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Resistance to proteasome inhibitors like Bortezomib is a major challenge in the treatment of multiple myeloma (MM). Proteolysis targeting chimeras (PROTACs), an emerging therapeutic approach that induces selective degradation of target proteins, offer a promising solution to overcome drug resistance. In this study, we designed and synthesized novel small-molecule PROTACs that induce 20S proteasome subunit β5 degradation as a strategy to overcome Bortezomib resistance. These 20S proteasome subunit β5 PROTACs demonstrated considerable binding affinity to 20S proteasome subunit β5 and cereblon (CRBN), effectively induced 20S proteasome subunit β5 degradation, and exhibited potent antiproliferative activity against a panel of cancer cell lines. Notably, PROTACs 12f and 14 displayed robust antitumor effects against both the pharyngeal carcinoma cell line FaDu and the Bortezomib-resistant MM cell line KM3/BTZ in vitro and in vivo with excellent safety profiles. Taken together, our findings highlight the potential of PROTACs 12f and 14 as novel 20S proteasome subunit β5-degrading agents for the treatment of pharyngeal carcinoma and overcoming Bortezomib resistance in MM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this study, Cu-doped NH 2 -MIL-88(Fe) metal-organic frameworks (MOF) were synthesized via a one-step method. Characterization techniques such as XPS, XRD and FTIR confirmed the successful incorporation of Cu 2+ into NH 2 -MIL-88(Fe), naming this MOF as NH 2 -MIL-88(Fe)@Cu 2+ . This MOF was employed to develop a highly sensitive fluorescence sensing platform for detecting 3-nitro-L-tyrosine(3-NT). The potential for fluorescence resonance energy transfer (FRET) was suggested by the spectral overlap between NH 2 -MIL-88(Fe)@Cu 2+ 's emission and 3-NT's UV absorption. To augment this effect, cationic surfactant hexadecyltrimethylammonium bromide (CTAB), which self-assembled into nanostructured microspheres above its critical micelle concentration, was utilized. The charged surface of these microspheres, formed by the self-assembly of CTAB, is bound to the MOF surface through electrostatic force and simultaneously attracts 3-NT. Adjusting the solution's pH strengthened the interaction between NH 2 -MIL-88(Fe)@Cu 2+ and 3-NT, thereby enhancing their mutual FRET interaction. Experimental results indicated that CTAB's introduction markedly improved the FRET effects, potentially converting a weak FRET into a strong one and enhancing detection sensitivity and accuracy. Under optimal conditions, NH 2 -MIL-88(Fe)@Cu 2+ detected 3-NT within 0-30 μM range, with a limit of detection (LOD, S/N = 3) of 41.1 nM. Finally, the applicability of the sensor is tested by calibrating measurements in fetal bovine serum samples, achieving good performance in terms of sensitivity, selectivity and reproducibility. This research provides a method for efficient and highly sensitive 3-NT detection and insights into the FRET effect between MOF and target molecules, likely advancing related fields and inspiring future fluorescence sensor designs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ischemic stroke (IS) has attracted worldwide attention due to the high mortality and disability rate. Raw rhubarb (RR) is a traditional medicinal plant and whole-food that has been used in China for its various pharmacological activities, such as antioxidant and anti-inflammatory properties. Recent pharmacological research has shown the role of RR against IS, but its mechanism of action remains unclear, particularly in the context of the brain-gut axis. To address this gap in knowledge, the present study was conducted in the middle cerebral artery occlusion/reperfusion (MCAO/R) model with the aim of investigating the effects of RR on regulating the intestinal microbiota barrier and metabolism and thereby reducing inflammatory response so as to improve the IS. The results showed that pre-treatment of RR attenuated cerebral infarct area and inflammation response in MCAO rats. Furthermore, RR also improved intestinal barrier function, including the integrity and permeability of the intestinal barrier. Additionally, RR intervention significantly attenuated gut microbiota dysbiosis caused by ischemic stroke, especially the increased Firmicutes. Notably, the pseudo-germ-free (PGF) rats further demonstrated that the anti-stroke effect of RR might rely on intestinal microbiota. In addition, the UPLC/Q-Orbitrap-MS-Based metabolomics revealed the disrupted metabolic profiles caused by MCAO/R, and a total of 11 differential metabolites were modulated by RR administration, especially bile acids. Further correlation analysis and network pharmacology analysis also demonstrated a strong association between specific bacteria, such as Firmicutes and bile acids. In conclusion, our work demonstrated that RR could effectively ameliorate ischemic stroke by modulating the microbiota and metabolic disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Turmeric (Curcuma longa), a typical source with recognized anti-inflammatory activity, is one such medicine-food homology source, yet its anti-inflammatory mechanisms and specific component combinations remain unclear. In this study, a net fishing method combining bio-affinity ultrafiltration and ultra-high performance liquid chromatography-mass spectrometry (AUF-LC/MS) was employed and 13 potential COX-2 inhibitors were screened out from C. longa. 