A strong, silk protein-inspired tissue adhesive with an enhanced drug release mechanism for transdermal drug delivery.

In transdermal drug delivery system (TDDS) patches, achieving prolonged adhesion, high drug loading, and rapid drug release simultaneously presented a significant challenge. In this study, a PHT-SP-Cu2+ adhesive was synthesized using polyethylene glycol (PEG), hexamethylene diisocyanate (HDI), trimethylolpropane (TMP), and silk protein (SP) as functional monomers which were combined with Cu2+ to improve the adhesion, drug loading, and drug release of the patch. The structure of the adhesion chains and the formation of Cu2+-p-π conjugated network in PHT-SP-Cu2+ were characterized and elucidated using different characterization methods including FT-IR, 13C NMR, XPS, SEM imaging and thermodynamic evaluation. The formulation of pressure-sensitive adhesive (PSA) was optimized through comprehensive research on adhesion, mechanics, rheology, and surface energy. The formulation of 3 wt.% SP and 3 wt.% Cu2+ provided superior adhesion properties compared to commercial standards. Subsequently, the peel strength of PHT-SP-Cu2+ was 7.6 times higher than that of the commercially available adhesive DURO-TAK® 87-4098 in the porcine skin peel test. The adhesion test on human skin confirmed that PHT-SP-Cu2+ could adhere to the human body for more than six days. Moreover, the drug loading, in vitro release test and skin permeation test were investigated using ketoprofen as a model drug, and the results showed that PHT-SP-Cu2+ had the efficacy of improving drug compatibility, promoting drug release and enhancing skin permeation as a TDDS. Among them, the drug loading of PHT-SP-Cu2+ was increased by 6.25-fold compared with PHT, and in the in vivo pharmacokinetic analysis, the AUC was similarly increased by 19.22-fold. The mechanism of α-helix facilitated drug release was demonstrated by Flori-Hawkins interaction parameters, molecular dynamics simulations and FT-IR. Biosafety evaluations highlighted the superior skin cytocompatibility and safety of PHT-SP-Cu2+ for transdermal applications. These results would contribute to the development of TDDS patch adhesives with outstanding adhesion, drug loading and release efficiency. STATEMENT OF SIGNIFICANCE: A new adhesive, PHT-SP-Cu2+, was created for transdermal drug delivery patches. Polyethylene glycol, hexamethylene diisocyanate, trimethylolpropane, silk protein, and Cu2+ were used in synthesis. Characterization techniques confirmed the structure and Cu2+-p-π conjugated networks. Optimal formulation included 3 wt.% SP and 3 wt.% Cu2+, exhibiting superior adhesion. PHT-SP-Cu2+ showed 7.6 times higher peel strength than DURO-TAK® 87-4098 on porcine skin and adhered to human skin for over six days. It demonstrated a 6.25-fold increase in drug loading compared to PHT, with 19.22-fold higher AUC in in vivo studies. α-helix facilitated drug release, proven by various analyses. PHT-SP-Cu2+ showed excellent cytocompatibility and safety for transdermal applications. This study contributes to developing efficient TDDS patches.

How work stress influence turnover intention among Chinese local undergraduate university teachers: the mediating effect of job burnout and the moderating effect of self-efficacy.

