Glymphatic function and its influencing factors in different glucose metabolism states.

BACKGROUND: Dysfunction of the glymphatic system in the brain in different stages of altered glucose metabolism and its influencing factors are not well characterized. AIM: To investigate the function of the glymphatic system and its clinical correlates in patients with different glucose metabolism states, the present study employed diffusion tensor imaging along the perivascular space (DTI-ALPS) index. METHODS: Sample size was calculated using the pwr package in R software. This cross-sectional study enrolled 22 patients with normal glucose metabolism (NGM), 20 patients with prediabetes, and 22 patients with type 2 diabetes mellitus (T2DM). A 3.0T magnetic resonance imaging was used to evaluate the function of the glymphatic system. The mini-mental state examination (MMSE) was used to assess general cognitive function. The DTI-ALPS index of bilateral basal ganglia and the mean DTI-ALPS index was calculated. Further, the correlation between DTI-ALPS and clinical features was assessed. RESULTS: The left-side, right-side, and mean DTI-ALPS index in the T2DM group were significantly lower than that in the NGM group. The right-side DTI-ALPS and mean DTI-ALPS index in the T2DM group were significantly lower than those in the prediabetes group. DTI-ALPS index lateralization was not observed. The MMSE score in the T2DM group was significantly lower than that in the NGM and prediabetes group. After controlling for sex, the left-side DTI-ALPS and mean DTI-ALPS index in the prediabetes group were positively correlated with 2-hour postprandial blood glucose level; the left-side DTI-ALPS index was negatively correlated with total cholesterol and low-density lipoprotein level. The right-side DTI-ALPS and mean DTI-ALPS index were negatively correlated with the glycosylated hemoglobin level and waist-to-hip ratio in the prediabetes group. The left-side, right-side, and mean DTI-ALPS index in the T2DM group were positively correlated with height. The left-side and mean DTI-ALPS index in the T2DM group were negatively correlated with high-density lipoprotein levels. CONCLUSION: Cerebral glymphatic system dysfunction may mainly occur in the T2DM stage. Various clinical variables were found to affect the DTI-ALPS index in different glucose metabolism states. This study enhances our understanding of the pathophysiology of diabetic brain damage and provides some potential biological evidence for its early diagnosis.

Study on the Multitarget Mechanism and Active Compounds of Essential Oil from Artemisia argyi Treating Pressure Injuries Based on Network Pharmacology.

In order to comprehensively explore multitarget mechanism and key active compounds of Artemisia argyi essential oil (AAEO) in the treatment of pressure injuries (PIs), we analyzed the biological functions and pathways involved in the intersection targets of AAEO and PIs based on network pharmacology, and the affinity of AAEO active compounds and core targets was verified by molecular docking finally. In our study, we first screened 54 effective components according to the relative content and biological activity. In total, 103 targets related to active compounds of AAEO and 2760 targets associated with PIs were obtained, respectively, and 50 key targets were overlapped by Venny 2.1.0. The construction of key targets-compounds network was achieved by the STRING database and Cytoscape 3.7.2 software. GO analysis from Matespace shows that GO results are mainly enriched in biological processes, including adrenergic receptor activity, neurotransmitter clearance, and neurotransmitter metabolic process. KEGG analysis by the David and Kobas website shows that the key targets can achieve the treatment on PIs through a pathway in cancer, PI3K-Akt signaling pathway, human immunodeficiency virus 1 infection, MAPK signaling pathway, Wnt signaling pathway, etc. In addition, molecular docking results from the CB-Dock server indicated that active compounds of AAEO had good activity docking with the first 10 key targets. In conclusion, the potential targets and regulatory molecular mechanisms of AAEO in the treatment of PIs were analyzed by network pharmacology and molecular docking. AAEO can cure PIs through the synergistic effect of multicomponent, multitarget, and multipathway, providing a theoretical basis and new direction for further study.

Reduction-active Fe3O4-loaded micelles with aggregation- enhanced MRI contrast for differential diagnosis of Neroglioma.

Differential diagnosis between inflammatory mass and malignant glioma is of great significance to patients, which is the basis for developing accurate individualized treatment. Due to the lack of non-invasive imaging characterization methods in the clinical application, the current diagnosis grading of glioma mainly depended on the pathological biopsy, which is complicated and risky. This study aims to develop a non-invasive imaging differential diagnosis method of glioma based on the reduction activated strategy of intracellular aggregation of sensitive superparamagnetic Fe3O4 nanoparticles (SIONPs). In vitro and in vivo magnetic resonance imaging results indicated that SIONPs could specifically increase the T2 relaxation rate and enhance MR imaging in tumor with redox microenvironment by the response-aggregation in the tumorous site. In vivo experiments also demonstrate that the substantial improvement of T2-weighted imaging contrast could be used to differentiate inflammatory mass and malignant glioma. The reduction-active MR imaging contrast agent offers a new paradigm for designing "smart" MR imaging probes of differential diagnosis of the tumor.

