EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in non-small cell lung cancer.

Lung cancer is a leading cause of cancer-related deaths worldwide. Recent studies have identified pyroptosis, a type of programmed cell death, as a critical process in the development and progression of lung cancer. In this study, we investigated the effect of EEBR, a new compound synthesized by our team, on pyroptosis in non-small cell lung cancer cells (NSCLC) and the underlying molecular mechanisms. Our results demonstrated that EEBR significantly reduced the proliferation and metastasis of NSCLC cells in vitro. Moreover, EEBR-induced pyroptosis in NSCLC cells, as evidenced by cell membrane rupture, the release of cytokines such as interleukin-18 and interleukin-1 beta and the promotion of Gasdermin D cleavage in a Caspase-1-dependent manner. Furthermore, EEBR promoted the nuclear translocation of NF-κB and upregulated the protein level of NLRP3. Subsequent studies revealed that EEBR-induced pyroptosis was suppressed by the inhibition of NF-κB. Finally, EEBR effectively suppressed the growth of lung cancer xenograft tumours by promoting NSCLC pyroptosis in animal models. Taken together, our findings suggest that EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in NSCLC, highlighting its potential as a candidate drug for NSCLC treatment.

Remote coupling of electrical and mechanical cues by diurnal photothermal irradiation synergistically promotes bone regeneration.

Recapitulating the natural extracellular physical microenvironment has emerged as a promising method for tissue regeneration, as multiple physical interventions, including ultrasound, thermal and electrical therapy, have shown great potential. However, simultaneous coupling of multiple physical cues to highly bio-mimick natural characteristics for improved tissue regeneration still remains formidable. Coupling of intrinsic electrical and mechanical cues has been regarded as an effective way to modulate tissue repair. Nevertheless, precise and convenient manipulation on coupling of mechano-electrical signals within extracellular environment to facilitate tissue regeneration remains challengeable. Herein, a photothermal-sensitive piezoelectric membrane was designed for simultaneous integration of electrical and mechanical signals in response to NIR irradiation. The high-performance mechano-electrical coupling under NIR exposure synergistically triggered the promotion of osteogenic differentiation of stem cells and enhances bone defect regeneration by increasing cellular mechanical sensing, attachment, spreading and cytoskeleton remodeling. This study highlights the coupling of mechanical signals and electrical cues for modulation of osteogenesis, and sheds light on alternative bone tissue engineering therapies with multiple integrated physical cues for tissue repair.

Wireless Electric Cues Mediate Autologous DPSC-Loaded Conductive Hydrogel Microspheres to Engineer the Immuno-Angiogenic Niche for Homologous Maxillofacial Bone Regeneration.

Stem cell therapy serves as an effective treatment for bone regeneration. Nevertheless, stem cells from bone marrow and peripheral blood are still lacking homologous properties. Dental pulp stem cells (DPSCs) are derived from neural crest, in coincidence with maxillofacial tissues, thus attracting great interest in in situ maxillofacial regenerative medicine. However, insufficient number and heterogenous alteration of seed cells retard further exploration of DPSC-based tissue engineering. Electric stimulation has recently attracted great interest in tissue regeneration. In this study, a novel DPSC-loaded conductive hydrogel microspheres integrated with wireless electric generator is fabricated. Application of exogenous electric cues can promote stemness maintaining and heterogeneity suppression for unpredictable differentiation of encapsulated DPSCs. Further investigations observe that electric signal fine-tunes regenerative niche by improvement on DPSC-mediated paracrine pattern, evidenced by enhanced angiogenic behavior and upregulated anti-inflammatory macrophage polarization. By wireless electric stimulation on implanted conductive hydrogel microspheres, loaded DPSCs facilitates the construction of immuno-angiogenic niche at early stage of tissue repair, and further contributes to advanced autologous mandibular bone defect regeneration. This novel strategy of DPSC-based tissue engineering exhibits promising translational and therapeutic potential for autologous maxillofacial tissue regeneration.

Antibacterial and osteoconductive polycaprolactone/polylactic acid/nano-hydroxyapatite/Cu@ZIF-8 GBR membrane with asymmetric porous structure.

