Cell-mediated drug-delivery systems have received considerable attention for their enhanced therapeutic specificity and efficacy in cancer treatment. Neutrophils (NEs), the most abundant type of ...immune cells, are known to penetrate inflamed brain tumours. Here we show that NEs carrying liposomes that contain paclitaxel (PTX) can penetrate the brain and suppress the recurrence of glioma in mice whose tumour has been resected surgically. Inflammatory factors released after tumour resection guide the movement of the NEs into the inflamed brain. The highly concentrated inflammatory signals in the brain trigger the release of liposomal PTX from the NEs, which allows delivery of PTX into the remaining invading tumour cells. We show that this NE-mediated delivery of drugs efficiently slows the recurrent growth of tumours, with significantly improved survival rates, but does not completely inhibit the regrowth of tumours.
Deep learning provides a great potential for in-loop filtering to improve both coding efficiency and subjective quality in video coding. State-of-the-art work focuses on network structure design and ...employs a single powerful network to solve all problems. In contrast, this paper proposes a deep learning based systematic approach that includes an effective Convolutional Neural Network (CNN) structure, a hierarchical training strategy, and a video codec oriented switchable mechanism. First, we propose a novel CNN structure, i.e., Squeeze-and-Excitation Filtering CNN (SEFCNN), as an optional in-loop filter. To capture the non-linear interaction between channels, the SEFCNN is comprised of two subnets, i.e., Feature EXtracting (FEX) subnet and Feature ENhancing (FEN) subnet. Then, we develop a hierarchical model training strategy to adapt the two subnets to different coding scenarios. For high-rate videos with small artifacts, we train a single global model using the FEX for all types of frames, whereas for low-rate videos with large artifacts, different models are trained using both FEX and FEN for different types of frames. Finally, we propose an adaptive enhancing mechanism which is switchable between the CNN-based and the conventional methods. We selectively apply the CNN model to some frames or some regions in a frame. Experimental results show that the proposed scheme outperforms state-of-the-art work in coding efficiency, while the computational complexity is acceptable after GPU acceleration.
Chronic stress is known to promote inflammatory bowel disease (IBD), but the underlying mechanism remains largely unresolved. Here, we found chronic stress to sensitize mice to dextran sulfate sodium ...(DSS)-induced colitis; to increase the infiltration of B cells, neutrophils, and proinflammatory ly6Chi macrophages in colonic lamina propria; and to present with decreased thymus and mesenteric lymph node (MLN) coefficients. Circulating total white blood cells were significantly increased after stress, and the proportion of MLN-associated immune cells were largely changed. Results showed a marked activation of IL-6/STAT3 signaling by stress. The detrimental action of stress was not terminated in IL-6−/− mice. Interestingly, the composition of gut microbiota was dramatically changed after stress, with expansion of inflammation-promoting bacteria. Furthermore, results showed stress-induced deficient expression of mucin-2 and lysozyme, which may contribute to the disorder of gut microbiota. Of note is that, in the case of cohousing, the stress-induced immune reaction and decreased body weight were abrogated, and transferred gut microbiota from stressed mice to control mice was sufficient to facilitate DSS-induced colitis. The important role of gut microbiota was further reinforced by broad-spectrum antibiotic treatment. Taken together, our results reveal that chronic stress disturbs gut microbiota, triggering immune system response and facilitating DSS-induced colitis.
Head and neck cancers are the seventh most frequent malignancy worldwide, consisting of a heterogeneous group of cancers that develop in the oral cavity, pharynx, and larynx, with head and neck ...squamous cell carcinoma (HNSCC) being the most common pathology. Due to limitations with screening and physical examination, HNSCC often presents in advanced disease states and is thus associated with poor survival. In this setting, liquid biopsies, or obtaining patient bodily fluid samples for cancer diagnosis and prognosis, may play a dramatic role in optimizing care for HNSCC patients. In recent years, there have been dramatic advancements in investigations focused on optimizing and implementing liquid biopsies in general, and specifically for HNSCC patients. Moving forward, there remain significant challenges in liquid biopsy technological development, as well as opportunities for the development of HNSCC liquid biopsy clinical trials and treatment paradigms. In this review, we discuss the current state of liquid biopsy technologies via circulating tumor cells, circulating tumor DNA and exosomes, approaches in head and neck cancer, challenges to optimization and application of liquid biopsies for clinical study, and future prospects for this field of research as it applies to head and neck cancer.
