Improved Antitumor Efficacy of a Dextran-based Docetaxel-coupled Conjugate against Triple-Negative Breast Cancer.

BACKGROUND: Most chemotherapeutic agents are characterized by poor water solubility and non-specific distribution. Polymer-based conjugates are promising strategies for overcoming these limitations. OBJECTIVE: This study aims to fabricate a polysaccharide, dextran-based, dual-drug conjugate by covalently grafting docetaxel (DTX) and docosahexaenoic acid (DHA) onto the bifunctionalized dextran through a long linker, and to investigate the antitumor efficacy of this conjugate against breast cancer. METHODS: DTX was firstly coupled with DHA and covalently bounded with the bifunctionalized dextran (100 kDa) through a long linker to produce a conjugate dextran-DHA-DTX (termed C-DDD). Cytotoxicity and cellular uptake of this conjugate were measured in vitro. Drug biodistribution and pharmacokinetics were investigated through liquid chromatography/mass spectrometry analysis. The inhibitory effects on tumor growth were evaluated in MCF-7- and 4T1-tumor-bearing mice. RESULTS: The loading capacity of the C-DDD for DTX was 15.90 (weight/weight). The C-DDD possessed good water solubility and was able to self-assemble into nanoparticles measuring 76.8 ± 5.5 nm. The maximum plasma concentration and area under the curve (0-∞) for the released DTX and total DTX from the C-DDD were significantly enhanced compared with the conventional DTX formulation. The C-DDD selectively accumulated in the tumor, with limited distribution was observed in normal tissues. The C-DDD exhibited greater antitumor activity than the conventional DTX in the triplenegative breast cancer model. Furthermore, the C-DDD nearly eliminated all MCF-7 tumors in nude mice without leading to systemic adverse effects. CONCLUSION: This dual-drug C-DDD has the potential to become a candidate for clinical application through the optimization of the linker.

Influence of unsaturated fatty acids on the antitumor activity of polymeric conjugates grafted with cabazitaxel against prostate cancer.

Cabazitaxel (CTX) is a medication used for treating metastatic prostate cancer. However, its effectiveness is majorly limited by its poor water solubility and lack of tumor targeting. In this study, three unsaturated fatty acids, GLA, ALA and DHA, were separately connected with CTX and then covalently attached to bifunctionalized dextran through a linker to produce three dual drug conjugates named dextran-GLA-CTX, dextran-ALA-CTX and dextran-DHA-CTX. The three conjugates displayed enhanced solubility of CTX in water and improved antitumor effects compared to the conventional CTX formulation. The results also confirmed that dextran-GLA-CTX exhibited the strongest antitumor activity, while dextran-DHA-CTX displayed less efficacy, as evaluated through xenografted nude mice bearing PC-3 and DU145 prostate cancer cells. Additionally, dextran-GLA-CTX showed greater inhibition of tumor growth than dextran-CTX. Moreover, the dextran-GLA-CTX conjugate was found to prolong the half-life of CTX in plasma and selectively accumulate in tumors. This study revealed that unsaturated fatty acids can enhance the antitumor activity of dextran-based conjugates grafted with CTX.

Synthesis and application of quaternary amine-functionalized core-shell-shell magnetic polymers for determination of metabolites of benzene, toluene and xylene in human urine samples and study of exposure assessment.

