The discovery of tertiary lymphoid structures (TLS) within tumor tissues provides a promising avenue to promote the efficacy of cancer immunotherapy. Yet, the lack of effective strategies to induce TLS formation poses a substantial obstacle. Thus, the exploration of potential inducers for TLS formation is of great interest but remains challenging. Here, inspired by the mechanism of artificially cultivated pearls, a covalent organic framework (COF) is employed to induce TLS formation. Single-cell sequencing analysis reveals that this is achieved by promotion of cytokine hypersecretion, which facilitates the maturation, proliferation, and migration of T and B cells, critical for triggering TLS formation. Furthermore, the efficacy of COF-mediated phototherapy in inducing TLS formation is validated in both the MC38 and 4MOSC1 female tumor models. Notably, a strong synergistic effect between COF-mediated phototherapy and αCTLA-4 is observed, resulting in the effective eradication of both primary and distant tumors, while also inhibiting tumor recurrence. The formation of tertiary lymphoid structures (TLS) is promising for boosting cancer immunotherapy, but it is challenging to develop potential inducers for TLS formation. Here, the authors report a covalent organic framework (COF) that is able to trigger TLS formation.
Temporomandibular joint osteoarthritis (TMJOA) is one of the most common diseases causing chronic pain in the oral and maxillofacial region. So far, there are few ways to relieve the pain of TMJOA. Melatonin (MT) has a good analgesic effect in many diseases, including fibromyalgia, neuropathic pain, chronic headache, and burn pain, with very low acute toxicity and side effects. This study was to investigate the role and mechanism of MT in TMJOA chronic pain. In rats TMJOA chronic pain occurred at day 14 after an intra–temporomandibular joint injection of monosodium iodoacetate, which we previously reported. The enzyme-linked immunosorbent assay results showed that MT levels were higher in the synovial fluid from patients and rats with TMJOA as compared with those from control. Fluorescent retrograde tracing (Dil) identified that upregulation of MT type 2 receptor (MT 2 R) in trigeminal ganglion (TG) neurons innervating rat temporomandibular joints was accompanied by TMJOA chronic pain. Nociceptive behavior as assessed by von Frey and the Rat Grimace Scale demonstrated that exogenous administration of MT relieved chronic pain in TMJOA rats, whereas blocking MT 2 R with 4P-PDOT reversed the analgesic effect of MT. Immunofluorescence analysis also confirmed that MT inhibited CGRP and IB4 expression of TG neurons, and this inhibition was reversed by administering the MT 2 R antagonist in TMJOA rats. By using Fluo-3 AM-based calcium imaging in vitro, MT elicited calcium transients in Dil + TG neurons, which were significantly abolished by 4P-PDOT. Collectively, this study suggested that MT relieves the TMJOA chronic pain of rats through downregulation of sensitized CGRP + and IB4 + neurons in TG via MT 2 R. This will be helpful for health care professionals utilizing MT as an option against TMJOA chronic pain.
Abstract The thalamocortical pathway exhibits neuroplasticity not only during the critical period but also in adulthood. Here, we aimed to investigate the modulation of age-dependent thalamocortical plasticity by cholecystokinin (CCK). Our findings revealed the expression of CCK in thalamocortical neurons, and high-frequency stimulation (HFS) of the thalamocortical pathway elicited the release of CCK in auditory cortex (ACx), as evidenced by CCK sensor. HFS of the medial geniculate body (MGB) induced thalamocortical long-term potentiation (LTP) in wildtype young adult mice. However, knockdown of Cck expression in MGB neurons or blockade of the CCK-B receptor (CCKBR) in ACx effectively abolished HFS-induced LTP. Notably, this LTP could not be elicited in both juvenile mice (week 3) and mice over 18 months old, due to the absence of CCKBR in juvenile mice and the inability of CCK to be released in aged mice. Remarkably, the administration of exogenous CCK into the auditory cortex of the aged mice restored this LTP, accompanied by a significant improvement in frequency discrimination. These findings suggest the potential of CCK as a therapeutic intervention for addressing neurodegenerative deficits associated with thalamocortical neuroplasticity.