Background: Turnover intention is one of the common disturbances that affect the career development and management of university teachers. With an aim to solve this thorny issue, the study examined the associations between turnover intention and work stress among local undergraduate university teachers in China. Methods: A questionnaire survey was carried out on 7,565 local university teachers. Initially, confirmatory factor analysis was employed to validate the reliability and validity of the scale. Subsequently, descriptive statistics and correlation analyses were conducted. Following this, a latent moderated structural equation (LMS) was used to explore the relationship among work stress, job burnout, self-efficacy, and turnover intention. Moreover, the bias-corrected Bootstrap method was applied to further examine the mediating effects, moderating effects, and moderated mediating effects in the model. Results: The hypothesized moderated mediation model was verified significant. Work stress directly and positively predicted job burnout and turnover intention, with job burnout serving a partial mediating role between work stress and turnover intention. Additionally, self-efficacy negatively moderated the direct impact of work stress on job burnout, as well as the mediating effect of job burnout. As the self-efficacy of university teachers increased, the direct effect of work stress on job burnout and the mediating effect of job burnout decreased. Conclusion: This study expanded the research on the antecedent variables of university teachers' turnover intention and revealed the individual contingency mechanism by which work stress affected turnover intention: the negative moderating effect of self-efficacy. Work stress induced university teachers' turnover intention, and this phenomenon was more obvious for faculties with low self-efficacy. Administrators of local undergraduate universities need to rationalize the allocation of teachers' job responsibilities and pay attention to the negative consequences of work stress in order to reduce turnover intentions. Particular attention should be paid to enhance teachers' self-efficacy. The findings of this study can provide in-depth recommendations for university faculty management and policy making, which can help shape a working atmosphere more conducive to teaching and research, thus enhancing the overall quality and competitiveness of faculty members within universities.

Modulating macrophage phenotype for accelerated wound healing with chlorogenic acid-loaded nanocomposite hydrogel.

Wound healing involves distinct phases, including hemostasis, inflammation, proliferation, and remodeling, which is a complex and dynamic process. Conventional preparations often fail to meet multiple demands and provide prompt information about wound status. Here, a pH/ROS dual-responsive hydrogel (OHA-PP@Z-CA@EGF) was constructed based on oxidized hyaluronic acid (OHA), phenylboronic acid-grafted ε-polylysine (PP), chlorogenic acid (CA)-loaded ZIF-8 (Z-CA), and epidermal growth factor (EGF), which possesses intrinsic antibacterial, antioxidant, and angiogenic capacities. Due to the Schiff base and Phenylboronate ester bonds, the hydrogel exhibited excellent mechanical properties, strong adhesion, good biodegradability, high biocompatibility, stable rheological properties, and self-healing ability. Moreover, introducing Z-CA as an initiator and nanofiller led to the additional cross-linking of hydrogel through coordination bonds, which further improved the mechanical properties and antioxidant capabilities. Bleeding models of liver and tail amputations demonstrated rapid hemostatic properties of the hydrogel. Besides, the hydrogel regulated macrophage phenotypes via the NF-κB/JAK-STAT pathways, relieved oxidative stress, promoted cell migration and angiogenesis, and accelerated diabetic wound healing. The hydrogel also enabled real-time monitoring of the wound healing stages by colorimetric detection. This multifunctional hydrogel opens new avenues for the treatment and management of full-thickness diabetic wounds.

Water-compatible cross-linked pyrrolidone acrylate pressure-sensitive adhesives with persistent adhesion for transdermal delivery: Synergistic effect of hydrogen bonding and electrostatic force.

Poor skin adhesion and mechanical properties are common problems of pressure-sensitive adhesive (PSA) in transdermal drug delivery system (TDDS). Its poor water compatibility also causes the patch to fall off after sweating or soaking in the application site. To solve this problem, poly (2-Ethylhexyl acrylate-co-N-Vinyl-2-pyrrolidone-co-N-(2-Hydroxyethyl)acrylamide) (PENH), a cross-linked pyrrolidone polyacrylate PSA, was designed to improve the adhesion and water resistance of PSA through electrostatic force and hydrogen bonding system. The structure of PENH was characterized by 1H NMR, FTIR, DSC, and other methods. The mechanism was studied by FTIR, rheological test, and molecular simulation. The results showed that the PENH patch could adhere to human skin for more than 10 days without cold flow, and it could still adhere after sweating or water contact. In contrast, the commercial PSA Duro-Tak® 87-4098 and Duro-Tak® 87-2852 fell off completely on the 3rd and 6th day, respectively, and Duro-Tak® 87-2510 showed a significant dark ring on the second day. Mechanism studies have shown that the hydrogen bond formed by 2-ethylhexyl acrylate (2-EHA), N-vinyl-2-pyrrolidinone (NVP), and N-(2-Hydroxyethyl)acrylamide (HEAA) enhances cohesion, the interaction with skin improves skin adhesion, and the electrostatic interaction with water or drug molecules enhances the ability of water absorption and drug loading. Due to the synergistic effect of hydrogen bonds and electrostatic force, PENH can maintain high cohesion after drug loading or water absorption. PENH provides a choice for the development of water-compatible patches with long-lasting adhesion. STATEMENT OF SIGNIFICANCE: Based on the synergistic effect of hydrogen bonding and electrostatic force, a hydrogen-bonded, cross-linked pyrrolidone acrylate pressure-sensitive adhesive for transdermal drug delivery was designed and synthesized, which has high adhesion and cohesive strength and is non-irritating to the skin. The patch can be applied on the skin surface continuously for more than 10 days without the phenomenon of "dark ring", and the patch can remain adherent after the patient sweats or bathes. This provides a good strategy for choosing a matrix for patches that require prolonged administration.

