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1.
Int J Gen Med ; 17: 2055-2063, 2024.
Article in English | MEDLINE | ID: mdl-38751493

ABSTRACT

Surveillance of drug safety is an important aspect in the routine medical care. Adverse events caused by real-world drug utilization has become one of the leading causes of death and an urgent issue in the field of toxicology. Cardiovascular disease is now the leading cause of fatal diseases in most countries, especially in the elderly population who often suffer from multiple diseases and need long-term multidrug therapy. Among which, statins have been widely used to lower bad cholesterol and regress coronary plaque mainly in patients with hyperlipidemia and atherosclerotic cardiovascular diseases (ASCVD). Although the real-world benefits of statins are significant, different degrees and types of adverse drug reactions (ADR) such as liver dysfunction and muscle injury, have a great impact on the original treatment regimens as well as the quality of life. This review describes the epidemiology, mechanisms, early identification and post-intervention of statin-associated liver dysfunction and muscle injury based on the updated clinical evidence. It provides systematic and comprehensive guidance and necessary supplement for the clinical safety of statin use in cardiovascular diseases.

2.
Talanta ; 277: 126323, 2024 May 25.
Article in English | MEDLINE | ID: mdl-38810384

ABSTRACT

Due to its advantages of label-free and highly sensitive, the resistive pulse sensing with a nanopore has recently become even more potent for the discrimination of analytes in single molecule level. Generally, a transient interruption of ion current originated from the captured molecule passing through a nanopore will provide the rich information on the structure, charge and translocation dynamics of the analytes. Therefore, nanopore sensors have been widely used in the fields of DNA sequencing, protein recognition, and the portable detection of varied macromolecules and particles. However, the conventional nanopore devices are still lack of sufficient selectivity and sensitivity to distinguish more metabolic molecules involving ATP, glucose, amino acids and small molecular drugs because it is hard to receive a large number of identifiable signals with the fabricated pores comparable in size to small molecules for nanopore sensing. For all this, a series of innovative strategies developed in the past decades have been summarized in this review, including host-guest recognition, engineering alteration of protein channel, the introduction of nucleic acid aptamers and various delivery carriers integrating signal amplification sections based on the biological and solid nanopore platforms, to achieve the high resolution for the small molecules sensing in micro-nano environment. These works have greatly enhanced the powerful sensing capabilities and extended the potential application of nanopore sensors.

3.
PLoS One ; 19(4): e0300440, 2024.
Article in English | MEDLINE | ID: mdl-38598505

ABSTRACT

The automatic detection of the degree of surface corrosion on metal structures is of significant importance for assessing structural damage and safety. To effectively identify the corrosion status on the surface of coastal metal facilities, this study proposed a CBG-YOLOv5s model for metal surface corrosion detection, based on the YOLOv5s model. Firstly, we integrated the Convolutional Block Attention Module (CBAM) into the C3 module and developed the C3CBAM module. This module effectively enhanced the channel and spatial attention capabilities of the feature map, thereby improving the feature representation. Second, we introduced a multi-scale feature fusion concept in the feature fusion part of the model and added a small target detection layer to improve small target detection. Finally, we designed a lighter C3Ghost module, which reduced the number of parameters and the computational load of the model, thereby improving the running speed of the model. In addition, to verify the effectiveness of our method, we constructed a dataset containing 6000 typical images of metal surface corrosion and conducted extensive experiments on this dataset. The results showed that compared to the YOLOv5s model and several other commonly used object detection models, our method achieved superior performance in terms of detection accuracy and speed.


Subject(s)
Household Articles , Recognition, Psychology , Corrosion , Metals
4.
Int Immunopharmacol ; 132: 111918, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38537539

