Dual-Emissive Detection of ATP and Hypochlorite Ions for Monitoring Inflammation-Driven Liver Injury In Vitro and In Vivo.

Reactive oxygen species play a pivotal role in liver disease, contributing to severe liver damage and chronic inflammation. In liver injury driven by inflammation, adenosine-5'-triphosphate (ATP) and hypochlorite ion (ClO-) emerge as novel biomarkers, reflecting mitochondrial dysfunction and amplified oxidative stress, respectively. However, the dynamic fluctuations of ATP and ClO- in hepatocytes and mouse livers remain unclear, and multidetection techniques for these biomarkers are yet to be developed. This study presents RATP-NClO, a dual-channel fluorescent bioprobe capable of synchronously detecting ATP and ClO- ions. RATP-NClO exhibits excellent selectivity and sensitivity for ATP and ClO- ions, demonstrating a dual-channel fluorescence response in a murine hepatocyte cell line. Upon intravenous administration, RATP-NClO reveals synchronized ATP depletion and ClO- amplification in the livers of mice with experimental metabolic dysfunction-associated steatohepatitis (MASH). Through a comprehensive analysis of the principal mechanism of the developed bioprobe and the verification of its reliable detection ability in both in vitro and in vivo settings, we propose it as a unique tool for monitoring changes in intracellular ATP and ClO- level. These findings underscore its potential for practical image-based monitoring and functional phenotyping of MASH pathogenesis.

Chlorophyll a and novel synthetic derivatives alleviate atopic dermatitis by suppressing Th2 cell differentiation via IL-4 receptor modulation.

Atopic dermatitis (AD) treatment has largely relied on non-specific broad immunosuppressants despite their long-term toxicities until the approval of dupilumab, which blocks IL-4 signaling to target Th2 cell responses. Here, we report the discovery of compound 4aa, a novel compound derived from the structure of chlorophyll a, and the efficacy of chlorophyll a to alleviate AD symptoms by oral administration in human AD patients. 4aa downregulated GATA3 and IL-4 in differentiating Th2 cells by potently blocking IL-4 receptor dimerization. In the murine model, oral administration of 4aa reduced the clinical severity of symptoms and scratching behavior by 76% and 72%, respectively. Notably, the elevated serum levels of Th2 cytokines reduced to levels similar to those in the normal group after oral administration of 4aa. Additionally, the toxicological studies showed favorable safety profiles and good tolerance. In conclusion, 4aa may be applied for novel therapeutic developments for patients with AD.

Gastrointestinal Delivery of an mRNA Vaccine Using Immunostimulatory Polymeric Nanoparticles.

mRNA vaccines can be translated into protein antigens, in vivo, to effectively induce humoral and cellular immunity against these proteins. While current mRNA vaccines have generated potent immune responses, the need for ultracold storage conditions (- 80 °C) and healthcare professionals to administer the vaccine through the parenteral route has somewhat limited their distribution in rural areas and developing countries. Overcoming these challenges stands to transform future deployment of mRNA vaccines. In this study, we developed an mRNA vaccine that can trigger a systemic immune response through administration via the gastrointestinal (GI) tract and is stable at 4 °C. A library of cationic branched poly(ß-amino ester) (PBAE) polymers was synthesized and characterized, from which a polymer with high intracellular mRNA delivery efficiency and immune stimulation capacity was down-selected. mRNA vaccines made with the lead polymer-elicited cellular and humoral immunity in mice. Furthermore, lyophilization conditions of the formulation were optimized to enable storage under refrigeration. Our results suggest that PBAE nanoparticles are potent mRNA delivery platforms that can elicit B cell and T cell activation, including antigen-specific cellular and humoral responses. This system can serve as an easily administrable, potent oral mRNA vaccine.

The effects of workplace friendship network centrality on deep acting.

We integrated social network theory with conservation of resource theory to predict that workplace friendship network centrality provides service employees with critical psychological resources that foster deep acting: positive affect and positive self-perception. In Study 1, we conducted a survey (N = 105) in a Korean banking firm, revealing that these resources mediate the relationship between workplace friendship network centrality and deep acting. Studies 2 and 3, both experimental studies, investigated the hypothesized causal relationships. In Study 2 (N = 151), we found that workplace friendship network centrality increases the intention toward deep acting. Further, Study 3 (N = 140) confirmed the direct effects of friendship network centrality on positive affect and self-perception. By providing insights into the structural antecedents of emotional labor, we inform managers in service organizations of the value of creating avenues for their employees to form and maintain friendships within the organization.

