Integration of Zn2+, ATP, and bFGF to Nanodressing with Core-Shell Structure Fabricated by Emulsion Electrospinning for Wound Healing.

Basic fibroblast growth factor (bFGF) plays an important role in active wound repair. However, the existing dosage forms in clinical applications are mainly sprays and freeze-dried powders, which are prone to inactivation and cannot achieve a controlled release. In this study, a bioactive wound dressing named bFGF-ATP-Zn/polycaprolactone (PCL) nanodressing with a "core-shell" structure was fabricated by emulsion electrospinning, enabling the sustained release of bFGF. Based on the coordination and electrostatic interactions among bFGF, ATP, and Zn2+, as well as their synergistic effect on promoting wound healing, a bFGF-ATP-Zn ternary combination system was prepared with higher cell proliferation activity and used as the water phase for emulsion electrospinning. The bFGF-ATP-Zn/PCL nanodressing demonstrated improved mechanical properties, sustained release of bFGF, cytocompatibility, and hemocompatibility. It increased the proliferation activity of human dermal fibroblasts (HDFs) and enhanced collagen secretion by 1.39 and 3.45 times, respectively, while reducing the hemolysis rate to 3.13%. The application of the bFGF-ATP-Zn/PCL nanodressing in mouse full-thickness skin defect repair showed its ability to accelerate wound healing and reduce wound scarring within 14 days. These results provide a research basis for the development and application of this bioactive wound dressing product.

Shape Memory Polyurethane Composite With Fast Response to Near-Infrared Light Based on Tannic Acid-Iron and Dynamic Phenol-Carbamate Network.

Intelligent materials derived from green and renewable bio-based materials garner widespread attention recently. Herein, shape memory polyurethane composite (PUTA/Fe) with fast response to near-infrared (NIR) light is successfully prepared by introducing Fe3+ into the tannic acid-based polyurethane (PUTA) matrix through coordination between Fe3+ and tannic acid. The results show that the excellent NIR light response ability is due to the even distribution of Fe3+ filler with good photo-thermal conversion ability. With the increase of Fe3+ content, the NIR light response shape recovery rate of PUTA/Fe composite films is significantly improved, and the shape recovery time is reduced from over 60 s to 40 s. In addition, the mechanical properties of PUTA/Fe composite film are also improved. Importantly, owing to the dynamic phenol-carbamate network within the polymer matrix, the PUTA/Fe composite film can reshape its permanent shape through topological rearrangement and show its good NIR light response shape memory performance. Therefore, PUTA/Fe composites with high content of bio-based material (TA content of 15.1-19.4%) demonstrate the shape memory characteristics of fast response to NIR light; so, it will have great potential in the application of new intelligent materials including efficient and environmentally friendly smart photothermal responder.

A real-world analysis of FDA Adverse Event Reporting System (FAERS) events for liposomal and conventional doxorubicins.

The clinical application of conventional doxorubicin (CDOX) was constrained by its side effects. Liposomal doxorubicin was developed to mitigate these limitations, showing improved toxicity profiles. However, the adverse events associated with liposomal doxorubicin and CDOX have not yet been comprehensively evaluated in clinical settings. The FAERS data from January 2004 to December 2022 were collected to analyze the adverse events of liposomal doxorubicin and CDOX. Disproportionate analysis and Bayesian analysis were employed to quantify this association. Our analysis incorporated 68,803 adverse event reports related to Doxil/Caelyx, Myocet and CDOX. The relative odds ratios (RORs, 95%CI) for febrile neutropenia associated with CDOX, Doxil/Caelyx, and Myocet were 42.45 (41.44; 43.48), 17.53 (16.02; 19.20), and 34.68 (26.63; 45.15) respectively. For cardiotoxicity, they were 38.87(36.41;41.49), 17.96 (14.10; 22.86), and 37.36 (19.34; 72.17). For Palmar-Plantar Erythrodysesthesia (PPE), the RORs were 6.16 (5.69; 6.68), 36.13 (32.60; 40.06), and 19.69 (11.59; 33.44). Regarding onset time, significant differences adverse events including neutropenia, PPE, pneumonia and malignant neoplasm progression. This study indicates that clinical monitoring for symptoms of cardiotoxicity of CDOX and Myocet, and PPE and interstitial lung disease of Doxil should be performed. Additionally, the onset time of febrile neutropenia, malignant neoplasm progression, and pneumonia associated with Doxil and Myocet merits particular attention. Continuous surveillance, risk evaluations, and additional comparative studies between liposomal doxorubicin and CDOX were recommended.