ABSTRACT

BACKGROUND: Sideroflexin 1 (SFXN1), a mitochondrial serine transporter implicated in one-carbon metabolism, is a prognostic biomarker in lung adenocarcinoma (LUAD). However, its role in LUAD progression remains elusive. This study aimed to investigate the functional significance of SFXN1 in LUAD and evaluate its potential as a therapeutic target. METHODS: We analyzed SFXN1 expression and its diagnostic and prognostic value in LUAD using the Pan-cancer TCGA dataset. In vitro assays (CCK-8, cell cycle, EDU, wound-healing, and transwell) were employed to assess the role of SFXN1, complemented by in vivo experiments. RNA sequencing elucidated SFXN1-mediated cellular functions and potential mechanisms. Bulk RNA-seq and scRNA-seq data from TCGA and GEO were used to investigate the correlation between SFXN1 and the tumor immune microenvironment. RT-qPCR, Western blot, and IHC assays validated SFXN1 expression and its impact on the immune microenvironment in LUAD. RESULTS: SFXN1 was upregulated in LUAD tissues and associated with poor prognosis. RNA-seq and scRNA-seq analyses revealed increased SFXN1 expression in tumor cells, accompanied by decreased infiltration of NK and cytotoxic T cells. SFXN1 knockdown significantly reduced cell proliferation and migration, and the inhibition of ERK phosphorylation and CCL20 expression may be the molecular mechanism involved. In vivo, targeting SFXN1 decreased Tregs infiltration and inhibited tumor growth. CONCLUSIONS: Our findings suggest that SFXN1 may be a potential therapeutic target for LUAD treatment.


Subject(s)
Adenocarcinoma of Lung , Amino Acid Transport Systems, Neutral , Lung Neoplasms , Lymphocytes, Tumor-Infiltrating , Tumor Microenvironment , Humans , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/immunology , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinogenesis/genetics , Carcinogenesis/immunology , Cell Line, Tumor , Cell Movement , Cell Proliferation , Gene Expression Regulation, Neoplastic , Lung Neoplasms/immunology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lymphocytes, Tumor-Infiltrating/immunology , Prognosis , Tumor Microenvironment/immunology , Amino Acid Transport Systems, Neutral/genetics , Amino Acid Transport Systems, Neutral/metabolism
5.
Biomed Pharmacother ; 174: 116462, 2024 May.
Article in English | MEDLINE | ID: mdl-38513598

ABSTRACT

BACKGROUND: Acute kidney injury (AKI) was reported to be one of the initiators of chronic kidney disease (CKD) development. Necroinflammation may contribute to the progression from AKI to CKD. Dexmedetomidine (Dex), a highly selective α2-adrenoreceptor (AR) agonist, has cytoprotective and "anti-" inflammation effects. This study was designed to investigate the anti-fibrotic properties of Dex in sepsis models. METHODS: C57BL/6 mice were randomly treated with an i.p. injection of lipopolysaccharides (LPS) (10 mg/kg) alone, LPS with Dex (25 µg/kg), or LPS, Dex and Atipamezole (Atip, an α2-adrenoreceptor antagonist) (500 µg/kg) (n=5/group). Human proximal tubular epithelial cells (HK2) were also cultured and then exposed to LPS (1 µg/ml) alone, LPS and Dex (1 µM), transforming growth factor-beta 1 (TGF-ß1) (5 ng/ml) alone, TGF-ß1 and Dex, with or without Atip (100 µM) in culture media. Epithelial-mesenchymal transition (EMT), cell necrosis, necroptosis and pyroptosis, and c-Jun N-terminal kinase (JNK) phosphorylation were then determined. RESULTS: Dex treatment significantly alleviated LPS-induced AKI, myofibroblast activation, NLRP3 inflammasome activation, and necroptosis in mice. Atip counteracted its protective effects. Dex attenuated LPS or TGF-ß1 induced EMT and also prevented necrosis, necroptosis, and pyroptosis in response to LPS stimulation in the HK2 cells. The anti-EMT effects of Dex were associated with JNK phosphorylation. CONCLUSIONS: Dex reduced EMT following LPS stimulation whilst simultaneously inhibiting pyroptosis and necroptosis via α2-AR activation in the renal tubular cells. The "anti-fibrotic" and cytoprotective properties and its clinical use of Dex need to be further studied.


