Glucose Transporters Are Key Components of the Human Glucostat.

Mouse models are extensively used in metabolic studies. However, inherent differences between the species, notably their blood glucose levels, hampered data translation into clinical settings. In this study, we confirmed GLUT1 to be the predominantly expressed glucose transporter in both adult and fetal human ß-cells. In comparison, GLUT2 is detected in a small yet significant subpopulation of adult ß-cells and is expressed to a greater extent in fetal ß-cells. Notably, GLUT1/2 expression in INS+ cells from human stem cell-derived islet-like clusters (SC-islets) exhibited a closer resemblance to that observed in fetal islets. Transplantation of primary human islets or SC-islets, but not murine islets, lowered murine blood glucose to the human glycemic range, emphasizing the critical role of ß-cells in establishing species-specific glycemia. We further demonstrate the functional requirements of GLUT1 and GLUT2 in glucose uptake and insulin secretion through chemically inhibiting GLUT1 in primary islets and SC-islets and genetically disrupting GLUT2 in SC-islets. Finally, we developed a mathematical model to predict changes in glucose uptake and insulin secretion as a function of GLUT1/2 expression. Collectively, our findings illustrate the crucial roles of GLUTs in human ß-cells, and identify them as key components in establishing species-specific glycemic set points.

Tracheal regeneration and mesenchymal stem cell augmenting potential of natural polyphenol-loaded gelatinmethacryloyl bioadhesive.

Hydrogels incorporating natural biopolymer and adhesive substances have extensively been used to develop bioactive drugs and to design cells encapsulating sturdy structure for biomedical applications. However, the conjugation of the adhesive in most hydrogels is insufficient to maintain long-lasting biocompatibility inadequate to accelerate internal organ tissue repair in the essential native cellular microenvironment. The current work elaborates the synthesis of charged choline-catechol ionic liquid (BIL) adhesive and a hydrogel with an electronegative atom rich polyphenol (PU)-laden gelatinmethacryloyl (GelMA) to improve the structural bioactivities for in vivo tracheal repair by inducing swift crosslinking along with durable mechanical and tissue adhesive properties. It was observed that bioactive BIL and PU exhibited potent antioxidant (IC 50 % of 7.91 µg/mL and 24.55 µg/mL) and antibacterial activity against E. coli, P. aeruginosa and S. aureus. The novel integration of photocurable GelMA-BIL-PU revealed outstanding mechanical strength, biodegradability and sustained drug release. The in vitro study showed exceptional cell migration and proliferation in HBECs, while in vivo investigation of the GelMA-BIL-PU hydrogel on a rat's tracheal model revealed remarkable tracheal reconstruction, concurrently reducing tissue inflammation. Furthermore, the optimized GelMA-BIL-PU injectable adhesive bioink blend demonstrated superior MSCs migration and proliferation, which could be a strong candidate for developing stem cell-rich biomaterials to address multiple organ defects.

i-MYO: A multi-grasp prosthetic hand control system based on gaze movements, augmented reality, and myoelectric signals.

BACKGROUND: Controlling a multi-grasp prosthetic hand still remains a challenge. This study explores the influence of merging gaze movements and augmented reality in bionics on improving prosthetic hand control. METHODS: A control system based on gaze movements, augmented reality, and myoelectric signals (i-MYO) was proposed. In the i-MYO, the GazeButton was introduced into the controller to detect the grasp-type intention from the eye-tracking signals, and the proportional velocity scheme based on the i-MYO was used to control hand movement. RESULTS: The able-bodied subjects with no prior training successfully transferred objects in 91.6% of the cases and switched the optimal grasp types in 97.5%. The patient could successfully trigger the EMG to control the hand holding the objects in 98.7% of trials in around 3.2 s and spend around 1.3 s switching the optimal grasp types in 99.2% of trials. CONCLUSIONS: Merging gaze movements and augmented reality in bionics can widen the control bandwidth of prosthetic hand. With the help of i-MYO, the subjects can control a prosthetic hand using six grasp types if they can manipulate two muscle signals and gaze movement.

