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1.
Neural Regen Res ; 16(1): 6-11, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32788440

RESUMO

Microglia-associated neuroinflammation plays an important role in the pathophysiology of ischemic stroke. Microglial activation and polarization, and the inflammatory response mediated by these cells play important roles in the development, progression and outcome of brain injury after ischemic stroke. Currently, there is no effective strategy for treating ischemic stroke in clinical practice. Therefore, it is clinically important to study the role and regulation of microglia in stroke. In this review, we discuss the involvement of microglia in the neuroinflammatory process in ischemic stroke, with the aim of providing a better understanding of the relationship between ischemic stroke and microglia.

2.
Infect Dis Poverty ; 9(1): 137, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008476

RESUMO

BACKGROUND: A national control program for echinococcosis has been in effect since 2005 in China. This program has applied a comprehensive strategy, and good control results have been achieved. Human echinococcosis prevalence rate decrease from 1.08% in 2004 to 0.24% in 2012. The objective of this study is focusing on assessment of the programme with two indices, including patient treatment and registered dogs deworming, in endemic areas of echincoccosis control over the period of 10 years (2004-2014) in China. METHODS: We established the database including demography at county and township levels with coverage for ten provinces and autonomous regions of China in this study. We using methods of epidemiological descriptive, instead the expectation-maximization for missing value filling for grouping available patients into those subjected to surgery and those receiving drug treatment after population screening and the dogs population after registered by deworming. We performed Microsoft Excel software and SPSS software on the results as percentages with the corresponding 95% confidence intervals (95% CIs). We also statistically analyzed the economics data on patient treatment and dogs deworming after the corresponding discount with annual bank interest rates (USD 1 = CNY 6.5, bank discount average changes of 2.3-3.3%). RESULTS: During 2004-2014, the grant total average rate of surgical patient (after surgical operation) treatment had increased with 32.4% and with 81.3% for medical treatment with albendazole. Meanwhile, it increased by 58.6% for the deworming of registered dog since 2007. The accumulated costs amounted to USD 27.03 million after discount for patients and registered dog treatment, which is 1/4 of the total accumulated financial inputs (USD 110.67 million from the Chinese Government). Since the implementation of the national program, it has increased 57 times with respect to the annual financial inputs (costs) and 368 times with respect to all accumulated financial inputs (costs). CONCLUSIONS: This study showed that in endemic areas, patient diagnosis and management, dog management and treatment over this period helped reduce the parasite load to control the disease. More attention should be paid to controlling wild canines during the ongoing program period and sustainable follow-up evaluations are crucial for success and continued implementation of the national program.

3.
Signal Transduct Target Ther ; 5(1): 231, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028807

RESUMO

Nicotinamide adenine dinucleotide phosphate (NADPH) is an essential electron donor in all organisms, and provides the reducing power for anabolic reactions and redox balance. NADPH homeostasis is regulated by varied signaling pathways and several metabolic enzymes that undergo adaptive alteration in cancer cells. The metabolic reprogramming of NADPH renders cancer cells both highly dependent on this metabolic network for antioxidant capacity and more susceptible to oxidative stress. Modulating the unique NADPH homeostasis of cancer cells might be an effective strategy to eliminate these cells. In this review, we summarize the current existing literatures on NADPH homeostasis, including its biological functions, regulatory mechanisms and the corresponding therapeutic interventions in human cancers, providing insights into therapeutic implications of targeting NADPH metabolism and the associated mechanism for cancer therapy.

4.
Purinergic Signal ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33025427

RESUMO

Several studies suggest a role of extracellular adenine nucleotides in regulating adipose tissue functions via the purinergic signaling network. Metabolic studies in mice with global deletion of the purinergic receptor P2X7 on the C57BL/6 background indicate that this receptor has only a minor role in adipose tissue for diet-induced inflammation or cold-triggered thermogenesis. However, recent data show that a polymorphism (P451L) present in C57BL/6 mice attenuates P2X7 receptor function, whereas BALB/c mice express the fully functional P451 allele. To determine the potential role of P2rx7 under metabolic and thermogenic stress conditions, we performed comparative studies using male P2rx7 knockout (KO) and respective wild-type controls on both BALB/c and C57BL/6 backgrounds. Our data show that adipose P2rx7 mRNA levels are increased in obese mice. Moreover, P2rx7 deficiency results in reduced levels of circulating CCL2 and IL6 with a moderate effect on gene expression of pro-inflammatory markers in white adipose tissue and liver of BALB/c and C57BL/6 mice. However, P2X7 expression does not alter body weight, insulin resistance, and hyperglycemia associated with high-fat diet feeding on both genetic backgrounds. Furthermore, deficiency of P2rx7 is dispensable for energy expenditure at thermoneutral and acute cold exposure conditions. In summary, these data show that-apart from a moderate effect on inflammatory cytokines-P2X7 plays only a minor role in inflammatory and thermogenic effects of white and brown adipose tissue even on the BALB/c background.