Repair of periodontal and maxillofacial bone defects is a major challenge in clinical. Guided bone regeneration (GBR) is considered one of the most effective methods. However, the efficacy of currently available GBR membranes for repair is frequently limited by their poor osteogenic potential and lack of antibacterial activity. The first step in this investigation was to construct a zinc-based zeolite-imidazolate framework loaded with copper ions (Cu@ZIF-8). Following that, a novel polycaprolactone/polylactic acid/nano-hydroxyapatite/Cu@ZIF-8 (PCL/PLA/n-HA/Cu@ZIF-8) GBR membrane was developed using a simple porogen with nonsolvent-induced phase separation (NIPS) approach. The produced membrane with asymmetric porous structure (one smooth side and one rough side) possesses hydrophilicity corresponding to the roughness of its two sides. The superior mechanical property, stability of degradation, and ion release capability of the membrane all contribute to the clinical feasibility. Additionally, in vitro biological experiments demonstrated that the PCL/PLA/n-HA/Cu@ZIF-8 membrane had favorable osteogenic and antibacterial properties, which suggests the high potential for application in the GBR procedure.

SHP2 potentiates anti-PD-1 effectiveness through intervening cell pyroptosis resistance in triple-negative breast cancer.

Triple negative breast cancer (TNBC) presents a formidable challenge due to the lack of effective treatment modalities. Immunotherapy stands as a promising therapeutic approach; however, the emergence of drug resistance mechanisms within tumor cells, particularly those targeting apoptosis and pyroptosis, has hampered its clinical efficacy. SHP2 is intricately involved in diverse physiological processes, including immune cell proliferation, infiltration, and tumor progression. Nevertheless, the precise contribution of SHP2 to tumor cell pyroptosis resistance remains inadequately understood. Herein, we demonstrate that SHP2 inhibition hampers the proliferative, migratory, and invasive capabilities of TNBC, accompanied by noticeable alterations in cellular membrane architecture. Mechanistically, we provide evidence that SHP2 depletion triggers the activation of Caspase-1 and GSDMD, resulting in GSDMD-dependent release of LDH, IL-1ß, and IL-18. Furthermore, computational analyses and co-localization investigations substantiate the hypothesis that SHP2 may hinder pyroptosis through direct binding to JNK, thereby impeding JNK phosphorylation. Our cellular experiments further corroborate these findings by demonstrating that JNK inhibition rescues pyroptosis induced by SHP2 knockdown. Strikingly, in vivo experiments validate the suppressive impact of SHP2 knockdown on tumor progression via enhanced JNK phosphorylation. Additionally, SHP2 knockdown augments tumor sensitivity to anti-PD-1 therapy, thus reinforcing the pro-pyroptotic effects and inhibiting tumor growth. In summary, our findings elucidate the mechanism by which SHP2 governs TNBC pyroptosis, underscoring the potential of SHP2 inhibition to suppress cell pyroptosis resistance and its utility as an adjunctive agent for tumor immunotherapy.

The Green Walnut Husks Induces Apoptosis of Colorectal Cancer through Regulating NLRC3/PI3K Pathway.

BACKGROUND: Colorectal cancer (CRC) is the most common type of gastrointestinal tumor, but the available pharmacological treatment is insufficient. As a traditional Chinese medicine, the green walnut husks (QLY) exhibit anti-inflammatory, analgesic, anti-bacterial and anti-tumor effects. However, the effects and molecular mechanisms of QLY extracts on CRC were not yet made known. OBJECTIVE: This study aims to provide efficient and low toxicity drugs for the treatment of CRC. The purpose of this study is to explore the anti-CRC effect and mechanism of QLY, providing preliminary data support for clinical research of QLY. METHODS: Western blotting, Flow cytometry, immunofluorescence, Transwell, MTT, Cell proliferation assay, and xenograft model were used to perform the research. RESULTS: In this study, the potential of QLY to inhibit the proliferation, migration invasion and induce apoptosis of the mouse colorectal cancer cell line CT26 in vitro was identified. The xenograft tumor model of CRC noted that QLY suppressed tumor growth without sacrificing body weight in mice. In addition, QLY-induced apoptosis in tumor cells through NLRC3/PI3K/AKT signaling pathway was revealed. CONCLUSION: QLY regulates the levels of mTOR, Bcl-2 and Bax by affecting the NLRC3/PI3K/AKT pathway to promote apoptosis of tumor cells, suppressing cell proliferation, invasion and migration, and subsequently preventing the progression of colon cancer.

