Boosting the LAC-like activity of tetrapeptide capped copper nanoparticle-based nanozymes for colorimetric determination of adrenaline.

Enzymatic activity is important for a variety of technological applications, but the limited stability and complex structures of enzymes often limit their use. Therefore, designing powerful nanomaterial catalysts that are more stable and have higher catalytic activity than natural catalysts has been the pursuit of biotechnology. Here, inspired by electron transfer and the active site of laccase (LAC), four types of copper particles with LAC-like activity were synthesized using a simple hydrothermal method. Copper particles coated with the L-phenylalanine (F)-L-phenylalanine (F)-L-cysteine (C)-L-histidine (H) tetrapeptide exhibited higher LAC-like activity compared to those coated with a CH dipeptide, C, and H. This enhancement could be attributed to the higher structural homology and amino acid composition similarity with the natural LAC active center. The FFCH@CuNP nanozyme was employed for adrenaline detection, and it demonstrated outstanding activity, stability, and recyclability. Additionally, a method for the quantitative detection of adrenaline was established using a smartphone based on the FFCH@CuNP nanozymes. And the FFCH@CuNPs exhibited excellent sensitivity and specificity to adrenaline in a saliva-based test. Therefore, this work provides a reasonable pathway for the design of catalysts for future biotechnological and industrial applications.

Golgi-targeting viscosity probe for the diagnosis of Alzheimer's disease.

Early diagnosis and intervention of Alzheimer's disease (AD) are particularly important to delay the pathological progression. Although fluorescent probes have been widely employed for investigating and diagnosing AD, their biological applications are significantly restricted due to the low penetration ability of the blood-brain barrier (BBB) in vivo. In this study, we reported the first Golgi-targeted two-photon (TP) fluorescent probe, DCM-DH, for detecting viscosity in the Golgi apparatus. The probe was rationally designed to exhibit superior analytical performance including high sensitivity, specific Golgi-targeting, efficient BBB penetration ability, and deep tissue penetration (247 µm) in the brains of AD model mice. Using the probe, we demonstrated that the fluorescence intensity in the human liver cancer cell (HepG2 cells) was higher than that of human normal liver cell (LO2 cells), and the brain viscosity of AD model mice increased significantly. We anticipate that this competent tool could be easily extended to other AD biomarkers for fundamental research on this detrimental disease.

Enhancing the catalytic performance of MOF-polymer@AuNP-based nanozymes for colorimetric detection of serum L-cysteine.

The dispersion of gold nanoparticles (AuNPs) on a metal-organic framework (MOF) surface greatly affects the catalytic activity of the material. However, regulating the catalytic performance of AuNP-MOF composite-based nanozymes is a great challenge. Herein, poly(dimethylvinyloxazolinone) (PV) was chemically bonded on the surface of UiO-66-NH2 (U66), followed by modification of pepsin (Pep) on the PV chains. U66-PV-Pep@AuNP composite nanozymes were fabricated after the AuNPs formed in situ with Pep as the capping and reducing reagent. Compared to Pep@AuNPs that were physically adsorbed onto the surface of U66, the U66-PV-Pep@AuNP composites exhibited superior peroxidase (POD)-mimetic activity in the oxidation of 3,3'5,5'-tetramethylbenzidine (TMB) with H2O2. Considering the surface dispersion uniformity and local concentration of Pep@AuNPs on the surface of the U66-PV-Pep@AuNP composites, the principle for improving the catalytic performance of the proposed nanozymes was explored. Furthermore, it was observed that the introduction of L-cysteine (L-Cys) into the U66-PV-Pep@AuNP-TMB-H2O2 system significantly reduced its oxidation activity and faded the color, allowing the development of a highly selective and sensitive colorimetric method for L-Cys detection. The UV-vis absorption intensity of oxTMB showed a good linear relationship with the concentration of L-Cys in the range of 2.5-40.0 µM (R2 = 0.996), with a detection limit of 0.33 µM. The proposed protocol using U66-PV-Pep@AuNP nanozymes was applied to monitor rat serum L-Cys following intraperitoneal injection. This study paves the way for the design and construction of MOF-polymer@AuNP nanozymes for drug detection in real bio-samples.

