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1.
Life Sci ; : 118758, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33188835

RESUMO

AIMS: Insulin-like growth factor (IGF) signaling has been documented in several human malignancies and is thought to contribute to cellular differentiation and migration, as well as malignant progression. A major binding molecule of IGF, IGF-binding protein 3 (IGFBP-3), regulates multiple IGF effects. Here, we focused on the effect of IGFBP-3 in the motility of osteosarcoma cells and examined signaling regulation. MATERIALS AND METHODS: Using a human osteosarcoma tissue array, immunohistochemical staining determined levels of IGFBP-3 expression in osteosarcoma tissue and in normal tissue. The wound healing migration assay, Transwell migration assay, luciferase reporter assay, immunofluorescence staining, Western blot and real-time quantitative PCR were performed to examine whether IGFBP-3 facilitates VCAM-1-dependent migration of osteosarcoma cells. KEY FINDINGS: In this study, we found significantly higher IGFBP-3 levels in osteosarcoma tissue compared with normal healthy tissue. IGFBP-3 treatment of two human osteosarcoma cell lines promoted cell migration and upregulated levels of VCAM-1 expression via PI3K/Akt and AP-1 signaling. SIGNIFICANCE: IGFBP-3 appears to be a novel therapeutic target in metastatic osteosarcoma.

2.
J Cell Mol Med ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33021341

RESUMO

Osteosarcoma is an extremely common primary bone malignancy that is highly metastatic, with most deaths resulting from pulmonary metastases. The extracellular matrix protein thrombospondin-2 (TSP-2) is key to many biological processes, such as inflammation, wound repair and tissue remodelling. However, it is unclear as to what biological role TSP-2 plays in human metastatic osteosarcoma. The immunochemistry analysis from osteosarcoma specimens identified marked up-regulation of TSP-2 in late-stage osteosarcoma. Furthermore, we found that TSP-2 increased the levels of matrix metallopeptidase 9 (MMP-9) expression and thereby increased the migratory potential of human osteosarcoma cells. Osteosarcoma cells pre-treated with an MMP-9 monoclonal antibody (mAb), an MMP-9 inhibitor, or transfected with MMP-9 small interfering RNA (siRNA) reduced the capacity of TSP-2 to potentiate cell migration. TSP-2 treatment activated the PLCß, PKCα, c-Src and nuclear kappa factor B (NF-κB) signalling pathways, while the specific siRNA, inhibitors and mutants of these cascades reduced TSP-2-induced stimulation of migration activity. Knockdown of TSP-2 expression markedly reduced cell metastasis in cellular and animal experiments. It appears that an interaction between TSP-2 and integrin αvß3 activates the PLCß, PKCα and c-Src signalling pathways and subsequently activates NF-κB signalling, increasing MMP-9 expression and stimulating migratory activity amongst human osteosarcoma cells.

3.
Arthritis Res Ther ; 22(1): 251, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087182

RESUMO

BACKGROUND: Osteoarthritis (OA) and rheumatoid arthritis (RA) are common joint disorders that are considered to be different diseases due to their unique molecular mechanisms and pathogenesis. Chemokines and their corresponding receptors have been well characterized in RA progression, but less so in OA pathogenesis. METHODS: The human primary synovial fibroblasts (SFs) were obtained from human OA and RA tissue samples. The Western blot and qPCR were performed to analyze the expression levels of CXCL1, as well as CXCL-promoted IL-6 expression in both OASFs and RASFs. The signal cascades that mediate the CXCL1-promoted IL-6 expression were identified by using chemical inhibitors, siRNAs, and shRNAs. RESULTS: Here, we found that both diseases feature elevated levels of CXCL1 and interleukin (IL)-6, an important proinflammatory cytokine that participates in OA and RA pathogenesis. In OASFs and RASFs, CXCL1 promoted IL-6 expression in a dose- and time-dependent manner. In OASFs and RASFs overexpressing CXCL1 or transduced with shRNA plasmid, IL-6 expression was markedly upregulated. CXCR2, c-Raf, and MAPKs were found to regulate CXCL1-induced IL-6 expression in OASFs and RASFs. Finally, CXCL1 triggered the transcriptional activities of c-Jun (which regulates the expression of proinflammatory proteins) in OASFs and RASFs. CONCLUSIONS: Our present work suggests that the CXCL1/CXCR2 axis helps to orchestrate inflammatory responses in OA and RA SFs.