Perspective insights into versatile hydrogels for stroke: From molecular mechanisms to functional applications.

As the leading killer of life and health, stroke leads to limb paralysis, speech disorder, dysphagia, cognitive impairment, mental depression and other symptoms, which entail a significant financial burden to society and families. At present, physiology, clinical medicine, engineering, and materials science, advanced biomaterials standing on the foothold of these interdisciplinary disciplines provide new opportunities and possibilities for the cure of stroke. Among them, hydrogels have been endowed with more possibilities. It is well-known that hydrogels can be employed as potential biosensors, medication delivery vectors, and cell transporters or matrices in tissue engineering in tissue engineering, and outperform many traditional therapeutic drugs, surgery, and materials. Therefore, hydrogels become a popular scaffolding treatment option for stroke. Diverse synthetic hydrogels were designed according to different pathophysiological mechanisms from the recently reported literature will be thoroughly explored. The biological uses of several types of hydrogels will be highlighted, including pro-angiogenesis, pro-neurogenesis, anti-oxidation, anti-inflammation and anti-apoptosis. Finally, considerations and challenges of using hydrogels in the treatment of stroke are summarized.

Identification of Comprehensive Biomarkers in Patients With Mismatch Repair-Deficient Colon Adenocarcinoma Based on Parallel Multiomics.

Immunocheckpoint inhibitors have shown impressive efficacy in patients with colon cancer and other types of solid tumor that are mismatch repair-deficient (dMMR). Currently, PCR-capillary electrophoresis is one of the mainstream detection methods for dMMR, but its accuracy is still limited by germline mismatch repair (MMR) mutations, the functional redundancy of the MMR system, and abnormal methylation of MutL Homolog 1 promoter. Therefore, this study aimed to develop new biomarkers for dMMR based on artificial intelligence (AI) and pathologic images, which may help to improve the detection accuracy. To screen for the differential expression genes (DEGs) in dMMR patients and validate their diagnostic and prognostic efficiency, we used the expression profile data from the Cancer Genome Atlas (TCGA). The results showed that the expression of Immunoglobulin Lambda Joining 3 in dMMR patients was significantly downregulated and negatively correlated with the prognosis. Meanwhile, our diagnostic models based on pathologic image features showed good performance with area under the curves (AUCs) of 0.73, 0.86, and 0.81 in the training, test, and external validation sets (Jiangsu Traditional Chinese Medicine Hospital cohort). Based on gene expression and pathologic characteristics, we developed an effective prognosis model for dMMR patients through multiple Cox regression analysis (with AUC values of 0.88, 0.89, and 0.88 at 1-, 3-, and 5-year intervals, respectively). In conclusion, our results showed that Immunoglobulin Lambda Joining 3 and nucleus shape-related parameters (such as nuclear texture, nuclear eccentricity, nuclear size, and nuclear pixel intensity) were independent diagnostic and prognostic factors, suggesting that they could be used as new biomarkers for dMMR patients.

A novel, simple near-infrared thoracoscopic technique by a particular route for locating lung nodules.

Background: The localization of pulmonary nodules prior to thoracoscopic surgery remains challenging for thoracic surgeons, especially for those nodules that are not visible or palpable on the lung surface. Our study is a simple and effective minimally invasive method using indocyanine green through a special pathway to locate pulmonary nodules and fluorescence thoracoscopic surgery. Methods: Thoracoscopic surgery was performed for 18 undiagnosed peripheral non-solid nodules no larger than 2 cm after location. After 0.3 mg/kg indocyanine green was injected through the peripheral vein, the puncture needle was pulled out after it reached approximately 1 cm of the pulmonary parenchyma near the nodules. This was followed by transfer to the operating room. The nodule was initially localized by using a near-infrared thoracoscope to visualize indocyanine green fluorescence. Then, thoracoscopic resection was performed. Results: Eighteen patients received this special and simple localization method, and underwent near-infrared, image-guided, video-assisted thoracoscopic surgery resection. Median computed tomography (CT) tumor size was 1.2 cm. Median depth from the pleural surface is 1.6 cm (range, 0.1-4.6 cm). The median time of CT-guided intervention was 12 min. The duration of thoracoscopic surgery was 67 min. Indocyanine green fluorescence was clearly identified in 17 of 18 patients (94.4%). The surgical margins were all negative on final pathology. The final diagnoses included 17 primary lung cancers, and 1 benign lung tumor. Conclusions: CT-guided single puncture of indocyanine green after peripheral intravenous injection is a simple, effective, and safe method to locate the nodule. This offers surgeons the ease of localization through direct indocyanine green fluorescence imaging, and it can be used as an effective alternative to other placement methods of locating pulmonary nodules.

