.

Synapses are fundamental units of communication in the brain. The prototypical synapse-organizing complex neurexin-neuroligin mediates synapse development and function and is central to a shared genetic risk pathway in autism and schizophrenia. Neurexin's role in synapse development is thought to be mediated purely by its protein domains, but we reveal a requirement for a rare glycan modification. Mice lacking heparan sulfate (HS) on neurexin-1 show reduced survival, as well as structural and functional deficits at central synapses. HS directly binds postsynaptic partners neuroligins and LRRTMs, revealing a dual binding mode involving intrinsic glycan and protein domains for canonical synapse-organizing complexes. Neurexin HS chains also bind novel ligands, potentially expanding the neurexin interactome to hundreds of HS-binding proteins. Because HS structure is heterogeneous, our findings indicate an additional dimension to neurexin diversity, provide a molecular basis for fine-tuning synaptic function, and open therapeutic directions targeting glycan-binding motifs critical for brain development.

PLOD3 facilitated T cell activation in the colorectal tumor microenvironment and liver metastasis by the TNF-α/ NF-κB pathway.

BACKGROUND: Colorectal cancer (CRC) has been the third most prevalent cancer worldwide. Liver metastasis is the critical factor for the poor prognosis of CRC. Here, we investigated the expression and role of PLOD3 in CRC. METHODS: Different liver metastasis models were established by injecting PLOD3 stable knockdown or overexpression CT26 or MC38 mouse CRC cells into the spleen of mice to verify the tumorigenicity and metastasis ability in vivo. RESULTS: We identified PLOD3 is significantly overexpressed in liver metastasis samples of CRC. High expression of PLOD3 was significantly associated with poor survival of CRC patients. The knockdown of PLOD3 exhibited remarkable inhibition of proliferation, migration, and invasion in CRC cells, while the opposite results could be found in different PLOD3-overexpressed CRC cells. Stable knockdown of PLOD3 also significantly inhibited liver metastasis of CRC cells in different xenografts models, while stable overexpression of PLOD3 promotes liver metastasis and tumor progression. Further studies showed that PLOD3 facilitated the T cell activation in the tumor microenvironment and affected the TNF-α/ NF-κB pathway. CONCLUSIONS: This study revealed the essential biological functions of PLOD3 in colon cancer progression and metastasis, suggesting that PLOD3 is a promising translational medicine target and bioengineering targeting PLOD3 overcomes CRC liver metastasis.

Acid-Responsive Polymer Micelles for Targeted Delivery and Bioorthogonal Activation of Prodrug through Ru Catalyst in Tumor Cells.

Bioorthogonal reactions present a promising strategy for minimizing off-target toxicity in cancer chemotherapy, yet a dependable nanoplatform is urgently required. Here, we have fabricated an acid-responsive polymer micelle for the specific delivery and activation of the prodrug within tumor cells through Ru catalyst-mediated bioorthogonal reactions. The decomposition of micelles, triggered by the cleavage of the hydrazone bond in the acidic lysosomal environment, facilitated the concurrent release of Alloc-DOX and the Ru catalyst within the cells. Subsequently, the uncaging process of Alloc-DOX was demonstrated to be induced by the high levels of glutathione within tumor cells. Notably, the limited glutathione inside normal cells prevented the conversion of Alloc-DOX into active DOX, thereby minimizing the toxicity toward normal cells. In tumor-bearing mice, this nanoplatform exhibited enhanced efficacy in tumor suppression while minimizing off-target toxicity. Our study provides an innovative approach for in situ drug activation that combines safety and effectiveness in cancer chemotherapy.

Effect of abdominal weight training with and without cough machine assistance on lung function in the patients with prolonged mechanical ventilation: a randomized trial.