Single-Component Bismuth Nanoparticles as a Theranostic Agent for Multimodal Imaging-Guided Glioma Therapy.

Single-component nanomaterials such as bismuth (Bi) based on nanoparticles (NPs) intrinsically having both diagnostic and therapeutic capabilities are widely needed in biomedical fields. However, their design and fabrication still face enormous challenges. Here, a kind of pure Bi NPs with ultrahigh X-ray attenuation coeffcient was developed and evaluated as a simple but powerful theranostic nanomaterals and potent light-to-heat conversion efficiency for photoacuostic imaging (PAI)/photothermal therapy (PTT) in this study. The prepared pure Bi NPs showed excellent photothermal performance and the temperature of NPs solution (1 mg/mL) increased to 70 °C under near-infrared light irradiation within 4 min. The pure Bi NPs showed obvious enhancement effect both in X-ray computed tomography (CT) and PA imaging modalities in vivo. In addition, the glioma growth was efficiently suppressed by the pure Bi NPs after 808 nm laser irradiation, while maintained the biosafety and low toxicity. Thus, it is notable that this type of Bi nanomaterial has great potential in multi-imaging guided cancer treatment.

Evaluation of methotrexate-conjugated gadolinium(III) for cancer diagnosis and treatment.

BACKGROUND: Gliomas are one of the most common types of primary brain tumors. It is usually evaluated by gadolinium(III)-based contrast agents by magnetic resonance imaging (MRI) in the clinic. Methotrexate (MTX), as a type of folate analog that inhibits the enzyme dihydrofolate reductase, is widely used as a chemotherapeutic agent to treat gliomas in the experiment. PURPOSE: In this study, a novel theranostic agent MTX-DOTA-Gd (MTX-Gd) was synthesized, which integrates magnetic resonance imaging (MRI) with anticancer treatment. METHODS: MTX-Gd was synthesized by connecting MTX and Gd through 1,4,7,10-tetraazacy-clododecane-1,4,7,10-tetraacetic acid (DOTA). The characterization of MTX-Gd was detected by ultraviolet (UV) and infrared spectroscopy (IR). To confirm the antitumor effect of MTX-Gd, the cytotoxicity of MTX-Gd was examined by the MTT assay. The contrast enhancement of the MTX-Gd was measured through MRI in vitro. Then, nude mice bearing C6 tumor xenografts were used to study in vivo imaging capabilities. RESULTS: The ultraviolet-visible-near infrared radiation (UV-NIR) absorption curve indicated that MTX-Gd had a broad absorption in the region of 500-700 nm. The formation of MTX-Gd was confirmed from the characteristic bands of MTX-DOTA-Gd in the 1413 cm-1 (C-N), 1577 cm-1 (-NH2), and 3429 cm-1 (N-H), in the fourier-transform infrared (FTIR) spectra. MTX-Gd showed little difference in the cell viability compared with MTX, except for the highest concentration (270 µM). In vitro, the imaging of MTX-Gd was significantly brighter than Gd-DOTA at the same concentration, and the brightness and signal intensity of MRI were increased followed by the increased concentration of MTX-Gd. And it also showed that MTX was not visualized on MRI. The other images revealed that the concentration of 4 mM MTX-Gd had the same imaging effect with the concentration of 10 mM Gd-DOTA. Then, MTX-Gd was injected in nude mice bearing C6 tumor xenografts through the tail vein. Significant contrast enhancement was observed at the tumor site from 0.5 h to 3 h. The signal of tumor area was strongest at 3 h due to accumulation by size effect of macromolecules. CONCLUSION: A novel stable and unique theranostic agent (MTX-Gd) was successfully synthe-sized, and it has good stability, strong anticancer ability and excellent magnetic capacity. The methotrexate component of MTX-Gd, as a chemotherapeutic agent, played an important role in targeted therapies of cancer. The DOTA-Gd component of MTX-Gd performed as the MRI contrast agent. The superior MRI imaging performance and synergetic chemical antineoplastic ability of MTX-Gd was revealed, and it has great potential in the diagnosis and treatment of glioma and potentially other cancers, with prospects of clinical application in the near future.

Gadolinium-chelate functionalized bismuth nanotheranostic agent for in vivo MRI/CT/PAI imaging-guided photothermal cancer therapy.

Multifunctional nanomaterials with simple structure and good biosafety, integrating multimodal imaging and therapeutic functions, can facilitate the development of clinical cancer treatments. Here, a simple but powerful pure bismuth based nanoparticle (Gd-PEG-Bi NPs) was developed from pure Bi NPs and gadolinium-diethylenetriaminepentaacetic acid-bis-tetradecylamide, which not only shows high quality MRI/CT/PAI triple-modal imaging, but can also be a potent photothermal therapy agent under the guidance of the triple-modal imaging. The Gd-PEG-Bi NPs showed good stability and excellent biocompatibility. In vitro and in vivo study demonstrated that Gd-PEG-Bi NPs have ultrahigh X-ray attenuation coefficient, short T1 relaxation time in MRI, and strong PAI signal. Following the imaging diagnosis, the excellent light-to-heat conversion efficiency of Gd-PEG-Bi NPs was capable of suppressing the tumor growth effectively under near-infrared laser radiation in vivo. Such multifunctional nanoparticles were ideal candidates for cancer diagnosis and treatment.