Biodegradable ring-shaped implantable device for intravesical therapy of bladder disorders.

Intravesical instillation is an efficient drug delivery route for the local treatment of various urological conditions. Nevertheless, intravesical instillation is associated with several challenges, including pain, urological infection, and frequent clinic visits for catheterization; these difficulties support the need for a simple and easy intravesical drug delivery platform. Here, we propose a novel biodegradable intravesical device capable of long-term, local drug delivery without a retrieval procedure. The intravesical device is composed of drug encapsulating biodegradable polycaprolactone (PCL) microcapsules and connected by a bioabsorbable Polydioxanone (PDS) suture with NdFeB magnets in the end. The device is easily inserted into the bladder and forms a 'ring' shape optimized for maximal mechanical stability as informed by finite element analysis. In this study, inserted devices were retained in a swine model for 4 weeks. Using this device, we evaluated the system's capacity for delivery of lidocaine and resiquimod and demonstrated prolonged drug release. Moreover, a cost-effectiveness analysis supports device implementation compared to the standard of care. Our data support that this device can be a versatile drug delivery platform for urologic medications.

Intravesical delivery of KDM6A-mRNA via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer.

Lysine-specific demethylase 6A (KDM6A), also named UTX, is frequently mutated in bladder cancer (BCa). Although known as a tumor suppressor, KDM6A's therapeutic potential in the metastasis of BCa remains elusive. It also remains difficult to fulfill the effective up-regulation of KDM6A levels in bladder tumor tissues in situ to verify its potential in treating BCa metastasis. Here, we report a mucoadhesive messenger RNA (mRNA) nanoparticle (NP) strategy for the intravesical delivery of KDM6A-mRNA in mice bearing orthotopic Kdm6a-null BCa and show evidence of KDM6A's therapeutic potential in inhibiting the metastasis of BCa. Through this mucoadhesive mRNA NP strategy, the exposure of KDM6A-mRNA to the in situ BCa tumors can be greatly prolonged for effective expression, and the penetration can be also enhanced by adhering to the bladder for sustained delivery. This mRNA NP strategy is also demonstrated to be effective for combination cancer therapy with other clinically approved drugs (e.g., elemene), which could further enhance therapeutic outcomes. Our findings not only report intravesical delivery of mRNA via a mucoadhesive mRNA NP strategy but also provide the proof-of-concept for the usefulness of these mRNA NPs as tools in both mechanistic understanding and translational study of bladder-related diseases.

Numeric Evaluation of Innovate Spring Machined Nickel-Titanium Rotary Instruments: A 3-dimensional Finite Element Study.

INTRODUCTION: The purpose of this study was to investigate if machined springs in nickel-titanium (NiTi) rotary instruments can improve their mechanical properties. The bending and torsion properties were assessed using finite element (FE) model analysis. METHODS: A basic 3-dimensional file model without a spring was created with apical size #25, 25-mm full length, and 16-mm cutting flutes. Three other models were created with a spring machined into their shaft portion with different numbers of spring coils: standard (STspr), 10% more (INspr), and 10% less (DEspr). To compare the mechanical responses among the 4 FE models, file bending and torsion were simulated using FE analysis. RESULTS: Spring machined NiTi rotary instruments showed higher torsional resistance and less bending stiffness than the same instrument without. The spring machined models required more torque to bend or rotate the DEspr model than was required for the STspr and INspr models; however, the STSpr and INSpr models were similar. CONCLUSIONS: Within the limitations of this study, the FE analysis indicated that machining a spring into the shaft of NiTi rotary instruments improved torsional resistance and bending flexibility. Therefore, spring machining has the potential to increase the durability of the NiTi rotary instruments.

Stimuli-responsive prodrug-based cancer nanomedicine.