4.
Bioorg Chem ; 105: 104371, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33075664

RESUMO

Blocking c-Met kinase activity by small-molecule inhibitors has been identified as a promising approach for the treatment of cancers. Herein, we described the design, synthesis, and biological evaluation of a series of 4-phenoxypyridine-based 3-oxo-3,4-dihydroquinoxaline derivatives as c-Met kinase inhibitors. Inhibitory activitives against c-Met kinase evaluation indicated that most of compounds showed excellent c-Met kinase activity in vitro, and IC50 values of ten compounds (23a, 23e, 23f, 23l, 23r, 23s, 23v, 23w, 23x and 23y) were less than 10.00 nM. Notably, three of them (23v, 23w and 23y) showed remarkable potency with IC50 values of 2.31 nM, 1.91 nM and 2.44 nM, respectively, and thus they were more potent than positive control drug foretinib (c-Met, IC50 = 2.53 nM). Cytotoxic evaluation indicated the most promising compound 23w showed remarkable cytotoxicity against A549, H460 and HT-29 cell lines with IC50 values of 1.57 µM, 0.94 µM and 0.65 µM, respectively. Furthermore, the acridine orange/ethidium bromide (AO/EB) staining, cell apoptosis assays by flow cytometry, wound-healing assays and transwell migration assays on HT-29 and/or A549 cells of 23w were performed. Especially compound 23w, which displayed potent antitumor, apoptosis induction and antimetastatic activity, could be used as a promising lead for further development. Meanwhile, their preliminary structure-activity relationships (SARs) were also discussed.

5.
Curr Drug Deliv ; 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32940181

RESUMO

PURPOSE: The purpose of this study is to develop a new PLGA based formulation for microspheres, which aims to release mometasone furoate for one month, so as to improve compliance. METHODS: The microspheres containing mometasone furoate were prepared by oil in water emulsion and solvent evaporation. The microspheres were characterized by surface morphology, shape, size and encapsulation efficiency. The release in vitro was studied in 37°C phosphate buffer, and in vivo, pharmacodynamics and preliminary safety evaluation were conducted in male Sprague Dawley rats. RESULTS: The morphology results show that the microspheres have smooth surface, spherical shape and the average diameter of 2.320-5.679µm. The encapsulation efficiency of the microspheres loaded with mometasone furoate is in the range of 53.1% to 95.2%, and the encapsulation efficiency of the microspheres can be greatly affected by the proportion of oil phase to water phase and other formulation parameters. In vitro release kinetics revealed that drug release from microspheres was through non Fick's diffusion and PLGA polymer erosion. Pharmacokinetic data showed that the initial release of microspheres was small and then sustained. The results of pharmacodynamic study fully proved the effectiveness and long-term effect of mometasone furoate microspheres. The results of in vivo safety evaluation showed that the preparation system had good in vivo safety. CONCLUSION: This study shows that the microspheres prepared in this study have sufficient ability of stable drug release at least 35 days, with good efficacy and high safety. In addition, mometasone furoate can be used as a potential candidate drug for 35 day long-term injection.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32970941

RESUMO

AIMS: Chronic inflammation is linked to cancer. This study aims to evaluate the association between chronic rhinosinusitis (CRS) and nasopharyngeal carcinoma (NPC) through a Taiwanese nationwide database. METHODS: We used the National Health Insurance Research Database between January 1, 2003, and December 31, 2012. The starting date is either the date of the first clinical visit or the diagnosis of CRS. Patients were followed up until the first occurrence of target disease or the last date of medical record. Propensity score 1 to 2 matching was used to match pairs of patients with/without CRS. RESULTS: A total of 951 380 eligible patients were included in our study, with 36 210 patients diagnosed with CRS. After 1 to 2 propensity score matching, non-CRS cohort consisted of 69 258 patients and CRS cohort consisted of 34 629 patients. CRS was associated with the risk of developing NPC (adjusted OR = 2.23; 95% CI, 1.61-3.09). However, no significant association among CRS and NPC was observed in patients followed up for more than 1 year (adjusted OR = 1.16; 95% CI, 0.76-1.78). CONCLUSIONS: Patients with CRS diagnosis have relationship with developing NPC within 1 year of follow-up, but not for longer intervals. The short-term association may be due to reversed causation or biased diagnosis. Accordingly, the study suggests CRS a weak role for NPC.