Liposomes embedded with PEGylated iron oxide nanoparticles enable ferroptosis and combination therapy in cancer.

Ferroptosis, an iron-dependent regulated cell death process driven by excessive lipid peroxides, can enhance cancer vulnerability to chemotherapy, targeted therapy and immunotherapy. As an essential upstream process for ferroptosis activation, lipid peroxidation of biological membranes is expected to be primarily induced by intrabilayer reactive oxygen species (ROS), indicating a promising strategy to initiate peroxidation by improving the local content of diffusion-limited ROS in the lipid bilayer. Herein, liposomes embedded with PEG-coated 3 nm γ-Fe2O3 nanoparticles in the bilayer (abbreviated as Lp-IO) were constructed to promote the intrabilayer generation of hydroxyl radicals (•OH) from hydrogen peroxide (H2O2), and the integration of amphiphilic PEG moieties with liposomal bilayer improved lipid membrane permeability to H2O2 and •OH, resulting in efficient initiation of lipid peroxidation and thus ferroptosis in cancer cells. Additionally, Lp-IO enabled traceable magnetic resonance imaging and pH/ROS dual-responsive drug delivery. Synergistic antineoplastic effects of chemotherapy and ferroptosis, and alleviated chemotherapeutic toxicity, were achieved by delivering doxorubicin (capable of xCT and glutathione peroxidase inhibition) with Lp-IO. This work provides an efficient alternative for triggering therapeutic lipid peroxidation and a ferroptosis-activating drug delivery vehicle for combination cancer therapies.

Abplatin(IV) inhibited tumor growth on a patient derived cancer model of hepatocellular carcinoma and its comparative multi-omics study with cisplatin.

BACKGROUND: Cisplatin, the alkylating agent of platinum(II) (Pt(II)), is the most common antitumor drug in clinic; however, it has many side effects, therefore it is higly desired to develop low toxicity platinum(IV) (Pt(IV)) drugs. Multi-omics analysis, as a powerful tool, has been frequently employed for the mechanism study of a certain therapy at the molecular level, which might be helpful for elucidating the mechanism of platinum drugs and facilitating their clinical application. METHODS: Strating form cisplatin, a hydrophobic Pt(IV) prodrug (CisPt(IV)) with two hydrophobic aliphatic chains was synthesized, and further encapsulated with a drug carrier, human serum albumin (HSA), to form nanoparticles, namely AbPlatin(IV). The anticancer effect of AbPlatin(IV) was investigated in vitro and in vivo. Moreover, transcriptomics, metabolomics and lipidomics were performed to explore the mechanism of AbPlatin(IV). RESULTS: Compared with cisplatin, Abplatin(IV) exhibited better tumor-targeting effect and greater tumor inhibition rate. Lipidomics study showed that Abplatin(IV) might induce the changes of BEL-7404 cell membrane, and cause the disorder of glycerophospholipids and sphingolipids. In addition, transcriptomics and metabolomics study showed that Abplatin(IV) significantly disturbed the purine metabolism pathway. CONCLUSIONS: This research highlighted the development of Abplatin(IV) and the use of multi-omics for the mechanism elucidation of prodrug, which is the key to the clinical translation of prodrug.

Temperature modulating the peroxidase-mimic activity of poly(N-isopropyl acrylamide) protected gold nanoparticles for colorimetric detection of glutathione.