Temporal Immunomodulation via Wireless Programmed Electric Cues Achieves Optimized Diabetic Bone Regeneration.

Mimicking the temporal pattern of biological behaviors during the natural repair process is a promising strategy for biomaterial-mediated tissue regeneration. However, precise regulation of dynamic cell behaviors allocated in a microenvironment post-implantation remains challenging until now. Here, remote tuning of electric cues is accomplished by wireless ultrasound stimulation (US) on an electroactive membrane for bone regeneration under a diabetic background. Programmable electric cues mediated by US from the piezoelectric membrane achieve the temporal regulation of macrophage polarization, satisfying the pattern of immunoregulation during the natural healing process and effectively promoting diabetic bone repair. Mechanistic insight reveals that the controllable decrease in AKT2 expression and phosphorylation could explain US-mediated macrophage polarization. This study exhibits a strategy aimed at precisely biosimulating the temporal regenerative pattern by controllable and programmable electric output for optimized diabetic tissue regeneration and provides basic insights into bionic design-based precision medicine achieved by intelligent and external field-responsive biomaterials.

F. nucleatum facilitates oral squamous cell carcinoma progression via GLUT1-driven lactate production.

BACKGROUND: Tumor-resident microbiota has been documented for various cancer types. Oral squamous cell carcinoma (OSCC) is also enriched with microbiota, while the significance of microbiota in shaping the OSCC microenvironment remains elusive. METHODS: We used bioinformatics and clinical sample analysis to explore relationship between F. nucleatum and OSCC progression. Xenograft tumor model, metabolic screening and RNA sequencing were performed to elucidate mechanisms of pro-tumor role of F. nucleatum. FINDINGS: We show that a major protumorigenic bacterium, F. nucleatum, accumulates in invasive margins of OSCC tissues and drives tumor-associated macrophages (TAMs) formation. The mechanistic dissection shows that OSCC-resident F. nucleatum triggers the GalNAc-Autophagy-TBC1D5 signaling, leading to GLUT1 aggregation in the plasma membrane and the deposition of extracellular lactate. Simultaneous functional inhibition of GalNAc and GLUT1 efficiently reduces TAMs formation and restrains OSCC progression. INTERPRETATION: These findings suggest that tumor-resident microbiota affects the immunomodulatory and protumorigenic microenvironment via modulating glycolysis and extracellular lactate deposition. The targeted intervention of this process could provide a distinct clinical strategy for patients with advanced OSCC. FUNDING: This work was supported by the National Natural Science Foundation of China for Key Program Projects (82030070, to LC) and Distinguished Young Scholars (31725011, to LC), as well as Innovation Team Project of Hubei Province (2020CFA014, to LC).

nHA-loaded gelatin/alginate hydrogel with combined physical and bioactive features for maxillofacial bone repair.

Critical-sized maxillofacial bone defects have been a tough clinical challenge considering their requirements for functional and structural repair. In this study, an injectable in-situ forming double cross-linked hydrogel was prepared from gelatin (Gel), 20 mg/mL alginate dialdehyde (ADA), 4.5 mg/mL Ca2+ and borax. Improved properties of composite hydrogel might well fit and cover irregular geometric shape of facial bone defects, support facial structures and conduct masticatory force. We innovatively constructed a bioactive poly-porous structure by decoration with nano-sized hydroxyapatite (nHA). The highly ordered, homogeneous and size-confined porous surface served as an interactive osteogenic platform for communication and interplay between macrophages and bone marrow derived stem cells (BMSCs). Effective macrophage-BMSC crosstalk well explained the remarkable efficiency of nHA-loaded gelatin/alginate hydrogel (nHA@Gel/ADA) in the repair of critical-size skull bone defect. Collectively, the composite hydrogel constructed here might serve as a promising alternative in repair process of complex maxillofacial bone defects.