PURPOSE: The patients with prolonged mechanical ventilation (PMV) have the risk of ineffective coughing and infection due to diaphragm weakness. This study aimed to explore the effect of abdominal weight training (AWT) intervention with/without cough machine (CM) assistance on lung function, respiratory muscle strength and cough ability in these patients. METHODS: Forty patients with PMV were randomly assigned to three groups: AWT group (n = 12), AWT + CM group (n = 14) and control group (n = 14). Change of maximum inspiratory pressure (MIP), Maximum expiratory pressure (MEP) and peak cough flow (PCF) between 1 day before and 2 weeks after the intervention were compared among these three groups. RESULTS: MIP before and after intervention in AWT group (30.50 ± 11.73 vs. 36.00 ± 10.79; p < 0.05) and AWT + CM group (29.8 ± 12.14 vs. 36.14 ± 10.42; p < 0.05) compared with control group (28.43 ± 9.74 vs 26.71 ± 10.77; p > 0.05) was significantly improved. MEP before and after intervention in AWT group (30.58 ± 15.19 vs. 41.50 ± 18.33; p < 0.05) and AWT + CM group (27.29 ± 12.76 vs 42.43 ± 16.96; p < 0.05) compared with control group (28.86 ± 10.25 vs. 29.57 ± 14.21; p > 0.05) was significantly improved. PCF before and after intervention in AWT group in AWT group (105.83 ± 16.21 vs. 114.17 ± 15.20; p < 0.05) and AWT + CM group (108.57 ± 18.85 vs. 131.79 ± 38.96; p < 0.05) compared to control group (108.57 ± 19.96 vs. 109.86 ± 17.44; p > 0.05) showed significant improvements. AWT + CM group had significantly greater improvements than control group in MIP and peak cough flow than control group (13.71 ± 11.28 vs 19.64 ± 29.90, p < 0.05). CONCLUSION: AWT can significantly improve lung function, respiratory muscle strength, and cough ability in the PMV patients. AWT + CM can further improve their expiratory muscle strength and cough ability. Trial registration ClinicalTrials.gov registry (registration number: NCT0529538 retrospectively registered on March 3, 2022).

Creating a Scoring System with an Armband Wearable Device for Table Tennis Forehand Loop Training: Combined Use of the Principal Component Analysis and Artificial Neural Network.

BACKGROUND: This study presents an intelligent table tennis e-training system based on a neural network (NN) model that recognizes data from sensors built into an armband device, with the component values (performances scores) estimated through principal component analysis (PCA). METHODS: Six expert male table tennis players on the National Youth Team (mean age 17.8 ± 1.2 years) and seven novice male players (mean age 20.5 ± 1.5 years) with less than 1 year of experience were recruited into the study. Three-axis peak forearm angular velocity, acceleration, and eight-channel integrated electromyographic data were used to classify both player level and stroke phase. Data were preprocessed through PCA extraction from forehand loop signals. The model was trained using 160 datasets from five experts and five novices and validated using 48 new datasets from one expert and two novices. RESULTS: The overall model's recognition accuracy was 89.84%, and its prediction accuracies for testing and new data were 93.75% and 85.42%, respectively. Principal components corresponding to the skills "explosive force of the forearm" and "wrist muscle control" were extracted, and their factor scores were standardized (0-100) to score the skills of the players. Assessment results indicated that expert scores generally fell between 60 and 100, whereas novice scores were less than 70. CONCLUSION: The developed system can provide useful information to quantify expert-novice differences in fore-hand loop skills.

Effects of Taping on Achilles Tendon Protection and Kendo Performance.

CONTEXT: It has been reported that there is a high rate of Achilles tendon injury among kendo athletes. For protection and to support the area, kendo athletes habitually use taping during practice or games. OBJECTIVE: To investigate the effect of various taping techniques on injury prevention and functional performance in kendo athletes. DESIGN: Case-control study. SETTING: Laboratory. PARTICIPANTS: 15 University Kendo Team athletes with at least 2 y kendo experience. MAIN OUTCOME MEASURES: Athletes completed 5 stepping backwards and striking cycles under 4 taping conditions: no taping, athletic taping of ankle joint (AT-Ankle), athletic taping of Achilles tendon (AT-Achilles), and Kinesio-Tex taping of Achilles tendon (KT-Achilles). Jump distance, lower limb angular motion, left foot-ground contact time, Achilles tendon force (ATF), and soleus and medial gastrocnemius muscle activities were measured. RESULTS: Lowest peak ATF was found in AT-Achilles during heel-down phase, with statistically significant difference from KT-Achilles peak force. Significant decline of soleus muscle electromyography amplitude was also found when compared to no taping during heel-down phase and other conditions during pushing phase. Conversely, KT-Achilles showed significant decrease in foot-ground contact time compared with no taping and greater ankle range of motion than in AT-Ankle. CONCLUSION: To protect the Achilles tendon, AT-Achilles taping is recommended since it tends to decrease ATF. Conversely, to enhance athlete performance, we recommend KT-Achilles taping to speed up kendo striking motion. However, the Achilles tendon must withstand greatest forces concurrently. This finding implies that AT-Achilles taping can protect the injured Achilles tendon and KT-Achilles taping can enhance performance on the kendo striking motion.