5 of them (C1, 17, 20, 22, 25) were accurately isolated and identified. Initially, their IC 50 values were measured (IC 50 of C1, 17, 20, 22 and 25 is 55.08, 48.26, 29.13, 111.28 and 150.48 μM, respectively), and their downregulation of COX-2 under safe concentrations (400, 40, 120, 50 and 400 μM for C1, 17, 20, 22 and 25, respectively) was confirmed on RAW 264.7 cells. Further, in transgenic zebrafish (Danio rerio), significant anti-inflammatory activity at safe concentrations (15, 3, 1.5, 1.5 and 3 μg/mL for C1, 17, 20, 22 and 25, respectively) were observed in a dose-dependent manner. More importantly, molecular docking analysis further revealed the mode of interaction between them and the key active site residues of COX-2. This study screened out and verified unreported COX-2 ligands, potentially accelerating the discovery of new bioactive compounds in other functional foods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ischemic/reperfusion (IR) can cause adverse reactions including apoptosis, oxidative stress, and inflammation, but the existing therapeutic strategies have been limited. Moreover, the regulation of microglia plays an important role in brain injury after reperfusion. Hence, it is imperative to find new and effective drugs for modulating microglia to treat IR brain injury. Cyclic peptide compound cyclo-(Phe-Tyr) (Sparganin C, SC) is a compound isolated from Sparganii Rhizoma. However, the protective effects of SC on the central nervous system are rather unclear. In an attempt to elucidate the protective effects and mechanism of SC on cerebral damage induced by the IR, we used a middle cerebral artery occlusion reperfusion (MCAO/R) model in rats and discovered that SC significantly decreased the size of cerebral infarcts, improved neurological scores, and blocked inflammatory and oxidative factor release. Using RNA-Seq and metabolomics association analyses, SC was shown to have a protective impact through the JUNB and SOX5-related pathways. Metabolomic analysis revealed twenty-eight differentially expressed biomarkers. In addition, the detection of SC content in brain tissue using LC/MS revealed that SC had blood-brain barrier penetration. To investigate the mechanism, we established an in vitro BV2 cell oxygen-glucose deprivation/reperfusion (OGD/R) model and used siRNA as well as an inhibitor. The protective effects of SC were dependent on the JUNB and SOX5 to inhibit inflammation and apoptosis in microglia. Our findings revealed for the first that SC against IR injury by reducing inflammation and apoptosis while simultaneously acting as potential therapeutic lead compound for ischemic stroke., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and a leading cause of vision impairment and blindness, which lacks effective diagnostic measures and therapeutic options. Sophora flavescens Aiton or "Kushen" is a traditional Chinese medicine used since ancient times, either alone or in combination, to clear heat, dampness, and tearing, and to treat ocular diseases and improve eyesight. Additionally, the flavonoids of Sophora flavescens Aiton extracted using ethyl acetate (EtOAc) (SFE) is effective in managing diabetes and diabetic vascular complications. In this study, we explored the pharmacodynamic effects and material basis of action of SFE on DR for the first time and elucidated the mechanism based on untargeted retinal metabolomics. Results from the pharmacodynamic studies showed that SFE could reduce blood glucose levels in rats, regulate serum lipopolysaccharide, tauroursodeoxycholic acid, and trimethylamine oxide levels, and significantly improve the structure of retina in rats with DR. Moreover, SFE could protect the blood-retinal barrier, reduce angiogenesis and capillary formation, and inhibit retinal nerve cell apoptosis. A total of 13 compounds were identified in the aqueous humor and retina, which were dihydroflavonoid, isoflavonoid, pterostane flavonoid, chalcone, and dihydroflavonol derivatives. In addition, 39 differential metabolites were screened based on retinal metabolomics data and 23 were found to be affected by SFE, indicating its anti-DR effect by regulating the synthetic metabolic pathways, including