Multidrug resistance is one of the major causes limiting the efficacy of chemotherapeutic agents used to control osteosarcoma. Multidrug resistance protein 1 (MDR1 or ABCB1) was considered to play a ...critical role in multidrug resistance. Agents from traditional Chinese medicines (TCMs) have great potential to prevent the onset or delay the progression of the carcinogenic process, and also to enhance the efficacy of mainstream antitumor agents. Herein, we investigated the effect and mechanism of icariin in the human osteosarcoma doxorubicin (DOX)-resistant cell line MG-63/DOX. In this study, icariin exhibited significant effects in sensitization of the resistant cancer cells at a concentration non-toxic to doxorubicin. It also increased the intracellular doxorubicin accumulation and retention in MG-63/DOX cells. In addition, an increase in Rh123 accumulation and a decrease in Rh123 efflux were observed in MG-63/DOX cells treated with icariin, indicating a blockage of the activity of MDR1. Furthermore, icariin enhanced the apoptosis induced by doxorubicin and down-regulated the expression of MDR1. The mechanism involves the inhibition of phosphatidyl inositol 3-kinase (PI3K)/Akt signaling. In conclusion, icariin possesses a reversal effect on multidrug resistance in MG-63/DOX cells through down-regulation of the MDR1 and the PI3K/Akt pathway, and has the potential to be an adjunct to chemotherapy for osteosarcoma.
Venenum Bufonis, a well-known traditional Chinese medicine, has been widely used in Asia and has gained popularity in Western countries over the last decade. Venenum Bufonis has obvious side effects ...that have been observed in clinical settings, but few studies have reported on its cardiotoxicity. In this work, the cardiotoxicity of Venenum Bufonis was investigated using a 11H NMR-based metabolomics approach. The 1H NMR profiles of the serum, myocardial extracts and liver extracts of specific-pathogen-free rats showed that Venenum Bufonis produced significant metabolic perturbations dose-dependently with a distinct time effect, peaking at 2 hr after dosing and attenuating gradually. Clinical chemistry, electrocardiographic recordings, and histopathological evaluation provided additional evidence of Venenum Bufonis-induced cardiac damage that complemented and supported the metabolomics findings. The combined results demonstrated that oxidative stress, mitochondrial dysfunction, and energy metabolism perturbations were associated with the cardiac damage that results from Venenum Bufonis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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Effective targeting of mitochondria has emerged as a beneficial strategy in cancer therapy. However, the development of mitochondria-targeting ligands is difficult because of the low ...permeability of the mitochondrial double membrane. We found that hypericin (HY), a natural product isolated from Hypericum perforatum L., is an effective mitochondria-targeting ligand. HY-functionalized graphene oxide (GO) loaded with doxorubicin (GO-PEG-SS-HY/DOX) increased the synergistic anticancer efficacy of phototherapy and chemotherapy in the absence of apparent adverse side effects. In vitro and in vivo assays suggested GO-PEG-SS-HY/DOX induced the expression of the key proteins of the mitochondria-mediated apoptosis pathway and caused apoptosis of breast carcinoma cells. In addition, GO vehicle exhibited low toxicity toward normal cells, indicating high safety of functionalized GO preparations in antitumor therapy. Therefore, HY-functionalized GO can be successfully used as a platform technology to target mitochondria in cancer cells and improve the therapeutic efficacy of chemotherapeutic drugs.
Induction of mitochondria-mediated apoptosis is a promising approach in cancer therapy. However, mitochondria are difficult to access and permeate because of their negative membrane potential and highly dense double membrane. Mitochondria-targeting ligands can be conjugated to nanoparticles or small-molecule drugs to enhance their antitumor effect. Here, we showed that the natural photosensitizer hypericin is a novel mitochondria-targeting ligand and that graphene oxide particles co-loaded with hypericin and the chemotherapeutic agent doxorubicin exhibited a synergistic antitumor effect mediated by the mitochondrial-mediated apoptosis. Treatment with such particles in combination with laser irradiation led to apoptosis of the tumor MDA-MB-231 and MCF-7 cells in vitro and in vivo. Furthermore, treatment with hypericin/doxorubicin-functionalized graphene oxide had low cellular toxicity.