7.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(5): 729-731, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-32975093

RESUMO

Desmoplastic small round cell tumor (DSRCT) is a rare malignant tumor, which is prone to occur in teenagers DSRCT is a rare malignant tumor that often occurs in adolescents. Early diagnosis is difficult and the prognosis is poor. In this case report, the ultrasonography of DSRCT showed that the huge solid mass was in the abdomen with unclear boundary, irregular shape, insufficient blood supply but without obvious liquefaction and calcification. The masses encircled the vessels, but no evidence of vascular invasion. Intrahepatic metastases with peripheral hypoechoic aureole and abdominal lymph node metastases were observed. The tumor mass compressed adjacent tissues and organs, causing bilateral hydronephrosis and bone erosion. In a word, the ultrasonographic characteristics could be used for diagnosing the DSRCT in the clinic.

8.
J Mol Model ; 26(10): 259, 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32895748

RESUMO

The present paper displays new supramolecular structural forms of ammonia molecules. The computation reveals that two novel threading structures of C2F2·(NH3)6 and C2F2·(NH3)12 can be assembled between difluoroethyne and ammonia molecules, in which cyclohexamer (NH3)6 and dicyclohexamer (NH3)12 are constructed by robust N-H···N hydrogen bonds and stabilized all by π-ring-hole···N bonds as supporting spokes of annular structures. More interestingly, annular structures of NH3 still maintain stability as C2F2 is removed. Additionally, the electronic properties and nature of the related noncovalent bonds are explored, which illuminate the important role of π-ring-hole bond for the stabilization of annular structures of NH3. This study could provide valuable insights into chemistry of ammonia, new energy and astronomy aspects by single or multiple noncovalent interactions.Graphical abstract Ammonia molecules can exist stably in dodecahedral cage C2F2·(NH3)12 and (NH3)12 via N-H···N hydrogen bonds and π-ring-hole···N bonds.

9.
Diab Vasc Dis Res ; 17(5): 1479164120953626, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32951444

RESUMO

PURPOSE: This study was conducted to investigate the relation of HP infection to peripheral arterial stiffness and 10-year cardiovascular risk in diabetes mellitus (DM). METHODS: DM subjects who underwent the C13-breath test were enrolled and divided into DMHP+ and DMHP- groups. Peripheral arterial stiffness was measured using brachial to ankle pulse wave velocity (baPWV). Framingham score (FRS) and Chinese evaluation method of ischemic cardiovascular diseases (ICVD) were used to clarify 10-year cardiovascular risk. RESULTS: A total of 6767 subjects were included, baPWV and proportion of subjects with severe peripheral arterial stiffness were lower in DMHP- group than DMHP+ group (1556.68 ± 227.54 vs 2031.61 ± 525.48 cm/s, p < 0.01; 21.9% vs 62.7%, p < 0.01). Multivariate logistic regression analysis demonstrated that HP infection was independently associated with baPWV. Furthermore, cardiovascular risk score and the proportion of subjects with high risk were lower in DMHP- group than DMHP+ group (FRS: 12.09 ± 3.77 vs 13.91 ± 3.77, 17.2% vs 38.8%; ICVD: 8.56 ± 2.99 vs 10.22 ± 3.16, 43.9% vs 65.4%, with all p < 0.05). CONCLUSION: DM subjects with HP infection had more severe peripheral arterial stiffness compared those without HP infection, a higher cardiovascular risk score and 10-year cardiovascular risk stratification were observed in those subjects.

