Exploring novel indazole derivatives as ASK1 inhibitors: Design, synthesis, biological evaluation and docking studies.

Apoptosis signal regulated kinase 1 (ASK1, MAP3K5) is a member of the mitogen activated protein kinase (MAPK) signaling pathway, involved in cell survival, differentiation, stress response, and apoptosis. ASK1 kinase inhibition has become a promising strategy for the treatment of Non-alcoholic steatohepatitis (NASH) disease. A series of novel ASK1 inhibitors with indazole scaffolds were designed and synthesized, and their ASK1 kinase activities were evaluated. The System Structure Activity Relationship (SAR) study discovered a promising compound 33c, which has a strong inhibitory effect on ASK1. Noteworthy observations included a discernible reduction in lipid droplets within LO2 cells stained with Oil Red O, coupled with a decrease in LDL, CHO, and TG content within the NASH model cell group. Mechanistic inquiries revealed that compound 33c could inhibit the protein expression levels of the upregulated ASK1-p38/JNK signaling pathway in TNF-α treated HGC-27 cells and regulate apoptotic proteins. In summary, these findings suggest that compound 33c may be valuable for further research as a potential candidate compound against NASH.

Novel Mn3 [Co(CN)6]2@SiO2@Ag Core-Shell Nanocube: Enhanced Two-Photon Fluorescence and Magnetic Resonance Dual-Modal Imaging-Guided Photothermal and Chemo-therapy.

The versatile Mn3[Co(CN)6]2@SiO2@Ag core-shell NCs are prepared by a simple coprecipitation method. Ag nanoparticles with an average diameter of 12 nm deposited on the surface of Mn3[Co(CN)6]2@SiO2 through S-Ag bonding are fabricated in ethanol solution by reducing silver nitrate (AgNO3 ) with NaBH4 . The NCs possess T1 -T2 dual-modal magnetic resonance imaging ability. The inner Prussian blue analogs (PBAs) Mn3[Co(CN)6]2 exhibit bright two-photon fluorescence (TPF) imaging when excited at 730 nm. Moreover, the TPF imaging intensity displays 1.85-fold enhancement after loading of Ag nanoparticles. Besides, the sample also has multicolor fluorescence imaging ability under 403, 488, and 543 nm single photon excitation. The as-synthesized Mn3[Co(CN)6]2@SiO2@Ag NCs show a DOX loading capacity of 600 mg g(-1) and exhibit an excellent ability of near-infrared (NIR)-responsive drug release and photothermal therapy (PTT) which is induced from the relative high absorbance in NIR region. The combined chemotherapy and PTT against cancer cells in vitro test shows high therapeutic efficiency. The multimodal treatment and imaging could lead to this material a potential multifunctional system for biomedical diagnosis and therapy.

BCAM (basal cell adhesion molecule) protein expression in different tumor populations.

Basal Cell Adhesion Molecule (BCAM), a receptor for laminin subunit α5, plays a crucial role in the pathogenesis of various malignancies. Notably, evidence of hypermethylation at multiple immune checkpoints in patients with low BCAM expression suggests these individuals may respond favorably to immunotherapy using ICIs (immune checkpoint inhibitors). This finding lays the foundation for the hypothesis that BCAM may serve as an important biomarker in cancer patients. To investigate this potential, we evaluated BCAM expression patterns in 3114 patients from both discovery and validation cohorts, spanning seven cancer types, using quantitative immunofluorescence (QIF). We also explored the correlation between BCAM and PD-L1 expressions within these cohorts, aiming to establish its potential predictive value for immunotherapy response. Our findings indicate that BCAM was highly expressed in ovarian (79.2%) and lung (78.5%) tumors, with lower yet significant expression in breast (37.7%), head and neck (31.3%), and bladder-urothelial tumors (27.6%). Notably, high BCAM expression was associated with better OS in NSCLC. More importantly, BCAM expression did not correlate with PD-L1 protein expression in any of these tumors, highlighting its independent predictive potential. The widespread expression of BCAM across multiple tumor types, coupled with its lack of correlation with PD-L1 expression, highlights its potential as a predictive novel biomarker across various cancer types.

Overcome the challenge for intratumoral injection of STING agonist for pancreatic cancer by systemic administration.

