Highly Efficient GSH-Responsive "Off-On" NIR-II Fluorescent Fenton Nanocatalyst for Multimodal Imaging-Guided Photothermal/Chemodynamic Synergistic Cancer Therapy.

Accurate diagnosis and effective treatment of malignant tumors under the interference of complex and diverse tumor microenvironments (TMEs) have become the focus of research. Herein, an innovative TME-activated biomimetic nanocatalyst with quad-modal imaging capabilities of second near-infrared (NIR-II) "turn-on" fluorescence imaging, magnetic resonance imaging (MRI), photoacoustic imaging (PAI), and photothermal imaging (PTI) was designed and developed for self-enhanced photothermal/chemodynamic synergistic therapy. The catalyst was fabricated by loading glucose oxidase (GOD) and Ag2S quantum dots (QDs) on MnO2 nanosheets and coating them with a 4T1 cell membrane (AMG@CM), which enables them to successfully escape immune clearance and have appealing tumor-targeting ability and biocompatibility. The NIR-II fluorescence at 1130 nm of Ag2S QDs quenched by MnO2 could be recovered in vivo through the glutathione (GSH)-induced degradation of MnO2, enabling excellent TME-responsive tumor visualization. Simultaneously, the released Mn2+ can catalyze H2O2 to produce abundant hydroxyl radicals (•OH), achieving photothermal synergistically enhanced chemodynamic therapy (CDT) under NIR-II radiation. Moreover, the CDT could be self-enhanced by GOD due to the extra produced H2O2. This work demonstrates a novel and highly efficient multimodal imaging-guided integrated treatment strategy for dual-enhanced CDT tumor precise diagnosis and treatment.

Surface Molecularly Engineered Mitochondria Conduct Immunophenotype Repolarization of Tumor-Associated Macrophages to Potentiate Cancer Immunotherapy.

Reprogramming tumor-associated macrophages (TAMs) to an inflammatory phenotype effectively increases the potential of immune checkpoint blockade (ICB) therapy. Artificial mitochondrial transplantation, an emerging and safe strategy, has made brilliant achievements in regulating the function of recipient cells in preclinic and clinic, but its performance in reprogramming the immunophenotype of TAMs has not been reported. Here, the metabolism of M2 TAMs is proposed resetting from oxidative phosphorylation (OXPHOS) to glycolysis for polarizing M1 TAMs through targeted transplantation of mannosylated mitochondria (mPEI/M1mt). Mitochondria isolated from M1 macrophages are coated with mannosylated polyethyleneimine (mPEI) through electrostatic interaction to form mPEI/M1mt, which can be targeted uptake by M2 macrophages expressed a high level of mannose receptors. Mechanistically, mPEI/M1mt accelerates phosphorylation of NF-κB p65, MAPK p38 and JNK by glycolysis-mediated elevation of intracellular ROS, thus prompting M1 macrophage polarization. In vivo, the transplantation of mPEI/M1mt excellently potentiates therapeutic effects of anti-PD-L1 by resetting an antitumor proinflammatory tumor microenvironment and stimulating CD8 and CD4 T cells dependent immune response. Altogether, this work provides a novel platform for improving cancer immunotherapy, meanwhile, broadens the scope of mitochondrial transplantation technology in clinics in the future.