Effects of Chalcogen Atoms on Excited-State Double-Proton Transfer Behavior for 3,6-bis(4,5-Dihydroxyoxazo-2-yl)benzene-1,2-diol Derivatives: A Computational Investigation.

The impact of the chalcogen atomic electronegativity (O, S, and Se atoms) of new organic molecules on excited-state dynamical reactions is self-evident. Inspired by this kind of distinguished photochemical characteristic, in this work, we performed a computational investigation of chalcogen-substituted 3,6-bis(4,5-dihydroxyoxazo-2-yl)benzene-1,2-diol (BDYBD) derivatives (i.e., BDYBD-O, BDYBD-S, and BDYBD-Se). In this paper, we pay close attention to characteristic BDYBD derivatives that contain intramolecular double hydrogen bonds (O1-H2···N3 and O4-H5···N6). The main goal of this study was to explore how changes in atomic electronegativity affect the way hydrogen bonds interact and how excited molecules affect transfer protons. We go into further detail in the main text of the paper. By fixing our attention to geometrical variations and infrared (IR) vibrational spectra between the S0 and S1 states, exploring hydrogen bonding behaviors using the core-valence bifurcation (CVB) index, and simulating hydrogen bonding energy (EHB) via the atom in molecule (AIM) method, we clarified the photo-induced strengthened dual hydrogen bonding interactions that facilitate the excited-state dual-proton transfer (ESDPT) behavior of BDYBD derivatives. The reorganization of charge stemming from photoexcitation further verifies the tendencies of ESDPT reactions. We relied on constructing potential energy surfaces (PESs) by adopting a restrictive optimization approach, and herein, we finally clarify the gradual ESDPT mechanism of BDYBD derivatives. Particularly, we confirm that the variation in chalcogen atomic electronegativity has a regulatory effect on the ESDPT behavior of BDYBD derivatives; that is, the lower the atomic electronegativity, the more favorable it is for the gradual ESDPT reaction.

Expression and role of melatonin membrane receptors in the hypothalamic-pituitary-testicular axis of Tibetan sheep in a plateau pastoral area.

MTNR1A and MTNR1B, two high-affinity MT membrane receptors found in mammals, mediate the activity of MT on the HPGA to regulate animal reproduction. Nevertheless, the expression patterns and function of the MTNR1A and MTNR1B genes in the HPTA of seasonal estrus sheep and perennial estrus sheep have not been elucidated. We studied the expression of MTNR1A and MTNR1B in the hypothalamic-pituitary-testicular axis (HPTA) of Tibetan sheep at different reproductive stages using histochemistry, enzyme linked immunosorbent assay (ELSIA), scanning electron microscopy, transmission electron microscopy, quantitative Real-time PCR (qRT-PCR), and Western blot (WB), and analyzed the relationship between their expression and reproductive hormone receptors. We also compared relevant characteristics between seasonal Tibetan sheep and non-seasonal Small Tail Han sheep in the same pastoral area. The results showed that MTNR1A and MTNR1B were expressed in all tissues of the Tibetan sheep HPTA, and both were co-expressed in the cytoplasm of epididymis basal and halo cells located at common sites of the epididymis basement membrane, forming an immune barrier. The qRT-PCR analysis showed that not only MTNR1A but also N-acetyltransferase (AANAT), hydroxyindole-oxygen- methyltransferase (HIOMT), androgen receptor (AR), and estrogen receptor α (ERα) mRNA expression was significantly upregulated in the testis and epididymis of Tibetan sheep during the breeding season, whereas no clear upregulation of these genes was observed in the tissues of Small Tail Han sheep. MTNR1A and MTNR1B are important regulators of the HPTA in sheep. MTNR1A mediates seasonal estrus regulation in Tibetan sheep. Both MTNR1A and MTNR1B may play important roles in formation of the blood-epididymal barrier. The results of this study should help advance research on the mechanism of reproductive regulation of the HPTA in male animals and provide reference data for improving the reproductive rate of seasonal breeding animals.