lactose, bile acid, glycerophospholipid, arginine, purine, and pyrimidine metabolism pathways. Collectively, our findings elucidated the effects, material basis, and treatment mechanism of SFE on DR systematically and could lay the foundation for promoting the clinical application of Sophora flavescens Aiton., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A novel TrxR inhibitor Au-24 and its inhibitory ability to hepatocellular carcinoma in vitro and in vivo is reported herein. Au-24 can suppress HepG2 cells from proliferating by lowering mitochondrial membrane potential (MMP) and increasing reactive oxygen species (ROS) levels, resulting in oxidative stress, which causes DNA damage, autophagy, cell cycle arrest, and apoptosis. This compound can also affect the normal function of apoptosis, MAPK, PI3K/AKT/mTOR, NF-κB, STAT3 signaling pathways. In vivo experiments revealed that Au-24 inhibited HepG2 tumor growth more effectively than AA1 (chloro(triethylphosphine)gold(I)) by decreasing Ki67 and CD31 protein expression and promoting tumor cell apoptosis and necrosis lesions. As a result, Au-24 was found to be a promising candidate as a TrxR inhibitor for the treatment of hepatocellular carcinoma (HCC) in both in vivo and in vitro experiments., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Carbon fiber microelectrode arrays based on diazonium salt and single-walled carbon nanotubes composites (DS-SWCNT/CFMEA) have been fabricated, and it developed for the simultaneous monitoring of dopamine (DA) and serotonin (5-HT) with differential pulse voltammary (DPV). The diazonium salt can improve the water-solubility of single-walled carbon nanotubes and show good selectivity to DA, thus DS-SWCNT/CFMEA exhibits enhanced electrocatalytic activity for the oxidation of DA and 5-HT, and well antifouling ability to the other biomolecules. Moreover, DS-SWCNT/CFMEA shows the wider liner range, and the good performance of precision, reproducibility and biocompatibility. The excellent characteristics of the prepared microsensor array make it to be used to monitor the release of DA and 5-HT in the mouse brain striatum of different group over time. Meanwhile, the results of in vivo on line assay further confirmed the pharmacological effects of Uncaria alkaloid extract solution on DA and 5-HT. This research may provide a new method for monitoring the release of neurobiomolecules, and the microsensor array are expected to be a tool for the study of pharmacological and physiological processes on line in vivo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Based on advantages of capillary electrophoresis (CE), a new solid-phase extraction (SPE) coupled with CE has been developed for preconcentration, enrichment and determination of anthraquinones and flavonoids (rutin, emodin, quercetin, 1,8-dihydroxyanthraquinone) in honey. The environmental-friendly chitin activated after an easy processing is selected as the adsorbent to enrich analytes. Then, chitin was filled into the filter as the solid phase. To improve the extraction effect, some key parameters of extraction were optimized. Under the optional extraction conditions, the chitin showed excellent adsorption capacity and selectivity over rutin, emodin, quercetin, and 1,8-dihydroxyanthraquinone, with enrichment factors reaching 5 folds. The CE coupled with fluorescence detection was used for the detection. Results prove the method is simple, fast, and highly sensitive, with the limit of detection (LOD) is 3.00-200.0 ng/mL; the recovery is 90.0-107.0%, and relative standard deviation of (RSD) is 1.8-8.3%., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Zingiberis Rhizome Carbonisata (ZRC) has been used as a hemostatic agent in traditional Chinese medicine (TCM). However, the underlying molecular mechanism remains unclear. In this study, network pharmacology method was used to predict the potential mechanism of ZRC on hemostasis, based on the structures of the main compounds. Then, iTRAQ-based quantitative proteomics analysis was used for verification of the candidate target proteins and pathways to illustrate the underlying mechanisms. Furthermore, the differentially expressed proteins (DEPs) in the enriched pathways were validated by Enzyme-linked immunosorbent assay. The results showed that the hemostasis mechanism of ZRC may be related to Platelet activation, Rap1 signaling pathway and Complement and coagulation cascades. And 10 proteins (Fermt3, ACTB, Talin, αIIbβ3, Fga, Fgb, Fgg, FXIIIb, Kng and PLC-β were identified as the target DEPs) are considered as the key factors related to hemostatic efficacy of ZRC. Thus, integrated network pharmacology and quantitative proteomics technology were applied for the effective illuminating the molecular mechanisms of Chinese material medica., (Copyright © 2021. Published by Elsevier B.V.)