Accurate tumor diagnosis is essential to achieve the ideal therapeutic effect. However, it is difficult to accurately diagnose cancer using a single imaging method because of the technical limitations. Multimodal imaging plays an increasingly important role in tumor treatment. Photodynamic therapy (PDT) has received widespread attention in tumor treatment due to its high specificity and controllable photocytotoxicity. Nevertheless, PDT is susceptible to tumor microenvironment (TME) hypoxia, which greatly reduces the therapeutic effect of tumor treatment.In this study, a novel multifunctional nano-snowflake probe (USPIO@MnO2@Ce6, UMC) for oxygen-enhanced photodynamic therapy was developed. We have fabricated the honeycomb-like MnO2 to co-load chlorin e6 (Ce6, a photosensitizer) and ultrasmall superparamagnetic iron oxide (USPIO, T1-T2 double contrast agent). Under the high H2O2 level of tumor cells, UMC efficiently degraded and triggered the exposure of photosensitizers to the generated oxygen, accelerating the production of reactive oxygen species (ROS) during PDT. Moreover, the resulting USPIO and Mn2+ allow for MR T1-T2 imaging and transformable PAI for multimodal imaging-guided tumor therapy.TEM and UV-vis spectroscopy results showed that nano-snowflake probe (UMC) was successfully synthesized, and the degradation of UMC was due to the pH/ H2O2 responsive properties. In vitro results indicated good uptake of UMC in 4T-1 cells, with maximal accumulation at 4 h. In vitro and in vivo experimental results showed their imaging capability for both T1-T2 MR and PA imaging, providing the potential for multimodal imaging-guided tumor therapy. Compared to the free Ce6, UMC exhibited enhanced treatment efficiency due to the production of O2 with the assistance of 660 nm laser irradiation. In vivo experiments confirmed that UMC achieved oxygenated PDT under MR/PA imaging guidance in tumor-bearing mice and significantly inhibited tumor growth in tumor-bearing mice, exhibiting good biocompatibility and minimal side effects.The multimodal imaging contrast agent (UMC) not only can be used for MR and PA imaging but also has oxygen-enhanced PDT capabilities. These results suggest that UMC may have a good potential for further clinical application in the future.
Hepatic ischemia-reperfusion injury (HIRI) and induced systemic inflammation is a time-dependent multistage process which poses a risk of causing direct hepatic dysfunction and multiorgan failure. Real-time in situ comprehensive visualization assessment is important and scarce for imaging-guided therapeutic interventions and timely efficacy evaluation. Here, a logically activatable nanoreporter (termed QD@IR783-TK-FITC) is developed for time-phase imaging quantification of HIRI and induced systemic inflammation. The nanoreporters could be used for in vivo ratiometric NIR-IIb fluorescence sensing of reactive oxygen species (ROS), which can depict the in situ hepatic ROS fluctuation for the early diagnosis of HIRI in the initial 3 h. Meanwhile, the ROS-specific reaction releases renal-clearable fluorophore fragments from nanoreporters for monitoring the systematic inflammation induced by HIRI via longitudinal urinalysis. In addition, a functional relationship between digitized signal outputs (NIR-IIb ratios, urinary fluorescence) with hepatic injury scores has been established, realizing precise prediction of HIRI severity and preassessment of therapeutic efficacy. Such a time-phased modular toolbox can dynamically report HIRI-induced systemic inflammation in vivo, providing an efficient approach for HIRI treatment.
Abstract The blood-brain barrier breakdown, as a prominent feature after traumatic brain injury, always triggers a cascade of biochemical events like inflammatory response and free radical-mediated oxidative damage, leading to neurological dysfunction. The dynamic monitoring the status of blood-brain barrier will provide potent guidance for adopting appropriate clinical intervention. Here, we engineer a near-infrared-IIb Ag 2 Te quantum dot-based Mn single-atom catalyst for imaging-guided therapy of blood-brain barrier breakdown of mice after traumatic brain injury. The dynamic change of blood-brain barrier, including the transient cerebral hypoperfusion and cerebrovascular damage, could be resolved with high spatiotemporal resolution (150 ms and ~ 9.6 µm). Notably, the isolated single Mn atoms on the surface of Ag 2 Te exhibited excellent catalytic activity for scavenging reactive oxygen species to alleviate neuroinflammation in brains. The timely injection of Mn single-atom catalyst guided by imaging significantly promoted the reconstruction of blood-brain barrier and recovery of neurological function after traumatic brain injury.
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