Severe cutaneous adverse reactions associated with immune checkpoint inhibitors therapy and anti-VEGF combination therapy: a real-world study of the FDA adverse event reporting system.

BACKGROUND: Immune checkpoint inhibitors (ICIs) therapy combined with anti-vascular endothelial growth factor (anti-VEGF) regimens showed new hope for cancer patients and considered as future pillar of cancer therapy. However, severe cutaneous adverse reactions (SCARs) in patients with ICIs and anti-VEGF combined therapy raise a serious concern and remain thoroughly assessed in clinics. RESEARCH DESIGN AND METHODS: Data retrieved from the first quarter of 2004 to the third quarter of 2022 in FAERS database underwent disproportionality analysis and Bayesian analysis were utilized to detect and assess the SCAR signals of ICIs and ICIs and anti-VEGF combined therapy for comparison. RESULTS: In total, 854 (1.10%) and 80 (1.06%) reports on SCARs associated with ICIs and a combination of ICIs and anti-VEGF therapy, respectively, were analyzed. Most of SCARs reports were associated with the use of pembrolizumab (36.01%), nivolumab (23.97%) and a combination of ipilimumab and nivolumab (19.71%). A use of atezolizumab and bevacizumab combined therapy (60.00%) caused the most SCARs records out of ICIs and anti-VEGF combined therapies. CONCLUSIONS: Treatment with joint therapy of ICIs and anti-VEGF agents may cause severe cutaneous adverse events. It is vital to identify ICI-related SCARs early, and to manage them appropriately.

Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway.

Non-small-cell lung cancer (NSCLC) is a dominating type of lung cancer with high morbidity and mortality. Midazolam has been reported to promote cell apoptosis in NSCLC, but the molecular mechanism of midazolam remains to be further explored. In the current work, cell viability, proliferation, migration, and apoptosis rates of NSCLC cells treated with midazolam were measured using cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) and colony formation assays, transwell, and flow cytometry assay, respectively, to evaluate the malignant behaviors. Western blot was applied to access EGFR/MEK/ERK pathway-related protein levels. The results demonstrated midazolam significantly declined the viability of NSCLC cells. Furthermore, midazolam restrained cell proliferation and migration and contributed to cell apoptosis in NSCLC. Midazolam exerted suppressive function to EGFR pathway during NSCLC development. Moreover, the activation of EGFR/MEK/ERK pathway abrogated the effects of midazolam on NSCLC cell proliferation, apoptosis, and migration. Taken together, midazolam exhibited anti-tumor effects hallmarked by EGFR pathway inhibition, providing a novel insight into the treatment of NSCLC.

Research on Mechanisms of Chinese Medicines in Prevention and Treatment of Postoperative Adhesion.

Postoperative adhesion (PA) is currently one of the most unpleasant complications following surgical procedures. Researchers have developed several new strategies to alleviate the formation of PA to a great extent, but so far, no single measure or treatment can meet the expectations and requirements of clinical patients needing complete PA prevention. Chinese medicine (CM) has been widely used for thousands of years based on its remarkable efficacy and indispensable advantages CM treatments are gradually being accepted by modern medicine. Therefore, this review summarizes the formating process of PA and the efficacy and action mechanism of CM treatments, including their pharmacological effects, therapeutic mechanisms and advantages in PA prevention. We aim to improve the understanding of clinicians and researchers on CM prevention in the development of PA and promote the in-depth development and industrialization process of related drugs.

Thermal-triggered loading and GSH-responsive releasing property of HBc particles for drug delivery.