The rapid development of nanotechnology results in the emergence of nanomedicines, but the effective delivery of drugs to tumor sites remains a great challenge. Prodrug-based cancer nanomedicines thus emerged due to their unique advantages, including high drug load efficiency, reduced side effects, efficient targeting, and real-time controllability. A distinctive characteristic of prodrug-based nanomedicines is that they need to be activated by a stimulus or multi-stimulus to produce an anti-tumor effect. A better understanding of various responsive approaches could allow researchers to perceive the mechanism of prodrug-based nanomedicines effectively and further optimize their design strategy. In this review, we highlight the stimuli-responsive pathway of prodrug-based nanomedicines and their anticancer applications. Furthermore, various types of prodrug-based nanomedicines, recent progress and prospects of stimuli-responsive prodrug-based nanomedicines and patient data in the clinical application are also summarized. Additionally, the current development and future challenges of prodrug-based nanomedicines are discussed. We expect that this review will be valuable for readers to gain a deeper understanding of the structure and development of prodrug-based cancer nanomedicines to design rational and effective drugs for clinical use.

Development of UHPLC-MS/MS Method for Indirubin-3'-Oxime Derivative as a Novel FLT3 Inhibitor and Pharmacokinetic Study in Rats.

This study aimed to develop and validate a sensitive liquid chromatography-coupled tandem mass spectrometry method for the quantification of LDD-2614, an indirubin derivative and novel FLT3 inhibitor, in rat plasma. In addition, the developed analytical method was applied to observe the pharmacokinetic properties of LDD-2614. Chromatographic separation was achieved on a Luna omega C18 column using a mixture of water and acetonitrile, both containing 0.1% formic acid. Quantitation was performed using positive electrospray ionization in a multiple reaction monitoring (MRM) mode. The MRM transitions were optimized as m/z 426.2→113.1 for LDD-2614 and m/z 390.2→113.1 for LDD-2633 (internal standard), and the lower limit of quantification (LLOQ) for LDD-2614 was determined as 0.1 ng/mL. Including the LLOQ, the nine-point calibration curve was linear with a correlation coefficient greater than 0.9991. Inter- and intraday accuracies (RE) ranged from -3.19% to 8.72%, and the precision was within 9.02%. All validation results (accuracy, precision, matrix effect, recovery, stability, and dilution integrity) met the acceptance criteria of the U.S. Food and Drug Administration and the Korea Ministry of Food and Drug Safety guidelines. The proposed method was validated and demonstrated to be suitable for the quantification of LDD-2614 for pharmacokinetics studies.

Discovery of orally active indirubin-3'-oxime derivatives as potent type 1 FLT3 inhibitors for acute myeloid leukemia.

FMS-like receptor tyrosine kinase-3 (FLT3) is expressed on acute leukemia cells and is implicated in the survival, proliferation and differentiation of hematopoietic cells in most acute myeloid leukemia (AML) patients. Despite recent achievements in the development of FLT3-targeted small-molecule drugs, there are still unmet medical needs related to kinase selectivity and the progression of some mutant forms of FLT3. Herein, we describe the discovery of novel orally available type 1 FLT3 inhibitors from structure-activity relationship (SAR) studies for the optimization of indirubin derivatives with biological and pharmacokinetic profiles as potential therapeutic agents for AML. The SAR exploration provided important structural insights into the key substituents for potent inhibitory activities of FLT3 and in MV4-11 cells. The profile of the most optimized inhibitor (36) showed IC50 values of 0.87 and 0.32 nM against FLT3 and FLT3/D835Y, respectively, along with potent inhibition against MV4-11 and FLT3/D835Y expressed MOLM14 cells with a GI50 value of 1.0 and 1.87 nM, respectively. With the high oral bioavailability of 42.6%, compound 36 displayed significant in vivo antitumor activity by oral administration of 20 mg/kg once daily dosing schedule for 21 days in a mouse xenograft model. The molecular docking study of 36 in the homology model of the DFG-in conformation of FLT3 resulted in a reasonable binding mode in type 1 kinases similar to the reported type 1 FLT3 inhibitors Crenolanib and Gilteritinib.

Linking individuation and organizational identification: Mediation through psychological safety.

This paper examines how individuation, a view that organizational members are all unique individuals, induces a perception of psychological safety and how perception of psychological safety, in turn, increases one's organizational identification. Results from 66 respondents in Study 1 provided first support for the proposed mechanism. In Study 2, data collected from 176 employees in work organizations also provided evidence for this mediation model. It was found in both studies that individuation has a significantly positive association with the perception of psychological safety such that the more employees view individual members of the organization as unique individuals, the more likely they perceive that their organization is a safe environment for self-expression. Furthermore, perception of psychological safety was found to serve as a mediator linking individuation and organizational identification.

Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition.