Block copolymer conjugated Au-coated Fe3O4 nanoparticles as vectors for enhancing colloidal stability and cellular uptake.

BACKGROUND: Polymer surface-modified inorganic nanoparticles (NPs) provide a multifunctional platform for assisting gene delivery. Rational structure design for enhancing colloidal stability and cellular uptake is an important strategy in the development of safe and highly efficient gene vectors. RESULTS: Heterogeneous Au-coated Fe3O4 (Fe3O4@Au) NPs capped by polyethylene glycol-b-poly1-(3-aminopropyl)-3-(2-methacryloyloxy propylimidazolium bromine) (PEG-b-PAMPImB-Fe3O4@Au) were prepared for DNA loading and magnetofection assays. The Au outer shell of the NPs is an effective platform for maintaining the superparamagnetism of Fe3O4 and for PEG-b-PAMPImB binding via Au-S covalent bonds. By forming an electrostatic complex with DNA at the inner PAMPImB shell, the magnetic nanoplexes offer steric protection from the outer corona PEG, thereby promoting high colloidal stability. Transfection efficiency assays in human esophageal cancer cells (EC109) show that the nanoplexes have high transfection efficiency at a short incubation time in the presence of an external magnetic field, due to increased cellular internalization via magnetic acceleration. Finally, after transfection with the magnetic nanoplexes EC109 cells acquire magnetic properties, thus allowing for selective separation of transfected cells. CONCLUSION: Precisely engineered architectures based on neutral-cationic block copolymer-conjugated heterogeneous NPs provide a valuable strategy for improving the applicability and efficacy of synthesized vectors.

Acute Effects of Foam Rolling, Static Stretching, and Dynamic Stretching During Warm-ups on Muscular Flexibility and Strength in Young Adults.

CONTEXT: Foam rolling has been proposed to improve muscle function, performance, and joint range of motion (ROM). However, whether a foam rolling protocol can be adopted as a warm-up to improve flexibility and muscle strength is unclear. OBJECTIVES: To examine and compare the acute effects of foam rolling, static stretching, and dynamic stretching used as part of a warm-up on flexibility and muscle strength of knee flexion and extension. DESIGN: Crossover study. SETTING: University research laboratory. PARTICIPANTS: 15 male and 15 female college students (age 21.43 ± 1.48 y, weight 65.13 ± 12.29 kg, height 166.90 ± 6.99 cm). MAIN OUTCOME MEASURES: Isokinetic peak torque was measured during knee extension and flexion at an angular velocity of 60°/second. Flexibility of the quadriceps was assessed by the modified Thomas test, while flexibility of the hamstrings was assessed using the sit-and-reach test. The 3 interventions were performed by all participants in random order on 3 days separated by 48-72 hours. RESULTS: The flexibility test scores improved significantly more after foam rolling as compared with static and dynamic stretching. With regard to muscle strength, only knee extension peak torque (pre vs. postintervention) improved significantly after the dynamic stretching and foam rolling, but not after static stretching. Knee flexion peak torque remained unchanged. CONCLUSIONS: Foam rolling is more effective than static and dynamic stretching in acutely increasing flexibility of the quadriceps and hamstrings without hampering muscle strength, and may be recommended as part of a warm-up in healthy young adults.

[Research progress on medicinal values of scorpion venom components].

For thousands of years, scorpions and their venoms have been applied in traditional medicine in China to treat a variety of difficult miscellaneous diseases. The venom is a complex mixture of bioactive molecules, such as peptides and proteins (e.g. neurotoxins). Among them, neurotoxins (named scorpion toxins) are the most important bioactive components. Up to now, more and more characterized venom components have been isolated from different scorpions, providing numerous candidate molecules for drug design and development. Many investigations have shown the potent effects of venom or its components against the nervous, immune, infection, cardiovascular and neoplastic diseases. Moreover, the scorpion toxins could be used as molecular backbone to develop new specific drugs based on their unique structures and functions. In this review, we focus on the medicinal values and the possible mechanisms of scorpion toxins with promising medicinal prospect against the relative diseases, providing the data basis for further development of relative drugs.