10.
Cell Death Discov ; 6: 84, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32963812

RESUMO

Sustained activation of NLRP3 inflammasome and release of neutrophil extracellular traps (NETs) impair wound healing of diabetic foot ulcers (DFUs). Our previous study reported that milk fat globule epidermal growth factor VIII (MFG-E8) attenuates tissue damage in systemic lupus erythematosus. However, the functional effect of MFG-E8 on "NLRP3 inflammasome-NETs" inflammatory loop in wound healing of diabetes is not completely elucidated. In this study, neutrophils from DFU patients are susceptible to undergo NETosis, releasing more NETs. The circulating levels of NET components neutrophil elastase and proteinase 3 and inflammatory cytokines IL-1ß and IL-18 were significantly elevated in DFU patients compared with healthy controls or diabetic patients, in spite of higher levels of MFG-E8 in DFU patients. In Mfge8 -/- diabetic mice, skin wound displayed exaggerated inflammatory response, including leukocyte infiltration, excessive activation of NLRP3 inflammasome (release of higher IL-1ß, IL-18, and TNF-α), largely lodged NETs, resulting in poor angiogenesis and wound closure. When stimulated with high-dose glucose or IL-18, MFG-E8-deficient neutrophils release more NETs than WT neutrophils. After administration of recombinant MFG-E8, IL-18-primed NETosis of WT or Mfge8 -/- neutrophils was significantly inhibited. Furthermore, NET and mCRAMP (component of NETs, the murine equivalent of cathelicidin LL-37 in human)-mediated activation of NLRP3 inflammasome and production of IL-1ß/IL-18 were significantly elevated in Mfge8 -/- macrophages compared with WT macrophages, which were also significantly dampened by the administration of rmMFG-E8. Therefore, our study demonstrated that as inhibitor of the "NLRP3 inflammasome-NETs" inflammatory loop, exogenous rMFG-E8 improves angiogenesis and accelerates wound healing, highlighting possible therapeutic potential for DFUs.

11.
Adv Ther ; 37(11): 4660-4674, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32970315

RESUMO

INTRODUCTION: Simultaneous administration of acetylsalicylic acid (ASA) and clopidogrel has demonstrated efficacy in the treatment of acute coronary syndrome. Clopidogrel + ASA in a fixed-dose combination (FDC) provides a pharmaceutical option to enhance adherence to the coadministration of dual antiplatelet therapy (DAPT). Herein, we evaluate the bioequivalence of enteric ASA and clopidogrel in an FDC compared with simultaneous administration of the individual formulations. METHODS: This study is a randomized, single-center, open-label, three-sequence, three-period, two-treatment, crossover study conducted in healthy Chinese male and female subjects under fed conditions. Subjects were randomized to receive, in each period, a single dose of (1) a combination tablet containing 75-mg clopidogrel and 100-mg enteric ASA (test formulation) or (2) coadministration of one 75-mg clopidogrel tablet and one 100-mg enteric-coated ASA tablet (reference formulations) under fed conditions. Plasma samples were analyzed for ASA, salicylic acid, clopidogrel, and the clopidogrel metabolite SR26334. For ASA, the reference-scaled average bioequivalence (RSABE) analysis was conducted for Cmax of ASA because within-subject standard deviation (SDW) was ≥ 0.294 for log-transformed Cmax. RESULTS: The point estimate (test/reference geometric mean ratio) was between 0.80 and 1.25, and the upper one-sided 95% confidence interval (CI) for the scaled average bioequivalence metric was ≤ 0 (-0.08). AUC of ASA as SDW was < 0.294 for log-transformed AUClast and AUC. Estimates of 90% CIs for log-transformed AUClast and AUC ratios were within the bioequivalence range of 0.80 to 1.25 (0.98-1.08 and 1.00-1.10, respectively). For clopidogrel, the 90% CIs for the ratios comparing log-transformed Cmax, AUClast, and AUC ratios of clopidogrel following administration of test versus reference formulation were calculated using the ABE method and were well within the acceptable range of 0.80 to 1.25 (1.02-1.12, 0.92-0.99, and 0.92-0.98, respectively). CONCLUSION: FDC of ASA and clopidogrel was bioequivalent to the simultaneous administration of the individual formulations in healthy Chinese subjects under fed conditions. TRIAL REGISTRATION: CTR20190376.

