Microtubule-associated protein tau forms insoluble neurofibrillary tangles (NFTs), which is one of the major histopathological hallmarks of Alzheimer’s disease (AD). Many studies have demonstrated that tau causes early functional deficits prior to the formation of neurofibrillary aggregates. The redistribution of tau from axons to the somatodendritic compartment of neurons and dendritic spines causes synaptic impairment, and then leads to the loss of synaptic contacts that correlates better with cognitive deficits than amyloid-β (Aβ) aggregates do in AD patients. In this review, we discuss the underlying mechanisms by which tau is mislocalized to dendritic spines and contributes to synaptic dysfunction in AD. We also discuss the synergistic effects of tau and oligomeric forms of Aβ on promoting synaptic dysfunction in AD.
The aim of this study was to construct an RNA-interference plasmid (p-HIF-1α RNAi) targeting the human HIF-1α gene and assess its effects on HIF-1α expression and its anti-tumour functions in vitro. p-HIF-1α RNAi was constructed and confirmed by polymerase chain reaction (PCR) and DNA sequencing. Reverse transcriptase PCR (RT-PCR) and western blot were performed to detect HIF-1α expression in HCT116 cells following transfection of p-HIF-1α RNAi and p-control. The anti-tumour effects and mechanism of action of p-HIF-1α RNAi in HCT116 cells were further investigated. p-HIF-1α RNAi significantly inhibited HIF-1α expression in the HCT116 cell line. p-HIF-1α RNAi inhibited cell viability and reduced VEGF but not bFGF expression in the supernatant of HCT116 cells, down-regulated b-catenin and VEGF expression, and altered β-catenin location in the HCT116 cell nucleus. The plasmid p-HIF-1α RNAi can effectively and specifically inhibit HIF-1α expression, inhibit cell proliferation, and alter the expression of key components in the Wnt/β-catenin signaling pathway. Thus, p-HIF-1α RNAi is a novel and extremely promising therapeutic inhibitor of HIF-1α.
Multi-modal imaging based on multifunctional nanoparticles is a promising alternative approach to improve the sensitivity of early cancer diagnosis. In this study, highly upconverting fluorescence and strong relaxivity rare-earth nanoparticles coated with paramagnetic lanthanide complex shells and polyethylene glycol (PEGylated UCNPs@DTPA-Gd3+) are synthesized as dual-modality imaging contrast agents (CAs) for upconverting fluorescent and magnetic resonance dual-modality imaging. PEGylated UCNPs@DTPA-Gd3+ with sizes in the range of 32–86 nm are colloidally stable. They exhibit higher longitudinal relaxivity and transverse relaxivity in water (r1 and r2 values are 7.4 and 27.8 s−1 per mM Gd3+, respectively) than does commercial Gd–DTPA (r1 and r2 values of 3.7 and 4.6 s−1 per mM Gd3+, respectively). They are found to be biocompatible. In vitro cancer cell imaging shows good imaging contrast of PEGylated UCNPs@DTPA-Gd3+. In vivo upconversion fluorescent imaging and T1-weighted MRI show excellent enhancement of both fluorescent and MR signals in the livers of mice administered PEGylated UCNPs@DTPA-Gd3+. All the experimental results indicate that the synthesized PEGylated UCNPs@DTPA-Gd3+ present great potential for biomedical upconversion of fluorescent and magnetic resonance dual-modality imaging applications.
Abstract Objective Bufalin, the main active anti-tumor monomer of toad venom, is crucial in cancer treatment. However, intrinsic issues, such as poor solubility and systematic toxicity, have considerably mitigated its anticancer functions and caused unwanted side effects. It is essential to develop innovative targeting systems to precisely and efficiently deliver anticancer drugs to achieve satisfying therapeutic efficiency. Methods This work established a novel and more efficient system for simultaneously detecting and killing colorectal cancer cells. The proposed method designed two allosteric probes, a report probe and a recognize probe. The method exhibited high sensitivity towards cell detection via the recognizing probe identifying target cancer cells and the report probe’s signal report. Combining bufalin and fluorouracil endowed better tumor cell inhibition. Results We observed significantly enhanced fluorescence dots surrounding the HCT-116 cell membranes. No fluorescence increments in the other three cells were identified, indicating that the established liposome complex could specifically bind with target cells. In addition, the best ratio of bufalin to fluorouracil was 0.15 and 0.5, respectively. This improved the anti-tumor effects and achieved more than 60% tumor cell inhibition. Conclusion This method will provide new opportunities for intracellular biomolecule detection and targeted cancer cell therapy.
Checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies, have been shown to be extraordinarily effective, but their durable response rate remains low, especially in colorectal cancer (CRC). Recent studies have shown that photodynamic therapy (PDT) could effectively enhance PD-L1 blockade therapeutic effects, although the reason is still unclear. Here, we report the use of multifunctional nanoparticles (NPs) loaded with photosensitized mTHPC ([email protected]/T-RGD NPs)-mediated PDT treatment to potentiate the anti-tumor efficacy of PD-L1 blockade for CRC treatment and investigate the underlying mechanisms of PDT enhancing PD-L1 blockade therapeutic effect in this combination therapy. In this study, the [email protected]/T-RGD NPs under the 660-nm near infrared (NIR) laser could kill tumor cells by inducing apoptosis and/or necrosis and stimulating systemic immune response, which could be further promoted by the PD-L1 blockade to inhibit primary and distant tumor growth, as well as building long-term host immunological memory to prevent tumor recurrence. Furthermore, we detected that [email protected]/T-RGD NP-mediated PDT sensitizes tumors to PD-L1 blockade therapy mainly because PDT-mediated hypoxia could induce the hypoxia-inducible factor 1α (HIF-1α) signaling pathway that upregulates PD-L1 expression in CRC. Taken together, our work demonstrates that [email protected]/T-RGD NP-mediated PDT is a promising strategy that may potentiate the response rate of anti-PD-L1 checkpoint blockade immunotherapies in CRC. Checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies, have been shown to be extraordinarily effective, but their durable response rate remains low, especially in colorectal cancer (CRC). Recent studies have shown that photodynamic therapy (PDT) could effectively enhance PD-L1 blockade therapeutic effects, although the reason is still unclear. Here, we report the use of multifunctional nanoparticles (NPs) loaded with photosensitized mTHPC ([email protected]/T-RGD NPs)-mediated PDT treatment to potentiate the anti-tumor efficacy of PD-L1 blockade for CRC treatment and investigate the underlying mechanisms of PDT enhancing PD-L1 blockade therapeutic effect in this combination therapy. In this study, the [email protected]/T-RGD NPs under the 660-nm near infrared (NIR) laser could kill tumor cells by inducing apoptosis and/or necrosis and stimulating systemic immune response, which could be further promoted by the PD-L1 blockade to inhibit primary and distant tumor growth, as well as building long-term host immunological memory to prevent tumor recurrence. Furthermore, we detected that [email protected]/T-RGD NP-mediated PDT sensitizes tumors to PD-L1 blockade therapy mainly because PDT-mediated hypoxia could induce the hypoxia-inducible factor 1α (HIF-1α) signaling pathway that upregulates PD-L1 expression in CRC. Taken together, our work demonstrates that [email protected]/T-RGD NP-mediated PDT is a promising strategy that may potentiate the response rate of anti-PD-L1 checkpoint blockade immunotherapies in CRC.
The imidazoline I 2 receptor is an emerging drug target for analgesics. This study extended previous studies by examining the antinociceptive effects of three I 2 receptor agonists (2-BFI, BU224, and CR4056) in the formalin test. The receptor mechanisms and anatomical mediation of I 2 receptor agonist-induced antinociception were also examined. Formalin-induced flinching responses (2%, 50 μl) were quantified after treatment with I 2 receptor agonists alone or in combination with the I 2 receptor antagonist idazoxan. Anatomical mediation was studied by locally administering 2-BFI into the plantar surface or into the right lateral ventricle through cannulae (intracerebroventricular). The locomotor activity was also examined after central (intracerebroventricular) administration of 2-BFI. 2-BFI (1–10 mg/kg, intraperitoneal) and BU224 (1–10 mg/kg, intraperitoneal) attenuated the spontaneous flinching response observed during 10 min (phase 1) and 20–60 min (phase 2) following formalin treatment, whereas CR4056 (1–32 mg/kg, intraperitoneal) decreased only phase 2 flinching response. The I 2 receptor antagonist idazoxan attenuated the antinociceptive effects of 2-BFI and BU224 during phase 1, but not phase 2. Peripheral administration of 2-BFI (1–10 mg/kg, intraplantar) to the hind paw of rats had no antinociceptive effect. In contrast, centrally delivered 2-BFI (10–100 µg, intracerebroventricular) dose-dependently attenuated phase 1 and phase 2 flinching at doses that did not reduce the locomotor activity. Together, these data revealed the differential antinociceptive effects of I 2 receptor agonists and the differential antagonism profiles by idazoxan, suggesting the involvement of different I 2 receptor subtypes in reducing different phases of formalin-induced pain-like behaviors. In addition, the results also suggest the central mediation of I 2 receptor agonist-induced antinociceptive actions.
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