As production processes have evolved, airborne concentrations of benzene, toluene and xylene in many workplaces are already well below the occupational exposure limits. However, studies have shown that low levels of exposure to benzene, toluene and xylene can still cause health effects in people exposed occupationally. However, there is no literature on health risk assessment of internal exposure. In view of this, an analytical method based on quaternary amine-functionalized core-shell-shell magnetic polymers (QA-CSS-MPs) was developed for the determination of seven metabolites in urine by MSPE-UPLC-DAD-HRMS. Furthermore, an improved QuEChERS method for the extraction of seven metabolites from human urine samples was introduced for the first time and satisfactory extraction rates were achieved. In addition, QA-CSS-MPs microspheres with core-shell-shell structure were designed and synthesized, and the morphology, composition and magnetic properties of the materials were fully characterized to verify the rationality of the synthetic route. Subsequently, QA-CSS-MPs microspheres were used as magnetic solid-phase extraction (MSPE) adsorbents for the purification of urine extracts, and UPLC-DAD-HRMS was used for the detection of seven metabolites. As a result, this method allows the accurate determination of seven metabolites in urine samples over an ultra-wide concentration range (0.001-100 mg/L). Under optimal experimental conditions, i.e., 2% hydrochloric acid in urine for the hydrolysis and 20 mg of QA-CSS-MPs for 5 min purification, the spiked recoveries of the seven target metabolites ranged from 81.5% to 117.7% with RSDs of 1.0%-9.4%. The limits of detection (LODs, S/N≥3) for the established method were in the range of 0.2-0.3 µg/L. The developed method was applied to 254 human urine samples for the determination of seven metabolites. The results showed that the concentration distributions of three xylene metabolites in urine, 2-MHA, 3-MHA, 4-MHA and total MHA, showed statistically significant differences for occupational exposure (p<0.001). In addition, the results of the internal exposure assessment showed that there is a high potential health risk associated with occupational exposure processes.

Characteristics and occupational risk assessment of occupational silica-dust and noise exposure in ferrous metal foundries in Ningbo, China.

Introduction: To investigate the major existing occupational hazards and to assess the occupational health risks for ferrous metal foundries (FMFs) in Ningbo, China. Methods: Unified questionnaires were formulated to investigate the information on the basic situations, occupational hazards, and occupational health management for 193 FMFs in Ningbo. Furthermore, we used the semi-quantitative risk assessment model, which was developed by the International Council on Mining and Metals (ICMM), to assess occupational health risks for 59 of 193 the FMFs. Results: The casting process of FMFs in Ningbo was mainly divided into sand casting and investment casting, and silica-dust and noise were the major occupational hazards in both sand casting and investment casting foundries. Silica-dust mainly occurred in industries with such work as sand handling, modeling, falling sand, and sand cleaning, with the median of the permissible concentration-time weighted average (PC-TWA) was 0.80, 1.15, 3.52, 0.83 mg/m3, respectively. The noise mainly existed in industries with such work as sand handling, core making, falling sand, sand cleaning, cutting and grinding, and smelting with median of PC-TWA was 81.72 dB(A), 82.93 dB(A), 90.75 dB(A), 80.18 dB(A), 90.05 dB(A), 82.70 dB(A), respectively. In addition, the results of the ICMM assessment model indicated that 100 and 98.7% of the jobs exposed to silica-dust and noise in 59 FMFs have an "intolerable risk" level of risks of causing pneumoconiosis and noise deaf, respectively. Discussion: The hazard risk of silica-dust and noise is serious for FMFs in Ningbo. It is necessary to supervise enterprises to improve operating environmental conditions, accelerate the reduction of silica-dust and noise exposure risks, and promote the healthy and sustainable development of the foundry industry.

Profiling microRNA from peripheral blood mononuclear cells in early-onset familial Alzheimer's disease.

MicroRNAs (miRNAs) refer to short in-length, noncoding RNAs that regulate numerous cellular functions by targeting mRNA, and numerous types of research have shown that miRNA is vitalin Alzheimer's disease. For identifying differentially expressed miRNAs in the peripheral blood mononuclear cell (PBMC) of early-onset familial Alzheimer's disease (EOFAD), we conducted this study which might give a reference for potential therapeutic targets or biomarkers for this disease. On the basis of high-throughput sequencing, we screened the miRNAs expression profiles in PBMC regarding both EOFAD patients and healthy controls, and the biological information was analyzed. Compared with the PBMC of healthy controls, 142 miRNAs were differentially expressed in EOFAD patients ( P < 0.05), including 48 significantly differentially expressed miRNAs, 37 of which were significantly upregulated, including miR-3614-5p, miR-193A-5p, miR-2115-5p, miR-143-3p, etc. and 11 were significantly downregulated, including miR-484, miR-708-5p, miR-205-5p, miR-31-5p, etc. According to biological information analysis, 768 miRNA target genes were differentially expressed, which may be involved in multiple gene functions and cell cycle, cell senescence, and several signaling pathways, including FoxO, MAPK, Ras, mTOR, neurotrophin, etc. There are differential expressions of miRNAs in PBMC of EOFAD patients and controls, revealing their importance in Alzheimer's disease as indicated by co-expression network analysis; this may support basic information for new biomarkers or treatment exploring.