More recently, loading polymer-ligand onto the surface of gold nanoparticles (AuNPs) as nanozymes has gained considerable attention. However, the efficient modulation of the nanozymes catalytic capability depending on external stimuli remains challenging. Herein, utilizing the thermo-responsive poly(N-isopropyl acrylamide) (PNIPAM) as a stabilizer and a reducing agent to make PNIPAM@AuNPs, we reported a straightforward and efficient protocol for modulating the peroxidase-mimic catalytic capability of PNIPAM@AuNPs in oxidation of 3,3',5,5'-tetramethyl benzidine (TMB)-H2O2 system by change of environmental temperature. More hydroxylradicals yielded and surface confinement effect induced by the coiled PNIPAM chains at high temperature could further significantly boost the nanozymes catalytic capability. In the presence of glutathione, the generation of oxidized TMB was inhibited and the absorption intensity of the reaction system decreased at 650 nm. The color-fadingproperty provided a highly selective assay for visualized and quantitative test of glutathione ranging 1.0 ～ 17.0 µM (R2 = 0.993), the limit of detection was 0.8 µM. Moreover, the proposed method exhibited a promising application in analysis of rat serum glutathione following an intravenous injection. The strategy supplies a facile guideline for preparation of stimuli-responsive polymer@AuNPs with improved peroxidase-mimic catalytic activity toward application in real living bio-systems.

Design and synthesis of a deep tissue penetrating near-infrared two-photon fluorescence probe for the specific detection of NQO1.

NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in a broad range of human tumors but remains difficult to study. Herein, we report a novel two-photon fluorescent probe with NIR emission for NQO1 detection. The probe demonstrated superior analytical performance with a large Stokes shift and deep tissue penetration.

Design and Application of Near-Infrared Nanomaterial-Liposome Hybrid Nanocarriers for Cancer Photothermal Therapy.

Liposomes are attractive carriers for targeted and controlled drug delivery receiving increasing attention in cancer photothermal therapy. However, the field of creating near-infrared nanomaterial-liposome hybrid nanocarriers (NIRN-Lips) is relatively little understood. The hybrid nanocarriers combine the dual superiority of nanomaterials and liposomes, with more stable particles, enhanced photoluminescence, higher tumor permeability, better tumor-targeted drug delivery, stimulus-responsive drug release, and thus exhibiting better anti-tumor efficacy. Herein, this review covers the liposomes supported various types of near-infrared nanomaterials, including gold-based nanomaterials, carbon-based nanomaterials, and semiconductor quantum dots. Specifically, the NIRN-Lips are described in terms of their feature, synthesis, and drug-release mechanism. The design considerations of NIRN-Lips are highlighted. Further, we briefly introduced the photothermal conversion mechanism of NIRNs and the cell death mechanism induced by photothermal therapy. Subsequently, we provided a brief conclusion of NIRNs-Lips applied in cancer photothermal therapy. Finally, we discussed a synopsis of associated challenges and future perspectives for the applications of NIRN-Lips in cancer photothermal therapy.

An Integrated Transcriptomics and Proteomics Analysis Implicates lncRNA MALAT1 in the Regulation of Lipid Metabolism.

Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is upregulated in various cancers, and its overexpression is associated with tumor growth and metastasis. MALAT1 has been recognized as a key player in the regulation of RNA splicing and transcription; however, the landscape of gene expression regulated by MALAT1 remains unclear. In this study, we employed an integrated transcriptomics and proteomics strategy to characterize the alterations in gene expression induced by MALAT1 knockdown in hepatocellular carcinoma (HCC) cells and identified 2662 differentially expressed transcripts and 1149 differentially expressed proteins. Interestingly, downregulation of MALAT1 reduced the abundances of multiple genes in the AMP-activated protein kinase (AMPK) signaling and biosynthesis of unsaturated fatty acids pathways. Further investigation showed that MALAT1 knockdown inhibited glucose uptake and lipogenesis by reducing the expression levels of these lipid metabolism related genes, which contributes to the oncogenic role of MALAT1 in tumor cell proliferation and invasion. This study uncovers the function of MALAT1 in the modulation of cancer lipid metabolism, reveals the underlying molecular mechanism, and further supports the potential therapeutic opportunities for targeting MALAT1 in HCC treatment.

Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance.