Structural and biochemical characterization of active sites mutant in human inorganic pyrophosphatase.

Inorganic pyrophosphatases (PPases) are enzymes that catalyze the conversion of inorganic pyrophosphate (PPi) into phosphate (Pi). Human inorganic pyrophosphatase 1 (Hu-PPase) exhibits high expression levels in a variety of tumors and plays roles in cell proliferation, apoptosis, invasion and metastasis, making it a promising prognostic biomarker and a target for cancer therapy. Despite its widespread presence, the catalytic mechanism of Hu-PPase in humans remains inadequately understood. The signature motif amino acid sequence (DXDPXD) within the active sites of PPases is preserved across different species. In this research, an enzymatic activity assay revealed that mutations led to a notable reduction in enzymatic function, although the impact of the four amino acids on the activity of the pocket varied. To investigate the influence of these residues on the substrate binding and enzymatic function of PPase, the crystal structure of the Hu-PPase-ED quadruple mutant (D116A/D118A/P119A/D121A) was determined at 1.69 Å resolution. The resulting structure maintained a barrel-like shape similar to that of the wild-type, albeit lacking Mg2+ ions. Molecular docking analysis demonstrated a decreased ability of Hu-PPase-ED to bind to PPi. Further, molecular dynamics simulation analysis indicated that the mutation rendered the loop of Mg2+ ion-binding residues less stable. Therefore, the effect on enzyme activity did not result from a change in the gross protein structure but rather from a mutation that abolished the Mg2+-coordinating groups, thereby eliminating Mg2+ binding and leading to the loss of enzyme activity.

A Rhamnose-PEG-Modified Dendritic Polymer for Long-Term Efficient Transdermal Drug Delivery.

This study introduces a dendronized pressure-sensitive adhesive, TMPE@Rha, addressing Food and Drug Administration (FDA) concerns about traditional pressure-sensitive adhesives (PSAs) in transdermal drug delivery systems. The unique formulation, composed of rhamnose, trihydroxypropane, and poly(ethylene glycol), significantly enhances cohesion and tissue adhesion. Leveraging rhamnose improves intermolecular interactions and surface chain mobility, boosting tissue adhesion. Compared to acrylic pressure-sensitive adhesive 87-DT-4098, TMPE@Rha shows substantial advantages, with up to 5 to 6 times higher peel strength on porcine and wood substrates. Importantly, it maintains strong human skin adhesion beyond 7 days without the typical "dark ring" phenomenon. When loaded with diclofenac, the adhesive exhibits 3.12 times greater peeling strength than commercial alternatives, sustaining human adhesion for up to 6 days. Rigorous analyses confirm rhamnose's role in increasing interaction strength. In vitro studies and microscopy demonstrate the polymer's ability to enhance drug loading and distribution on the skin, improving permeability. Biocompatibility tests affirm TMPE@Rha as nonirritating. In summary, TMPE@Rha establishes a new standard for PSAs in transdermal drug delivery systems, offering exceptional adhesion, robustness, and biocompatibility. This pioneering work provides a blueprint for next-generation, highly adhesive, drug-loaded PSAs that meet and exceed FDA criteria.

An organic state trace element solution for rheumatoid arthritis treatment by modulating macrophage phenotypic from M1 to M2.