Hepatitis B core protein virus-like particles (HBc VLPs) have attracted wide attentions using as drug delivery vehicles, due to its excellent stability and easy in large scale production. Here in the present work, we report unique thermal-triggered loading and glutathione-responsive releasing property of the HBc particles for anticancer drug delivery. Through reversible temperature-dependent hole gating of the HBc particle capsid, about 4248 doxorubicin (DOX) were successfully encapsulated inside nanocage of a single nanoparticle at high HBc recovery of 83.2%, by simply incubating the DOX with HBc at 70 °C for 90 min. The new strategy was significantly superior to the disassembly-reassembly methods, which can only yield 3556 DOX loading at 52.3% HBc recovery. The thermal-sensitive drug entry channel in HBc was analyzed by molecular dynamic simulations, and the G113, G117 and R127 were identified as the key amino acid residues that are not conducive to the entrance of DOX but sensitive to temperature. Especially, the ΔGbind of R127 become even higher at high temperature, mutation of the R127 would be the first choice to make the drug entry thermodynamically easier. Due to plenty of disulfide bonds linking the HBc subunits, the HBc particles loaded with DOX exhibited intrinsic glutathione (GSH) responsivity for efficient controlled release in tumor sites. To further increase the tumor-targeting effect of the drug, Cyclo(Arg-Gly-Asp-d-Tyr-Lys) peptide was conjugated to the surface of HBc through a PEG linker. The prepared HBc-based anticancer drug showed significantly improved stability, tumor specificity, and in vivo anticancer activity on MCF7-bearing Balb/c-nu mice. Overall, our work demonstrated that the HBc VLPs can be an ideal drug carrier to fulfill requirement of the intelligent loading and "on demand" release of the therapeutic agents for efficient cancer therapy with minimal adverse effects.

Immune-related thyroid dysfunction is associated with improved long-term prognosis in patients with non-small cell lung cancer treated with immunotherapy: a systematic review and meta-analysis.

Background: Immunotherapy has changed the treatment landscape of lung cancer (LC), but its prognosis is still poor. Whether immunorelated thyroid dysfunction associated with the prognosis of LC patients remains controversial. We aimed to summarize the scientific evidence on whether thyroid dysfunction associated with immunotherapy for LC has a beneficial outcome on the survival of LC patients. Methods: We searched the databases of MEDLINE and Embase for articles published until 31 December 2021 that quantified the impact on non-small cell lung cancer (NSCLC) patients' survival of immune-related thyroid dysfunction. Study-specific data were pooled into hazard ratio (HR) and corresponding 95% confidence intervals (CIs) using random effect models of meta-analysis. Meta-analysis was used to evaluate the relationship between immune-associated thyroid dysfunction and prognosis. Results: A total of 11 articles published between 2015 and 2021 were included, which encompassed a total of over 1,962 NSCLC patients. The studies differed in terms of design, patient characteristics, treatment received, rate/time to immunotherapy-related thyroid dysfunction, and duration of follow-up. But after immunotherapy, we extract survival data. Patients with immunotherapy-associated thyroid dysfunction had better progression-free survival (PFS) (HR 0.54, 95% CI: 0.44-0.64) and overall survival (OS) rate (HR 0.34, 95% CI: 0.25-0.44). Conclusions: Thyroid dysfunction associated with immunotherapy is common and associated with a good prognosis. It can be used as a biological indicator of good prognosis of immunotherapy.

Isokinetic kneel muscle strength characteristics in high jump athletes / Características da força muscular isocinética na articulação do joelho em atletas de salto em altura / Características de la fuerza muscular isocinética en la articulación de la rodilla en atletas de salto de altura