Loss of function in tumor suppressor genes is commonly associated with the onset/progression of cancer and treatment resistance. The p53 tumor suppressor gene, a master regulator of diverse cellular pathways, is frequently altered in various cancers, for example, in ~36% of hepatocellular carcinomas (HCCs) and ~68% of non-small cell lung cancers (NSCLCs). Current methods for restoration of p53 expression, including small molecules and DNA therapies, have yielded progressive success, but each has formidable drawbacks. Here, a redox-responsive nanoparticle (NP) platform is engineered for effective delivery of p53-encoding synthetic messenger RNA (mRNA). We demonstrate that the synthetic p53-mRNA NPs markedly delay the growth of p53-null HCC and NSCLC cells by inducing cell cycle arrest and apoptosis. We also reveal that p53 restoration markedly improves the sensitivity of these tumor cells to everolimus, a mammalian target of rapamycin (mTOR) inhibitor that failed to show clinical benefits in advanced HCC and NSCLC. Moreover, cotargeting of tumor-suppressing p53 and tumorigenic mTOR signaling pathways results in marked antitumor effects in vitro and in multiple animal models of HCC and NSCLC. Our findings indicate that restoration of tumor suppressors by the synthetic mRNA NP delivery strategy could be combined together with other therapies for potent combinatorial cancer treatment.

Curcumin Ameliorates Benzo[a]pyrene-Induced DNA Damages in Stomach Tissues of Sprague-Dawley Rats.

Benzo[a]pyrene (BaP) is a well-known carcinogen formed during the cooking process. Although BaP exposure has been implicated as one of the risk factors for lung cancer in animals and humans, there are only limited data on BaP-induced gastrointestinal cancer. Therefore, this study investigated the protective effects of curcumin on BaP-induced DNA damage in rat stomach tissues. BaP (20 mg/kg/day) and curcumin (50, 100, or 200 mg/kg) were administered daily to Sprague-Dawley rats by oral gavage over 30 days. Curcumin was pre-administered before BaP exposure. All rats were euthanized, and liver, kidney, and stomach tissues were removed at 24 h after the last treatment. We observed that aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glucose levels were significantly reduced in rats treated with high dose co-administration of curcumin (200 mg/kg) compared to BaP alone. The expression levels of cytochrome P450 (CYP) 1A1 and CYP1B1 were significantly increased in the liver of rats treated with BaP. However, co-administration of curcumin (200 mg/kg) with BaP markedly reduced CYP1A1 expression in a dose-dependent manner. Furthermore, plasma levels of BaP-diolepoxide (BPDE) and BaP metabolites were significantly reduced by co-administration of curcumin (200 mg/kg). Additionally, co-administration of curcumin (200 mg/kg) with BaP significantly reduced the formation of BPDE-I-DNA and 8-hydroxydeoxy guanosine (8-OHdG) adducts in the liver, kidney, and stomach tissues. The inhibition of these adduct formations were more prominent in the stomach tissues than in the liver. Overall, our observations suggest that curcumin might inhibit BaP-induced gastrointestinal tumorigenesis and shows promise as a chemopreventive agent.

Synthesis of Ultrathin Biotite Nanosheets as an Intelligent Theranostic Platform for Combination Cancer Therapy.

Biotite, also called black mica (BM), is a group of sheet silicate minerals with great potential in various fields. However, synthesis of high-quality BM nanosheets (NSs) remains a huge challenge. Here, an exfoliation approach is provided that combines calcination, n-butyllithium exchange and intercalation, and liquid exfoliating processes for the high-yield synthesis of ultrathin BM NSs. Due to the presence of MgO, Fe2O3, and FeO in these NSs, PEGylated BM can be engineered as an intelligent theranostic platform with the following unique features: i) Fe3+ can damage the tumor microenvironment (TME) through glutathione consumption and O2 production; ii) Generated O2 can be further catalyzed by MgO with oxygen vacancy to generate ·O2 -; iii) The Fe2+-catalyzed Fenton reaction can produce ·OH by disproportionation reactions of H2O2 in the TME; iv) Reactions in (i) and (iii) circularly regenerate Fe2+ and Fe3+ for continuous consumption of glutathione and H2O2 and constant production of ·OH and O2; v) The NSs can be triggered by a 650 nm laser to generate ·O2 - from O2 as well as by an 808 nm laser to generate local hyperthermia; and vi) The fluorescent, photoacoustic, and photothermal imaging capabilities of the engineered NSs allow for multimodal imaging-guided breast cancer treatment.