[Effect of electroacupuncture on laparoscope postoperative shivering in patients undergoing general anesthesia].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on laparoscope postoperative shivering in patients undergoing general anesthesia and explore its effect mechanism. METHODS: A total of 80 patients with elective laparoscopic resection of intestinal tumor under general anesthesia were randomly divided into an EA group and a tramadol group, 40 cases in each group. Thirty min prior to the end of the operation, in the EA group, EA was exerted at Neimadian and Zusanli (ST 36), with disperse-dense wave, 2 Hz/100 Hz in frequency, 1 mA in intensity, and lasting 30 min. In the tramadol group, tramadol hydrochloride injection was dropped intravenously, 1 mg/kg. The conditions of shivering, dizziness, nausea, vomiting and agitation were observed in the post-anesthesia care unit (PACU). Heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were observed before treatment (T0), at the moment of extubation (T1), in 3 min of extubation (T2) and 1 h after operation (T3). Using ELISA, at T0 and T3, the expression levels of interleukin 6 (IL-6) and 5-hydroxytryptamine (5-HT) in plasma were detected separately. Choking and agitation were recorded during extubation. RESULTS: ① In the EA group, the incidence of shivering, dizziness, nausea, vomiting and agitation in the PACU was lower than that in the tramadol group (P<0.05). ②Compared with T0, HR, SBP and DBP were increased at T1 and T2 in the tramadol group (P<0.05). HR, SBP and DBP in the EA group were lower than the tramadol group at T1 and T2 (P<0.05). ③Compared with T0, the expression levels of IL-6 and 5-HT in plasma were increased at T3 in the tramadol group (P<0.05). The expression levels of IL-6 and 5-HT in the EA group were lower than the tramadol group at T3 (P<0.05). ④The incidence of choking and agitation during exudation in the EA group was lower than that in the tramadol group (P<0.05). CONCLUSION: Electroacupuncture can reduce the incidence of laparoscopic postoperative shivering under general anesthesia. The potential mechanism mays related to the modulation of the expression levels of IL-6 and 5-HT caused by surgical trauma.

Fe-Based Theranostic Agents Respond to the Tumor Microenvironment for MRI-Guided Ferroptosis-/Apoptosis-Inducing Anticancer Therapy.

Tumor microenvironment-specific magnetic resonance imaging (MRI) contrast agents are conducive to accurate diagnoses by visualization of biochemical and pathological changes for suitable treatment. Herein, we reported a pH-responsive contrast agent DFeZd NP with MRI diagnosis and tumor treatment capabilities. DFeZd NPs can map the pH change by modulating the MR signal in different acid-base environments. Moreover, T1 signals are stronger in the tumor site, which proves efficient in distinguishing malignant tumors from normal tissues, as well as demarcating the tumor boundary. Subsequently, sustained supply of Fe through the Fe-based contrast agent leads to Fe redox cycling and lipid peroxides, inducing ferroptosis in tumor cells. Furthermore, under an acidic tumor microenvironment, in the presence of ascorbic acid, increased Fe2+ is generated, which serves as a stronger inducer of ferroptosis. Moreover, due to the different relaxivity of Fe3+ and Fe2+, redox cycling and ferroptosis in tumors can be monitored by MRI. Therefore, we propose DFeZd NPs as accessible and promising Fe-based dopamine-derived contrast agents for specific MRI imaging and ferroptosis induction for anticancer therapy.

Application of quinpirole in the paraventricular thalamus facilitates emergence from isoflurane anesthesia in mice.

BACKGROUND AND PURPOSE: Dopamine is well-known to contribute to emergence from anesthesia. Previous studies have demonstrated that the paraventricular thalamus (PVT) in the midline nuclei is crucial for wakefulness. Moreover, the PVT receives dopaminergic projections from the brainstem. Therefore, we hypothesize that the dopaminergic signaling in the PVT plays a role in emergence from isoflurane anesthesia. METHODS: We used c-Fos immunohistochemistry to reveal the activity of PVT neurons in three groups: The first group (iso+ EM- ) underwent the anesthesia protocol and was sacrificed before emergence. The second group (iso+ EM+ ) underwent passive emergence from the same anesthesia protocol. The last group (oxy+ ) received oxygen. D2-like agonist quinpirole (2 or 4 mM) or D2-like antagonist raclopride (2 or 5 mM) was microinjected into the PVT, and their effects on emergence and induction time were analyzed. Surface cortical electroencephalogram (EEG) recordings were used to explore the effects of quinpirole injection into the PVT on cortical excitability during isoflurane anesthesia. The activity of PVT neurons after quinpirole injection was assessed by c-Fos immunohistochemistry. RESULTS: The number of c-Fos-positive nuclei for the iso+ EM+ group was significantly higher than the oxy+ and iso+ EM- groups. Application of quinpirole (4 mM) into the PVT shortened emergence time compared with the saline group (p < .01). In contrast, administration of raclopride (2 mM) delayed emergence time (p < .05). Neither quinpirole nor raclopride exerted an effect on induction time. EEG analyses showed that quinpirole (4 mM) decreased the burst suppression ratio during isoflurane anesthesia (p < .01). The number of c-Fos-positive nuclei for the quinpirole (4 mM) group was significantly higher than saline group (p < .01). CONCLUSIONS: Our findings suggest that the activity of PVT neurons is enhanced after emergence from anesthesia, and the dopaminergic signaling in the PVT may facilitate emergence from isoflurane anesthesia.