ABSTRACT Introduction: Vertical jump is inherent to the practice of high jump and demands great capacity of force generation and work of the knee muscles, especially the quadriceps muscle. Due to this demand, imbalances between the extensor and flexor knee muscles may be present, leading to an overload of the musculotendinous structures of the knee joint. Therefore, it is necessary to establish the characteristics of isokinetic muscle strength in the knee joint of these athletes. Objective: This study aimed to analyze the biomechanical properties of the knee flexor and extensor muscles in high jump athletes. Methods: Ten high jumpers volunteered for the experiment. They were divided into experimental and control groups. Both groups performed basic strength training. The experimental group added isokinetic knee muscle training based on this training. Statistical analyses were performed on the training data of the two groups of athletes using relevant mathematical statistics. Results: The high jump consists of four phases being respectively the approach run, the jump itself (impulsion, elevation, transposition), and the fall. The strength of the ankle joint dorsiflexion and plantar flexors was significantly increased in the experimental group of athletes. In contrast, the strength of the plantar flexors in the control group was significantly increased. Statistical differences were found between the two groups (P<0.05). Conclusion: The isokinetic knee joint strength training mode can improve the leg support strength of jumpers. This paper suggests that high jump athletes can further adopt this lower limb strength training method. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: O salto vertical é inerente à prática do salto em altura e demanda grande capacidade de geração de força e trabalho da muscular do joelho, principalmente do músculo quadríceps. Devido a esta demanda, desequilíbrios entre os músculos extensores e flexores podem estar presentes, levando à sobrecarga das estruturas musculotendíneas da articulação do joelho. Sendo assim, torna-se necessário o estabelecimento das características da força muscular isocinética na articulação do joelho desses atletas. Objetivo: Este estudo teve como objetivo analisar as propriedades biomecânicas dos músculos flexores e extensores do joelho nos atletas de salto em altura. Métodos: Dez saltadores voluntariaram-se para o experimento. Eles foram divididos em grupos experimentais e grupos de controle. Ambos os grupos realizaram o treinamento básico de força. O grupo experimental adicionou treinamento muscular isocinético do joelho baseado neste treinamento. Foram realizadas análises estatísticas sobre os dados de treinamento dos dois grupos de atletas, utilizando estatísticas matemáticas pertinentes. Resultados: O salto em altura consiste de quatro fases, sendo respectivamente a corrida de aproximação, o salto em si (impulsão, elevação, transposição) e a queda. A força da dorsiflexão da articulação do tornozelo e dos flexores plantares foi significativamente aumentada no grupo experimental de atletas. Em contraste, somente a força dos flexores plantares no grupo de controle foi significativamente aumentada. Foram encontradas diferenças estatísticas entre os dois grupos (P<0,05). Conclusão: O modo de treinamento de força isocinética da articulação do joelho pode melhorar a força de apoio nas pernas dos saltadores. Este artigo sugere que os atletas de salto em altura podem adotar mais este método para o treinamento de força para membros inferiores. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: El salto vertical es inherente a la práctica del salto de altura y exige una gran capacidad de generación de fuerza y trabajo de los músculos de la rodilla, principalmente del cuádriceps. Debido a esta demanda, puede haber desequilibrios entre los músculos extensores y flexores, lo que lleva a la sobrecarga de las estructuras musculotendinosas de la articulación de la rodilla. Por lo tanto, es necesario establecer las características de la fuerza muscular isocinética en la articulación de la rodilla de estos atletas. Objetivo: El propósito de este estudio fue analizar las propiedades biomecánicas de los músculos flexores y extensores de la rodilla en atletas de salto de altura. Métodos: Diez saltadores de altura se ofrecieron como voluntarios para el experimento. Se dividieron en grupos experimentales y de control. Ambos grupos realizaron un entrenamiento de fuerza básico. El grupo experimental añadió un entrenamiento muscular isocinético de la rodilla basado en este entrenamiento. Se realizaron análisis estadísticos de los datos de entrenamiento de los dos grupos de atletas utilizando las estadísticas matemáticas pertinentes. Resultados: El salto de altura consta de cuatro fases, que son respectivamente la carrera de aproximación, el salto propiamente dicho (impulsión, elevación, transposición) y la caída. La fuerza de la dorsiflexión de la articulación del tobillo y de los flexores plantares aumentó significativamente en el grupo experimental de atletas. Por el contrario, sólo aumentó significativamente la fuerza de los flexores plantares en el grupo de control. Se encontraron diferencias estadísticas entre los dos grupos (P<0,05). Conclusión: El modo de entrenamiento isocinético de la fuerza de la articulación de la rodilla puede mejorar la fuerza de apoyo de la pierna en los saltadores. Este artículo sugiere que los atletas de salto de altura pueden adoptar este método para el entrenamiento de la fuerza de las extremidades inferiores. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Development and validation of a microenvironment-related prognostic model for hepatocellular carcinoma patients based on histone deacetylase family.