In patients with glioblastoma, resistance to the chemotherapeutic temozolomide (TMZ) limits any survival benefits conferred by the drug. Here we show that the convection-enhanced delivery of nanoparticles containing disulfide bonds (which are cleaved in the reductive environment of the tumour) and encapsulating an oxaliplatin prodrug and a cationic DNA intercalator inhibit the growth of TMZ-resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human glioblastoma tumours in mice without causing any detectable toxicity. Genome-wide RNA profiling and metabolomic analyses of a glioma cell line treated with the cationic intercalator or with TMZ showed substantial differences in the signalling and metabolic pathways altered by each drug. Our findings suggest that the combination of anticancer drugs with distinct mechanisms of action with selective drug release and convection-enhanced delivery may represent a translational strategy for the treatment of TMZ-resistant gliomas.

Distribution of perfluorooctane sulfonate in mice and its effect on liver lipidomic.

Perfluorooctane sulfonate (PFOS) is an emerging persistent organic pollutant (POP), and the harm caused by the enrichment of PFOS in living organism has attracted more and more attention. In this work, animal exposure model to PFOS was established. Mass spectrometry (MS), mass spectrometry imaging (MSI), hematoxylin and eosin (H&E) staining and lipidomics were combined for the study of the organ targeting of PFOS, the toxicity and possible mechanism caused by PFOS. PFOS most accumulated in the liver, followed by the lungs, kidneys, spleen, heart and brain. Combined with H&E staining and matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) results, it was found that the accumulation of PFOS indeed caused damage in particular areas of specific organ, like in the liver and in the marginal area of the heart. This work found that PFOS could cross the blood-brain barrier, entered the brain and caused the neurotoxicity, which was surprising and might be the reason that high dose of PFOS could cause convulsions. From the liver lipidomic analysis, we found that PFOS exposure mainly affected glycerophospholipid metabolism and sphingolipid metabolism. The up-regulated ceramide and lysophosphatidylcholine (LPC) might lead to liver cell apoptosis, and the decrease in liver triglyceride (TG) content might result in insufficient energy in mice and cause liver morphological damage. Phosphatidylcholine (PC) synthesis via phosphatidylethanolamine N-methyltransferase (PEMT) pathway might be a mechanism of self-protection in animals against PFOS induced inflammation. This study might provide new insight into underlying toxicity mechanism after exposure to PFOS.

Red Emissive Carbon Dots Prepared from Polymers as an Efficient Nanocarrier for Coptisine Delivery in†vivo and in†vitro.

Negatively charged fluorescent carbon dots (CDs, Em =608 nm) were hydrothermally prepared from thiophene phenylpropionic acid polymers and then successfully loaded with the positively charged anticancer cargo coptisine, which suffers from poor bioavailability. The formed CD-coptisine complexes were thoroughly characterized by particle size, morphology, drug loading efficiency, drug release, cellular uptake and cellular toxicity in vitro and antitumor activities in vivo. In this nano-carrier system, red emissive CDs possess multiple advantages as follows: 1) high drug loading efficiency (>96 %); 2) sustained drug release; 3) enhanced drug efficacy towards cancer cells; 4) EPR effect; 5) drug release tracing with near-infrared imaging. These properties indicated that red emissive CDs prepared from polymers could be used as a novel drug delivery system with integrated therapeutic and imaging functions in cancer therapy, which are expected to have great potential in future clinical applications.

Near-infrared fluorescent carbon dots encapsulated liposomes as multifunctional nano-carrier and tracer of the anticancer agent cinobufagin in vivo and in vitro.