Locus Coeruleus to Paraventricular Thalamus Projections Facilitate Emergence From Isoflurane Anesthesia in Mice.

Locus coeruleus (LC) sends widespread outputs to many brain regions to modulate diverse functions, including sleep/wake states, attention, and the general anesthetic state. The paraventricular thalamus (PVT) is a critical thalamic area for arousal and receives dense tyrosine-hydroxylase (TH) inputs from the LC. Although anesthesia and sleep may share a common pathway, it is important to understand the processes underlying emergence from anesthesia. In this study, we hypothesize that LC TH neurons and the TH:LC-PVT circuit may be involved in regulating emergence from anesthesia. Only male mice are used in this study. Here, using c-Fos as a marker of neural activity, we identify LC TH expressing neurons are active during anesthesia emergence. Remarkably, chemogenetic activation of LC TH neurons shortens emergence time from anesthesia and promotes cortical arousal. Moreover, enhanced c-Fos expression is observed in the PVT after LC TH neurons activation. Optogenetic activation of the TH:LC-PVT projections accelerates emergence from anesthesia, whereas, chemogenetic inhibition of the TH:LC-PVT circuit prolongs time to wakefulness. Furthermore, optogenetic activation of the TH:LC-PVT projections produces electrophysiological evidence of arousal. Together, these results demonstrate that activation of the TH:LC-PVT projections is helpful in facilitating the transition from isoflurane anesthesia to an arousal state, which may provide a new strategy in shortening the emergence time after general anesthesia.

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.

Effect of Poly(ethylene glycol) (PEG) Surface Density on the Fate and Antitumor Efficacy of Redox-Sensitive Hybrid Nanoparticles.

The effects of poly(ethylene glycol) (PEG) on improving the biological compatibility and circulation time of nanocarriers are determined by the surface density of PEG on nanoparticles. PEG with high surface density on nanocarriers has greater accumulation in tumor tissues. However, this impairs the release of drugs loaded in the nanoparticles in the tumor tissues. The relations and internal regularities between the controlled stripping of PEG of nanoparticles and its fate and antitumor efficacy in vivo remain unsolved. Redox-sensitive hybrid nanoparticles coated with varied PEG densities were prepared by blending a redox-sensitive polymer of DLPE-SS-MPEG. To keep identical nanoproperties, these nanoparticles were prepared with a similar size distribution of around 100 nm. The effects of controlled stripping of PEG on antitumor activities of nanoparticles were then investigated. As the PEG surface density increased, lower cellular internalization by tumor cells was observed. However, nanoparticles with higher controlled stripping of PEG showed greater accumulation in tumor tissues and advanced antitumor activities in vivo.

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.

[Clinical study of electroacupuncture on perioperative analgesia in patients with thyroid surgery under cervical plexus block].