BACKGROUND: Histone deacetylase (HDAC) family can remove acetyl groups from histone lysine residues, and their high expression is closely related to the poor prognosis of hepatocellular carcinoma (HCC) patients. Recently, it has been reported to play an immunosuppressive role in the microenvironment, but little is known about the mechanism. METHODS: Through machine learning, we trained and verified the prognostic model composed of HDACs. CIBERSORT was used to calculate the percentage of immune cells in the microenvironment. Based on co-expression network, potential targets of HDACs were screened. After that, qRT-PCR was employed to evaluate the expression of downstream genes of HDACs, while HPLC-CAD analysis was applied to detect the concentration of arachidonic acid (AA). Finally, Flow cytometry, WB and IHC experiments were used to detect CD86 expression in RAW246.7. RESULTS: We constructed a great prognostic model composed of HDAC1 and HDAC11 that was significantly associated with overall survival. These HDACs were related to the abundance of macrophages, which might be attributed to their regulation of fatty-acid-metabolism related genes. In vitro experiments, the mRNA expression of ACSM2A, ADH1B, CYP2C8, CYP4F2 and SLC27A5 in HCC-LM3 was significantly down-regulated, and specific inhibitors of HDAC1 and HDAC11 significantly promoted the expression of these genes. HDAC inhibitors can promote the metabolism of AA, which may relieve the effect of AA on the polarization of M1 macrophages. CONCLUSIONS: Our study revealed the blocking effect of HDAC1 and HDAC11 on the polarization of macrophages M1 in the microenvironment by inhibiting fatty acid metabolism.

Oil-in-ionic liquid nanoemulsion-based adjuvant simultaneously enhances the stability and immune responses of inactivated foot-and-mouth disease virus.

Maintaining structural integrity and enhancing stability of inactivated foot-and-mouth disease virus (iFMDV) antigen in adjuvants is crucial to ensure the vaccine potency. Unfortunately, formulation with most reported adjuvants leads to the accelerated dissociation of iFMDV into inactive pentamers. Here, an ionic liquid, i.e., choline and niacin ([Cho][Nic]), which was found to stabilize iFMDV against the acid- and thermo- induced dissociation in buffer solution, was applied to construct a novel oil-in-ionic liquid (o/IL) nanoemulsion adjuvant composed of [Cho][Nic], squalene, and Tween 80. The o/IL nanoemulsion formulated with iFMDV has a monodisperse diameter of 135.8 ± 40.4 nm. The thermostability and long-term stability of iFMDV were remarkably enhanced in o/IL nanoemulsion compared with that in the o/w emulsion without [Cho][Nic] and in the commercial Montanide ISA 206 adjuvant. The o/IL nanoemulsion exerted its adjuvant effects by improving the humoral immune responses. Immunization of o/IL nanoemulsion adjuvanted iFMDV induced specific IgG titers similar to that adjuvanted by Montanide ISA 206 and about 4-fold higher than the un-adjuvanted iFMDV, also promoted the activation of B lymphocytes and the secretion of interleukin-4 in the mice model. This [Cho][Nic]-based o/IL nanoemulsion can serve as a promising adjuvant platform for the foot-and-mouth disease vaccine.

Anti-calcification potential of collagen based biological patch crosslinked by epoxidized polysaccharide.

Biological patch is a kind of tissue substitute material derived from natural polymer materials for the repair of human soft tissue defects. The serious calcification of biological patch after implantation is one of the reasons for the decline and failure of patch. In previous studies, we synthesized a new biomaterial crosslinker epoxidized chitosan quaternary ammonium salt (EHTCC) and used it for the crosslinking of porcine acellular dermal matrix (pADM). The prepared EHTCC-pADM had good mechanical properties, biocompatibility and healing promoting properties. In order to broaden its application scenarios, the related properties of EHTCC-pADM as implant patch were further explored in this study. The results of X-ray diffraction (XRD) measurements showed that the structure of pADM did not change much before and after the crosslinking of EHTCC, which was conducive to the maintenance of the excellent biological properties of pADM. According to the enzymatic degradation resistance test in vitro, the resistance of EHTCC-pADM to type I collagenase degradation was significantly improved compared with non -crosslinked pADM. And with the increase of the amount of EHTCC, its degradation resistance was stronger. The experimental results showed that EHTCC-pADM can well support the growth of L929 fibroblasts and has good anti-calcification properties in vitro and in vivo.

Oil-in-ionic liquid nanoemulsion-based intranasal delivery system for influenza split-virus vaccine.