Naringin Improves Neuronal Insulin Signaling, Brain Mitochondrial Function, and Cognitive Function in High-Fat Diet-Induced Obese Mice.

The epidemic and experimental studies have confirmed that the obesity induced by high-fat diet not only caused neuronal insulin resistance, but also induced brain mitochondrial dysfunction as well as learning impairment in mice. Naringin has been reported to posses biological functions which are beneficial to human cognitions, but its protective effects on HFD-induced cognitive deficits and underlying mechanisms have not been well characterized. In the present study Male C57BL/6 J mice were fed either a control or high-fat diet for 20 weeks and then randomized into four groups treated with their respective diets including control diet, control diet + naringin, high-fat diet (HFD), and high-fat diet + naringin (HFDN). The behavioral performance was assessed by using novel object recognition test and Morris water maze test. Hippocampal mitochondrial parameters were analyzed. Then the protein levels of insulin signaling pathway and the AMP-activated protein kinase (AMPK) in the hippocampus were detected by Western blot method. Our results showed that oral administration of naringin significantly improved the learning and memory abilities as evidenced by increasing recognition index by 52.5% in the novel object recognition test and inducing a 1.05-fold increase in the crossing-target number in the probe test, and ameliorated mitochondrial dysfunction in mice caused by HFD consumption. Moreover, naringin significantly enhanced insulin signaling pathway as indicated by a 34.5% increase in the expression levels of IRS-1, a 47.8% decrease in the p-IRS-1, a 1.43-fold increase in the p-Akt, and a 1.89-fold increase in the p-GSK-3ß in the hippocampus of the HFDN mice versus HFD mice. Furthermore, the AMPK activity significantly increased in the naringin-treated (100 mg kg(-1) d(-1)) group. These findings suggest that an enhancement in insulin signaling and a decrease in mitochondrial dysfunction through the activation of AMPK may be one of the mechanisms that naringin improves cognitive functions in HFD-induced obese mice.

Cardiotrophin-1 (CT-1) improves high fat diet-induced cognitive deficits in mice.

Previous studies demonstrated that a high fat diet (HFD) results in a loss of working memory in mice correlated with neuroinflammatory changes as well as synaptodendritic abnormalities and brain insulin resistance. Cardiotrophin-1 (CT-1), a member of the gp130 cytokine family, has been shown to potentially play a critical role in obesity and the metabolic syndrome. Our recent studies have demonstrated that CT-1 attenuates cognitive impairment and glucose-uptake defects induced by amyloid-ß in mouse brain through inhibiting GSK-3ß activity. In this study, we evaluated the effect of CT-1 on cognitive impairment induced by brain insulin resistance in mice fed a HFD, and explored its potential mechanism. CT-1 (1 µg/day, intracerebroventricular injection) was given for 14 days to mice that were fed with either a HFD or normal diet for 18 weeks. After 20 weeks of treatment, our results showed that in the HFD group, CT-1 significantly improved learning and memory deficits and alleviated neuroinflammation demonstrated by decreasing brain levels of proinflammatory cytokine tumour necrosis factor-α and interleukin-1ß, and increasing brain levels of anti-inflammatory cytokine IL-10. CT-1 significantly reduced body weight gain, restored normal levels of blood glucose, fatty acids and cholesterol. Furthermore, CT-1 significantly enhanced insulin/IGF signaling pathway as indicated by increasing the expression levels of insulin receptor substrate 1 (IRS-1) and the phosphorylation of Akt/GSK-3ß, and reducing the phosphorylation of IRS-1 in the hippocampus compared to control. Moreover, CT-1 increased the level of the post-synaptic protein, PSD95, and drebrin, a dendritic spine-specific protein in the hippocampus. These results indicate a previously unrecognized potential of CT-1 in alleviating high-fat diet induced cognitive impairment.

The effect of six weeks of sling exercise training on trunk muscular strength and endurance for clients with low back pain.