2D Monoelemental Germanene Quantum Dots: Synthesis as Robust Photothermal Agents for Photonic Cancer Nanomedicine.

As a new family member of the emerging two-dimensional (2D) monoelemental materials (Xenes), germanene has shown promising advantages over the prototypical 2D Xenes, such as black phosphorus (BP) and graphene. However, efficient manufacture of novel germanene nanostructures is still a challenge. Herein, a simple top-down approach for the liquid-exfoliation of ultra-small germanene quantum dots (GeQDs) is presented. The prepared GeQDs possess an average lateral size of about 4.5 nm and thickness of about 2.2 nm. The functionalized GeQDs were demonstrated to be robust photothermal agents (PTAs) with outstanding photothermal conversion efficacy (higher than those of graphene and BPQDs), superior stability, and excellent biocompatibility. As a proof-of-principle, 2D GeQDs-based PTAs were used in fluorescence/photoacoustic/photothermal-imaging-guided hyperpyrexia ablation of tumors. This work could expand the application of 2D germanene to the field of photonic cancer nanomedicine.

Emerging Two-Dimensional Nanomaterials for Cancer Therapy.

Two-dimensional (2D) nanomaterials have drawn tremendous attention due to their unique physicochemical properties and promising applications in the fields of electronics, energy storage, and catalysis. Recently, the biomedicine community has gradually started to recognize the great potential of these nanostructured materials for biomedical applications - in particular those related to cancer therapy. In this review, we provide a brief overview of a few representative 2D nanomaterials, discuss their preparation strategies and physicochemical properties, and highlight their applications in cancer nanomedicine. We expect that this review will shed some light on the new opportunities associated with 2D nanomaterials for biomedical research.

Targeted Delivery of Chlorin e6 via Redox Sensitive Diselenide-Containing Micelles for Improved Photodynamic Therapy in Cluster of Differentiation 44-Overexpressing Breast Cancer.

The off-target activation of photosensitizers is one of the most well-known obstacles to effective photodynamic therapy (PDT). The selected activation of photosensitizers in cancer cells is highly desired to overcome this problem. We developed a strategy that enabled diselenide bonds to link hyaluronic acid (HA) and photosensitizer chlorin e6 (Ce6) to assemble the micelles (HA-sese-Ce6 NPs) that can target cancer and achieve a redox responsive release of drugs to enhance the PDT efficiency in breast cancer. The HA was used to form a hydrophilic shell that can target cluster of differentiation 44 (CD44) on the cancer cells. The selenium-containing core is easily dissembled in a redox environment to release Ce6. The triggered release of Ce6 in a redox condition and the positive feedback release by activated Ce6 were observed in vitro. In cytotoxicity assays and in vitro cellular uptake assays, the increased PDT efficiency and targeted internalization of HA-sese-Ce6 NPs in the cells were verified, compared to a free Ce6 treated group. Similar results were showed in the therapeutic study and in vivo fluorescence imaging in an orthotopic mammary fat pad tumor model. In addition, a significant inhibition of metastasis was found after the HA-sese-Ce6 NPs treatment. In general, this study promises an ingenious and easy strategy for improved PDT efficiency.

Two-Dimensional Nanosheet-Based Photonic Nanomedicine for Combined Gene and Photothermal Therapy.

Two-dimensional (2D) nanosheets are characterized by their ultra-thin structure which sets them apart from their bulk materials. Due to this unique 2D structure, they have a high surface-to-volume ratio that can be beneficial for the delivery of various drugs including therapeutic DNAs and RNAs. In addition, various 2D materials exhibit excellent photothermal conversion efficiency when exposed to the near infrared (NIR) light. Therefore, this 2D nanosheet-based photonic nanomedicine has been gaining tremendous attention as both gene delivering vehicles and photothermal agents, which create synergistic effects in the treatment of different diseases. In this review, we briefly provide an overview of the following two parts regarding this type of photonic nanomedicine: (1) mechanism and advantages of nanosheets in gene delivery and photothermal therapy, respectively. (2) mechanism of synergistic effects in nanosheet-mediated combined gene and photothermal therapies and their examples in a few representative nanosheets (e.g., graphene oxide, black phosphorus, and translational metal dichalcogenide). We also expect to provide some deep insights into the possible opportunities associated with the emerging 2D nanosheets for synergistic nanomedicine research.