A Novel 1000 MPa Grade Ultrafine-Grained Dual-Phase Press Hardening Steel with Superior Oxidation Resistance and High Ductility.

1000 MPa grade low-carbon martensite press hardening steels (PHS) are widely used in energy-absorbing domains of automotive parts, such as the bottom of a B-pillar. To prevent oxide scale formation during hot forming, this PHS is often required to be protected by an additional Al-Si coating. In addition, although the low carbon martensitic microstructure grants it excellent bending toughness, the ductility tends to be limited. In this study, a novel 1000 MPa grade ultrafine-grained (UFG) martensite-ferrite (F-M) dual-phase (DP) PHS with superior oxidation resistance was designed using tailored additions of Cr, Mn, and Si, and refining the initial microstructure. Only 0.55 ± 0.18 µm thick oxide film is formed in the designed steel during austenitizing heating and stamping, which is significantly lower than the 24.6 ± 3.1 µm thick oxide film formed in conventional 1000 MPa grade low-carbon martensite PHS under the identical condition. The superior oxidation resistance of designed steel can be attributed to the rapid formation of the protective Si-rich, Cr-rich, and Mn-rich oxide layers during annealing. Moreover, due to the presence of ferrite and ultrafine microstructure, the designed steel also shows a significant improvement in ductility from 8.5% to 16.8% without sacrificing strength and bending toughness compared with conventional 1000 MPa grade low-carbon martensite PHS.

Carbon dots, cellulose nanofiber, and essential oil nanoemulsion from Torreya grandis aril added to fish scale gelatin film for tomato preservation.

In this study, carbon dots (CDs), cellulose nanofibers (CNF) and essential oil nanoemulsion (EON) were extracted from the aril waste of Torreya grandis following nuts production. These three nanomaterials were formulated for the preparation of a composite film to be employed for postharvest tomato storage. Visual, microscopical and physicochemical properties of the prepared nanocomposite films were analyzed at different levels of CDs and CNF for optimization purposes. The UV absorption and antioxidant capacity of gelatin film with 10 % CDs (G/10CD) were enhanced compared with gelatin (G) film, concurrent with a reduction in water barrier capacity, water contact angle (WCA) and tensile strength (TS). Compared with G/10CD film, the WCA of G film after incorporation of 10 % CDs and 3 wt% CNF (G/10CD/3CNF) was significantly increased by 14.5°at 55 s. In contrast, TS increased by 1.26 MPa, as well as the significant enhancement in water barrier capacity. The above composite film mixed with EON (G/10CD/3CNF/EON) exerted further antimicrobial effects against Escherichia coli. G/10CD/3CNF/EON coating effectively extended tomato shelf life compared with the control group. Therefore, this new eco-friendly film presents several advantages of biodegradability, sustainability as well as multifunctional properties posing it as potential packaging material for food applications.

The histologic comparison of submandibular gland between yak and yellow cattle.

The purpose of this study was to compare between the histochemical characteristics and the expression of epidermal growth factor (EGF) and it's receptor (EGFR) in the submandibular gland (SMG) of adult yaks and yellow cattle. The SMG tissues of yaks and yellow cattles were collected for histochemical, immunohistochemical (IHC), immunofluorescence (F-IHC)，real-time quantitative polymerasechain reaction (RT-qPCR) and Western blotting methods. The results showed that the striated ducts of SMG were highly developed and connected to the intercalated ducts, which were shorter and directly connected to the acini. Compared with yellow cattle, yak SMG contains more mucous acini. Immunofluorescence showed significant expression of EGF and its receptor in both striated and intercalated ducts of these two species of cattle. Statistical analysis divulged that the distribution density of EGF and EGFR in the SMG of the yak was both significantly higher than that in yellow cattle (p < 0.05). Furthermore, the mRNA expression of EGF and EGFR in yak SMG was also higher than that in yellow cattle. The above results indicated that the intercalated ducts and striated ducts are the main expression sites of EGF and EGFR, the acidic mucin and EGF secreted from SMG of yak were more than that from yellow cattle. The results of this study provide powerful data for the study of physiological functions of submaxillary gland in ruminants and also provide important clues for the study of adaptive physiological mechanisms in plateau organisms.