A highly sensitive electrochemical sensor for the simultaneous dual signal determination of dopamine (DA), uric acid (UA) and glucose (Glu) has been obtained using nanocomposites based on the copper and cerium bimetallic nanoparticles and carbon nanomaterials of graphene and single-walled carbon nanotubes in the presence of Tween 20 (GR-SWCNT-Ce-Cu-Tween 20) modified glassy carbon electrode. The surface morphology of the nanocomposites was characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD), and the electrochemical behavior of the sensor was investigated by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) with potassium ferricyanide as probe. In the coexistence system of DA, UA and Glu, three clear and well-isolated voltammetric peaks were obtained by CV and differential pulse voltammetry (DPV), and oxidation peak currents of DA and UA are positively correlated with their concentrations respectively, while the peak current of Glu is negatively correlated with its concentration. Linearity was obtained in the ranges of 0.1-100 µM for dopamine, 0.08-100 µM for uric acid and 1-1000 µM for glucose with DPV, and the detection limits (S/N = 3) of 0.0072 µM, 0.0063 µM, and 0.095 µM for DA, UA and Glu, respectively. The method was successfully applied to the determination of DA, UA and Glu in blood serum samples, which provided a reference for further sensor research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A high sampling rate, good stability, high throughput masking fluorescence detection system with easy positioning of each channel for capillary array electrophoresis was prepared and studied. A special mask combined with convex lenses was designed to modulate signals, without using any extra device to position each channel. The signal of each channel was detected by a photomultiplier tube, classified and saved by software. The design was used to evidently reduce the rotational vibration of optical components and to stabilize the system, so a high sampling rate was obtained by increasing the DC motor speed. To improve the optical system, optical fibers instead of conventional bulky optical components were used to transmit optical signal and to collect fluorescences in multiple directions, which greatly raised the sensitivity. Other important parameters including sampling rate, rotating speed and driven voltage laser diode (LDs) have also been investigated. Under optimal conditions, the performance of the detection system was evaluated. This novel system had a well-designed structure, and allowed independent multiple capillary operations and easy microanalysis. Its limit of detection for rhodamine 6G was 2.0 × 10 -2  µg/mL., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To establish calibration models for simultaneous determination of contents of liquirtin and glycyrrhizic acid, and to investigate the variable selection methods., Methods: The contents of liquirtin and glycyrrhizic acid determined by HPLC were as the reference values, which were associated with samples spectra by using near infrared spectrum (NIR) analysis technology. Calibration models were developed using partial least squares (PLS) regression algorithm, and evaluated by the independent dataset test with calculating the metrics of coefficients of determination of calibration and prediction (R 2 c , R 2 p ), the root mean square errors of calibration and prediction (RMSEC, RMSEP), the mean absolute errors of calibration and prediction (MAEC, MAEP), and the residual prediction deviation (RPD). Five variable selection methods including variable importance in projection (VIP), competitive adaptive reweighted sampling (CARS), Monte Carlo uninformative variable elimination (MCUVE), particle swarm optimization (PSO) and genetic algorithm (GA), were investigated., Results: Compared to the original full spectra, both quantification models for liquirtin and glycyrrhizic acid performed better with a clear ranking of GA>PSO>CARS>MCUVE≅VIP>Full. Especially for GA-PLS models, RMSEC and RMSEP were <0.05%, R 2 c and R 2 p were >0.94, and RPD were both >4, indicating that both the models had good robustness and excellent prediction accuracy., Conclusion: The present calibration models can be utilized to simultaneously determine the contents of liquirtin and glycyrrhizic acid in liquorice samples, and thus are of great help for rapid quality evaluation and control of liquorice., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The integration of sample pretreatment remains one of the hurdles towards a rapid, automated micro total analytical system (µ-TAS) for real samples. In this paper, a modular design, which was used for sample preparation, has been developed as the polydimethylsiloxane (PDMS) millifluidic chips with channels at a millimeter level. Multiple functional units, including extraction, filtration, mixing and solid phase extraction (SPE), for sample pretreatment were integrated in one chip. In this chip, each functional unit was connected by pump tubings and one-way valves in series to form a fully automated system. Based on the modular design, multiple functional units have been combined