Subject(s)
Adrenergic alpha-2 Receptor Agonists , Dexmedetomidine , Fibrosis , Mice, Inbred C57BL , Receptors, Adrenergic, alpha-2 , Animals , Humans , Mice , Acute Kidney Injury/drug therapy , Acute Kidney Injury/pathology , Acute Kidney Injury/metabolism , Acute Kidney Injury/chemically induced , Acute Kidney Injury/prevention & control , Adrenergic alpha-2 Receptor Agonists/pharmacology , Adrenergic alpha-2 Receptor Agonists/therapeutic use , Adrenergic alpha-2 Receptor Antagonists/pharmacology , Cell Line , Dexmedetomidine/pharmacology , Epithelial-Mesenchymal Transition/drug effects , Inflammation/drug therapy , Inflammation/pathology , Inflammation/metabolism , Kidney/pathology , Kidney/drug effects , Kidney/metabolism , Lipopolysaccharides/pharmacology , Necroptosis/drug effects , Phenotype , Receptors, Adrenergic, alpha-2/drug effects , Receptors, Adrenergic, alpha-2/metabolism
6.
FEBS Lett ; 598(10): 1154-1169, 2024 May.
Article in English | MEDLINE | ID: mdl-38355218

ABSTRACT

The cell death-inducing DFF45-like effector (CIDE) proteins, including Cidea, Cideb, and Cidec/Fsp27, regulate various aspects of lipid homeostasis, including lipid storage, lipolysis, and lipid secretion. This review focuses on the physiological roles of CIDE proteins based on studies on knockout mouse models and human patients bearing CIDE mutations. The primary cellular function of CIDE proteins is to localize to lipid droplets (LDs) and to control LD fusion and growth across different cell types. We propose a four-step process of LD fusion, characterized by (a) the recruitment of CIDE proteins to the LD surface and CIDE movement, (b) the enrichment and condensate formation of CIDE proteins to form LD fusion plates at LD-LD contact sites, (c) lipid transfer through lipid-permeable passageways within the fusion plates, and (d) the completion of LD fusion. Lastly, we outline CIDE-interacting proteins as regulatory factors, as well as their contribution in LD fusion.


Subject(s)
Apoptosis Regulatory Proteins , Lipid Droplets , Animals , Humans , Lipid Droplets/metabolism , Apoptosis Regulatory Proteins/metabolism , Apoptosis Regulatory Proteins/genetics , Lipid Metabolism
7.
Cell Death Discov ; 9(1): 409, 2023 Nov 07.
Article in English | MEDLINE | ID: mdl-37935670

ABSTRACT

Postoperative multi-organ dysfunction (MOD) is associated with significant mortality and morbidity. Necroptosis has been implicated in different types of solid organ injury; however, the mechanisms linking necroptosis to inflammation require further elucidation. The present study examines the involvement of necroptosis and NLR family pyrin domain containing 3 (NLRP3) inflammasome in small intestine injury following traumatic surgery. Kidney transplantation in rats and renal ischaemia-reperfusion (I/R) in mice were used as traumatic and laparotomic surgery models to study necroptosis and inflammasome activation in the small intestinal post-surgery; additional groups also received receptor-interacting protein kinase 1 (RIPK1) inhibitor necrostatin-1s (Nec-1s). To investigate whether necroptosis regulates inflammasome activity in vitro, necroptosis was induced in human colonic epithelial cancer cells (Caco-2) by a combination of tumour necrosis factor-alpha (TNFα), SMAC mimetic LCL-161 and pan-caspase inhibitor Q-VD-Oph (together, TLQ), and necroptosis was blocked by Nec-1s or mixed lineage kinase-domain like (MLKL) inhibitor necrosulfonamide (NSA). Renal transplantation and renal ischaemia-reperfusion (I/R) upregulated the expression of necroptosis mediators (RIPK1; RIPK3; phosphorylated-MLKL) and inflammasome components (P2X purinoceptor subfamily 7, P2X7R; NLRP3; caspase-1) in the small intestines at 24 h, and Nec-1s suppressed the expression of inflammasome components. TLQ treatment induced NLRP3 inflammasome, promoted cleavage of caspase-1 and interleukin-1 beta (IL-1ß), and stimulated extracellular ATP release from Caco-2 cells, and MLKL inhibitor NSA prevented TLQ-induced inflammasome activity and ATP release from Caco-2 cells. Our work suggested that necroptosis and inflammasome interactively promote remote postoperative small intestinal injury, at least in part, through ATP purinergic signalling. Necroptosis-inflammasome axis may be considered as novel therapeutic target for tackling postoperative MOD in the critical care settings.