Integrating the optical properties of near-infrared fluorescent carbon dots into liposomes may construct a multifunctional nano-system with the potential as a drug carrier, tracer and efficacy intensifier of the anticancer agent. In this study, the liposomes loaded with hydrophilic near-infrared carbon dots as a nano-carrier and tracer of lipophilic anticancer agent cinobufagin were developed. Prepared liposomes were characterized by particle size, morphology and entrapment efficiency. The drug release behavior, the tracer function, the anticancer effect and the side effect were investigated in vitro and in vivo. It was observed that the photoluminescence emission of carbon dots could be strongly enhanced up to 5 times by nano-liposomes. Due to this property, the bio-imaging of CDs + CB liposomes in vitro and in vivo could be clearly obtained. Our results also showed that the CDs + CB liposomes could be uptaken by cells (the lysosomes targeted) and delivered to the tumor site, and undoubtedly, the CDs + CB liposomes demonstrated sustained drug release, enhanced anticancer efficacy and low side effects in vivo. With the assistance of imaging function of CDs, the CDs + CB liposomes can easily display the distribution of drugs, which is very helpful for drug development and may open a novel avenue for drug delivery.

Metal-organic frameworks as affinity agents to enhance the microdialysis sampling efficiency of fatty acids.

Microdialysis (MD) has been extensively used for in vivo sampling of hydrophilic analytes such as neurotransmitters and drug metabolites. In contrast, there have been few reports on sampling of lipophilic analytes by MD. Lipophilic analytes are easily adsorbed on the surfaces of the dialysis membrane and the inner wall of tubing, which leads to a very low relative recovery (RR). In this work, a strategy to develop an enhanced MD sampling of fatty acids (FAs) by using metal-organic frameworks (MOFs) as affinity agents in the perfusion fluid was investigated. Two MOFs, MIL-101 and ZIF-8, were synthesized and tested for the first time. A 2 times higher RR, about 70% RR, was obtained. The FT-IR experiment showed that the unsaturated metal sites in MOFs could coordinate with FAs, therefore the FAs were encapsulated into MOFs, avoiding FAs to be absorbed on the surfaces of the dialysis membrane and the inner wall of tubing. Moreover, incorporation of FAs into MOFs led to a decrease of free concentration of FAs inside the MD membrane and an increase of concentration gradient, allowing more FAs to diffuse across the membrane. Consequentially, an enhanced RR was obtained. The approach was successfully used to monitor the time profile of targeted FAs in cell culture media after lipopolysaccharide (LPS)-induced inflammation.

Multi-component identification and target cell-based screening of potential bioactive compounds in toad venom by UPLC coupled with high-resolution LTQ-Orbitrap MS and high-sensitivity Qtrap MS.

Traditional Chinese medicines (TCMs) are undoubtedly treasured natural resources for discovering effective medicines in treating and preventing various diseases. However, it is still extremely difficult for screening the bioactive compounds due to the tremendous constituents in TCMs. In this work, the chemical composition of toad venom was comprehensively analyzed using ultra-high performance liquid chromatography (UPLC) coupled with high-resolution LTQ-Orbitrap mass spectrometry and 93 compounds were detected. Among them, 17 constituents were confirmed by standard substances and 8 constituents were detected in toad venom for the first time. Further, a compound database of toad venom containing the fullest compounds was further constructed using UPLC coupled with high-sensitivity Qtrap MS. Then a target cell-based approach for screening potential bioactive compounds from toad venom was developed by analyzing the target cell extracts. The reliability of this method was validated by negative controls and positive controls. In total, 17 components in toad venom were discovered to interact with the target cancer cells. Further, in vitro pharmacological trials were performed to confirm the anti-cancer activity of four of them. The results showed that the six bufogenins and seven bufotoxins detected in our research represented a promising resource to explore bufogenins/bufotoxins-based anticancer agents with low cardiotoxic effect. The target cell-based screening method coupled with the compound database of toad venom constructed by UPLC-Qtrap-MS with high sensitivity provide us a new strategy to rapidly screen and identify the potential bioactive constituents with low content in natural products, which was beneficial for drug discovery from other TCMs. ᅟ Graphical abstract.

Silver nanoparticles as matrix for MALDI FTICR MS profiling and imaging of diverse lipids in brain.