in different sequences according to practical needs. In addition, the proposed system has characteristics of miniaturization, portability, and real-time application. Herein, spiked benzoyl peroxide (BPO) in flour samples was used as a model compound to study the system's performances. With a portable integrated Raman spectrometer for detection, the detection limit of BPO was 0.017gkg -1 , with a linear relationship from 0.025 to 0.5gkg -1 . This modular design was demonstrated to be effective and it can be expanded for pretreatment of other food samples., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Alantolactone (AL) and isoalantolactone (IAL), two major active sesquiterpene lactones isolated from Radix Inulae extract, have a wide range of pharmacological activities. The predominant metabolic pathway of AL and IAL observed was glutathione (GSH) conjugation in vitro, which could occur in the absence of metabolic enzymes. Non-enzymatic conjugation with cysteine (Cys) couldalso be observed. Four metabolites (AL-GSH, AL-Cys, IAL-GSH, IAL-Cys) were subsequently isolated and confirmed by nuclear magnetic resonance (NMR). The results indicated that the thiol of GSH or Cys can be reacted with the exomethylene carbon atoms of α, β-unsaturated carbonyl of AL and IAL. After intravenous administration in rats, AL and IAL were extensively metabolized, and the exposure, as measured by area under the concentration-time curve (AUC), for AL-GSH, AL-Cys, IAL-GSH, and IAL-Cys was approximately 1.54-, 0.96-, 1.50-, and 0.91-fold that of the parent drug, respectively. The AUC ratio of metabolites to parent compounds of oral administration was 3.66-, 9.19-, 12.97-, and 9.92-fold that of the parent drug for the above metabolites, respectively. The bioavailability of AL-total (AL, AL-GSH, AL-Cys) and IAL-total (IAL, IAL-GSH, IAL-Cys) was, respectively, 8.39% and 13.07%, which was 3.62- and 6.95- fold that of AL (2.32%) and IAL (1.88%), respectively. The oral exposure will be underestimated if the parent drugs are tested alone. These findings provide useful information for preclinical safety evaluation, and for predicting AL and IAL metabolism in humans., (Copyright © 2017. Published by Elsevier B.V.)

The design, construction and testing for integration of liquid-liquid extraction (EX) and capillary electrophoretic (CE) separation on one glass microchip was reported. In this EX-CE chip, a 1.5 cm-long and 200 μm-wide EX channel was used for extraction based on the two-phase laminar flow, followed by a single-cross CE unit for on-line analysis without any auxiliary devices. One side of the EX channel surface for the organic solvent phase was selectively modified to be hydrophobic while the surface of the other side for the aqueous phase remained hydrophilic, and the extraction product reservoir is also used as the sample reservoir for the subsequent chip separation in the CE channel. With the surface-directed liquid flow behavior and liquid level adjustment in various reservoirs of the EX-CE chip, no disturbance occurred between the extraction (EX) and capillary electrophoretic (CE) units. A small heating block was placed under the chip to accelerate solvent evaporation after liquid-liquid extraction. Sanguinarine (SAN), a plant alkaloid, was used as a model analyte to evaluate the performance of the EX-CE chip. The influences of organic solvent type and liquid flow speed on the extraction efficiency were investigated. Rhodamine 123 (Rh123) was used as an internal standard for quantification of Sanguinarine (SAN) in a physiological buffer (e.g. PBS) or blood samples. A good linearity in the concentration range of 0.05 μg mL -1 to 0.1 mg mL -1 for SAN in PBS was obtained, with the detection limit of 0.5 ng mL -1 . Good repeatibilities for migration times (RSD of SAN is 0.63%, Rh123 is 0.91%, n = 5) and peak area ratio of SAN to Rh123 (RSD is 1.3%, n = 5) were obtained. For blood sample analysis, only 20 μL of sample was needed, and the whole analysis was finished in 17 min. In addition to the advantages in fast analysis speed, minimum sample handling, potential automation, the reported method showed an on-line sample pre-concentration capability., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Atherosclerosis is a chronic inflammatory cardiovascular disease with high mortality worldwide. Tofacitinib (CP-690,550), an oral small-molecule Janus kinase inhibitor, has been shown to be effective in the treatment of rheumatoid arthritis, autoimmune encephalomyelitis and ulcerative colitis. However, its protective effect against atherosclerosis remains poorly understood. The aim of the present study was to evaluate the effects of Tofacitinib on atherogenic diet (ATD)-induced atherosclerosis using apolipoprotein E deficient (apoE-/-) mice. Atherosclerosis-prone apoE-/- mice were fed with ATD and treated with or without Tofacitinib through intragastrical administration (10 mg kg -1 day -1 ) for 8 weeks. Our results showed that Tofacitinib did not change plasma lipids, while significantly reduced the levels of plasma pro-inflammatory cytokines IL-6 and TNF-α. It also significantly attenuated atherosclerotic