Polysaccharide dextran-based conjugate for selective co-delivery of two synergistic drugs docetaxel and docosahexaenoic acid to tumor cells.

Most chemotherapeutic agents are nonspecific distribution and cause systemic toxicities. Polysaccharide-based conjugates are promising strategies to overcome these drawbacks. To this end, two synergistic drugs docetaxel (DTX) and docosahexaenoic acid (DHA) were independently covalently bonded through individual linkers to dextran (100 kDa) to produce a novel dual-drug conjugate dextran-DHA-DTX. The single-drug conjugates dextran-DHA and dextran-DTX were also prepared for comparison. Fluorescent dye Cy7.5-based conjugates dextran-Cy7.5 and dextran-DHA-Cy7.5 were synthesized for cellular uptake study. The dual-drug conjugate dextran-DHA-DTX self-assembled into nanoparticles with the diameter of 102.3 ± 8.3 nm and demonstrated enhanced water solubility and improved pharmacokinetic profiles. Cellular uptake results showed that the dual-drug conjugate entered cells more than the parent DTX by determining the intracellular DTX contents via HPLC/MS analysis and by determining the fluorescent intensity of dextran-Cy7.5 and dextran-DHA-Cy7.5. Importantly, the dual-drug conjugate dextran-DHA-DTX significantly accumulated in tumor tissues and dramatically reduced the DTX concentrations in normal tissues. The dual-drug conjugate completely eradicated all the MCF-7 xenograft tumors without obvious side effects and showed more superior antitumor activity than parent DTX and single-drug conjugate dextran-DTX and dextran-DHA. Both in vitro and in vivo studies showed that DHA enhanced the antitumor activity of dextran-DTX. The polysaccharide dextran-based dual-drug conjugates may represent an effective way to improve the chemotherapeutic agents.

A Novel Dextran-Based Dual Drug Conjugate Targeted Tumors with High Biodistribution Ratio of Tumors to Normal Tissues.

Purpose: Most chemotherapeutic agents possess poor water solubility and show more significant accumulations in normal tissues than in tumor tissues, resulting in serious side effects. To this end, a novel dextran-based dual drug delivery system with high biodistribution ratio of tumors to normal tissues was developed. Methods: A bi-functionalized dextran was developed, and several negatively charged dextran-based dual conjugates containing two different types of drugs, docetaxel and docosahexaenoic acid (DTX and DHA, respectively) were synthesized. The structures of these conjugates were characterized using nuclear magnetic resonance and liquid chromatography/mass spectrometry (1H-NMR and LC/MS, respectively) analysis. Cell growth inhibition, apoptosis, cell cycle distribution, and cellular uptake were measured in vitro. Drug biodistribution and pharmacokinetics were investigated in mice bearing 4T1 tumors using LC/MS analysis. Drug biodistribution was also explored by in vivo imaging. The effects of these conjugates on tumor growth were evaluated in three mice models. Results: The dextran-docosahexaenoic acid (DHA)- docetaxel (DTX) conjugates caused a significant enhancement of DTX water solubility and improvement in pharmacokinetic characteristics. The optimized dextran-DHA-DTX conjugate A treatment produced a 2.1- to 15.5-fold increase in intra-tumoral DTX amounts for up to 96 h compared to parent DTX treatment. Meanwhile, the concentrations of DTX released from conjugate A in normal tissues were much lower than those of the parent DTX. This study demonstrated that DHA could lead to an improvement in the efficacy of the conjugates and that the conjugate with the shortest linker displayed more activity than conjugates with longer linkers. Moreover, conjugate A completely eradicated all MCF-7 xenograft tumors without causing any obvious side effects and totally outperformed both the conventional DTX formulation and Abraxane in mice. Conclusion: These dextran-based dual drug conjugates may represent an innovative tumor targeting drug delivery system that can selectively deliver anticancer agents to tumors.

Complete regression of xenografted breast tumors by dextran-based dual drug conjugates containing paclitaxel and docosahexaenoic acid.