Trace elements (TEs) are essential for the treatment of rheumatoid arthritis (RA). This study aimed to prepare a TEs solution enriched with various organic states to evaluate its preventive, therapeutic effects, and mechanism of action in RA and to provide a treatment method for RA treatment. The TEs in natural ore were extracted and added to 0.5% (W/V) L-alanyl-L-glutamine (LG) to obtain a TEs solution (LG-WLYS), which was examined for its concentration and quality. The antioxidant properties and effects of LG-WLYS on cell behavior were evaluated at the cellular level. The preventive and therapeutic effects and mechanism of action of LG-WLYS in rats with RA were explored. The LG-WLYS solution was clear, free from visible foreign matter, and had a pH of 5.33 and an osmolality of 305.67 mOsmol/kg. LG-WLYS inhibited cell migration and angiogenesis. LG-WLYS solution induced macrophages to change from M1-type to M2-type, increased the content of antioxidant enzymes (glutathione, superoxide dismutase, and IL-10), decreased the levels of nitric oxide, malondialdehyde, TNF-α, IL-1ß, IL-6, COX-2, and iNOs, scavenging reactive oxygen species from the lesion site, inhibiting the apoptosis of chondrocytes, regulating inflammatory microenvironment, and decreasing inflammation response to exert the therapeutic effect for RA. In conclusion, LG-WLYS has outstanding therapeutic and preventive effects against RA and has enormous potential for further development.

Triple Cross-linked Dynamic Responsive Hydrogel Loaded with Selenium Nanoparticles for Modulating the Inflammatory Microenvironment via PI3K/Akt/NF-κB and MAPK Signaling Pathways.

Modulating the inflammatory microenvironment can inhibit the process of inflammatory diseases (IDs). A tri-cross-linked inflammatory microenvironment-responsive hydrogel with ideal mechanical properties achieves triggerable and sustained drug delivery and regulates the inflammatory microenvironment. Here, this study develops an inflammatory microenvironment-responsive hydrogel (OD-PP@SeNPs) composed of phenylboronic acid grafted polylysine (PP), oxidized dextran (OD), and selenium nanoparticles (SeNPs). The introduction of SeNPs as initiators and nano-fillers into the hydrogel results in extra cross-linking of the polymer network through hydrogen bonding. Based on Schiff base bonds, Phenylboronate ester bonds, and hydrogen bonds, a reactive oxygen species (ROS)/pH dual responsive hydrogel with a triple-network is achieved. The hydrogel has injectable, self-healing, adhesion, outstanding flexibility, suitable swelling capacity, optimal biodegradability, excellent stimuli-responsive active substance release performance, and prominent biocompatibility. Most importantly, the hydrogel with ROS scavenging and pH-regulating ability protects cells from oxidative stress and induces macrophages into M2 polarization to reduce inflammatory cytokines through PI3K/AKT/NF-κB and MAPK pathways, exerting anti-inflammatory effects and reshaping the inflammatory microenvironment, thereby effectively treating typical IDs, including S. aureus infected wound and rheumatoid arthritis in rats. In conclusion, this dynamically responsive injectable hydrogel with a triple-network structure provides an effective strategy to treat IDs, holding great promise in clinical application.

Qianjin Wenwu decoction suppresses renal interstitial fibrosis by enhancing the degradation of extracellular matrix in mice with unilateral ureteral obstruction.

Diabetic kidney disease (DKD) is the most common complication of diabetes mellitus (DM). Qianjin Wenwu decoction (QWD), a well-known traditional Korean medicine, has been used for the treatment of DKD, with satisfactory therapeutic effects. This study was designed to investigate the active components and mechanisms of action of QWD in the treatment of DKD. The results demonstrated that a total of 13 active components in five types were found in QWD, including flavonoids, flavonoid glycosides, phenylpropionic acids, saponins, coumarins, and lignins. Two key proteins, TGF-ß1 and TIMP-1, were identified as the target proteins through molecular docking. Furthermore, QWD significantly suppressed Scr and BUN levels which increased after unilateral ureteral obstruction (UUO). Hematoxylin & eosin (H&E) and Masson staining results demonstrated that QWD significantly alleviated renal interstitial fibrosis in UUO mice. We also found that QWD promoted ECM degradation by regulating MMP-9/TIMP-1 homeostasis to improve renal tubulointerstitial fibrosis and interfere with the expression and activity of TGF- ß1 in DKD treatment. These findings explain the underlying mechanism of QWD for the treatment of DKD, and also provide methodological reference for investigating the mechanism of traditional medicine in the treatment of DKD.