12.
Biomed Chromatogr ; : e4994, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32986878

RESUMO

This study established and validated an LC-MS/MS method for the ultrasensitive determination of cetagliptin in human plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and chromatographic separation was performed on an XB-C18 analytical column (50 × 2.1 mm, 5 µm) with gradient elution (0.1% formic acid in acetonitrile and 0.1% formic acid) at a flow rate of 1.0 mL/min. For mass spectrometric detection, multiple reaction monitoring was used, and the ion transitions monitored were m/z 421.2-86.0 for cetagliptin and m/z 424.2-88.0 for cetagliptin-d3. Method validation was performed according to the U.S. Food and Drug Administration Bioanalytical Method Validation Guidance, for which the calibration curve was linear in the range of 50.0-2000 pg/mL. All of the other results, such as selectivity, lower limit of quantitation, precision, accuracy, matrix effect, recovery, and stability, met the acceptance criteria. The validated method was successfully applied in a microdose clinical trial to systematically investigate the pharmacokinetic profile of cetagliptin in healthy subjects. Both rapid absorption and prolonged duration demonstrate the potential value of cetagliptin for diabetes treatment.

13.
J Cell Physiol ; 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32808296

RESUMO

Osteoarthritis (OA) is a progressive degenerative joint disorder characterized by synovial inflammation. Interleukin-6 (IL-6) is a key proinflammatory cytokine in OA progression. Particulate matter 2.5 (PM2.5) exposure increases the risk of different diseases, including OA. Up until now, no studies have described any association between PM2.5 and IL-6 expression in human OA synovial fibroblasts (OASFs). Here, our data show that PM2.5 concentration- and time-dependently promoted IL-6 synthesis in human OASFs. We also found that reactive oxygen species (ROS) generation potentiated the effects of PM2.5 on IL-6 production. ASK1, ERK, p38, and JNK inhibitors reduced PM2.5-induced increases of IL-6 expression. Treatment of OASFs with PM2.5 promoted phosphorylation of these signaling cascades. We also found that PM2.5 enhanced c-Jun phosphorylation and its translocation into the nucleus. Thus, PM2.5 increases IL-6 production in human OASFs via the ROS, ASK1, ERK, p38, JNK, and AP-1 signaling pathways. Our evidence links PM2.5 with OA progression.

14.
Int J Mol Sci ; 21(17)2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32847038

RESUMO

Osteosarcoma is the most common primary tumor of the skeletal system and is well-known to have an aggressive clinical outcome and high metastatic potential. The chemokine (C-X-C motif) ligand 13 (CXCL13) plays a vital role in the development of several cancers. However, the effect of CXCL13 in the motility of osteosarcoma cells remains uncertain. Here, we found that CXCL13 increases the migration and invasion potential of three osteosarcoma cell lines. In addition, CXCL13 expression was upregulated in migration-prone MG-63 cells. Vascular cell adhesion molecule 1 (VCAM-1) siRNA and antibody demonstrated that CXCL13 promotes migration via increasing VCAM-1 production. We also show that CXCR5 receptor controls CXCL13-mediated VCAM-1 expression and cell migration. Our study identified that CXCL13/CXCR5 axis facilitate VCAM-1 production and cell migration in human osteosarcoma via the phospholipase C beta (PLCß), protein kinase C α (PKCα), c-Src, and nuclear factor-κB (NF-κB) signaling pathways. CXCL13 and CXCR5 appear to be a novel therapeutic target in metastatic osteosarcoma.