5.
Behav Brain Res ; : 112949, 2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33053385

RESUMO

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may modulate the link between childhood trauma experience and psychopathology by altering trophic signaling on neuroplasticity. However, few multimodal magnetic resonance imaging (MRI) researches have investigated this gene-environment interaction on both structural and functional plasticity, thereby advancing knowledge about the etiology, prevention, and customized therapeutic directions of mental disease in individuals with childhood trauma experience. We recruited a large non-clinical sample of young adults that completed Childhood Trauma Questionnaire (CTQ), behavioral scores, multimodal MRI scans, and genotyping. Morphometric similarity network (MSN) and independent component analysis were adopted to quantify brain structural and functional changes. Gene-environment-brain-behavior relationships were identified by multiple regression and mediation effect analysis. CTQ score was positively associated with depression and anxiety scores. We found interactions on MSN in sensorimotor, temporal, and orbitofrontal cortex. For intra-network connectivity, significant interaction was noted in clusters within sensorimotor network. For inter-network connectivity, connectivity between dorsal attention network and salience network showed an interactive effect. For mean connectivity strength of each network, we found a main effect of CTQ score on self-reference network that was an outstanding mediator supporting the relationship between CTQ score and anxiety. Our findings demonstrate that childhood trauma and the BDNF Val66Met polymorphism are associated with brain plasticity involving emotion regulation, structurally and functionally, which may contribute to understanding psychotic mechanisms and predicting differential susceptibility. Imaging genetics may be useful as biomarkers to provide early assessment and guide cognitive interventions to avoid or decrease the risk of developing psychopathology.

6.
Transl Psychiatry ; 10(1): 350, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067412

RESUMO

Mounting evidence suggests that gut microbiota can play an important role in pathophysiology of depression, but its specific molecular mechanisms are still unclear. This study was conducted to explore the associations between changes in neurotransmitters and short-chain fatty acids (SCFAs) and altered gut microbiota in depressed mice. Here, the chronic restraint stress (CRS) model of depression was built. The classical behavioral tests were conducted to assess the depressive-like behaviors of mice. The 16S rRNA gene sequence extracted from fecal samples was used to assess the gut microbial composition. Liquid and gas chromatography mass spectroscopy were used to identify neurotransmitters in hypothalamus and SCFAs in fecal samples, respectively. Finally, 29 differential bacteria taxa between depressed mice and control mice were identified, and the most differentially abundant bacteria taxa were genus Allobaculum and family Ruminococcaceae between the two groups. The acetic acid, propionic acid, pentanoic acid, norepinephrine, 5-HIAA and 5-HT were significantly decreased in depressed mice compared to control mice. Genus Allobaculum was found to be significantly positively correlated with acetic acid and 5-HT. Taken together, these results provided novel microbial and metabolic frameworks for understanding the role of microbiota-gut-brain axis in depression, and suggested new insights to pave the way for novel therapeutic methods.

7.
Chem Pharm Bull (Tokyo) ; 68(10): 962-970, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32999148

RESUMO

Oleanolic and ursolic acids were used as lead compounds to synthesize a series of pentacyclic triterpenoid derivatives bearing ethylenediamine, butanediamine, or hexanediamine groups at the C-3 position. The potential antiproliferative activity of these compounds was examined in A549 (human non-small cell lung cancer cells), MCF-7 (human breast cancer cells), and HeLa (human cervical carcinoma cells) cells. Methyl 3ß-O-[4-(2-aminoethylamino)-4-oxo-butyryl]olean-12-ene-28-oate (DABO-Me) was identified as a promising antiproliferative agent in vitro and in vivo. DABO-Me strongly suppressed the proliferation of A549, MCF-7, and HeLa cells (IC50 = 4-7 µM). In MCF-7 cells, DABO-Me upregulated the pro-apoptotic protein Bax, downregulated the anti-apoptotic protein Bcl-2, promoted the release of cytochrome c, and activated caspase-3/9. Transwell and flow cytometry assays showed that DABO-Me inhibited MCF-7 cell proliferation, migration, and invasion, and induced apoptosis and S phase arrest. In vitro and in vivo experiments indicated that DABO-Me inhibited MCF-7 cell proliferation and suppressed tumor growth. Taken together, these results indicate that DABO-Me could be developed as an effective antitumor drug.