plaque lesion in the aortic root and macrophages contained in plaque as shown with Mac2 immuno-staining. Peritoneal macrophages (PMC) were separated from apoE-/- mice fed with 8-week ATD, and then subjected to inflammation tests. Flow cytometry analysis of F4/80 and CD206 and mRNA levels of M1 and M2 macrophages markers showed that M1 macrophages decreased while M2 macrophages increased in Tofacitinib treated group. Expressions of other inflammatory genes also indicated an anti-inflammatory status in mice treated with Tofacitinib. Ox-LDL was used to induce foam cell formation from PMC in wild type mice, and the results displayed a reduced formation of foam cells and decreased inflammation in mice with Tofacitinib administration (1 μM). The mRNA and protein levels of ATP binding cassette subfamily A member 1 (ABCA1), a key gene involved in cholesterol efflux, remarkably increased, while it was absence of alterations in scavenger receptors expression. Therefore, we demonstrated that Tofacitinib could attenuate atherosclerosis and foam cells formation by inhibiting inflammation and upregulating ABCA1 expression., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The objectives of this study were to evaluate the anti-diabetic and anti-hyperlipidemic effects and relative mechanisms of guava polysaccharides (GPs) in rats with type 2 diabetic mellitus (T2DM). The chemical characterization and monosaccharide compositions of GPs, named as GP-1, GP-2, GP-3, and GP-4, were determined by PMP-HPLC and FT-IR. The results revealed that all GPs had the typical saccharide absorptions, and all were heteropolysaccharides. In addition, GPs efficiently decreased levels of fasting blood glucose, glucosylated serum protein, serum insulin, homeostasis model assessment of insulin resistance, total cholesterol, triglyceride and serum alanine transaminase, improved oral glucose tolerance, and increased insulin sensitivity in rats with T2DM. Histopathological observations suggested that GP-1, GP-3, and GP-4 could alleviate injury in pancreatic islet cells, and Western blot analysis showed that these GPs upregulated gene expression of the insulin receptor, insulin receptor substrate 2, Akt, and glucose transporter type 4. Taken together, these data suggest that GPs may be beneficial in treating T2DM and reducing the risk of hyperlipidemia, vascular disease, and cirrhosis via the PI3K/Akt signaling pathway., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To construct different calibration models by using FTIR/ATR spectra and apply them for the screening of phenylketonuria for the newborns., Method: 69 dried blood spots samples were collected, of which the concentrations of phenylalanine (Phe) and tyrosine (Tyr) were determined by tandem mass spectrometry method. The FTIR/ATR method was used to collect the spectra of the samples. After various pretreatments with the original spectra, such as smoothing, derivative, vector normalization, Concave rubberband correction, the new spectra were fed into different methods to construct calibration models for the Phe concentrations of the samples. The kernel function, consensus strategy and their combination were integrated into the popular partial least squares method. The obtained models were then assessed by calculating coefficient of determination, root mean square error, mean relative error, etc., Result: After a careful comparison, the cKPLS model performed the best, and the result yielded were much more accurate and stable., Conclusion: The present cKPLS model, due to the combination of the kernel function and the consensus strategy, can be successfully applied to the prediction of Phe concentration for the phenylketonuria newborns. Also, we believe that the cKPLS method will be of help for FTIR/ATR spectra calibration problems in other complex systems., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: PTPN13 is a new candidate tumor-suppressing gene. To investigate the PTPN13 expression and its potential function in the invasion and metastasis of lung squamous cell carcinoma (LSCC), we performed this study in 91 primary LSCC tissues and the adjacent non-cancerous tissues., Methods: The mRNA expression of PTPN13 and FAK was quantitated by reverse transcription polymerase chain reaction. The protein expression of PTPN13, focal adhesion kinase (FAK) and phosphorylated FAK (P-FAK) was evaluated using immunohistochemical staining and western blotting. The association among PTPN13 expression, FAK expression and the clinicopathological parameters were analyzed., Results: PTPN13 expression was down-regulated in LSCC, and was negatively correlated with the cancer grade and stage. FAK mRNA, as well as FAK protein level was elevated in LSCC tissues. P-FAK level, also found increased, had no association with FAK mRNA and FAK protein expression, but had a negative correlation with the PTPN13 expression. P-FAK level had a significant positive correlation with the TNM classification., Conclusion: The over-expression of FAK and increased FAK phosphorylation plays an important role in the invasion and metastasis of LSCC., (© 2013 Elsevier Inc. All rights reserved.)