In this study, a novel carboxymethyl dextran (CMD)-based dual drug delivery system that delivering two water insoluble drugs to tumor sites was developed and evaluated for anticancer activities. Paclitaxel (PTX) and docosahexaenoic acid (DHA) were covalently coupled with CMD to generate CMD-DHA-PTX conjugate S and conjugate L with different linkers containing amino acids Gly-Gly or Lys-Gly-Gly, respectively. Both conjugates possessed high PTX loading contents and enhanced water solubility, as well as the ability of being self-assembled into nanoparticles with the nanoparticle size ranged from 88.7 nm to 94.7 nm. These two conjugates released free PTX continuously in plasma and cancer cells. The conjugate S exhibited improved pharmacokinetic parameters and higher distribution extent in tumor sites than the parent PTX, Abraxane and the conjugate L. The antitumor efficacy of these two conjugates outperformed parent PTX formulation and Abraxane in nude mice bearing breast cancer cells MCF-7. More importantly, the conjugate S treatment eliminated all the xenograft tumors without causing any mice body weight loss in mice model. This study revealed that the dextran-based dual drug conjugates may represent an effective and innovative way to deliver anticancer agents to a variety of tumors.

The enhanced antitumor activity of the polymeric conjugate covalently coupled with docetaxel and docosahexaenoic acid.

Docetaxel (DTX) has been widely used for the treatment of many types of cancer. However, DTX is poorly water-soluble and commercial DTX is formulated in non-ionic surfactant polysorbate 80 and ethanol, thereby leading to hypersensitivity and serious side effects. Herein, a polymer dual drug conjugate was synthesized by coupling DTX and docosahexaenoic acid (DHA) with bifunctionalized dextran. The polysaccharide conjugate dextran-DHA-DTX possessed high water solubility and was self-assembled into nanoparticles with a diameter of 98.0 ± 6.4 nm. Pharmacokinetic and biodistribution studies showed that the dextran-DHA-DTX dual drug conjugate not only had significantly prolonged blood circulation but was also selectively accumulated in the tumor with reduced drug distribution in normal tissues. The conjugate exhibited a superior therapeutic effect in both xenograft nude mice models without causing any systemic side effects. Notably, the conjugate nearly eliminated all xenograft tumors in nude mice bearing breast cancer cells MCF-7. This study revealed that the dextran-based dual drug delivery system may provide an effective strategy to selectively deliver DTX to tumor sites.

Rectal administration of Panax notoginseng and Colla Corii Asini suppositories in ulcerative colitis: clinical effect and influence on immune function.

OBJECTIVE: This study was designed to evaluate the efficacy of rectal administration of different doses of Panax notoginseng and Colla Corii Asini (CCA) suppositories in the treatment of ulcerative colitis (UC) and the effect on immune function and recurrence. METHODS: Totally 120 UC patients admitted to our hospital from February 2019 to February 2020 were enrolled and randomized into experimental group (n=60) and control group (n=60). The experimental group received rectal administration of a high dose of Panax notoginseng and CCA suppositories, while the control group received a low dose. After three months of treatment, clinical symptom scores, inflammatory factor levels, scores of rectal mucosa, immune function, recurrence rates, adverse reaction rates, and clinical efficacy were compared between the two groups. RESULTS: After treatment, the experimental group obtained significantly lower clinical symptom scores, inflammatory factors, and scores of rectal mucosa than the control group (all P<0.001). The immune function of the observation group was significantly better than that of the control group (P<0.001). At 6, 8, and 12 months after treatment, the recurrence rates in the experimental group were all significantly lower than those in the control group (all P<0.001). The two groups showed no significant difference in the incidence of adverse reaction (P>0.05), and the experimental group obtained a higher clinical efficacy than the control group (P<0.001). CONCLUSION: For patients with UC, the rectal administration of Panax notoginseng and CCA suppositories can exert positive effects on their inflammatory factors, immune functions, UC severity, clinical symptoms, and recovery. In addition, higher doses were associated with better effects without increased adverse events.