[Purpose] The purpose of this study was to investigate the effects of 6 weeks sling exercise training for clients with low back pain on the levels of pain, disability, muscular strength and endurance. [Subjects and Methods] Twelve chronic LBP subjects participated in this study. Subjects were randomly divided into a control group and a training group. Subjects in the training group performed sling exercise training for six weeks, and participants in the control group did not perform any exercise. [Results] Pain, disability levels and muscular strength significantly improved in the training group, but not in the control group. The left multifidus showed a significant improvement in muscular endurance, measured as the slope of the median frequency after training. [Conclusion] Six weeks of sling exercise training was effective at reducing pain intensity, and improving the disability level and trunk muscular strength of subjects with low back pain.

Hesperidin alleviates cognitive impairment, mitochondrial dysfunction and oxidative stress in a mouse model of Alzheimer's disease.

The role of mitochondrial dysfunction and oxidative stress has been well-documented in Alzheimer's disease (AD). Bioflavonoids are being utilised as neuroprotectants in the treatment of various neurological disorders, including AD. Therefore, we conducted this current study in order to explore the effects of hesperidin (a flavanone glycoside) against amyloid-ß (Aß)-induced cognitive dysfunction, oxidative damage and mitochondrial dysfunction in mice. Three-month-old APPswe/PS1dE9 transgenic mice were randomly assigned to a vehicle group, two hesperidin (either 50 or 100 mg/kg per day) groups, or an Aricept (2.5 mg/kg per day) group. After 16 weeks of treatment, although there was no obvious change in Aß deposition in the hesperidin-treated (100 mg/kg per day) group, however, we found that the administration of hesperidin (100 mg/kg per day) resulted in the reduction of learning and memory deficits, improved locomotor activity, and the increase of anti-oxidative defense and mitochondrial complex I-IV enzymes activities. Furthermore, Glycogen synthase kinase-3ß (GSK-3ß) phosphorylation significantly increased in the hesperidin-treated (100 mg/kg per day) group. Taken together, these findings suggest that a reduction in mitochondrial dysfunction through the inhibition of GSK-3ß activity, coupled with an increase in anti-oxidative defense, may be one of the mechanisms by which hesperidin improves cognitive function in the APPswe/PS1dE9 transgenic mouse model of AD.

Effects of long-term treatment with quercetin on cognition and mitochondrial function in a mouse model of Alzheimer's disease.

Amyloid-ß (Aß)-induced mitochondrial dysfunction has been recognized as a prominent, early event in Alzheimer's disease (AD). Therefore, therapeutics targeted to improve mitochondrial function could be beneficial. Quercetin, a bioflavanoid, has been reported to have potent neuro-protective effects, but its preventive effects on Aß-induced mitochondrial dysfunction and cognitive impairment have not been well characterised. Three-month-old APPswe/PS1dE9 transgenic mice were randomly assigned to a vehicle group, two quercetin (either 20 or 40 mg kg(-1) day(-1)) groups, or an Aricept (2 mg kg(-1) day(-1)) group. After 16 weeks of treatment, we observed beneficial effects of quercetin (40 mg kg(-1) day(-1)), including lessening learning and memory deficits, reducing scattered senile plaques, and ameliorating mitochondrial dysfunction, as evidenced by restoration of mitochondrial membrane potential, reactive oxygen species and ATP levels in mitochondria isolated from the hippocampus compared to control. Furthermore, the AMP-activated protein kinase (AMPK) activity significantly increased in the quercetin-treated (40 mg kg(-1) day(-1)) group. These findings suggest that a reduction in plaque burden and mitochondrial dysfunction through the activation of AMPK may be one of the mechanisms by which quercetin improves cognitive functioning in the APPswe/PS1dE9 transgenic mouse model of AD.

Timeframe for return to driving for patients with minimally invasive knee arthroplasty is associated with knee performance on functional tests.