8.
J Invertebr Pathol ; 201: 108003, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37838064

ABSTRACT

In this study, silkworms were treated by injection of the bioactive depsipeptide beauvericin (BEA) to explore its effect on the cellular immunity of larvae of the silkworm Bombyx mori. The results showed that: The LC50 of BEA for silkworms on the 3rd day of the 4th instar was 362.36 µM. The total count of circulating hemocytes in the silkworms decreased at 12 h after injection with 350 µM BEA, and reached the minimum value at 72 h post-treatment; at 48 h post-treatment, a large number of nodules formed by the aggregation of blood cells of the silkworms were observed under the light microscope. The survival rate of hemocytes in the larvae treated with BEA was significantly reduced in a dose-dependent manner in vivo and in vitro. The encapsulation of Q-Sepharose Fast Flow (QFF) gel particles by hemocytes in the treatment group was significantly higher than that in the control group at 1.5 h and 3 h post-treatment (P < 0.05). Moreover, the melanization ratio of QFF gel particles kept increasing with treatment time. The melanization rate at 24 h after treatment was significantly higher than that at other times (P < 0.05), reaching 55.33 %. Under the scanning electron microscope, BEA-treated larvae showed protrusions on the surface of their blood cells in vivo. Under the transmission electron microscope, it was observed that silkworm hemocytes were vacuolated. This study demonstrated that BEA had an effect on the blood cells of silkworms, and has thrown some light on the inhibitory effect and mechanism of BEA on insect cellular immunity.


Subject(s)
Bombyx , Depsipeptides , Animals , Hemocytes , Depsipeptides/pharmacology , Larva , Insect Proteins
9.
Front Immunol ; 14: 1238022, 2023.
Article in English | MEDLINE | ID: mdl-37675117

ABSTRACT

Allergen-specific immunotherapy (AIT) describes the establishment of peripheral tolerance through repeated allergen exposure, which qualifies as the only curative treatment for allergic diseases. Although conventional subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have been approved to treat respiratory allergies clinically, the progress made is far from satisfactory. Epicutaneous immunotherapy (EPIT) exploits the skin's immune properties to modulate immunological response, which is emerging as a promising alternative and has shown effectiveness in many preclinical and clinical studies for both respiratory and food allergies. It is worth noting that the stratum corneum (SC) barrier impedes the effective delivery of allergens, while disrupting the SC layer excessively often triggers unexpected Th2 immune responses. This work aims to comprehend the immunological mechanisms of EPIT, and summarize the innovative system for sufficient delivery of allergens as well as tolerogenic adjuvants. Finally, the safety, acceptability, and cost-effectiveness of these innovative delivery systems are discussed, which directs the development of future immunotherapies with all desirable characteristics.


Subject(s)
Hypersensitivity , Humans , Hypersensitivity/therapy , Adjuvants, Immunologic , Adjuvants, Pharmaceutic , Desensitization, Immunologic , Epidermis
10.
Theranostics ; 13(13): 4376-4390, 2023.
Article in English | MEDLINE | ID: mdl-37649611

ABSTRACT

Background: Effective preservation strategies to ameliorate lung graft ischaemia injury are needed to rescue 'extended criteria' or 'marginal' lung grafts, and to improve recipient outcomes after transplantation. Methods: Lung grafts from male Lewis rats were extracted after 40 min of cardiocirculatory death, and healthy human lung tissues were collected from patients undergoing a lobectomy. Lung samples were then preserved in a 4°C preservation solution supplemented with 0.1 nM Dexmedetomidine (Dex, α2-adrenoceptor agonist) for 16 h. In vitro, human lung epithelial A549 cells were preserved in the 4°C preservation solution with 0.1 nM Dex for 24 h, then re-cultured in the cell culture medium at 37°C to mimic the clinical scenario of cold ischaemia and warm reperfusion. Lung tissues and cells were then analysed with various techniques including western blot, immunostaining and electron microscope, to determine injuries and the protection of Dex. Results: Prolonged warm ischaemia after cardiocirculatory death initiated Rip kinase-mediated necroptosis, which was exacerbated by cold storage insult and enhanced lung graft injury. Dex supplementation significantly reduced necroptosis through upregulating Nrf2 activation and reducing oxidative stress, thereby significantly improving lung graft morphology. Dex treatment also attenuated endoplasmic reticulum stress, stabilised lysosomes and promoted cell membrane resealing function, consequently reducing cell death and inflammatory activation after hypothermic hypoxia-reoxygenation in A549 cells. Conclusions: Inhibition of regulated cell death through Dex supplementation to the graft preservation solution improves allograft quality which may aid to expand the donor lung pool and enhance lung transplant outcomes per se.