Due to the challenge for intratumoral administration, innate agonists have not made it beyond preclinical studies for efficacy testing in most tumor types. Pancreatic ductal adenocarcinoma (PDAC) has a hostile tumor microenvironment that renders T cells dysfunctional. Innate agonist treatments may serve as a T cell priming mechanism to sensitize PDACs to anti-PD-1 antibody (a-PD-1) treatment. Using a transplant mouse model with spontaneously formed liver metastasis, a genetically engineered KPC mouse model that spontaneously develops PDAC, and a human patient-derived xenograft model, we compared the antitumor efficacy between intrahepatic/intratumoral and intramuscular systemic administration of BMS-986301, a next-generation STING agonist. Flow cytometry, Nanostring, and cytokine assays were used to evaluate local and systemic immune responses. This study demonstrated that administration of STING agonist systemically via intramuscular injection is equivalent to its intratumoral injection in inducing both effector T cell response and antitumor efficacy. Compared to intratumoral administration, T cell exhaustion and immunosuppressive signals induced by systemic administration were attenuated. Nonetheless, either intratumoral or systemic treatment of STING agonist was associated with increased expression of CTLA-4 on tumor-infiltrating T cells. However, the combination of a-PD-1 and anti-CTLA-4 antibody with systemic STING agonist demonstrated the antitumor efficacy in the KPC mouse spontaneous PDAC model. The mouse pancreatic and liver orthotopic model of human patient-derived xenograft reconstituted with PBMC also showed that antitumor and abscopal effects of both intratumoral and intramuscular STING agonist are equivalent. Taken together, this study supports the clinical development of innate agonists via systemic administration for treating PDAC.

Discovery and Characterization of a Novel Bacteriocin HA2-5 that Strongly Inhibits Propionibacterium acnes.

Increased drug resistance has significantly reduced the effectiveness of antibiotics used in the treatment of Propionibacterium acnes. Therefore, there has been a trend toward the development of new antimicrobial agents to circumvent drug resistance. In this study, we isolated and purified a novel bacteriocin, HA2-5, from Bacillus haynesii HA2, which effectively killed P. acnes through membrane disruption at a minimum inhibitory concentration (MIC) of 8 µg/mL. HA2-5 with 2× MIC was able to kill 99.9% of P. acnes within 24 h. HA2-5 shows excellent stability and tolerance to temperature, pH, proteases, chemical reagents, UV radiation, and metal ions, with almost no loss of inhibitory activity after treatment. In addition, the very low hemolytic activity and cytotoxicity suggest that HA2-5 is biosafe. Notably, HA2-5 exhibits preferred antibacterial activity against gram-positive pathogens with an MIC of 16-32 µg/mL. In conclusion, this study shows that bacteriocin HA2-5 has the potential to be used as an alternative to antibiotics for acne treatment.

Small-molecule inhibitors targeting apoptosis signal-regulated kinase 1.

Apoptosis signal regulated kinase 1 (ASK1, also known as MAP3K5) is a member of the mitogen activated protein kinase kinase kinase (MAP3K) family. Since its first isolation from a human macrophage library in 1996, its research has been ongoing for over 25 years. A large number of reports have revealed that ASK1, as a key activator of the p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK) signaling cascade, responds to various stressors, and its inhibitors have important potential value in the treatment of diseases such as inflammation, cancer, and the nervous system and so on. This review summarizes the recent development in this field, including the structure and signaling pathways of ASK1, with a particular focus on the structure-activity relationships, and the hit-to-lead optimization strategies.

Preclinical mouse models for immunotherapeutic and non-immunotherapeutic drug development for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is in urgent need of better diagnostic and therapeutic methods due to its late diagnosis, limited treatment options and poor prognosis. Finding the right animal models to recapitulate the tumor molecular pathogenesis and tumor microenvironment (TME) complexity is critical for preclinical immunotherapeutic and non-immunotherapeutic treatment developments. In this review, we summarize and evaluate popular preclinical animal models including patient-derived xenograft models, humanized mouse models, genetically engineered mouse models, and syngeneic mouse models. Through comparisons between these models in different research settings, we hope to provide guidance in finding the most relevant preclinical models to suit various research purposes.