MLL3 loss drives metastasis by promoting a hybrid epithelial-mesenchymal transition state.

Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) is crucial to metastatic seeding and outgrowth. However, the mechanisms governing the hybrid EMT state remain poorly defined. Here we showed that deletion of the epigenetic regulator MLL3, a tumour suppressor frequently altered in human cancer, promoted the acquisition of hybrid EMT in breast cancer cells. Distinct from other EMT regulators that mediate only unidirectional changes, MLL3 loss enhanced responses to stimuli inducing EMT and mesenchymal-epithelial transition in epithelial and mesenchymal cells, respectively. Consequently, MLL3 loss greatly increased metastasis by enhancing metastatic colonization. Mechanistically, MLL3 loss led to increased IFNγ signalling, which contributed to the induction of hybrid EMT cells and enhanced metastatic capacity. Furthermore, BET inhibition effectively suppressed the growth of MLL3-mutant primary tumours and metastases. These results uncovered MLL3 mutation as a key driver of hybrid EMT and metastasis in breast cancer that could be targeted therapeutically.

Sandwich-type electrochemical immunosensing of hypopharyngeal carcinoma biomarker carcinoembryonic antigen based on N-doped hollow mesoporous nanocarbon spheres/gold hybrids as sensing platform and gold/ferrocene as signal amplifier.

In the present work, a highly sensitive sandwich-type electrochemical immunosensor of carcinoembryonic antigen (CEA) was developed by preparing N-doped hollow mesoporous nanocarbon spheres/gold hybrids (NHMN/Au) hybridsas sensing platformand Au/ferrocene (Au/Fc) as signal amplifiers. The large surface area and high conductivity as well as good biocompatibility of NHMN/Au can increase the loading of primary antibody (Ab1) and accelerate the electron transport rate of the electrode surface, while Au can carry immobilized secondary antibodies (Ab2) and Fc derivative (Fc-SH).By using Fc-SH as response probe, the experiments show that the peak current of probe could increase after occurring the specific recognition of Ab1-CEA-Ab2, thus a novel sandwich-type immunosensor of CEA was developed. Finally, the proposed method for CEA detection was applied in human serum and the obtained results are satisfactory, indicating the developed method has important clinical applications for CEA determination.

Virtual-force-guided intraoperative ultrasound scanning with online lesion location prediction: A phantom study.

BACKGROUND: In ultrasound-guided minimally invasive surgery (MIS) of tumours, it is crucial to discover the optimal scanning plane (OSP) and organise the MIS scalpel work trajectory in this plane. The OSP can be altered and is challenging to track when the scalpel interacts with deformed tissues. Therefore, tracking the OSP becomes critical in MIS. In master-slave control, virtual force (VF) is used to assist the operator in completing the task. However, most literature assumes that the environment is sufficiently stable. No specific method focuses on tracking the OSP of the lesion within largely deformed tissues. METHODS: This paper used the improved artificial potential field method to establish the VF that could guide the operator to track the OSP. When tissue deformation occurred, an artificial neural network (ANN) was used to predict the target position, guiding the operator to find the new OSP. An experimental robot platform was built to verify the proposed algorithm's effects. Experiments to track the OSP were performed on a phantom. RESULTS: The results showed that the presented method could reduce the trajectory redundancy of ultrasonic scanning, shorten the time of OSP discovery and tracking, and decrease the deviation between the ultrasonic scanning position and the OSP. CONCLUSIONS: This method has significance for the accurate localization and successful removal of tumours. Future work will focus on improving the adaptability of the proposed ANN prediction model in different phantoms.