Subject(s)
Lung Transplantation , Regulated Cell Death , Rats , Animals , Humans , Male , Rats, Inbred Lew , Necroptosis , Lung
11.
iScience ; 26(4): 106534, 2023 Apr 21.
Article in English | MEDLINE | ID: mdl-37123239

ABSTRACT

The cellular and molecular actions of general anesthetics to induce anesthesia state and also cellular signaling changes for subsequent potential "long term" effects remain largely elusive. General anesthetics were reported to act on voltage-gated ion channels and ligand-gated ion channels. Here we used single-cell RNA-sequencing complemented with whole-cell patch clamp and calcium transient techniques to examine the gene transcriptome and ion channels profiling of sevoflurane and propofol, both commonly used clinically, on the human fetal prefrontal cortex (PFC) mixed cell cultures. Both propofol and sevoflurane at clinically relevant dose/concentration promoted "microgliosis" but only sevoflurane decreased microglia transcriptional similarity. Propofol and sevoflurane each extensively but transiently (<2 h) altered transcriptome profiling across microglia, excitatory neurons, interneurons, astrocytes and oligodendrocyte progenitor cells. Utilizing scRNA-seq as a robust and high-through put tool, our work may provide a comprehensive blueprint for future mechanistic studies of general anesthetics in clinically relevant settings.

12.
J Phys Chem B ; 127(21): 4790-4799, 2023 06 01.
Article in English | MEDLINE | ID: mdl-37197998

ABSTRACT

A single nucleotide variant present between two otherwise identical nucleic acids will have unexpected functional consequences frequently. Here, a neoteric single nucleotide variation (SNV) detection assay that integrates two complementary nanotechnology systems, nanoassembly technology and an ingenious nanopore biosensing platform, has been applied to this research. Specifically, we set up a detection system to reflect the binding efficiency of the polymerase and nanoprobe through the difference of nanopore signals and then explore the effect of base mutation at the binding site. In addition, machine learning based on support vector machines is used to automatically classify characteristic events mapped by nanopore signals. Our system reliably discriminates single nucleotide variants at binding sites, even possessing the recognition among transitions, transversions, and hypoxanthine (base I). Our results demonstrate the potential of solid-state nanopore detection for SNV and provide some ideas for expanding solid-state nanopore detection platforms.


Subject(s)
Nanopores , Nucleic Acids , Nucleotides , DNA/chemistry , DNA-Directed DNA Polymerase , Nanotechnology/methods
14.
J Biol Chem ; 299(7): 104856, 2023 07.
Article in English | MEDLINE | ID: mdl-37230388

ABSTRACT

Neuroblastoma (NB) is one of the most common extracranial solid tumors in children. MYCN gene amplification is highly associated with poor prognosis in high-risk NB patients. In non-MYCN-amplified high-risk NB patients, the expression of c-MYC (MYCC) and its target genes is highly elevated. USP28 as a deubiquitinase is known to regulate the stability of MYCC. We show here USP28 also regulates the stability of MYCN. Genetic depletion or pharmacologic inhibition of the deubiquitinase strongly destabilizes MYCN and stops the growth of NB cells that overexpress MYCN. In addition, MYCC could be similarly destabilized in non-MYCN NB cells by compromising USP28 function. Our results strongly suggest USP28 as a therapeutic target for NB with or without MYCN amplification/overexpression.