Relationships Between College Students' Belief in a Just World and Their Learning Satisfaction: The Chain Mediating Effects of Gratitude and Engagement.

Purpose: This paper reveals the mechanism of the influence of belief in a just world on college students' learning satisfaction, and provides reference for further improving the quality of talent training in higher education. Methods: By convenient sampling method, 131,894 college students from 348 undergraduate universities in China were investigated on the belief in a just world scale, gratitude scale, learning engagement scale and learning satisfaction scale. Then, SPSS, AMOS and other software were used to analyze the data. Results: 1) Belief in a just world, gratitude, learning engagement and learning satisfaction are positively correlated. 2) Belief in a just world can not only directly and positively predict college students' learning satisfaction, but also indirectly and positively predict college students' learning satisfaction through gratitude and learning engagement respectively. 3) Gratitude and learning engagement play a chain mediating role between belief in a just world and learning satisfaction. Conclusion: Belief in a just world positively predicts college students' learning satisfaction through gratitude and learning engagement, suggesting that colleges and universities should create a fair learning environment and enhance college students' sense of gratitude, so as to improve college students' belief in a fair world and gratitude level, thus promoting their learning engagement and finally improving their learning satisfaction.

Novel neuroprotective pyromeconic acid derivatives with concurrent anti-Aß deposition, anti-inflammatory, and anti-oxidation properties for treatment of Alzheimer's disease.

We synthesized a series of novel pyromeconic acid-styrene hybrid compounds and measured their activities in inhibiting Aß1-42 self-aggregation and promoting disaggregation, and their anti-inflammatory and antioxidant properties. The most potent compound, compound 30, had IC50 values of 11.15 µM and 6.87 µM for inhibition of fibril aggregation and promotion of fibril disaggregation, respectively. Because of its redox metal chelating property, 30 also inhibited Cu2+-induced Aß1-42 fibril aggregation and promoted fibril disaggregation with IC50 of 3.69 µM and 3.35 µM, respectively. Molecular docking demonstrated that 30 interacted with key amino acids of Aß1-42, and the reliability of the complex was confirmed by molecular dynamics. In addition, 30 displayed excellent antioxidative activity (oxygen radical absorbance capacity = 2.65 Trolox equivalents) and moderate anti-inflammatory activity and neuroprotection in cell culture assays. Compound 30 was safe in acute toxicity test in mice, and it exhibited favorable pharmacokinetic properties, particularly, accumulation in the hippocampus (maximum ratio of hippocampus to plasma = 7.12). Compound 30 alleviated cognitive deficits in scopolamine-induced amnesia mice; this property may have been attributed to reducing neuroinflammation by inhibiting ionized calcium binding adapter molecule 1 and glial fibrillary acidic protein expression and reducing oxidative stress by activating the Nrf2/HO-1 signaling pathway. In view of its many properties, we envision that 30 is a promising lead for the treatment of Alzheimer's disease.

An empirical study on the influencing mechanism of Chinese university teachers' wellbeing.