Purpose: To assess the effect of metformin intake on cancer incidence and mortality., Methods: Original articles in English published until June 15, 2012 were searched for in electronic databases (MEDLINE, ISI Web of Science and EMBASE databases) and relevant reviews were examined. Meta-analysis was applied to calculate the summary relative risk (SRR) and their 95% confidence intervals (95% CI). Sensitivity analysis was conducted to assess the robustness of the pooled estimator. The risk of publication bias was assessed by the Egger regression asymmetry test., Results: According to the eligibility criteria, 37 studies comprising 1,535,636 participants, were selected in terms of intervention and data of cancer incidence or mortality. Among metformin users compared with non-users, the SRR for overall-cancer incidence was 0.73 (95% CI, 0.64-0.83) and that for mortality was 0.82 (95% CI, 0.76-0.89). The risk reductions for liver, pancreatic, colorectal and breast cancer incidence were 78%, 46%, 23% and 6%, respectively. Also, metformin can reduce the mortality of liver cancer (SRR, 0.23; 95% CI, 0.09-0.60) and breast cancer (SRR, 0.63; 95% CI, 0.40-0.99). No statistically significant association between metformin and prostate cancer incidence was found., Conclusions: Metformin can reduce the incidence of overall cancer, liver cancer, pancreatic cancer, colorectal cancer and breast cancer as well as the mortality of overall cancer, liver cancer and breast cancer. No beneficial effect on prostate cancer incidence was found for meformin intake in the meta-analysis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Induction of immune tolerance to ox-LDL could reduce atherosclerosis by modulation immune response. We suppose that very low density lipoprotein (VLDL) may have a similar role to ox-LDL in autoimmune response of atherosclerosis. In this study, neonatal rats were injected with ox-LDL, VLDL, or equal-volume saline, respectively. Vaccination with ox-LDL reduced the level of specific antibody, T cells proliferation response, and the level of endothelins. The method also had a tendency of reducing blood lipids. Vaccination with VLDL obviously reduced the level of specific antibody and T cells proliferation. Though there was also a tendency of reducing blood lipids and endothelins, the effect was less prominent than that with ox-LDL. We conclude that, although the effect was less obvious, vaccination with VLDL to induce neonatal tolerance had an effect on modulating immune response, protecting endothelial cells, and reducing blood lipids., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The hydrolysis is known to be the rate-limiting step of biological sludge anaerobic degradation. The disruptions of sludge flocs and microbial cell walls by ultrasound combined with ozone treatment (US/O(3)) were investigated in laboratory-scale experiments. The results showed that temperature, O(3) dose, US energy density and pH had a positive effect on the disintegration of sludge. The organic substrates were released into the liquor, which induced the increases of soluble chemical oxygen demand (COD(S)) and turbidity in the aqueous phase. Accordingly, the biodegradability of sludge was improved. The COD(S) increased from 1821 to 2513 mg/l after reaction for 30 min when NaHCO(3) was added, which indicated that the ozone molecule played a major role in the disintegration of waste activated sludge. The COD(S) was 2483 mg/l after 60 min O(3) treatment followed by 60 min US treatment, and it changed into 3040 mg/l after 60 min US/O(3) treatment, which proved that US/O(3) induced a synergetic effect. The pH-drop of sludge from 6.8 to 5.21 might be attributed to the increase of volatile fatty acid from 61.35 to 111.96 mg/l during the US/O(3) treatment process., (Copyright 2010 Elsevier B.V. All rights reserved.)