Gallium oxide (Ga2O3) films were deposited on MgO (100) substrates by metalorganic vapor phase epitaxy. Structure analyses showed that the films deposited at 550–700°C were epitaxial β-Ga2O3 films ...with an out of plane relationship of β-Ga2O3(100)||MgO(100). The film deposited at 650°C showed the best crystallinity and the microstructure of the film was investigated by high resolution transmission electron microscopy. A theoretical model of the growth mechanism was proposed and the in-plane epitaxial relationship was given to be β-Ga2O3001||MgO . A four-domain structure inside the epitaxial film was clarified. The β-Ga2O3 film deposited at 650°C showed an absolute average transmittance of 95.9% in the ultraviolet and visible range, which had an optical band gap of 4.87eV.
► Beta Ga2O3 epitaxial films were deposited on MgO(100) substrate. ► A theoretical model of the growth mechanism was proposed. ► The transmittance of the film in the ultraviolet and visible region exceeded 95.9%.
Key Message
Psoralen synthase and angelicin synthase responsible for the formation of psoralen and angelicin in Peucedanum praeruptorum Dunn were identified and functionally characterized, ...respectively.
Furanocoumarins were reported to possess several activities such as anticancer, anti-inflammatory and neuroprotective, and function as phytotoxin and allelochemical in plants. Furanocoumarins are the main bioactive ingredient in
P. praeruptorum
which is a commonly used traditional Chinese medicine. Phenylalanine ammonia lyase (PAL), 4-coumarate: CoA ligase (4CL),
p
-coumaroyl CoA 2’-hyfroxylase (C2’H) were cloned previously to elucidate the biosynthetic mechanism of coumarin lactone ring. However, the genes involved in complex coumarins in
P. praeruptorum
have not been explored. Herein, putative psoralen synthase
CYP71AJ49
and angelicin synthase
CYP71AJ51
were cloned from
P. praeruptorum
. In vivo and in vitro yeast assays were conducted to confirm their activities. Furthermore, the results of High Performance Liquid Chromatography–Electrospray Ionization Mass Spectrometry (HPLC–ESI–MS) verified that CYP71AJ49 catalyzed the conversion of marmesin to psoralen, and CYP71AJ51 catalyzed columbianetin to angelicin. Subsequently, the expression profile showed that
CYP71AJ49
and
CYP71AJ51
were easily affected by environmental conditions, especially UV and temperature. The genes tissue-specific expression and compounds tissue-specific distribution pattern indicated the existence of substance transport in
P. praeruptorum
. Phylogenetic analysis was conducted with 27 CYP71AJs, CYP71AJ49 and CYP71AJ51 were classified in I-4 and I-2, respectively. These results provide further insight to understand the biosynthetic mechanism of complex coumarins.
•A goldfish model was established to investigate the toxicity of lambda-cyhalothrin (LCT) exposure on multiple organs.•NMR based metabolomics approach were firstly used to provide a global view of ...the toxicity of LCT.•LCT induced neurotransmitters and osmoregulatory imbalances, oxidative stress, energy and amino acid metabolic disorders.•Glutamate–glutamine–GABA axis as a potential target for LCT toxicity was first found.
In this study, a 1H nuclear magnetic resonance (NMR) based metabolomics approach was applied to investigate the toxicity of lambda-cyhalothrin (LCT) in goldfish (Carassius auratus). LCT showed tissue-specific damage to gill, heart, liver and kidney tissues of goldfish. NMR profiling combined with statistical methods such as orthogonal partial least squares discriminant analysis (OPLS-DA) and two-dimensional statistical total correlation spectroscopy (2D-STOCSY) was developed to discern metabolite changes occurring after one week LCT exposure in brain, heart and kidney tissues of goldfish. LCT exposure influenced levels of many metabolites (e.g., leucine, isoleucine and valine in brain and kidney; lactate in brain, heart and kidney; alanine in brain and kidney; choline in brain, heart and kidney; taurine in brain, heart and kidney; N-acetylaspartate in brain; myo-inositol in brain; phosphocreatine in brain and heart; 2-oxoglutarate in brain; cis-aconitate in brain, and etc.), and broke the balance of neurotransmitters and osmoregulators, evoked oxidative stress, disturbed metabolisms of energy and amino acids. The implication of glutamate–glutamine–gamma-aminobutyric axis in LCT induced toxicity was demonstrated for the first time. Our findings demonstrated the applicability and potential of metabolomics approach for the elucidation of toxicological effects of pesticides and the underlying mechanisms, and the discovery of biomarkers for pesticide pollution in aquatic environment.
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