Current studies on teachers' wellbeing are mainly on lowering stress or burnout. Few studies have noted that faculty wellbeing is related to teaching activities. Teaching engagement and teaching experience are important predictor variables of teachers' wellbeing, but the internal and external influencing mechanisms of teachers' wellbeing have not been clearly revealed. Based on the survey data of 7,408 teachers from 271 undergraduate colleges and universities across China, the internal and external influencing mechanisms of teaching engagement and teaching experience on teachers' wellbeing were investigated through multicluster structural equation modeling. The results were that teachers' wellbeing was influenced by both teaching engagement and teaching experience. Among teaching engagement, teachers' pre-class preparation and post-class communication positively influenced teaching experience, but in-class delivery negatively influenced teaching experience. Teaching experience partially mediates the relationship between engagement and wellbeing. At the level of internal influence, the more teachers identify with and feel accomplished by teaching, the more they invest time and energy in teaching; at the level of external influence, the school environment, leadership, and colleague support affect teachers' wellbeing through the teaching experience. Universities should offer good teaching hardware and software for teachers, provide adequate teaching support, especially encourage teacher-student communication after class, weaken the rigid constraints and controls on teachers' teaching in class, give teachers enough teaching autonomy, and reduce their teaching burden to inspire teachers to be more actively involved in teaching, improve their teaching experience, and thus enhance their sense of wellbeing.

Fe(III)-coordinated N-[tris(hydroxymethyl)methyl]acrylamide-modified acrylic pressure-sensitive adhesives with enhanced adhesion and cohesion for efficient transdermal application.

Pressure-sensitive adhesives are critical to the product's safety, efficacy, and quality in transdermal drug delivery systems. However, many defects of transdermal patches (e.g., insufficient adhesion, patch displacement, and "dark ring" phenomenon) remain. Herein, the N-[tris(hydroxymethyl)methyl]acrylamide (NAT)-modified acrylic pressure-sensitive adhesive coordinated with Fe(III) (AA-NAT/Fe3+) was creatively proposed. Results demonstrated that the adhesiveness and cohesiveness of the optimized AA-NAT/Fe3+ were higher by 1.8- and 9.7-fold, respectively, than those of commercially available DURO-TAK® 87-4098 due to the hydrogen bonding interaction of NAT-skin interface and coordination of NAT-Fe3+. Moreover, compared with that of DURO-TAK® 87-4098, the adhesion time of AA-NAT/Fe3+ on the human forearm was remarkably prolonged, and no "dark ring" phenomenon was observed for AA-NAT/Fe3+ after removal. After clonidine (CLO) was loaded into AA-NAT/Fe3+, controlled drug release and a drug transdermal behavior were endowed for CLO@AA-NAT/Fe3+in vitro and in vivo. AA-NAT/Fe3+ still maintained superiority in adhesion and cohesion properties after CLO loading. These observations would contribute to the development of pressure-sensitive adhesives with outstanding adhesion and cohesion for transdermal patches. STATEMENT OF SIGNIFICANCE: This N-[tris(hydroxymethyl)methyl]acrylamide-modified acrylic pressure-sensitive adhesive coordinated with Fe(III) has enhanced adhesion and cohesion properties, which provide a simple but effective strategy to solve the problems (e.g., insufficient adhesion, patch displacement, and "dark ring" phenomenon) in existing transdermal patches.

Ventrolateral Periaqueductal Gray Astrocytes Regulate Nociceptive Sensation and Emotional Motivation in Diabetic Neuropathic Pain.

Diabetic neuropathic pain (DNP) is a diabetes complication experienced by many patients. Ventrolateral periaqueductal gray (vlPAG) neurons are essential mediators of the descending pain modulation system, yet the role of vlPAG astrocytes in DNP remains unclear. The present study applied a multidimensional approach to elucidate the role of these astrocytes in DNP. We verified the activation of astrocytes in different regions of the PAG in male DNP-model rats. We found that only astrocytes in the vlPAG exhibited increased growth. Furthermore, we described differences in vlPAG astrocyte activity at different time points during DNP progression. After the 14th day of modeling, vlPAG astrocytes exhibited obvious activation and morphologic changes. Furthermore, activation of Gq-designer receptors exclusively activated by a designer drug (Gq-DREADDs) in vlPAG astrocytes in naive male rats induced neuropathic pain-like symptoms and pain-related aversion, whereas activation of Gi-DREADDs in vlPAG astrocytes in male DNP-model rats alleviated sensations of pain and promoted pain-related preference behavior. Thus, bidirectional manipulation of vlPAG astrocytes revealed their potential to regulate pain. Surprisingly, activation of Gi-DREADDs in vlPAG astrocytes also mitigated anxiety-like behavior induced by DNP. Thus, our results provide direct support for the hypothesis that vlPAG astrocytes regulate diabetes-associated neuropathic pain and concomitant anxiety-like behavior.SIGNIFICANCE STATEMENT Many studies examined the association between the ventrolateral periaqueductal gray (vlPAG) and neuropathic pain. However, few studies have focused on the role of vlPAG astrocytes in diabetic neuropathic pain (DNP) and DNP-related emotional changes. This work confirmed the role of vlPAG astrocytes in DNP by applying a more direct and robust approach. We used chemogenetics to bidirectionally manipulate the activity of vlPAG astrocytes and revealed that vlPAG astrocytes regulate DNP and pain-related behavior. In addition, we discovered that activation of Gi-designer receptors exclusively activated by a designer drug in vlPAG astrocytes alleviated anxiety-like behavior induced by DNP. Together, these findings provide new insights into DNP and concomitant anxiety-like behavior and supply new therapeutic targets for treating DNP.