Effective antigen delivery and immune stimulation in nasal mucosa determine the success of mucosal immunity. Here, an oil-in-ionic liquid (o/IL) nanoemulsion formulated with choline and niacin IL ([Cho][Nic]), squalene, and Tween 80 surfactant is explored as a vaccine delivery system for intranasal mucosal immunization. Compared to the o/w emulsion counterpart without the ILs, the o/IL manoemulsion showed a reduced and more uniform size of approximately 168 nm and significantly improved stability. Studies in mice model showed that when was used as an intranasal vaccine delivery system for influenza split-virus antigens, the antigens in the o/IL nanoemulsion induced strong mucosal immune responses with secretory IgA titers 25- and 5.8-fold higher than those of naked and commercial MF59-adjuvanted antigens, respectively. The o/IL nanoemulsion system also induced stronger systemic humoral responses. The excellent mucosal adjuvant effects of the o/IL nanoemulsion mainly benefited from the prolonged retention of antigens in the nasal cavity, enhanced antigen permeation into the submucosa, and the consequently promoted proliferation of CD11b cells and CD4+ T cells in nasal mucosa-associated lymphoid tissue. Moreover, when used as an injection adjuvant, the o/IL nanoemulsion also induced stronger humoral immune responses than MF59. Thus, the [Cho][Nic]-based o/IL nanoemulsion vaccine delivery system can serve as a promising adjuvant platform.

Elucidating the Novel Mechanism of Ligustrazine in Preventing Postoperative Peritoneal Adhesion Formation.

Postoperative peritoneal adhesion (PPA) is a major clinical complication after open surgery or laparoscopic procedure. Ligustrazine is the active ingredient extracted from the natural herb Ligusticum chuanxiong Hort, which has promising antiadhesion properties. This study is aimed at revealing the underlying mechanisms of ligustrazine in preventing PPA at molecular and cellular levels. Both rat primary peritoneal mesothelial cells (PMCs) and human PMCs were used for analysis in vitro. Several molecular biological techniques were applied to uncover the potential mechanisms of ligustrazine in preventing PPA. And molecular docking and site-directed mutagenesis assay were used to predict the binding sites of ligustrazine with PPARγ. The bioinformatics analysis was further applied to identify the key pathway in the pathogenesis of PPA. Besides, PPA rodent models were prepared and developed to evaluate the novel ligustrazine nanoparticles in vivo. Ligustrazine could significantly suppress hypoxia-induced PMC functions, such as restricting the production of profibrotic cytokines, inhibiting the expression of migration and adhesion-associated molecules, repressing the expression of cytoskeleton proteins, restricting hypoxia-induced PMCs to obtain myofibroblast-like phenotypes, and reversing ECM remodeling and EMT phenotype transitions by activating PPARγ. The antagonist GW9662 of PPARγ could restore the inhibitory effects of ligustrazine on hypoxia-induced PMC functions. The inhibitor KC7F2 of HIF-1α could repress hypoxia-induced PMC functions, and ligustrazine could downregulate the expression of HIF-1α, which could be reversed by GW9662. And the expression of HIF-1α inhibited by ligustrazine was dramatically reversed after transfection with si-SMRT. The results showed that the benefit of ligustrazine on PMC functions is contributed to the activation of PPARγ on the transrepression of HIF-1α in an SMRT-dependent manner. Molecular docking and site-directed mutagenesis tests uncovered that ligustrazine bound directly to PPARγ, and Val 339/Ile 341 residue was critical for the binding of PPARγ to ligustrazine. Besides, we discovered a novel nanoparticle agent with sustained release behavior, drug delivery efficiency, and good tissue penetration in PPA rodent models. Our study unravels a novel mechanism of ligustrazine in preventing PPA. The findings indicated that ligustrazine is a potential strategy for PPA formation and ligustrazine nanoparticles are promising agents for preclinical application.

Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Psoriasis-like Skin Inflammation.