Fabricating Dual-Functional Plasmonic-Magnetic Au@MgFe2O4 Nanohybrids for Photothermal Therapy and Magnetic Resonance Imaging.

Bifunctional nanohybrids possessing both plasmonic and magnetic functionalities are of great interest for biomedical applications owing to their capability for simultaneous therapy and diagnostics. Herein, we fabricate a core-shell structured plasmonic-magnetic nanocomposite system that can serve as a dual-functional agent due to its combined photothermal therapeutic and magnetic resonance imaging (MRI) functions. The photothermal activity of the hybrid is attributed to its plasmonic Au core, which is capable of absorbing near-infrared (NIR) light and converting it into heat. Meanwhile, the magnetic MgFe2O4 shell exerts its ability to act as a MRI contrast agent. Our in vivo studies using tumor-bearing mice demonstrated the nanohybrids' excellent photothermal and MRI properties. As a photothermal therapeutic agent, the nanohybrids were able to dramatically shrink solid tumors in mice through NIR-induced hyperthermia. As T 2-weighted MRI contrast agents, the nanohybrids were found capable of substantially reducing the MRI signal intensity of the tumor region at 10 min postinjection. With their dual plasmonic-magnetic functionality, these Au@MgFe2O4 nanohybrids hold great promise not only in the biomedical field but also in the areas of catalysis and optical sensing.

Injectable hydrogel for postoperative synergistic photothermal-chemodynamic tumor and anti-infection therapy.

Tumor surgery is usually accompanied by neoplasm residual, tissue defects, and multi-drug resistant bacterial infection, causing high tumor recurrence, low survival rate, and chronic wounds. Herein, a light-activated injectable hydrogel based on bioactive nanocomposite system is developed by incorporating Ag2S nanodots conjugated Fe-doped bioactive glass nanoparticles (BGN-Fe-Ag2S) into biodegradable PEGDA and AIPH solution for inhibiting tumor growth, treating bacterial infection, and promoting wound healing. Under laser irradiation, the photothermal effect mediated by Ag2S nanodots would trigger the decomposition of AIPH, generating alkyl radicals to initiate the gelation of PEGDA. The in-situ gelatinized hydrogel, with outstanding photothermal effect and chemodynamic effect derived from the doped Fe in BGN-Fe-Ag2S, can not only eliminate multidrug-resistant bacteria but also efficiently ablated tumor during treatment. Moreover, the hydrogel significantly accelerated wound healing with more skin appendages in the full-thickness cutaneous wounds model because of the hydrolysis of bioactive glass. These results manifest that this multifunctional hydrogel is a suitable biomaterial to inhibit tumor proliferation and overcome tissue bacterial infection after surgical removal of tumors.

Integrating waste fish scale-derived gelatin and chitosan into edible nanocomposite film for perishable fruits.

Petroleum-based plastics (such as polyethylene, polypropylene, polyvinyl chloride, polystyrene, etc.) as white waste have caused great concern in the environment. It is urgent to develop a kind of biodegradable, biocompatible and non-toxic materials to replace them. Herein, an environmental-friendly edible film for postharvest fruits refreshing application was prepared by combining the waste fish scale-derived gelatin, chitosan as well as CaCO3 nanoparticles. The as-prepared nanocomposite film showed the multifunctional features, such as UV absorption, antimicrobial, oxygen screening, excellent mechanical properties and non-toxic. In addition, the protein-polysaccharide based nanocomposite film was hydrophilic and can be easily washed away on fruits before eating. In order to inspect its preservative effect on fruits, longan and banana were chosen as the testing object. Our results showed that the edible multifunctional nanocomposite film can effectively extend the shelf life of longan by more than 3 days and banana by more than 5 days, compared with the control groups. Integrating natural biological macromolecules gelatin and chitosan into a multifunctional nanocomposite film with series of advantages of biodegradability, sustainability as well as multifunction is expected to be a potential preservative material for food packaging applications.