15.
Zhen Ci Yan Jiu ; 45(6): 461-7, 2020 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-32643882

RESUMO

OBJECTIVE: To observe the effect of catgut implantation at "Yingxiang"(LI20) on lower airway remodeling and levels of osteopon-tin (OPN) protein in allergic rhinitis (AR) rats, so as to reveal its mechanisms underlying improvement of AR. METHODS: Male SD rats were randomly divided into control, model and catgut implantation groups, with 10 rats in each group. The AR model was established by intraperitoneal injection and nasal drip of ovalbumin. The catgut implantation was applied to bilateral "Yingxiang"(LI20) for 28 days in rats of the catgut implantation group. The total score of allergic symptoms of rats in each group were observed. The histopathological changes of lower airway were observed under light microscope after Hematoxylineosin, Periodic acid-Schiff and Masson staining. The expression of OPN protein was detected by immunohistochemistry and Western blot, separately. RESULTS: The total score of allergic symptoms of nose-wiping, running nose and sneezing, count of lung goblet cells, lung fiber content, and immunoactivity and expression levels of OPN protein were significantly increased in the model group in contrast to the control group (P<0.05). After the intervention, the total score of allergic symptoms, count of lung goblet cells, immunoactivity and expression levels of OPN protein were considerably down-regulated in the catgut implantation group relevant to the model group (P<0.05). H.E. stain showed thickening of partial airway wall, narrowing of lumen, increase of mucus section, widened alveolar septum, infiltration of inflammatory cells, lymphocytes and eosinophil around the bronchus and in the lung interstitium in AR rats, which was milder in the catgut implantation group. The immunoactivity and expression levels of OPN protein were positively related with the lung goblet cells count and lung fiber content (P<0.05,P<0.01). CONCLUSION: Acupoint implantation of catgut can improve pathological changes of lower airway remodeling, which may be related to its effect in down-regulating the expression of OPN protein in the lung tissue.


Assuntos
Categute , Rinite Alérgica , Pontos de Acupuntura , Remodelação das Vias Aéreas , Animais , Masculino , Ratos , Ratos Sprague-Dawley
16.
Mol Med Rep ; 22(3): 2227-2234, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32705194

RESUMO

Acute gouty arthritis (AGA) is characterized by the accumulation of pro­inflammatory cytokines, which are immunological responses to monosodium urate (MSU) crystals. It has been demonstrated that long non­coding RNA (lncRNA)­MM2P is a novel regulator of M2 polarization of macrophages. The aim of the present study was to investigate whether lncRNA­MM2P regulates the MSU­induced inflammatory process. In cell models of RAW 264.7 and THP­1­derived macrophages, decreased expression of lncRNA­MM2P was observed in lipopolysaccharide­ and MSU­treated macrophages, which was accompanied with obvious inflammatory responses. Using small interfering RNA to knockdown lncRNA­MM2P led to the upregulation of MSU­mediated inflammatory responses, both in RAW 264.7 and THP­1­derived macrophages. In conclusion, lncRNA­MM2P could be an important regulator of MSU­induced inflammation, and therefore could be involved in the development of AGA.

17.
Biochem Biophys Res Commun ; 529(2): 296-302, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32703426

RESUMO

Dedicator of cytokinesis 2 (DOCK2) is essential for the B cell differentiation, BCR signaling and humoral immune response. However, the role of DOCK2 in the memory response of B cell is unknown. By using two DOCK2 deficient patients, we found that the memory B cells were decreased and the early activation of DOCK2 deficient memory B cells was abolished to the degree of naïve B cells due to the decreased expression of CD19 and CD21 mechanistically. Interestingly the expression of LEF-1, a negative regulator of CD21, was increased in DOCK2 deficient B cells. This was linked to the increased expression of HIF-1α and cell metabolism, which in turn affected the ER structure. Finally, the reduction of memory B cells in DOCK2 patients was due to the increased apoptosis, which might be related with the increased metabolism.

18.
Huan Jing Ke Xue ; 41(2): 691-701, 2020 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-32608728

RESUMO

The Le'an River is a main tributary of the Poyang Lake, which is the largest freshwater lake in China. The aim of this study is to research the distribution and potential ecological risks of heavy metals in the middle and lower reaches of the Le'an River, which is contaminated by nearby copper mines. Sediment and water samples were collected from 12 stations during the dry, wet, and normal season in 2016, respectively. The geo-accumulation index and potential ecological risk index were used to determine general pollution characteristics of trace metals in sediments. Results suggested that sediments in the Le'an River were considerably polluted by Cd, Pb, Cu, and Zn. Sediment concentrations of heavy metals showed significant spatial variations. The concentrations of heavy metals such as Cu, Zn, and Cd in water are higher in the dry season than in the normal and wet seasons. The distribution of heavy metals along the river is influenced by hydraulic conditions. The flow velocities in wet and normal seasons are positively correlated with the concentrations of heavy metals such as Cd, Pb, Cu, and Cr. There are seasonal differences in the distribution characteristics of heavy metals in surface sediments. In the dry season, the concentration of heavy metals in sediments is the highest in the middle reaches of rivers near mining areas, while during the wet and normal season, it reaches the highest value in the lower reach near the estuary. Except for Cd, whose major form of heavy metal in the sediment is in an exchanging state, the other heavy metals occur mainly in stable states. The assessment of the geo-accumulation index showed significant Cu, Cd, and Cr pollution. Among the heavy metals investigated, Cd was likely to result in more harmful effects.