Subject(s)
Neural Stem Cells , Neuroblastoma , Child , Humans , Cell Line, Tumor , Deubiquitinating Enzymes/metabolism , Gene Expression Regulation, Neoplastic , N-Myc Proto-Oncogene Protein/genetics , N-Myc Proto-Oncogene Protein/metabolism , N-Myc Proto-Oncogene Protein/therapeutic use , Neural Stem Cells/metabolism , Neuroblastoma/pathology , Transcription Factors/metabolism , Ubiquitin Thiolesterase/metabolism
15.
Eur J Pharmacol ; 945: 175580, 2023 Apr 15.
Article in English | MEDLINE | ID: mdl-36758782

ABSTRACT

Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, is commonly used to induce anaesthesia during cancer surgery and relieve neuropathic and cancer pain. This study was conducted to assess whether ketamine has any inhibiting effects on neuroglioma (H4) and lung cancer cells (A549) in vitro. The cultured H4 and A549 cells were treated with ketamine and MK801 (0.1, 1, 10, 100, or 1000 µM) for 24 h. The expressions of glutamate receptors on both types of cancer cells were assessed with qRT-PCR. In addition, cell proliferation and migration were assessed with cell counting Kit-8 and wound healing assays. Cyclin D1, matrix metalloproteinase 9 (MMP9), phosphorylation of extracellular signal-regulated kinase (pERK), and cleaved-caspase-3 expression together with reactive oxygen species (ROS) were also assessed with Western blot, immunostaining, and/or flowcytometry. NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors were expressed on both H4 and A549 cells. Ketamine inhibited cancer cell proliferation and migration in a dose-dependent manner by suppressing the cell cycle and inducing apoptosis. Ketamine decreased cyclin D1, pERK, and MMP9 expression. In addition, ketamine increased ROS and cleaved caspase-3 expression and induced apoptosis. The anti-cancer effect of ketamine was more pronounced in A549 cells when compared with H4 cells. MK801 showed similar effects to those of ketamine. Ketamine suppressed cell proliferation and migration in both neuroglioma and lung cancer cells, likely through the antagonization of NMDA receptors.


Subject(s)
Ketamine , Lung Neoplasms , Humans , Ketamine/pharmacology , Ketamine/therapeutic use , Dizocilpine Maleate/pharmacology , Caspase 3/metabolism , Cyclin D1/metabolism , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , N-Methylaspartate/pharmacology , Reactive Oxygen Species/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Apoptosis , Receptors, N-Methyl-D-Aspartate/metabolism
16.
Neural Comput Appl ; 35(3): 2103-2117, 2023.
Article in English | MEDLINE | ID: mdl-35496654

ABSTRACT

Public health machinery learning platform based on cloud-native is a system platform that combines machine learning frameworks and cloud-native technology for public health services. The problem of how its flexible value is realized has been widely concerned by all public health network intelligent researchers. Thus, this article examines the relationship between cloud-native architecture flexibility and cloud provider value and the processes and the boundary condition by which cloud-native architecture flexibility affects cloud provider value based on innovation theory and dynamic capability theory. The results of a survey of 509 platform-related respondents in China show that cloud-native architecture flexibility is positively related to cloud provider value, and both absorptive capacity and supply chain agility mediate the above-mentioned effect. Moreover, R&D subsidies strengthen both the positive relationship between absorptive capacity and cloud provider value and the relationship between supply chain agility and cloud provider value. In this study, cloud-native architecture flexibility, unit absorptive capacity, supply chain agility and R&D subsidies are considered into a flexible value generation mechanism model that extend the relevant research on the value generation mechanism of information system under the background of network intelligence, and to provide relevant enterprises with suggestions on upgrade strategies.