8.
Arch Gynecol Obstet ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33009996

RESUMO

PURPOSE: To compare the survival outcome of neoadjuvant therapy (NAT) (chemotherapy or chemotherapy and intracavitary brachytherapy (ICBT) followed by radical surgery and of concomitant chemotherapy and radiotherapy (CCRT) in patients with locally advanced cervical adenocarcinoma and identify predictors of cervical adenocarcinoma. METHODS: We retrospectively reviewed our medical records of cervical adenocarcinoma patients treated with either NAT + surgery or CCRT in our institution from January 2013 to December 2017. The patients were treated with two-dimensional radiotherapy or three-dimensional-conformal or intensity-modulated radiotherapy combined with intracavitary brachytherapy. The regimen of concomitant chemotherapy was weekly cisplatin. The neoadjuvant chemotherapy (NACT) was paclitaxel plus cisplatin. The primary end points were overall survival (OS) and progression-free survival (PFS). RESULTS: We enrolled 121 patients. There were 42 (34.7%) patients in the NAT + surgery group and 79 (65.3%) in the CCRT group. After univariate multivariate analysis, NAT was an independent predictor of OS (p = 0.008) and PFS (p = 0.006). After propensity score matching, the 5-year OS rates in the NAT + surgery and CCRT groups were 25% and 4%, respectively (p = 0.00014), and the 5-year PFS rates were 25% and 4%, respectively (p = 0.00015). Subgroup analysis showed that the 5-year OS and PFS rates in the NACT + surgery and CCRT groups were both 20% and 8%, respectively (p = 0.015). CONCLUSION: Compared with CCRT, NAT followed by radical surgery had better OS and PFS in locally advanced cervical adenocarcinoma. In subgroup analysis, OS and PFS were longer for NACT + surgery than for CCRT.

9.
Int J Hematol ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037588

RESUMO

The clinical features of patients with secondary hemophagocytic lymphohistiocytosis (sHLH) complicated with capillary leak syndrome (CLS) remain controversial. The data of 259 sHLH patients were retrospectively analyzed. The clinical manifestations, laboratory findings, treatment, and prognosis of the CLS-sHLH group and non-CLS-sHLH group were compared. The levels of fibrinogen, albumin, and serum calcium in the CLS-sHLH group were lower than in the non-CLS-sHLH group, and serum triglycerides in the CLS-sHLH group were higher than in the non-CLS-sHLH group (P < 0.05). Univariate analysis showed that fibrinogen level was an independent prognostic factor in sHLH patients complicated with CLS. The median survival time was significantly shorter in patients with fibrinogen ≤ 1.3 g/L than in patients with fibrinogen > 1.3 g/L (P < 0.05). Patients with improved CLS conditions in the CLS-sHLH group had significantly increased albumin and serum calcium after treatment (P < 0.05); patients without improved conditions in the CLS-sHLH group also had significantly increased albumin after treatment (P < 0.05), but the serum calcium did not change significantly (P > 0.05). sHLH patients complicated with CLS had significantly worse prognosis than without CLS. Significant reduction in fibrinogen may be an independent prognostic factor for poor prognosis in sHLH patients complicated with CLS.

10.
Int J Biol Sci ; 16(15): 3002-3017, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061812

RESUMO

Background: Abnormal transcriptional upregulation of telomerase reverse transcriptase (TERT) plays a dominant role in telomerase activation in various cancers. TERT promoter mutations (TPMs) have been identified as a key mechanism in TERT upregulation. However, the mechanism of TERT upregulation in cancers with low frequency of TPMs are not fully elucidated so far. Methods: The expression of PUF60 and TERT was detected by real-time PCR, western blot and immunohistochemistry. TERT promoter binding proteins were identified by streptavidin-agarose pulldown assay and mass spectrum (MS) analysis. The role of PUF60/TERT in renal cancer was evaluated on cell growth in vitro and in vivo. Results: In this study, we identify the regulation mechanism of TERT in renal cell carcinoma (RCC) cells which have rare TPMs but exert significant upregulation of TERT. We found that TERT was highly expressed in RCC tumor tissues, and elevated TERT expression was associated with poor prognosis for patients. We also detected the relatively rare TPM status in both RCC tumor tissues and RCC cell lines. Mechanistically, PUF60, a RNA binding protein, was identified as a novel TERT regulator which bound to the TERT and transcriptionally upregulated TERT expression in RCC cells. The in vitro and in vivo experiments also demonstrated that PUF60 could promote RCC cell growth through activation of TERT expression in a TPM status independent way. Furthermore, we showed that there was a strong correlation of the expression of PUF60 and TERT in RCC tumor tissues and RCC cell lines, and the patients with high expression of PUF60 and TERT had significantly shorter survival. Conclusions: Collectively, these results indicated that PUF60 transcriptionally upregulated TERT expression to promote RCC growth and progression in a TPM status independent way, suggesting that the PUF60/TERT signaling pathway may serve as potential prognostic biomarkers and therapeutic targets for RCC.