Effect of exposure to low concentrations of benzene on miR-223 and miR-155 expression in peripheral blood lymphocytes / 预防医学

Objective @#To investigate the effect of exposure to low concentrations of benzene on miR-155 and miR-223 expression in peripheral blood lymphocytes among workers with benzene exposure. @*Methods @#A hundred male employees at a risk of exposure to benzene (the exposed group) were randomly sampled from two small metal products manufacturing enterprises and one medium-sized chemical raw material and chemical products manufacturing enterprise in Ningbo City, Zhejiang Province, and 60 age-matched male employees without benzene exposure were randomly selected as the unexposed group. Age, body mass index ( BMI ), smoking status, alcohol consumption, disease history, medication history and routine blood testing results of subjects were collected using a questionnaire survey. The 8-hour time weighted average concentration ( CTWA ) of benzene was measured in the workplace using thermal desorption gas chromatography, and the urine 8-hydroxy-2' deoxyguanosine ( 8-OHdG ) levels were determined using high-performance liquid-chromatography tandem mass spectrometry (HPLC-MS/MS). The miR-155 and miR-223 expression was quantified in peripheral blood lymphocytes using quantitative fluorescent reverse transcription-polymerase chain reaction assay, and the factors affecting miR-155 and miR-223 expression were identified using multivariable logistic regression analysis. @*Results @#The subjects in the exposed group had a mean age of ( 31.17±7.30 ) years, and were exposed to low concentrations of benzene ( CTWA, 0.05 to 0.30 mg/m3 ) , while the subjects in the unexposed group had a mean age of ( 32.52±6.15 ) years. There were no significant differences between the exposed and unexposed groups in terms of age, BMI, proportion of smokers or proportion of alcohol consumers ( P>0.05 ). There was no significant difference in the median relative miR-155 expression between the exposed and unexposed groups ( 0.953 vs. 1.293, P>0.05 ), and lower median relative miR-223 expression was quantified in the exposed group than in the unexposed group ( 0.540 vs. 1.433, P<0.05 ). Multivariable logistic regression analysis revealed that down-regulation of miR-223 expression correlated with exposure to benzene ( OR=2.719, 95%CI: 1.308-5.651 ). @*Conclusion @#Down-regulation of miR-223 expression may be associated with exposure to low concentrations of benzene.

miR-1270 enhances the proliferation, migration, and invasion of osteosarcoma via targeting cingulin.

Osteosarcoma (OS), characterized by high morbidity and mortality, is the most common bone malignancy worldwide. MicroRNAs (miRNAs) play a crucial role in the initiation and development of OS. The purpose of this study was to investigate the roles of miR-1270 in OS. RT-qPCR and Western blot were applied to detect the mRNA and protein level, respectively. CCK-8, colony formation, and TUNEL assays were conducted to determine the cell viability, proliferation, and apoptosis of OS cells. Wound healing and transwell assay were performed to detect the migration and invasion ability of OS cells. Bioinformatics analysis and dual-luciferase reporter assay were used to predict the target genes of miR-1270. Tumor xenograft in vivo assay was carried out to determine miR-1270 effect on the tumor size, volume, and weight. In this study, miR-1270 was overexpressed in OS tissues and cells. However, miR-1270 knockdown inhibited the proliferation, migration and invasion, and promoted the OS cells' apoptosis. Mechanistically, cingulin (CGN) was predicted and proved to be a target of miR-1270 and partially alleviated the effects of miR-1270 on the proliferation, migration and invasion ability of OS cells. Taken together, knockdown of miR-1270 may inhibit the development of OS via targeting CGN. This finding may provide a novel therapeutic strategy for OS.

Oxidative Metabolism as a Modulator of Kratom's Biological Actions.

The leaves of Mitragyna speciosa (kratom), a plant native to Southeast Asia, are increasingly used as a pain reliever and for attenuation of opioid withdrawal symptoms. Using the tools of natural products chemistry, chemical synthesis, and pharmacology, we provide a detailed in vitro and in vivo pharmacological characterization of the alkaloids in kratom. We report that metabolism of kratom's major alkaloid, mitragynine, in mice leads to formation of (a) a potent mu opioid receptor agonist antinociceptive agent, 7-hydroxymitragynine, through a CYP3A-mediated pathway, which exhibits reinforcing properties, inhibition of gastrointestinal (GI) transit and reduced hyperlocomotion, (b) a multifunctional mu agonist/delta-kappa antagonist, mitragynine pseudoindoxyl, through a CYP3A-mediated skeletal rearrangement, displaying reduced hyperlocomotion, inhibition of GI transit and reinforcing properties, and (c) a potentially toxic metabolite, 3-dehydromitragynine, through a non-CYP oxidation pathway. Our results indicate that the oxidative metabolism of the mitragynine template beyond 7-hydroxymitragynine may have implications in its overall pharmacology in vivo.