Assuntos
Metais Pesados/análise , Rios/química , Poluentes Químicos da Água/análise , China , Monitoramento Ambiental , Sedimentos Geológicos , Medição de Risco , Análise Espaço-Temporal
19.
Curr Med Chem ; 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32586244

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a local or systemic inflammatory response. At present, the increasing research results show that the pathogenesis of the disease is complex, and the methods of clinical treatment also show diversity. This review analyzes and summary the existing mechanism research and drug treatment methods, in order to provide reference value for further drug research and development. METHOD: We carried out a thorough literature search using databases. According to the main purpose of the article, irrelevant articles were excluded after further examination and directly relevant articles were included. Finally, summarize the information of the article. RESULT: In this article, sixty-five articles were included. According to related articles, there are mainly four kinds of drugs, namely antimalarial drugs, glucocorticoids, immunosuppressive agents and biological agents. About forty-five articles summarize the drugs for the treatment of systemic lupus erythematosus. The rest articles were about the research progress of the mechanism of systemic lupus erythematosus. CONCLUSION: This article summarizes the pathogenesis of systemic lupus erythematosus, and summarizes the traditional and new therapeutic drugs, which is not only beneficial to the treatment of lupus erythematosus patients, but also plays a vital reference significance for the future development of new systemic lupus erythematosus drugs.

20.
PLoS Genet ; 16(6): e1008838, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32544191

RESUMO

Reactive oxygen species (ROS) are signalling molecules whose study in intact organisms has been hampered by their potential toxicity. This has prevented a full understanding of their role in organismal processes such as development, aging and disease. In Caenorhabditis elegans, the development of the vulva is regulated by a signalling cascade that includes LET-60ras (homologue of mammalian Ras), MPK-1 (ERK1/2) and LIN-1 (an ETS transcription factor). We show that both mitochondrial and cytoplasmic ROS act on a gain-of-function (gf) mutant of the LET-60ras protein through a redox-sensitive cysteine (C118) previously identified in mammals. We show that the prooxidant paraquat as well as isp-1, nuo-6 and sod-2 mutants, which increase mitochondrial ROS, inhibit the activity of LET-60rasgf on vulval development. In contrast, the antioxidant NAC and loss of sod-1, both of which decrease cytoplasmic H202, enhance the activity of LET-60rasgf. CRISPR replacement of C118 with a non-oxidizable serine (C118S) stimulates LET-60rasgf activity, whereas replacement of C118 with aspartate (C118D), which mimics a strongly oxidised cysteine, inhibits LET-60rasgf. These data strongly suggest that C118 is oxidized by cytoplasmic H202 generated from dismutation of mitochondrial and/or cytoplasmic superoxide, and that this oxidation inhibits LET-60ras. This contrasts with results in cultured mammalian cells where it is mostly nitric oxide, which is not found in worms, that oxidizes C118 and activates Ras. Interestingly, PQ, NAC and the C118S mutation do not act on the phosphorylation of MPK-1, suggesting that oxidation of LET-60ras acts on an as yet uncharacterized MPK-1-independent pathway. We also show that elevated cytoplasmic superoxide promotes vulva formation independently of C118 of LET-60ras and downstream of LIN-1. Finally, we uncover a role for the NADPH oxidases (BLI-3 and DUOX-2) and their redox-sensitive activator CED-10rac in stimulating vulva development. Thus, there are at least three genetically separable pathways by which ROS regulates vulval development.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Peróxidos/metabolismo , Vulva/crescimento & desenvolvimento , Proteínas ras/genética , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Feminino , Mutação com Ganho de Função , Genes de Helmintos/genética , Oxirredução , Oxirredutases/metabolismo , Peróxidos/análise , Transdução de Sinais/genética , Fatores de Transcrição/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo , Proteínas ras/metabolismo
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