11.
HPB (Oxford) ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33051141

RESUMO

BACKGROUND: The study aimed at establishing a nodal staging score (NSS) to quantify the likelihood that pathologic node-negative gallbladder cancer (GBC) patients are indeed free of lymph node (LN) metastasis. METHODS: Clinicopathological data of 1374 GBC patients with T1b-T2 stages were collected from the Surveillance, Epidemiology and End Result database (design cohort [DC], n = 1289) and the First Affiliated Hospital of Sun Yat-sen University (validation cohort [VC], n = 85). NSS was derived from the count of examined LNs (ELNs) and T stage by using a beta-binomial model, and represented the probability that a node-negative patient is correctly staged. The prognostic value of NSS in node-negative GBC was evaluated by survival analysis. RESULTS: The probability of missing a nodal disease in node-negative GBC patients with T1b-T2 stages (pT1bN0 and pT2N0) decreased as the number of ELNs increased. NSS increased as the number of ELNs increased. For pT1bN0 and pT2N0 patients, examination of 5 and 27 lymph nodes could ensure an NSS of 90.0%, respectively. Multivariate analysis revealed that NSS was an independent predictor for overall survival in pT1bN0 and pT2N0 GBC patients (DC, HR:0.53, 95%CI: 0.42-0.66, p < 0.001; VC, HR: 0.33, 95%CI: 0.14-0.76, p = 0.009). CONCLUSION: NSS could evaluate the adequacy of nodal staging and predict the prognosis in pT1bN0 and pT2N0 GBC patients, and hence was helpful to guide their treatment strategies.

12.
Pharm Dev Technol ; : 1-9, 2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33070673

RESUMO

Multidrug resistance (MDR) is a serious challenge in chemotherapy and also a major threat to breast cancer treatment. As an intracellular energy factory, mitochondria provide energy for drug efflux and are deeply involved in multidrug resistance. Mitochondrial targeted delivery of doxorubicin can overcome multidrug resistance by disrupting mitochondrial function. By incorporating a reactive oxygen species (ROS)-responsive hydrophobic group into the backbone structure of hyaluronic acid - a natural ligand for the highly expressed CD44 receptor on tumor surfaces, a novel ROS-responsive and CD44-targeting nano-carriers was constructed. In this study, mitochondria-targeted triphenylphosphine modified-doxorubicin (TPP-DOX) and amphipathic ROS-responsive hyaluronic acid derivatives (HA-PBPE) were synthesized and confirmed by 1H NMR. The nanocarriers TPP-DOX @ HA-PBPE was prepared in a regular shape and particle size of approximately 200 nm. Compared to free DOX, its antitumor activity in vitro and tumor passive targeting in vivo has been enhanced. The ROS-responsive TPP-DOX@HA-PBPE nanocarriers system provide a promising strategy for the reverse of MDR and efficient delivery of doxorubicin derivatives into drug-resistant cancer cells.