Epithelial cell plasticity drives endoderm formation during gastrulation.

It is generally accepted that epiblast cells ingress into the primitive streak by epithelial-to-mesenchymal transition (EMT) to give rise to the mesoderm; however, it is less clear how the endoderm acquires an epithelial fate. Here, we used embryonic stem cell and mouse embryo knock-in reporter systems to combine time-resolved lineage labelling with high-resolution single-cell transcriptomics. This allowed us to resolve the morphogenetic programs that segregate the mesoderm from the endoderm germ layer. Strikingly, while the mesoderm is formed by classical EMT, the endoderm is formed independent of the key EMT transcription factor Snail1 by mechanisms of epithelial cell plasticity. Importantly, forkhead box transcription factor A2 (Foxa2) acts as an epithelial gatekeeper and EMT suppressor to shield the endoderm from undergoing a mesenchymal transition. Altogether, these results not only establish the morphogenetic details of germ layer formation, but also have broader implications for stem cell differentiation and cancer metastasis.

QSER1 protects DNA methylation valleys from de novo methylation.

DNA methylation is essential to mammalian development, and dysregulation can cause serious pathological conditions. Key enzymes responsible for deposition and removal of DNA methylation are known, but how they cooperate to regulate the methylation landscape remains a central question. Using a knockin DNA methylation reporter, we performed a genome-wide CRISPR-Cas9 screen in human embryonic stem cells to discover DNA methylation regulators. The top screen hit was an uncharacterized gene, QSER1, which proved to be a key guardian of bivalent promoters and poised enhancers of developmental genes, especially those residing in DNA methylation valleys (or canyons). We further demonstrate genetic and biochemical interactions of QSER1 and TET1, supporting their cooperation to safeguard transcriptional and developmental programs from DNMT3-mediated de novo methylation.

Effects of Austenitizing Temperature on Tensile and Impact Properties of a Martensitic Stainless Steel Containing Metastable Retained Austenite.

Austenitizing temperature is one decisive factor for the mechanical properties of medium carbon martensitic stainless steels (MCMSSs). In the present work, the effects of austenitizing temperature (1000, 1020, 1040 and 1060 °C) on the microstructure and mechanical properties of MCMSSs containing metastable retained austenite (RA) were investigated by means of electron microscopy, X-ray diffraction (XRD), as well as tensile and impact toughness tests. Results suggest that the microstructure including an area fraction of undissolved M23C6, carbon and chromium content in matrix, prior austenite grain size (PAGS), fraction and composition of RA in studied MCMSSs varies with employed austenitizing temperature. By optimizing austenitizing temperature (1060 °C for 40 min) and tempering (250 °C for 30 min) heat treatments, the MCMSS demonstrates excellent mechanical properties with the ultimate tensile strength of 1740 ± 8 MPa, a yield strength of 1237 ± 19 MPa, total elongation (ductility) of 10.3 ± 0.7% and impact toughness of 94.6 ± 8.0 Jcm-2 at room temperature. The increased ductility of alloys is mainly attributed to the RA with a suitable stability via a transformation-induced plasticity (TRIP) effect, and a matrix containing reduced carbon and chromium content. However, the impact toughness of MCMSSs largely depends on M23C6 carbides.

Study on the correlation of bisphenol A exposure, pro-inflammatory gene expression, and C-reactive protein with potential cardiovascular disease symptoms in young adults.