MRI-guided targeting delivery of doxorubicin with reduction-responsive lipid-polymer hybrid nanoparticles.

In recent years, there has been increasing interest in developing a multifunctional nanoscale platform for cancer monitoring and chemotherapy. However, there is still a big challenge for current clinic contrast agents to improve their poor tumor selectivity and response. Herein, we report a new kind of Gd complex and folate-coated redox-sensitive lipid-polymer hybrid nanoparticle (Gd-FLPNP) for tumor-targeted magnetic resonance imaging and therapy. Gd-FLPNPs can simultaneously accomplish diagnostic imaging, and specific targeting and controlled release of doxorubicin (DOX). They exhibit good monodispersity, excellent size stability, and a well-defined core-shell structure. Paramagnetic nanoparticles based on gadolinium-diethylenetriaminepentaacetic acid-bis-cetylamine have paramagnetic properties with an approximately two-fold enhancement in the longitudinal relaxivity compared to clinical used Magnevist. For targeted and reduction-sensitive drug delivery, Gd-FLPNPs released DOX faster and enhanced cell uptake in vitro, and exhibited better antitumor effect both in vitro and in vivo.

Near-infrared light-triggered theranostics for tumor-specific enhanced multimodal imaging and photothermal therapy.

The major challenge in current clinic contrast agents (CAs) and chemotherapy is the poor tumor selectivity and response. Based on the self-quench property of IR820 at high concentrations, and different contrast effect ability of Gd-DOTA between inner and outer of liposome, we developed "bomb-like" light-triggered CAs (LTCAs) for enhanced CT/MRI/FI multimodal imaging, which can improve the signal-to-noise ratio of tumor tissue specifically. IR820, Iohexol and Gd-chelates were firstly encapsulated into the thermal-sensitive nanocarrier with a high concentration. This will result in protection and fluorescence quenching. Then, the release of CAs was triggered by near-infrared (NIR) light laser irradiation, which will lead to fluorescence and MRI activation and enable imaging of inflammation. In vitro and in vivo experiments demonstrated that LTCAs with 808 nm laser irradiation have shorter T1 relaxation time in MRI and stronger intensity in FI compared to those without irradiation. Additionally, due to the high photothermal conversion efficiency of IR820, the injection of LTCAs was demonstrated to completely inhibit C6 tumor growth in nude mice up to 17 days after NIR laser irradiation. The results indicate that the LTCAs can serve as a promising platform for NIR-activated multimodal imaging and photothermal therapy.

MRI-guided tumor chemo-photodynamic therapy with Gd/Pt bifunctionalized porphyrin.

Porphyrin derivatives have been widely applied in MR imaging and photodynamic cancer therapy. We here report a novel Gd/Pt bifunctionalized porphyrin derivative (Gd/Pt-P1) for MRI-guided chemo-photodynamic cancer therapy. Gd/Pt-P1 was prepared from tetra(4-pyridyl) porphyrin (P1) via step by step coordination to cisplatin and gadolinium (Gd(iii)). Gd/Pt-P1 showed a particularly high synergetic chemo-photodynamic antitumor effect in vivo with a tumor inhibition rate (TIR) of 96.6% and excellent MR imaging performance.

Codelivery of doxorubicin and triptolide with reduction-sensitive lipid-polymer hybrid nanoparticles for in vitro and in vivo synergistic cancer treatment.

Codelivery is a promising strategy to overcome the limitations of single chemotherapeutic agents in cancer treatment. Despite progress, codelivery of two or more different functional drugs to increase anticancer efficiency still remains a challenge. Here, reduction-sensitive lipid-polymer hybrid nanoparticles (LPNPs) drug delivery system composed of monomethoxy-poly(ethylene glycol)-S-S-hexadecyl (mPEG-S-S-C16), soybean lecithin, and poly(D,L-lactide-co-glycolide) (PLGA) was used for codelivery of doxorubicin (DOX) and a Chinese herb extract triptolide (TPL). Hydrophobic DOX and TPL could be successfully loaded in LPNPs by self-assembly. More importantly, drug release and cellular uptake experiments demonstrated that the two drugs were reduction sensitive, released simultaneously from LPNPs, and taken up effectively by the tumor cells. DOX/TPL-coloaded LPNPs (DOX/TPL-LPNPs) exhibited a high level of synergistic activation with low combination index (CI) in vitro and in vivo. Moreover, the highest synergistic therapeutic effect was achieved at the ratio of 1:0.2 DOX/TPL. Further experiments showed that TPL enhanced the uptake of DOX by human oral cavity squamous cell carcinoma cells (KB cells). Overall, DOX/TPL-coencapsulated reduction-sensitive nanoparticles will be a promising strategy for cancer treatment.