Owing to the diversity of lipids, profiling and imaging multiple classes of lipids in one analysis by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) is a great challenge. In this work, polyvinylpyrrolidone (PVP) capped silver nanoparticles (AgNPs) was used as the matrix for MALDI MSI for the first time to simultaneously analyze 10 classes of lipids from the brain. This analysis included fatty acids and their derivatives, sterols, CPAs, LPA and PAs, LPE and PEs, LPC and PCs, PS, Cers, SMs, and MAGs and DAGs, and other small metabolites. Owing to the abundant silver ions on the surface of PVP-capped AgNPs, compounds with poor ionization efficiency such as FAs and sterols can be detected. The PVP-capped AgNPs based MALDI MSI analysis of mouse brain showed that lipid distributions in the substructures of the mouse brain can be connected with their biological functions. The brain lipids in rats with middle cerebral artery occlusion (MCAO) were also investigated. Most unsaturated FAs, prostaglandins, CPAs, vitamin A, neuraminic acid, 5-OH-tryptophan and the K+ adducts of most phospholipids (PAs, LPE, PEs, PCs, PS) and SMs were extremely down regulated in the ischemic region and saturated FA, Cers, hexanoylcarnitine, stearaldehyde, the Na+ adduct of phospholipids (LPA, PAs, LPE, PEs, LPC, PCs) and SMs were highly expressed in the damaged section. These novel findings could be very significant for elucidating the disease mechanism. MALDI MSI using PVP-capped AgNPs as a matrix can be a powerful tool in histopathology and pathology studies.

Organic washes of tissue sections for comprehensive analysis of small molecule metabolites by MALDI MS imaging of rat brain following status epilepticus.

INTRODUCTION: In-situ detection and in particular comprehensive analysis of small molecule metabolites (SMMs, m/z < 500) using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) remain a challenge, mainly due to ion suppression effects from more abundant molecules in tissue section like lipids. OBJECTIVE: A strategy based on organic washes to remove most ionization-suppressing lipids from tissue section was firstly explored for improved analysis of SMMs by MALDI MSI. METHODS: The tissue sections after rinse with different organic solvents were analyzed by MALDI MSI, and the results were compared for the optimized washing conditions. RESULTS: The rinse with chloroform for 15 s at - 20 °C significantly removed most glycerophospholipids and glycerolipids from tissue section. Consequentially, ATP-related energy metabolites, amino acids and derivatives, glucose derivatives, glycolysis pathway metabolites and other SMMs were able to be well-visualized with enhanced ion intensity and good reproducibility. The organic washes-based MALDI MSI was applied to the metabolic pathway analysis in rat brain following status epilepticus (SE) model, which was, as far as we know, the first report about in-situ detection of a broad range of metabolites in the model of SE by MALDI MSI technique. The alterations of cyclic adenosine monophosphate (cyclic AMP), inosine, glutamine, glutathione, taurine and spermine during SE were observed. CONCLUSION: A simple organic washing protocol enables comprehensive analysis of tissue SMMs in MALDI MSI by removing ionization-suppressing lipids. The application in the SE model indicates that MALDI MSI analysis potentially provides new insight for understanding the disease mechanism.

Aberrant Lipid Metabolism in Hepatocellular Carcinoma Revealed by Liver Lipidomics.