Nano electrochemical reactors of Fe2O3 nanoparticles embedded in shells of nitrogen-doped hollow carbon spheres as high-performance anodes for lithium-ion batteries.

Iron oxides are extensively investigated as anode materials for lithium-ion batteries (LIBs) because of their large specific capacities. However, they undergo huge volume changes during cycling that result in anode pulverization and loss of electrical connectivity. As a result, the capacity retention of the iron oxide anodes is poor and should be improved for commercial applications. Herein, we report the preparation of ultrasmall Fe2O3 nanoparticles embedded in nitrogen-doped hollow carbon sphere shells (Fe2O3@N-C) by the direct pyrolysis of Fe-based zeolitic imidazolate frameworks (Fe-ZIF) at 620 °C in air. As an anode material for LIBs, the capacity retained was 1573 mA h g(-1) after 50 cycles at a current density of 0.1 C (1 C = 1000 mA g(-1)). Even undergoing the high-rate capability test twice, it can still deliver a remarkably reversible and stable capacity of 1142 mA h g(-1) after 100 cycles at a current density of 1 C. The excellent electrochemical performance is attributed to the unique structure of ultrasmall Fe2O3 nanoparticles uniformly distributed in the shell of nitrogen-doped carbon spheres, which simultaneously solve the major problems of pulverization, facilitate rapid electrochemical kinetics, and effectively avoid the aggregation of Fe2O3 nanoparticles during de/lithiation. The novel method developed in this work for the synthesis of functional hybrid materials can be extended to the preparation of various MOFs-derived functional nanocomposites owing to the versatility of links and metal centers in MOFs.

Fe3O4@carbon@zeolitic imidazolate framework-8 nanoparticles as multifunctional pH-responsive drug delivery vehicles for tumor therapy in vivo.

Controlled drug release is a promising approach for cancer therapy due to its merits of reduced systemic toxicity and enhanced antitumor efficacy. Here, multifunctional Fe3O4@carbon@zeolitic imidazolate framework-8 (FCZ) hybrid nanoparticles (NPs) were successfully constructed. Owing to the porosity and acid-sensitivity of zeolitic imidazolate framework-8 (ZIF-8), FCZ NPs not only displayed an improved drug loading capacity compared to most of the polymeric nanocarriers, but also exhibited excellent pH-triggered release of doxorubicin (DOX) in vitro. Moreover, carbon dots (CDs) embedded in the porous carbon shell and superparamagnetic iron oxide nanocrystals could simultaneously function as intracellular fluorescence imaging and T2*-weighted magnetic resonance imaging (MRI) contrast agents, respectively. The results obtained from the MTT assay demonstrated good biocompatibility of FCZ NPs. DOX release experiments showed pH regulation-dominated drug release kinetics: a weak acidic pH in tumor areas could trigger sustained drug release, suggesting that FCZ NPs are ideal drug delivery systems. Moreover, the remarkable inhibition of tumor growth without side effects was confirmed in vivo. These results provide convincing evidence establishing the multifunctional FCZ NPs as promising candidates for tumor therapy.

Mn(II) mediated degradation of artemisinin based on Fe3O4@MnSiO3-FA nanospheres for cancer therapy in vivo.

Artemisinin (ART) is a natural drug with potent anticancer activities related with Fe(2+) mediated cleavage of the endoperoxide bridge in ART. Herein, we reported that Mn(2+) could substitute for Fe(2+) to react with ART and generate toxic products, inducing a much higher anticancer efficiency. On this basis, we prepared pH-responsive Fe3O4@MnSiO3-FA nanospheres which can efficiently deliver hydrophobic ART into tumors in mice models. Mn(2+) was released in acidic tumor environments and intracellular lysosomes, interacting with ART to kill cancer cells. The ART-loaded nanocarriers could suppress tumor growth more efficiently than free ART, which could be further illustrated by magnetic resonance imaging (MRI). Histological analysis revealed that the drug delivery system had no obvious effect on the major organs of mice. ART has been reported to have lower toxicity than chemotherapeutics. The ART-loaded nanocarriers are promising to be used in improving the survival of chemotherapy patients, providing a novel method for clinical tumor therapy.