Protective effects of panax notoginseng saponin on dextran sulfate sodium-induced colitis in rats through phosphoinositide-3-kinase protein kinase B signaling pathway inhibition.

BACKGROUND: Intestinal inflammation is a common digestive tract disease, which is usually treated with hormone medicines. Hormone medicines are effective to some extent, but long-term use of them may bring about many complications. AIM: To explore the protective effects of panax notoginseng saponin (PNS) against dextran sulfate sodium (DSS)-induced intestinal inflammatory injury through phosphoinositide-3-kinase protein kinase B (PI3K/AKT) signaling pathway inhibition in rats. METHODS: Colitis rat models were generated via DSS induction, and rats were divided into control (no modeling), DSS, DSS + PNS 50 mg/k, and DSS + PNS 100 mg/kg groups. Then, the intestinal injury, oxidative stress parameters, inflammatory indices, tight junction proteins, apoptosis, macrophage polarization, and TLR4/AKT signaling pathway in colon tissues from rats in each of the groups were detected. The PI3K/AKT signaling pathway in the colon tissue of rats was blocked using the PI3K/AKT signaling pathway inhibitor, LY294002. RESULTS: Compared with rats in the control group, rats in the DSS group showed significantly shortened colon lengths, and significantly increased disease activity indices, oxidative stress reactions and inflammatory indices, as well as significantly decreased expression of tight junction-associated proteins. In addition, the DSS group showed significantly increased apoptotic cell numbers, and showed significantly increased M1 macrophages in spleen and colon tissues. They also showed significantly decreased M2 macrophages in colon tissues, as well as activation of the PI3K/AKT signaling pathway (all P < 0.05). Compared with rats in the DSS group, rats in the DSS + PNS group showed significantly lengthened colon lengths, decreased disease activity indices, and significantly alleviated oxidative stress reactions and inflammatory responses. In addition, this group showed significantly increased expression of tight junction-associated proteins, significantly decreased apoptotic cell numbers, and significantly decreased M1 macrophages in spleen and colon tissues. This group further showed significantly increased M2 macrophages in colon tissues, and significantly suppressed activation of the PI3K/AKT signaling pathway, as well as a dose dependency (all P < 0.05). When the PI3K/AKT signaling pathway was inhibited, the apoptosis rate of colon tissue cells in the DSS + LY294002 group was significantly lower than that of the DSS group (P < 0.05). CONCLUSION: PNS can protect rats against DSS-induced intestinal inflammatory injury by inhibiting the PI3K/AKT signaling pathway, and therefore may be potentially used in the future as a drug for colitis.

Mitochondrial dependent pathway is involved in the protective effects of carboxymethylated chitosan on nitric oxide-induced apoptosis in chondrocytes.

BACKGROUND: Chondrocyte apoptosis activated by the mitochondrial dependent pathway serves a crucial role in cartilage degeneration of osteoarthritis (OA). In the present study, the protective effects of CMCS against sodium nitroprusside (SNP)-induced chondrocyte apoptosis were evaluated and the underlying molecular mechanisms were elucidated. METHODS: Chondrocytes were isolated from articular cartilage of SD rats and identified by type II collagen immunohistochemistry. The chondrocytes stimulated with or without SNP to induce apoptosis, were treated by CMCS for various concentrations. The cell viability were determined by MTT and LDH assays. Cell apoptotic ratio was determined by Annexin V-FITC/PI staining. Mitochondrial membrane potential (ΔΨm) was detected by using Rhodamine123 (Rho123) staining. To understand the mechanism, the mRNA expression levels of Bcl-2, Bax, cytochrome c (Cyt c) and cleaved caspase-3 were detected by real-time PCR and western blot analysis, respectively. RESULTS: It was shown using the MTT and LDH assays that CMCS protected the viability of chondrocyte against SNP damage. Annexin V-FITC/PI and Rho123 staining showed that CMCS not only inhibited the cell apoptosis but also restored the reduction of the ΔΨm in chondrocytes. In SNP-induced chondrocytes, CMCS down-regulated the expression of Bax, Cyt c and cleaved caspase-3 but upregulated the expression of Bcl-2, as shown by real-time PCR and western blot. CONCLUSIONS: Taken together, these results indicated that CMCS has the protective effect on chondrocytes against SNP-induced apoptosis, at least partly, via inhibiting the mitochondrial dependent apoptotic pathway. Thus, CMCS may be potentially used as a biological agent for prevention and treatment of OA.