Hollow mesoporous silica nanoparticles-loaded ion-crosslinked bilayer films with excellent mechanical properties and high bioavailability for buccal delivery.

Mucoadhesive buccal films (MBFs) become the most promising buccal mucosal delivery system duo to its advantageous properties, including simple preparation technique and better patient compliance. The mechanical properties and mucoadhesion of MBFs are crucial in their successful performance as well as manufacturing and administration. In this study, we prepared hollow mesoporous silica nanoparticles-loaded ion-crosslinked bilayer films (CCS-PVA-TPP-FSM@HMSNs) using carboxymethyl chitosan (CCS) and polyvinyl alcohol (PVA) for buccal delivery of furosemide (FSM). The FSM-loaded hollow mesoporous silica nanoparticles (FSM@HMSNs) were firstly characterized by SEM, TEM, and nitrogen adsorption/desorption. Then, we constructed an ion-crosslinked network using CCS and PVA employed with the solution casting method, and sodium tripolyphosphate (TPP) was used as a hydrogen bond crosslinking agent. The formulation was optimized through Box-Behnken design, where the impact of the proportion of the ingredients on the quality of the films was evaluated entirely. Herein, folding endurance, swelling, tensile strength, and adhesion force were selected as response variables. Morphology, mechanical, spectroscopic, thermal, and safety of CCS-PVA-TPP-FSM@HMSNs films were also investigated. The release and permeability behaviors of CCS-PVA-TPP-FSM@HMSNs films were evaluated by in vitro drug release, across isolated porcine buccal and TR146 cell model. The CCS-PVA-TPP-FSM@HMSNs films showed outstanding mechanical properties, suitable bioadhesion, high drug loading, significant sustained-release properties, and improved permeability. In pharmacokinetic study with golden hamster models, the relative bioavailability was increased by 191.54%, and the absolute bioavailability was 82.20%. In summary, this study provides evidence that this innovative CCS-PVA-TPP-FSM@HMSNs films could be a promising and industrialized buccal drug delivery system.

A method for evaluating drug penetration and absorption through isolated buccal mucosa with highly accuracy and reproducibility.

The purpose of the project is to establish a standardized operation method of the in vitro permeability model to maximize mucosal integrity and viability. The model drug lidocaine permeability, 20 kDa fluorescein isothiocyanate-dextran, H&E staining, and mucosal viability were used as evaluation indicators. Firstly, the buccal mucosae of rats, rabbits, dogs, porcine, and humans were analyzed by H&E staining and morphometric analysis to compare the differences. Then, we studied a series of operation methods of isolated mucosa. The buccal mucosae were found to retain their integrity in Kreb's bicarbonate ringer solution at 4 °C for 36 h. Under the long-term storage method with program cooling, freezing at -80 °C, thawing at 37 °C, and using cryoprotectants of 20% glycerol and 20% trehalose, mucosal integrity and biological viability can be maintained for 21 days. The heat separation method was used to prepare a permeability model with a mucosal thickness of 500 µm, which was considered to be the optimal operation. In summary, this study provided an experimental basis for the selection and operation of in vitro penetration models, standardized the research process of isolated mucosa, and improved the accuracy of permeability studies.