BACKGROUND: This study hopes to establish the timeframe for a safe return to driving under different speed conditions for patients after minimally invasive total knee arthroplasty and further explores how well various kinds of functional tests on knee performance can predict the patients' braking ability. METHODS: 14 patients with right knee osteoarthritis were included in the present study and instructed to perform three simulated driving tasks at preoperative, 2 weeks postoperative and 4 weeks postoperative. RESULTS: The results showed that the total braking time at 4 week postoperative has attained the preoperative level at the driving speed 50 and 70 km/hr but not at the driving speed 90 km/hr. It had significantly improving in knee reaction time and maximum isometric force at 4 weeks postoperative. Besides, there was a moderate to high correlation between the scores of the step counts and the total braking time. CONCLUSIONS: Summary, it is recommended that driving may be resumed 4 weeks after a right knee replacement but had to drive at low or moderate speed and the best predictor of safety driving is step counts.

Adaptive Patterns of Movement during Downward Reach and Pick-up Movements in Knee Osteoarthritis Patients with Mild Low Back Pain.

[Purpose] Patients with severe bilateral knee osteoarthritis (KOA) often suffer from low back pain (LBP). However, few studies have examined the relationship between LBP and KOA in downward reach and pick-up movements. [Subjects] Eight KOA patients with LBP (LBP group), 8 KOA patients without LBP (NLBP group), and 7 healthy participants (Control group), without osteoarthritis or low back pain, were recruited for this study. [Methods] All subjects were asked to pick up a bottle with one hand, placed at the diagonal on the opposite side of the body. A 3D motion analysis system was used to record trunk and lower limb movements. [Results] The knee flexion angle on the side ipsilateral to the bottle was significantly smaller in both KOA groups than in the controls in the downward reach and pick-up movements. KOA patients showed a significantly lower trunk flexion angle and greater pelvis anterior tilt angle than the controls. In addition, no significant differences were found between the LBP and NLBP group. [Conclusion] We suspect that severe knee pain due to OA determines the priority of movement in strategic planning for the execution of pick-up movements. The knee strategy was abandoned by our severe knee OA patients, even when they had mild LBP.

Efficient delivery of curcumin by functional solid lipid nanoparticles with promoting endosomal escape and liver targeting properties.

In the realm of intracellular drug delivery, overcoming the barrier of endosomal entrapment stands as a critical factor influencing the effectiveness of nanodrug delivery systems. This study focuses on the synthesis of an acid-sensitive fatty acid derivative called imidazole-stearic acid (IM-SA). Leveraging the proton sponge effect attributed to imidazole groups, IM-SA was anticipated to play a pivotal role in facilitating endosomal escape. Integrated into the lipid core of solid lipid nanoparticles (SLNs), IM-SA was paired with hyaluronic acid (HA) coating on the surface of SLNs loading with curcumin (CUR). The presence of IM-SA and HA endowed HA-IM-SLNs@CUR with dual functionalities, enabling the promotion of endosomal escape, and specifical targeting of liver cancer. HA-IM-SLNs@CUR exhibited a particle size of ∼228 nm, with impressive encapsulation efficiencies (EE) of 87.5 % ± 2.3 % for CUR. Drugs exhibit significant pH sensitive release behavior. Cellular experiments showed that HA-IM-SLN@CUR exhibits enhanced drug delivery capability. The incorporation of IM-SA significantly improved the endosomal escape of HA-IM-SLN@CUR, facilitating accelerated intracellular drug release and increasing intracellular drug concentration, exhibiting excellent growth inhibitory effects on HepG2 cells. Animal experiments revealed a 3.4-fold increase in CUR uptake at the tumor site with HA-IM-SLNs@CUR over the free CUR, demonstrating remarkable tumor homing potential with the tumor growth inhibition rate of 97.2 %. These findings indicated the significant promise of HA-IM-SLNs@CUR in the realm of cancer drug delivery.

Fabrication of antimicrobial cationic hydrogels driven by physically and chemically crosslinking for wound healing.