13.
Med Sci Monit ; 26: e926407, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33071278

RESUMO

BACKGROUND Achilles tendinopathy commonly occurs in specific regions of the tendon, and Achilles tendon stiffness can be related to local pathological changes in the tendon. The MyotonPRO is a new handheld device that conveniently assesses stiffness of muscles and tendons. This study aimed to 1) evaluate the intra- and inter-rater reliability of stiffness measurements of the Achilles tendon at different ankle positions, 2) investigate the modulation of stiffness at different ankle joint angles, and 3) examine the differences between 2 regions of Achilles tendon stiffness. MATERIAL AND METHODS Thirty healthy young adults (15 men and 15 women) participated in this study. The regional Achilles tendon stiffness at 0 cm (AT-0) and 6 cm (AT-6) above the tendon insertion were evaluated by the MyotonPRO in the neutral position and 10° dorsiflexion of the ankle joint. Measurements of stiffness were taken by 2 raters on the first day and 5 days later. The stiffness data were compared by repeated measures analysis of variance (ANOVA). RESULTS The intra- and inter-rater reliability of stiffness measurements at AT-0 and AT-6 for each ankle position were good (all intraclass correlation coefficients >0.84). A significant modulation of Achilles tendon stiffness was obtained at different ankle joint angles (P<0.05). Stiffness at AT-0 was higher than at AT-6 (P<0.05) in both positions. CONCLUSIONS These results suggest the MyotonPRO reliably assessed Achilles tendon stiffness and monitors its modulation, and tendon stiffness increased with ankle dorsiflexion. Stiffness was also nonuniform along the length of the tendon.

14.
Int J Hyperthermia ; 37(1): 1060-1065, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32892661

RESUMO

OBJECTIVE: To investigate the safety and efficacy of high-intensity focused ultrasound (HIFU) treatment for diffuse uterine leiomyomatosis (DUL). METHODS: Eight patients with DUL were admitted to the Department of Gynecology of Shanghai First Maternity and Infant Hospital and underwent HIFU treatment. MRI was performed before and one day after HIFU treatment for the evaluation of lesion ablation. The uterine size was measured at 3-8 months after HIFU ablation. The menstrual volume score and serum levels of hemoglobin and CA-125 were measured pre-HIFU ablation and 12-36 months post-HIFU ablation. RESULTS: After an average of 5.9 months of follow-up after HIFU treatment, an average uterine volume reduction of 67.6% was observed. Menstruation returned to normal in all patients, and their serum HGB and CA-125 levels also returned to normal after an average of 19.1 months of clinical follow-up. The quality of life of all patients improved significantly. CONCLUSION: HIFU treatment is safe and effective in the treatment of patients with DUL.

15.
Sci Total Environ ; 753: 142054, 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32896729

RESUMO

Sediment microorganisms are influenced by various biotic and abiotic factors. However, information concerning the spatial factors that determine the functional diversity of sediment bacterial communities at an island scale is limited. Here, we conducted an island-scale study to assess the driving forces governing the functional diversity of sediment bacterial communities in different mangroves around the coast of Hainan Island, southern China. For mangrove sediments in Hainan Island, differences in the metabolic activity and functional diversity among four sites were context dependent, while that showed a trend of East > North > West > South. Furthermore, total carbon, nitrite nitrogen, and salinity are important environmental factors that determine the metabolic functional diversity of bacterial communities. This study also provided important insights for explaining the metabolic functional diversity of bacterial communities in tropical mangrove sediments. The metabolic activity had a significantly response to environmental variables (13.2% of pure variance was explained) and spatial variables (12.4%). More importantly, given that spatial variables may contribute to the bacterial functional as important as environmental variables, this spatial variety of bacterial functional provides new insight into studying bacterial functional biogeographic patterns and impacts on sediment-associated function.

16.
Zhongguo Zhen Jiu ; 40(8): 897-901, 2020 Aug 12.
Artigo em Chinês | MEDLINE | ID: mdl-32869603

RESUMO

The rule and characteristics of clinical acupoint selection were explored in treatment of puerperal insufficient lactation with acupuncture and moxibustion. The clinical articles on the treatment of puerperal insufficient lactation with acupuncture and moxibustion were retrieved from the databases of CNKI, VIP and Wanfang from the date of establishment to June 1, 2019. The articles were screened in accordance with the inclusion and exclusion criteria. The prescriptions of acupuncture and moxibustion were extracted and normalized. Using Microsoft Excel 2016 software, the use frequency, meridians involved and acupoint distributions were analyzed. Using SPSS Statistics 21.0 software, the cluster and factor analyses were conducted. Totally, 102 articles were included,108 acupoint prescriptions were extracted, 65 acupoitns were designed and the total use frequency was 654 times. The top three acupoints used in treatment of puerperal insufficient lactation were Danzhong (CV 17), Rugen (ST 18) and Shaoze (SI 1). The most frequently involved meridians were the stomach meridian, the conception vessel, the small intestine meridian and the liver meridian. The acupoints were mainly distributed in the chest and four extremities. It was showed in cluster analysis that Rugen (ST 18), Shaoze (SI 1), Zusanli (ST 36) and Danzhong (CV 17) represent 3 clusters and a total of 7 common factors were extracted. The acupoint selection is based on syndrome differentiation in treatment of puerperal insufficient lactation with acupuncture and moxibustion, of which, the local acupoints are predominated and the distal acupoints are combined.