Synergistic protection of astragalus polysaccharides and matrine against ulcerative colitis and associated lung injury in rats.

BACKGROUND: Ulcerative colitis (UC) is a main form of inflammatory bowel disease. Due to complicated etiology and a high rate of recurrence, it is quite essential to elucidate the underlying mechanism of and search for effective therapeutic methods for UC. AIM: To investigate the effects of astragalus polysaccharides (APS) combined with matrine on UC and associated lung injury. METHODS: UC was induced in rats by colon mucosal tissue sensitization combined with trinitro-benzene-sulfonic acid-ethanol. Then, the effects of the treatments of salazopyrine, APS, matrine, and APS combined with matrine on histopathological changes of lung and colon tissues, disease activity index (DAI), colon mucosal damage index (CMDI), serum endotoxin (ET) level, serum diamine oxidase (DAO) activity, the contents of tumor necrosis factor-α and interleukin-1ß, and the activities of myeloperoxidase, superoxide dismutase, and malondialdehyde in lung tissues, as well as the protein expression of zonula occludens (ZO)-1, Occludin, and trefoil factor 3 (TFF3) were detected in UC rats. RESULTS: The treatments of salazopyrine, APS, matrine, and APS combined with matrine reduced DAI scores and improved histopathological changes of colon and lung tissues, as well as decreased CMDI scores, ET levels, and DAO activities in UC rats. Moreover, in lung tissues, inflammatory response and oxidative stress injury were relieved after the treatments of salazopyrine, APS, matrine, and APS combined with matrine in UC rats. Furthermore, the expression of ZO-1, Occludin, and TFF3 in lung and colon tissues was increased after different treatments in UC rats. Notably, APS combined with matrine exerted a better protective effect against UC and lung injury compared with other treatments. CONCLUSION: APS combined with matrine exert a synergistic protective effect against UC and lung injury, which might be associated with regulating TFF3 expression.

Site-Selective Antibody Functionalization via Orthogonally Reactive Arginine and Lysine Residues.

Homogeneous antibody-drug conjugates (ADCs) that use a highly reactive buried lysine (Lys) residue embedded in a dual variable domain (DVD)-IgG1 format can be assembled with high precision and efficiency under mild conditions. Here we show that replacing the Lys with an arginine (Arg) residue affords an orthogonal ADC assembly that is site-selective and stable. X-ray crystallography confirmed the location of the reactive Arg residue at the bottom of a deep pocket. As the Lys-to-Arg mutation is confined to a single residue in the heavy chain of the DVD-IgG1, heterodimeric assemblies that combine a buried Lys in one arm, a buried Arg in the other arm, and identical light chains, are readily assembled. Furthermore, the orthogonal conjugation chemistry enables the loading of heterodimeric DVD-IgG1s with two different cargos in a one-pot reaction and thus affords a convenient platform for dual-warhead ADCs and other multifaceted antibody conjugates.

Co-exposure to metals and polycyclic aromatic hydrocarbons, microRNA expression, and early health damage in coke oven workers.