The wound therapy based on antibiotic delivery inevitably leads to the emergence of drug resistance. Hydrogel biomaterials with inherent antibacterial activities have emerged as promising candidates for addressing this issue. However, developing an inherently antibacterial hydrogel through simple and facile strategies to promote localized wound infection healing remains a challenge. In this study, we successfully constructed antimicrobial cationic hydrogels with self-healing and injectable properties through physically and chemically dual-crosslinked networks. The networks were formed by the copolymers poly[(di(ethylene glycol) methyl ether methacrylate)-co-(4-formylphenyl methacrylate)-co-(2-(methacryloyloxy)ethyl]trimethylammonium chloride solution)] (PDFM) and poly[(di(ethylene glycol) methyl ether methacrylate)-co-(2-aminoethyl methacrylate hydrochloride)-co-(2-(((6-(6-methyl-4[1H]pyrimidionylureido) hexyl)carbamoyl)oxy)ethyl methacrylate)] (PDAU). The hydrogel systems effectively facilitate the regeneration and healing of infected wounds through the contact bactericidal feature of quaternary ammonium cations. The presence of Schiff base bonds in the injectable hydrogels imparts remarkable pH responsiveness and self-healing properties. In vitro experiments verified their intrinsic antibacterial activities along with their favorable cytocompatibility and hemocompatibility in both in vitro and in vivo. In addition, the hydrogel significantly accelerated the healing of bacterially infected in a full-thickness skin wound. This facilely prepared dual-crosslinked hydrogel, without antibiotics loading, holds significant prospects for treating infected wounds.

Protective effects of hesperidin against amyloid-ß (Aß) induced neurotoxicity through the voltage dependent anion channel 1 (VDAC1)-mediated mitochondrial apoptotic pathway in PC12 cells.

Amyloid-ß (Aß) is known to exert cytotoxic effects by inducing mitochondrial dysfunction. Additionally, the mitochondrial voltage-dependent anion channel 1 (VDAC1), which is involved in the release of apoptotic proteins with possible relevance in Alzheimer's disease (AD) neuropathology, plays an important role in maintaining mitochondrial function and integrity. However, the application of therapeutic drugs, especially natural products in (AD) therapy via VDAC1-regulated mitochondrial apoptotic pathway has not aroused extensive attention. In the present study, we investigated neuroprotective effects of hesperidin, a bioactive flavonoid compound, on Aß25-35-induced neurotoxicity in PC12 cells and also examined the potential cellular signalling mechanism. Our results showed that treatment with hesperidin significantly inhibited Aß25-35-induced apoptosis by reversing Aß-induced mitochondrial dysfunction, including the mitochondrial permeability transition pore opening, intracellular free calcium increase and reactive oxygen species production. Further study indicated that hesperidin can decrease the level ofVDAC1 phosphorylation through inhibiting the activity of the glycogen synthase kinase-3b and increase the level of hexokinaseI in mitochondria, preventing release of cytochrome c from mitochondria [corrected]. Furthermore, hesperidin inhibited mitochondria-dependent downstream caspase-mediated apoptotic pathway, such as that involving caspase-9 and caspase-3. These results demonstrate that hesperidin can protect Aß-induced neurotoxicity via VDAC1-regulated mitochondrial apoptotic pathway, and they raise the possibility that hesperidin could be developed into a clinically valuable treatment for AD and other neuronal degenerative diseases associated with mitochondrial dysfunction.

Preparation of nano-sized multi-vesicular vesicles (MVVs) and its application in co-delivery of doxorubicin and curcumin.

Multi-vesicular vesicles (MVVs) offer structural advantages in terms of drug encapsulation and physiological stability. In this study, we address the challenge of preparing small-sized MVVs for drug delivery. The nano-sized MVVs (∼120 nm) loaded with doxorubicin (DOX) and curcumin (CUR) (DOX/CUR@MVVs) were successfully prepared using a glass bead combined with a thin film dispersion method. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis confirmed the independent non-homocentric vesicle structures of DOX/CUR@MVVs with homogeneous particle sizes. The experimental results showed high encapsulation rates of DOX and CUR in DOX/CUR@MVVs, reaching 82.5 ± 0.75 % and 85.9 ± 0.69 %, respectively. Moreover, the MVVs exhibited good biosafety and sustained release properties. Notably, the bioavailability of DOX and CUR in DOX/CUR@MVVs was enhanced compared to free DOX and CUR, with increases of 4.2 and 2.1 times, respectively. And the half-life of DOX and CUR was extended by 10 times in DOX/CUR@MVVs. In vivo antitumor experiments demonstrated that nano-sized DOX/CUR@MVVs significantly improved the antitumor activity while reducing the toxic side effects of DOX. Overall, the successful preparation of nano-sized DOX/CUR@MVVs and their potent and low-toxic antitumor effects provide a critical experimental reference for the combined antitumor therapy of MVVs and liposomes.