BACKGROUND: The aim of this study was to characterize the disorder of lipid metabolism in hepatocellular carcinoma (HCC). HCC is a worldwide disease. The research into the disorder of lipid metabolism in HCC is very limited. Study of lipid metabolism in liver cancer tissue may have the potential to provide new insight into HCC mechanisms. METHODS: A lipidomics study of HCC based on Ultra high performance liquid chromatography-electronic spray ionization-QTOF mass spectrometer (UPLC-ESI-QTOF MS) and Matrix assisted laser desorption ionization-fourier transform ion cyclotron resonance mass spectrometer (MALDI-FTICR MS) was performed. RESULTS: Triacylglycerols (TAGs) with the number of double bond (DB) > 2 (except 56:5 and 56:4 TAG) were significantly down-regulated; conversely, others (except 52:2 TAG) were greatly up-regulated in HCC tissues. Moreover, the more serious the disease was, the higher the saturated TAG concentration and the lower the polyunsaturated TAG concentration were in HCC tissues. The phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) were altered in a certain way. Sphingomyelin (SM) was up-regulated and ceramide (Cer) were down-regulated in HCC tissues. CONCLUSIONS: To our knowledge, this is the first such report showing a unique trend of TAG, PC, PE and PI. The use of polyunsaturated fatty acids, like eicosapentanoic and docosahexanoic acid, as supplementation, proposed for the treatment of Non-alcoholic steatohepatitis (NASH), may also be effective for the treatment of HCC.

Blocking gp130 signaling suppresses autotaxin expression in adipocytes and improves insulin sensitivity in diet-induced obesity.

Autotaxin (ATX), which is highly expressed and secreted by adipocytes, functions as the key enzyme to generate lysophosphatidic acid (LPA) from lysophosphatidylcholine. Adipose tissue is the main source of circulating ATX that modulates plasma LPA levels. Upregulation of ATX expression in obese patients and mice is closely related with insulin resistance and impaired glucose tolerance. However, the mechanism of ATX expression in adipocytes remains largely unknown. In this study, we found that glycoprotein 130 (gp130)-mediated Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) activation was required for abundant ATX expression in adipocytes. Through gp130, the interleukin 6 (IL-6) family cytokines, such as IL-6, leukemia inhibitory factor, cardiotrophin-1, and ciliary neurotrophic factor, upregulated ATX expression in adipocytes. ATX contributes to the induction of insulin resistance and lipolysis in IL-6-stimulated adipocytes. Oral administration of gp130 inhibitor SC144 suppressed ATX expression in adipose tissue, decreased plasma ATX, LPA, and FFA levels, and significantly improved insulin sensitivity and glucose tolerance in high-fat diet-fed obese mice. In summary, our results indicate that the activation of gp130-JAK-STAT3 pathway by IL-6 family cytokines has an important role in regulating ATX expression in adipocytes and that gp130 is a promising target in the management of obesity-associated glucose metabolic diseases.

Comprehensive qualification and quantification of triacylglycerols with specific fatty acid chain composition in horse adipose tissue, human plasma and liver tissue.

High levels of triacylglycerols (TGs) have been linked to cardiovascular disease and liver diseases. Comprehensively analyzing TGs is helpful to understand the TGs functions in these diseases. However, due to the existence of a large number of isomers TGs and the lack of commercial standards, precise analysis of individual triacylglycerol (TG) with specific fatty acid chain composition is full of challenge. In this work, ultra-performance liquid chromatography (UPLC) coupled with electrospray ionization (ESI) mass spectrometry (MS) were employed for comprehensive qualification and quantification of TGs with specific fatty acid chain composition in horse adipose tissue, human plasma and liver tissues including hepatocellular carcinoma (HCC) and para-carcinoma tissues. Multiple MS detection modes from QTRAP MS and FT-ICR MS were utilized, and hundreds of TG species (including many oxidized TG species) with their specific fatty acid chain compositions have been qualified and quantified. The isomer TGs interference, the isobaric interference, and oxidized TG species interference were firstly indicated. Several isomer TGs, for example, 18:1/20:1/18:2 TG and 20:3/18:1/18:0 TG, which were all 56:4 TG, demonstrated different trends in HCC tissue compared with para-carcinoma tissue, which showed the importance of analysis of TG with specific fatty acid chain composition. In addition, 10 TGs with the degree of unsaturation beyond three were significantly decreased, while 16:0/17:0/18:0 TG, no double bond, was significantly increased in the HCC tissue, which firstly revealed aberrant specific TG metabolism in HCC. This is a systematic report about comprehensive analysis of TGs by UPLC-ESI-MS, which is of significance for accurate analysis of these lipids.