Interferon-gamma (IFN-gamma) inhibits graft-versus-host disease (GVHD) in lethally irradiated mice receiving allogeneic hematopoietic cell transplantation (allo-HCT) but promotes lethality in unirradiated and sublethally irradiated recipients. We investigated the role of IFN-gamma in GVHD in sublethally irradiated B6D2F1 recipients of B6 allo-HCT. B6D2F1 mice receiving wild-type B6 splenocytes alone died rapidly, whereas those receiving wild-type B6 splenocytes plus marrow survived long-term. Mice in both groups showed rapid elimination of host hematopoietic cells but minimal parenchymal tissue injury. However, mice receiving allo-HCT from IFN-gamma-deficient donors died rapidly regardless of whether donor marrow was given, and they exhibited severe parenchymal injury but prolonged survival of host hematopoietic cells. IFN-gamma plays a similar role in another model involving delayed B6 donor leukocyte infusion (DLI) to established mixed allogeneic (B6-->BALB/c) chimeras. IFN-gamma promotes DLI-mediated conversion from mixed to full donor chimerism while attenuating GVHD. Importantly, IFN-gamma enhances graft-versus-leukemia (GVL) effects in both models. Our data indicate that previously reported IFN-gamma-induced early mortality in allo-HCT recipients is due to augmentation of lymphohematopoietic graft-versus-host reaction (LGVHR) and can be avoided by providing an adequate source of donor hematopoietic stem/progenitor cells. Furthermore, the magnitude of GVL is correlated with the strength of LGVHR, and IFN-gamma reduces the potential of this alloreactivity to cause epithelial tissue GVHD.

Signal regulatory protein alpha (SIRPalpha) is a critical immune inhibitory receptor on macrophages, and its interaction with CD47, a ligand for SIRPalpha, prevents autologous phagocytosis. We hypothesized that interspecies incompatibility of CD47 may contribute to the rejection of xenogeneic cells by macrophages. Here, we show that pig CD47 does not interact with mouse SIPRalpha. Similar to CD47-/- mouse cells, porcine red blood cells (RBCs) failed to induce SIRPalpha tyrosine phosphorylation in mouse macrophages. Blocking SIRPalpha with antimouse SIRPalpha mAb (P84) significantly enhanced the phagocytosis of CD47+/+ mouse cells, but did not affect the engulfment of porcine or CD47-/- mouse cells by mouse macrophages. CD47-deficient mice, whose macrophages do not phagocytose CD47-/- mouse cells, showed markedly delayed clearance of porcine RBCs compared with wild-type mouse recipients. Furthermore, mouse CD47 expression on porcine cells markedly reduced their phagocytosis by mouse macrophages both in vitro and in vivo. These results indicate that interspecies incompatibility of CD47 contributes significantly to phagocytosis of xenogeneic cells by macrophages and suggest that genetic manipulation of donor CD47 to improve its interaction with the recipient SIRPalpha may provide a novel approach to prevent phagocyte-mediated xenograft rejection.

Studies of the human immune system have been limited by the lack of an appropriate in vivo model. For this reason, efforts have been made to develop murine models with a functional human immune system. We report here that cotransplantation of human fetal thymus/liver tissues and CD34(+) hematopoietic stem/progenitor cells led to the development of sustained human hematopoiesis and a functional human immune system in immunodeficient NOD/SCID mice. The humanized mice showed systemic repopulation with a comprehensive array of human lymphohematopoietic cells, including T cells, B cells, and dendritic cells, and the formation of secondary lymphoid organs. Furthermore, these mice produce high levels of human IgM and IgG antibodies and mediate strong immune responses in vivo as demonstrated by skin xenograft rejection. Thus, the humanized NOD/SCID mice described in this paper provide a powerful model system to study human immune function.