OBJECTIVE: To investigate the change trend and correlation between the perioperative pain degree and neuroendocrine hormone levels in the perioperative period on patients with thyroid surgery by electroacupuncture combined with cervical plexus block. METHODS: Forty patients with elective thyroidectomy were enrolled and divided into a control group and an observation group according to the random number table method, 20 cases in each group. In the control group, cervical plexus block was performed. In the observation group, the cervical plexus block combined with electroacupuncture (EA) were given. After the cervical plexus block was completed, the EA was applied at the bilateral Hegu (LI 4) and Neiguan (PC 6) for 30 min. The visual analog scale (VAS) was used to assess the pain level before anesthesia (T0), 2 h after operation (T1), 12 h after operation (T2), 24 h after operation (T3) and 48 h after operation (T4). Blood samples such as adrenocorticotropic hormone (ACTH), C-reactive protein (CRP) and ß-endorphin (ß-EP) were collected to measure the level of neuroendocrine hormones, and to analyze the correlation between ACTH, CRP, ß-EP and VAS scores. RESULTS: The VAS scores at T1, T2, T3 were higher than those at T0 in the two groups (all P<0.05). The VAS scores T1, T2 and T3 in the observation group were lower than those in the control group (all P<0.05). The ACTH and CRP in the control group at T1, T2 and T3 were significantly higher than those at T0 (all P<0.05). The ß-EP in the observation group at T1, T2 and T3 was significantly higher than that at T0 (all P<0.05). The ACTH and CRP in the observation group at T1, T2 and T3 were lower than those in the control group,and the ß-EP level was higher than that in the control group (all P<0.05).The VAS score was significantly positively correlated with ACTH and CRP levels, and negatively correlated with ß-EP. CONCLUSION: EA stimulation can inhibit the secretion of ACTH and CRP, promote the release of ß-EP, reduce the perioperative pain score, and inhibit the body's stress response.

[Effect of electroacupuncture combined with cervical plexus block on stress responses in patients undergoing thyroid surgery].

OBJECTIVE: To observe the effect of electroacupuncture (EA) combined with cervical plexus block (CPB) on the stress response of patients undergoing thyroid surgery. METHODS: Forty thyroidectomy patients were randomly divided into sham EA plus CPB group (sham group) and EA+CPB group (20 cases in each group). For patients of the sham group, deep cervical plexus block (25% ropivacaine hydrochloride + 1% lidocaine hydrochloride) was performed first, followed by inserting acupuncture needles into bilateral Hegu (LI 4) and Neiguan (PC 6) separately without needle manipulation and then connecting the output wires of the EA therapeutic instrument to the handles of the acupuncture needles but without electric current output. For patients of the EA+CPB group, deep cervical plexus block was performed first followed by EA stimulation [10 Hz, (6 +/- 2) mA] of the bilateral LI 4 and PC 6 for 20 min. Systolic blood pressure (SBP), heart rate (HR) and breathing frequency were detected using a multipurpose monitor. Plasma adrenocorticotropic hormone (ACTH) and cortisol (Cor) contents were determined using chemiluminescence method, plasma epinephrine (E) level was detected by enzyme-linked immunosorbent assay, glucose (Glu) assayed by oxidase method, and plasma C-reactive protein (CRP) level detected using immumofluorescence technique. RESULTS: (1) During surgery, the patients' SBP and HR of both sham and EA groups were increased significantly compared with their basic values (P < 0.05), but the levels of the increased SBP and HR of the EA group were obviously lower than those of the sham group (P < 0.05). (2) The levels of plasma ACTH during surgery and at the immediate time after surgery, Cor level at the immediate time after surgery, plasma E and Glu contents during surgery, at the immediate time and on day 1 after surgery, and plasma CRP at the immediate time, and on day 1 and 3 after surgery in the sham group were upregulated considerably (P < 0.05), while the levels of plasma ACTH, Cor, E, Glu and CRP in the above-mentioned time-points of the EA group were all remarkably lower than those of the sham group (P < 0.05). CONCLUSION: EA combined with cervical plexus block significantly reduces peri-operative cardiovascular stress responses and inhibits abnormal increases of plasma stress hormones and inflammatory reaction in patients undergoing thyroid surgery.