17.
Cell Biol Toxicol ; 39(4): 1561-1575, 2023 08.
Article in English | MEDLINE | ID: mdl-35953652

ABSTRACT

Anaesthetics may modify colorectal cancer cell biology which potentially affects long-term survival. This study aims to compare propofol and sevoflurane regarding with the direct anaesthetic effects on cancer malignancy and the indirect effects on host immunity in a cancer xenograft mode of mice. Cultured colon cancer cell (Caco-2) was injected subcutaneously to nude mice (day 1). Mice were exposed to either 1.5% sevoflurane for 1.5 h or propofol (20 µg g-1; ip injection) with or without 4 µg g-1 lipopolysaccharide (LPS; ip) from days 15 to 17, compared with those without anaesthetic exposure as controls. The clinical endpoints including tumour volumes over 70 mm3 were closely monitored up to day 28. Tumour samples from the other cohorts were collected on day 18 for PCR array, qRT-PCR, western blotting and immunofluorescent assessment. Propofol treatment reduced tumour size (mean ± SD; 23.0 ± 6.2mm3) when compared to sevoflurane (36.0 ± 0.3mm3) (p = 0.008) or control (23.6 ± 4.7mm3). Propofol decreased hypoxia inducible factor 1α (HIF1α), interleukin 1ß (IL1ß), and hepatocyte growth factor (HGF) gene expressions and increased tissue inhibitor of metalloproteinases 2 (TIMP-2) gene and protein expression in comparison to sevoflurane in the tumour tissue. LPS suppressed tumour growth in any conditions whilst increased TIMP-2 and anti-cancer neutrophil marker expressions and decreased macrophage marker expressions compared to those in the LPS-untreated groups. Our data indicated that sevoflurane increased cancer development when compared with propofol in vivo under non-surgical condition. Anaesthetics tested in this study did not alter the effects of LPS as an immune modulator in changing immunocyte phenotype and suppressing cancer development.


Subject(s)
Anesthetics, Inhalation , Methyl Ethers , Neoplasms , Propofol , Humans , Mice , Animals , Propofol/pharmacology , Propofol/therapeutic use , Sevoflurane/pharmacology , Anesthetics, Intravenous/pharmacology , Tissue Inhibitor of Metalloproteinase-2 , Anesthetics, Inhalation/pharmacology , Methyl Ethers/pharmacology , Heterografts , Lipopolysaccharides/pharmacology , Caco-2 Cells , Mice, Nude , Neoplasms/drug therapy
19.
Biosensors (Basel) ; 12(12)2022 Dec 09.
Article in English | MEDLINE | ID: mdl-36551119

ABSTRACT

Nanopores are promising single-molecule sensing devices that have been successfully used for DNA sequencing, protein identification, as well as virus/particles detection. It is important to understand and characterize the current pulses collected by nanopore sensors, which imply the associated information of the analytes, including the size, structure, and surface charge. Therefore, a signal processing program, based on the MATLAB platform, was designed to characterize the ionic current signals of nanopore measurements. In a movable data window, the selected current segment was analyzed by the adaptive thresholds and corrected by multi-functions to reduce the noise obstruction of pulse signals. Accordingly, a set of single molecular events was identified, and the abundant information of current signals with the dwell time, amplitude, and current pulse area was exported for quantitative analysis. The program contributes to the efficient and fast processing of nanopore signals with a high signal-to-noise ratio, which promotes the development of the nanopore sensing devices in various fields of diagnosis systems and precision medicine.


Subject(s)
Nanopores , Nanotechnology , Proteins , Signal-To-Noise Ratio
20.
Cancer Sci ; 113(10): 3463-3475, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35880246

ABSTRACT

Overexpression of ubiquitin-specific protease 28 (USP28) is found in hepatic carcinoma. It is unclear whether the deubiquitinase plays a role in hepatocarcinogenesis. Deregulation of the Wnt signaling pathway is frequently associated with liver cancer. Transcription factor 7-like 2 (TCF7L2) is an important downstream transcription factor of the Wnt/ß-catenin signaling pathway, but the mechanisms by which TCF7L2 itself is regulated have not yet been revealed. Here, we report that USP28 promotes the activity of the Wnt signaling pathway through maintaining the stability of TCF7L2. We further show that FBXW7 is the E3 ubiquitin ligase for TCF7L2. By regulating the levels of TCF7L2, USP28 modulates the Wnt/ß-catenin signaling in liver cancer and USP28 depletion or inhibition by a small molecule inhibitor leads to a halt of growth in liver cancer cells. These results suggest that USP28 could be a potential therapeutic target for liver cancer.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Cell Line, Tumor , Deubiquitinating Enzymes , F-Box-WD Repeat-Containing Protein 7/metabolism , Humans , T Cell Transcription Factor 1/metabolism , Transcription Factor 7-Like 2 Protein/genetics , Transcription Factor 7-Like 2 Protein/metabolism , Ubiquitin Thiolesterase/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Specific Proteases/metabolism , Wnt Signaling Pathway/physiology , beta Catenin/metabolism
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