Bisphenol A (BPA) is a plasticizer used in the manufacture of polycarbonate and epoxy resins. It was found that higher urinary BPA levels are more likely to be associated with coronary artery disease (CVD). In recent years, the increasing incidence of CVD among young people is observed, which may be related with inflammation rather than the traditional triple-H risk factors. BPA is an endocrine-disrupting chemical, and can induce oxidative stress and chronic inflammation since its estrogenic effect. Inflammatory responses could come from the stimulation of IκB kinases (IKKs) by estrogen receptors (ERs). Therefore, this study investigated the association of BPA exposure with the gene expression of pro-inflammatory response (ERs and IKKs), an inflammation biomarker of CVD (C-reactive protein, CRP), and physiologic index potency of CVD development symptoms in young adults. This study divided BPA exposure levels into high and low groups based on the median plasma BPA level (4.34 ng/mL), and found that the high BPA group obviously had higher BMI, blood pressure, plasma CRP levels, and gene expression of ERß and IKKß. BMI and gene expression of IKKß were also positively correlated with plasma CRP secretion. Furthermore, the study subjects with potential CVD development symptoms had the increased levels of BPA (OR 2.10, 95% CI 0.83-5.39), CRP (OR 2.61, 95% CI 1.03-10.6) and IKKß (OR 4.29, 95% CI 1.51-15.6). These results indicated that exposure to BPA is potentially associated with expression of pro-inflammatory genes related to CRP secretion, which may promote the risk of CVD development symptoms in young adults. This study highlighted the possible connection between BPA exposure and CVD development but the mechanism between them needs to be further explored.

Mitoxantrone as photothermal agents for ultrasound/fluorescence imaging-guided chemo-phototherapy enhanced by intratumoral H2O2-Induced CO.

Multimodal imaging integrated theranostic nanomaterials provides broad prospects for noninvasive and precise cancer treatment. However, the uncertain physiological metabolism of the existing phototherapy nanoagents greatly prevents its clinical application. Herein, a smart nanoplatform based on clinically chemotherapeutic drugs mitoxantrone (MTO) was prepared to realize ultrasound/fluorescence imaging-guided chemo-photothermal combined therapy. The nanoplatform encapsulating MTO and manganese carbonyl (MnCO), which denoted as MCMA NPs, could accumulate at tumor sites by enhanced permeability and retention (EPR) effect and effectively induce cell apoptosis. MTO with near-infrared absorption (~676 nm) not only acted as chemotherapy drug, but also served as photothermal reagent with high photothermal conversion efficiency (ƞ = 42.2%). Especially, H2O2 in tumor sites and the photothermal effect of MTO could trigger MnCO to generate CO, which made cancer cells more sensitive to MTO and significantly alleviated cell resistance. Simultaneously, CO released in tumor also could act as contrast agent for tumor ultrasound imaging to provide accurate guidance for anticancer treatment. Moreover, MCMA NPs could further promote oxidative stress damage in mitochondria and protect normal cells from side effects of chemotherapy. Both in vivo and in vitro studies indicated that MCMA NPs possessed excellent synergetic tumor inhibition ability with high efficiency and low chemotherapy resistance.

Activation of muscarinic acetylcholine receptor 1 promotes invasion of hepatocellular carcinoma by inducing epithelial-mesenchymal transition.

Hepatocellular carcinoma is the second leading cause of cancer-related death worldwide. Neural regulation plays an important role in the development of hepatocellular carcinoma, and activation of sympathetic nervous system can promote the migration and invasion of cancer cells. However, little research has been conducted on how the vagus nerve influences hepatocellular carcinoma. In this study, we found that the expression of vesicular acetylcholine transporter, a biomarker of vagus nerve, was associated with hepatocellular carcinoma patients' clinicopathological characteristics by immunohistochemistry. Further, activation of muscarinic acetylcholine receptor 1 (M1R) promoted HepG2 and SMMC-7721 cells migration and invasion and epithelial-mesenchymal transition via PI3K/Akt pathway. Moreover, inhibition of M1R by antagonist or shRNA suppressed hepatocellular carcinoma cells migration and invasion in vitro and in vivo, inhibited epithelial-mesenchymal transition and PI3K/Akt pathway. Therefore, these results indicate that activation of M1R promotes invasion of hepatocellular carcinoma through epithelial-mesenchymal transition and PI3K/Akt pathway.