Immunomodulatory effects of mesenchymal stem cells (MSCs) in inflammatory diseases, including psoriasis, are well documented. However, the role of MSC-derived exosomes (MSCs-Exo) in psoriasis-like skin inflammation remains largely unknown. This study aimed to investigate whether MSCs-Exo play a regulatory role in psoriasis-like skin inflammation. We found that subcutaneous injection of human umbilical cord MSCs-Exo (hucMSCs-Exo) significantly suppressed the proliferation of epidermis and reduced Psoriasis Area and Severity Index (PASI) scores in imiquimod (IMQ)-induced mice. hucMSCs-Exo also reduced the expression of interleukin (IL)-17, IL-23, and chemokine C-C-motif ligand 20 (CCL20) and inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) in the skin of IMQ-induced mice and in human keratinocyte (HaCaT) cells. In addition, co-cultured with hucMSCs-Exo in vitro, the maturation and activation of dendritic cells (DCs) were suppressed, and the expression level of IL-23 was decreased. These results indicate that hucMSCs-Exo can effectively ameliorate psoriasis-like skin inflammation in mice by regulating the expression of IL-23 and IL-17, and inhibiting the maturation and activation of DCs. Our data offer a promising therapeutic approach for psoriasis by leveraging the immunomodulatory effects of hucMSCs-Exo.

Synthesis of red/black phosphorus-based composite nanosheets with a Z-scheme heterostructure for high-performance cancer phototherapy.

Two dimensional black phosphorus nanosheets (BP NSs) have attracted plenty of attention in the research field of cancer photonic therapy. However, the poor stability and relatively low efficiency of reactive oxygen species (ROS) generation of BP NSs limit their practical application. To address these drawbacks, herein we report a red/black phosphorus (RP/BP) composite nanosheet, M-RP/BP@ZnFe2O4, which was synthesized by (1) partially converting red phosphorus (RP) to black phosphorus (BP) followed by liquid-phase ultrasonic exfoliation to form RP/BP NSs, (2) in situ synthesis of ZnFe2O4 nanoparticles on the surface of RP/BP NSs, (3) and wrapping with the MCF-7 cell membrane. Due to the presence of RP, BP, ZnFe2O4 and the cell membrane, the M-RP/BP@ZnFe2O4 NSs exhibited high performance in cancer phototherapy with the following features: (i) a Z-scheme heterojunction structure was formed between RP/BP NSs thus enabling high separation efficiency of the photogenerated electrons and holes; (ii) the photoexcitation holes in the valence band of RP can break the tumor microenvironment by oxidizing glutathione; (iii) the NSs could decompose water to produce H2O2 and O2, which can be further converted to toxic ˙OH through the ZnFe2O4 catalyzed Fenton reaction and 1O2 through energy transfer, respectively; and (iv) the cell membrane wrapping improved the targeting of the composite NSs at the tumor site and photonic therapy can be finally triggered by a 660 nm laser to convert O2 to ˙O2- and 1O2. The in vitro cytotoxicity experiments showed that more than 90% cells were killed after photodynamic therapy (PDT) at 0.3 mg mL-1 M-RP/BP@ZnFe2O4 NSs, and the animal experiments with xenograft tumor model mice indicated that tumor growth was completely inhibited and the highest survival rate of 83.3% at 60 days post PDT was obtained.

Thermal-triggered packing of lipophilic NIR dye IR780 in hepatitis B core at critical ionic strength and cargo-host ratio for improved stability and enhanced cancer phototherapy.

Virus-like particles (VLPs) holding internal cavity with diameter from tens up to one hundred nanometers are attractive platform for drug delivery. Nevertheless, the packing of drugs in the nanocage mainly relies on complicated disassembly-reassembly process. In this study, hepatitis B core protein (HBc) VLPs which can withstand temperature up to 90 °C was employed as carrier to load a lipophilic near infrared dye IR780. It was found that an attaching-dis-atching-diffusing process was involved for the entering of IR780 in the cavity of HBc. The first two steps were associated with the electrostatic interactions between oppositely charged HBc and IR780, which was critically manipulated by ionic strength and HBc/IR780 mass ratio at which they were mixed; while the diffusion of IR780 across the shell of HBc showed a temperature-dependent manner that can be triggered by thermal induced pore-opening of the HBc capsid. At optimized condition, about 1055 IR780 molecules were encapsulated in each HBc by simply mixing them for 10 min at 60 °C. Compared with free IR780, the HBc-IR780 particles showed significantly improved aqueous and photostability, as well as enhanced photothermal and photodynamic performance for cancer therapy. This study provides a novel drug loading strategy and nanomemedicine for cancer phototherapies.