RESUMEN
Periprosthetic osteolysis and subsequent aseptic loosening are the primary causes of failure following total joint arthroplasty. Wear particle-induced osteogenic impairment is recognized as an important contributing factor in the development of osteolysis, with endoplasmic reticulum (ER) stress emerging as a pivotal underlying mechanism. Hence, searching for potential therapeutic targets and agents capable of modulating ER stress in osteoblasts is crucial for preventing aseptic loosening. Kaempferol (KAE), a natural flavonol compound, has shown promising osteoprotective effects and anti-ER stress properties in diverse diseases. However, the influence of KAE on ER stress-mediated osteogenic impairment induced by wear particles remains unclear. In this study, we observed that KAE effectively relieved TiAl6V4 particles-induced osteolysis by improving osteogenesis in a mouse calvarial model. Furthermore, we demonstrated that KAE could attenuate ER stress-mediated apoptosis in osteoblasts exposed to TiAl6V4 particles, both in vitro and in vivo. Mechanistically, our results revealed that KAE mitigated ER stress-mediated apoptosis by upregulating the IRE1α-XBP1s pathway while concurrently partially inhibiting the IRE1α-regulated RIDD and JNK activation. Collectively, our findings suggest that KAE is a prospective therapeutic agent for treating wear particle-induced osteolysis and highlight the IRE1α-XBP1s pathway as a potential therapeutic target for preventing aseptic loosening.
Asunto(s)
Estrés del Retículo Endoplásmico , Endorribonucleasas , Quempferoles , Osteoblastos , Osteogénesis , Osteólisis , Proteínas Serina-Treonina Quinasas , Proteína 1 de Unión a la X-Box , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Quempferoles/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína 1 de Unión a la X-Box/metabolismo , Proteína 1 de Unión a la X-Box/genética , Ratones , Osteogénesis/efectos de los fármacos , Endorribonucleasas/metabolismo , Endorribonucleasas/genética , Osteoblastos/metabolismo , Osteoblastos/efectos de los fármacos , Osteólisis/metabolismo , Osteólisis/inducido químicamente , Osteólisis/patología , Osteólisis/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Masculino , Humanos , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Carbon monoxide (CO) is an important signaling molecule participating in multiple biological functions. Previous studies have confirmed the valuable roles of CO in cancer therapies. If the CO concentration and distribution can be controlled in tumors, new cancer therapeutic strategy may be developed to benefit the patient survival. RESULTS: In this study, a UiO-67 type metal-organic framework (MOF) nanoplatform was produced with cobalt and ruthenium ions incorporated into its structure (Co/Ru-UiO-67). Co/Ru-UiO-67 had a size range of 70-90 nm and maintained the porous structure, with cobalt and ruthenium distributed uniformly inside. Co/Ru-UiO-67 was able to catalyze carbon dioxide into CO upon light irradiation in an efficient manner with a catalysis speed of 5.6 nmol/min per 1 mg Co/Ru-UiO-67. Due to abnormal metabolic properties of tumor cells, tumor microenvironment usually contains abundant amount of CO2. Co/Ru-UiO-67 can transform tumor CO2 into CO at both cellular level and living tissues, which consequently interacts with relevant signaling pathways (e.g. Notch-1, MMPs etc.) to adjust tumor microenvironment. With proper PEGylation (pyrene-polyacrylic acid-polyethylene glycol, Py-PAA-PEG) and attachment of a tumor-homing peptide (F3), functionalized Co/Ru-UiO-67 could accumulate strongly in triple-negative MDA-MB-231 breast tumors, witnessed by positron emission tomography (PET) imaging after the addition of radioactive zirconium-89 (89Zr) into Co-UiO-67. When applied in vivo, Co/Ru-UiO-67 could alter the local hypoxic condition of MDA-MB-231 tumors, and work synergistically with tirapazamine (TPZ). CONCLUSION: This nanoscale UiO-67 MOF platform can further our understanding of CO functions while produce CO in a controllable manner during cancer therapeutic administration.
Asunto(s)
Estructuras Metalorgánicas , Rutenio , Neoplasias de la Mama Triple Negativas , Humanos , Estructuras Metalorgánicas/farmacología , Estructuras Metalorgánicas/química , Monóxido de Carbono , Rutenio/farmacología , Rutenio/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Dióxido de Carbono , Cobalto , Microambiente TumoralRESUMEN
Shikonin (Shik), a natural pigment, has received growing interest in various biomedical fields due to its anti-inflammatory, antitumor, antimicrobial, and antioxidant ability. However, some inherent characteristics of Shik, such as its virulence, low bioavailability, and poor solubility, have limited its biomedical applicability. Here, we reported a facile synthetic method to produce the Shik-iron (III) nanoparticles (Shik-Fe NPs), which could overcome these limitations of Shik. The synthesized Shik-Fe NPs possessed a uniform size range of 110 ± 10 nm, negative surface charges, good water dispersity, and high safety. Iron distributed uniformly inside Shik-Fe NPs, and iron constituted 20% of total mass in PEGylated Shik-Fe NPs. When interacting with activated macrophages, Shik-Fe NPs significantly reduced the level of cellular inflammatory factors, for example, iNOS, IL-1ß, and TNF-α. Furthermore, the Shik-Fe NPs demonstrated synergistic anti-inflammation and anti-bacterial properties in vivo, since they could release Fe3+ and Shik to eradicate bacteria (Staphylococcus aureus and P. aeruginosa were used as model microbes here) during wound infections and provide full recovery for scald wounds. Collectively, the study established a dual-functional Shik-derived nanoplatform, which could be useful for the treatment of various inflammation-involved diseases.