BACKGROUND: All humans are now co-exposed to multiple toxic chemicals, among which metals and polycyclic aromatic hydrocarbons (PAHs) are of special concern as they are often present at high levels in various human environments. They can also induce similar early health damage, such as genetic damage, oxidative stress, and heart rate variability (HRV). Exposure to metals, PAHs, and their combined pollutants can alter microRNA (miRNA) expression patterns. OBJECTIVES: To explore the associations of metal-PAH co-exposure with miRNA expression, and of the associated miRNAs with early health damage. METHODS: We enrolled 360 healthy male coke oven workers and quantified their exposure levels of metals and PAHs by urinary metals, urinary monohydroxy-PAHs (OH-PAHs), and plasma benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts, respectively. We selected and measured ten miRNAs: let-7b-5p, miR-126-3p, miR-142-5p, miR-150-5p, miR-16-5p, miR-24-3p, miR-27a-3p, miR-28-5p, miR-320b, and miR-451a. For miRNAs influenced by the effect modification of metals or PAHs and/or metal-PAH interactions, we further evaluated their associations with biomarkers for genetic damage, oxidative stress, and HRV. RESULTS: After adjusting for PAHs and other metals, miRNA expression was found to be negatively associated with aluminum, antimony, lead, and titanium, and positively associated with molybdenum and tin (p < 0.05). Antimony showed modifying effects on the PAH-miRNA associations, while OH-PAHs and BPDE-Alb adducts modified the associations of metals with miRNAs (p for modifying effect < 0.05). Furthermore, miRNA expression was influenced by the antagonistic interactions between antimony and OH-PAHs, and by the synergistical interactions between metals and BPDE-Alb adducts (pinteraction < 0.05). Let-7b-5p, miR-126-3p, miR-16-5p, and miR-320b were additionally found to be associated with increased genetic damage in the present study [false discovery rate (FDR)-adjusted p < 0.05]. CONCLUSIONS: Associations of metal-PAH co-exposure with miRNA expression, and of associated miRNAs with early health damage, suggested potential mechanistic connections between the complex metal-PAH interactions and their deleterious effects that are worthy of further investigation.

Nonderivatization method for determination of glyphosate, glufosinate, bialaphos, and their main metabolites in environmental waters based on magnetic metal-organic framework pretreatment.

A novel magnetic metal-organic framework composite was prepared by a self-assembly approach. The material properties were characterized by Fourier-transform infrared spectroscopy, vibrating sample magnetometry, thermogravimetry and differential thermogravimetric analysis, and X-photoelectron spectroscopy. Then, the as-prepared material was used as an adsorbent and indicated great enrichment ability toward glyphosate, glufosinate, bialaphos, and their main metabolites aminomethylphosphonic acid and 3-methylphosphinicopropionic acid. Based on this, an efficient magnetic solid-phase extraction method combined with ultra high performance liquid chromatography with high-resolution mass spectrometry for the pretreatment and determination of five target compounds in environmental waters was established. Parameters that could impact on the adsorption performance had been studied in detail. The proposed method was successfully applied for the simultaneous determination of glyphosate, glufosinate, bialaphos, and their main metabolites aminomethylphosphonic acid and 3-methylphosphinicopropionic acid in environmental water with recoveries in range of 86.2-104.6% with relative standard deviations less than 10%. Desired linearity was achieved varying from 1 to 100 µg/L for five target analytes, respectively. The limits of detection were between 0.01 and 0.03 µg/L.

One-pot synthesis of ceria and cerium phosphate (CeO2-CePO4) nanorod composites for selective catalytic reduction of NO with NH3: Active sites and reaction mechanism.

In this work, novel (CeO2)x-(CePO4)1-x (defined as CexP1-x) nanorod composites were prepared by a simple co-precipitation method, and the influence of CeO2 on the catalytic performance of CePO4 for selective catalytic reduction of NO by NH3 (NH3-SCR of NO) was investigated. The catalytic performance evaluation revealed that the CexP1-x catalysts, especially Ce0.2P0.8 exhibited a much better catalytic activity and H2O + SO2 resistance than CePO4. Structure characterizations via high-resolution transmission electron microscope (HRTEM) and Brunauer-Emmett-Teller (BET) revealed that the introduction of CeO2 had a little effect on the shape of CePO4 nanorods and it could promote the formation of new mesoporous then significantly enhance the surface area of catalyst. The analysis results of active sites suggested that phosphorus was the main adsorption site for NH3 and the redox sites were controlled by CeO2 on CexP1-x catalysts. Finally, reaction process study demonstrated that the NH3-SCR over CexP1-x was processed via Langmuir-Hinshelwood (L-H) mechanism. Combining the results of active sites and reaction mechanism analysis, it was drawn that the superior low temperature activity of CexP1-x could be attributed to its excellent redox properties, which promoted the oxidation of NO then facilitated the process of NH3-SCR via "fast SCR".