Preparation, in vitro and in vivo evaluation of chitosan-sodium alginate-ethyl cellulose polyelectrolyte film as a novel buccal mucosal delivery vehicle.

This paper describes the development of a film comprising chitosan (CS), sodium alginate (SA), and ethyl cellulose (EC) for buccal mucosal administration. A film of CS-SA unidirectional release drug-containing water-repellent layer EC was produced by interfacial reaction solvent-drying technique using self-made equipment. The CS-SA-EC film had superior mechanical properties compared to CS-EC and SA-EC films. The existence of the amide bond was confirmed by FT-IR. DSC confirmed that the drug was dispersed in the carrier material in an amorphous form. The drug release studies emerged that the model drugs from CS-SA-EC films presented better release properties. The Ritger-Peppas model best describes all ratios of drugs release mechanisms. The permeability characteristics of the films were evaluated in the TR146 cells model and the rabbit buccal mucosae. The cumulative penetration amounts of the model drugs were significantly increased. The permeability mechanism of the film was studied preliminarily using immunofluorescence and Western Blot. The results showed that the film inhibited the expression of ZO-1 protein, and the expressive trend of ZO-1 protein was consistent with the results of in vitro permeation experiments. The pharmacokinetics of the drugs loaded films were evaluated and compared with oral administration in rats. The relative bioavailability of the model drugs was 246.00% (Zolmitriptan) and 142.12% (Etodolac) relative to oral administration. The results of this study demonstrate the potential of CS-SA-EC vehicle in buccal mucosa drug delivery.

Discovery of bazedoxifene analogues targeting glycoprotein 130.

Deregulation of GP130 in signal transduction is involved in multiple types of human diseases, especially in cancers, indicating that GP130 is an attractive target for cancer therapy. However, GP130 was conventionally considered as an undruggable target thus the discovery of GP130 PPI inhibitors is extremely challenging. By the aid of structure-based drug design, in this study, two series of bazedoxifene based analogues were designed to target GP130 D1 domain and block the IL-6/GP130/STAT3 signaling pathway for antitumor treatment. Most of these designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 10a was demonstrated to directly bind to GP130 protein with an affinity (KD) value of 3.8 µM via both SPR and DARTS methods. Subsequently, molecular docking study predicted that 10a targeted D1 domain of GP130 and co-IP assay demonstrated that 10a did not inhibit IL-6R/GP130 interaction, which meant 10a did not bind to the D2 and D3 domains of GP130. Moreover, 10a selectively inhibited JAK2 and STAT3 phosphorylation as well as IL-6 induced STAT3 phosphorylation. 10a effectively inhibited tumor cell viability, migration and promoted apoptosis. Furthermore, 10a effectively suppressed xenograft model tumor growth in vivo. Taken together, this study described a new class of bazedoxifene derived GP130 inhibitors as antitumor agents.

Real-time monitoring of etoposide prodrug activated by hydrogen peroxide with improved safety.

Etoposide is one of the most used first-line chemotherapeutic drugs. However, its application is still limited by its side effects. Herein, we designed a novel H2O2 sensitive prodrug 6YT for selectively releasing the anti-cancer drug etoposide in cancer cells. In this paper, etoposide and a hydrogen peroxide (H2O2) sensitive aryl borate ester group were linked by a fluorescent coumarin and finally the prodrug 6YT was generated. The fluorescence of coumarin was quenched before the connected aryl borate ester group was cleaved by H2O2. However, in the high level H2O2 environment of the tumor, the fluorescence could be activated simultaneously with the release of etoposide, and the drug release state of the prodrug was monitored real-time. With the support of 6YT, we obtained direct and visual evidence of etoposide release in a high H2O2 environment both in cells and zebrafish. The prodrug 6YT was also verified with comparable activity and improved safety with etoposide both in cells and in a mouse model. As a safe and effective prodrug, 6YT is expected to be one of the promising candidates in chemotherapy against cancer.