17.
Environ Pollut ; 267: 115540, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32898731

RESUMO

The use of the phenicol antibiotic florfenicol in livestock can select for the optrA gene, which also confers resistance to the critically important oxazolidinone antibiotic linezolid. However, the occurrence and dissemination of florfenicol and linezolid cross-resistance genes in anaerobic treatment systems for livestock waste are unknown. Herein, the phenotypes and genotypes (optrA, fexA, fexB, and cfr) of florfenicol and linezolid cross-resistance were investigated in 339 enterococci strains isolated from lab- and full-scale mesophilic anaerobic digestion systems treating swine waste. It was found that optrA, fexA, and fexB were frequently detected in isolated enterococci in both systems by PCR screening, whereas cfr was not detected. The most abundant gene was optrA, which was detected in 73.5% (n = 50) and 38.9% (n = 23) of enterococci isolates in the full-scale influent and effluent, respectively. Most strains carried more than two resistance genes, and the average percentage of co-occurrence of optrA/fexA was 16.6%. Based on minimum inhibitory concentrations of the enterococci strain phenotypes, 85.7%, 77.5%, and 77.5% of strains in influent were resistant to chloramphenicol, florfenicol, and linezolid, respectively, while 56.3%, 65.2%, and 13% in the effluent isolates were found, respectively, which was consistent with the genotype results. The phenotypes and genotypes of florfenicol and linezolid resistance were relative stable in the enterococci isolated from the influent and effluent in lab-scale anaerobic digestion system. The findings signify the enterococci isolates harboring the optrA gene remained in effluents of both full- and lab-scale swine waste anaerobic digestion system; hence, effective management strategies should be implemented to prevent the discharge of antibiotic resistance from the livestock waste treatment systems.

18.
Redox Biol ; 36: 101642, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32863238

RESUMO

Normal high-density lipoprotein (nHDL) in normal, healthy subjects is able to promote angiogenesis, but the mechanism remains incompletely understood. HDL from patients with coronary artery disease may undergo a variety of oxidative modifications, rendering it dysfunctional; whether the angiogenic effect is mitigated by such dysfunctional HDL (dHDL) is unknown. We hypothesized that dHDL compromises angiogenesis. The angiogenic effects of nHDL and dHDL were assessed using endothelial cell culture, endothelial sprouts from cardiac tissue from C57BL/6 mice, zebrafish model for vascular growth and a model of impaired vascular growth in hypercholesterolemic low-density lipoprotein receptor null(LDLr-/-)mice. MiRNA microarray and proteomic analyses were used to determine the mechanisms. Lipid hydroperoxides were greater in dHDL than in nHDL. While nHDL stimulated angiogenesis, dHDL attenuated these responses. Protein and miRNA profiles in endothelial cells differed between nHDL and dHDL treatments. Moreover, nHDL suppressed miR-24-3p expression to increase vinculin expression resulting in nitric oxide (NO) production, whereas dHDL delivered miR-24-3p to inhibit vinculin expression leading to superoxide anion (O2•-) generation via scavenger receptor class B type 1. Vinculin was required for endothelial nitric oxide synthase (eNOS) expression and activation and modulated the PI3K/AKT/eNOS and ERK1/2 signaling pathways to regulate nHDL- and VEGF-induced angiogenesis. Vinculin overexpression or miR-24-3p inhibition reversed dHDL-impaired angiogenesis. The expressions of vinculin and eNOS and angiogenesis were decreased, but the expression of miR-24-3p and lipid hydroperoxides in HDL were increased in the ischemic lower limbs of hypercholesterolemic LDLr-/- mice. Overexpression of vinculin or miR-24-3p antagomir restored the impaired-angiogenesis in ischemic hypercholesterolemic LDLr-/- mice. Collectively, nHDL stimulated vinculin and eNOS expression to increase NO production by suppressing miR-24-3p to induce angiogenesis, whereas dHDL inhibited vinculin and eNOS expression to enhance O2•- generation by delivering miR-24-3p to impair angiogenesis, and that vinculin and miR-24-3p may be therapeutic targets for dHDL-impaired angiogenesis.

19.
J Org Chem ; 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32865421

RESUMO

Ru-catalyzed cross-coupling of secondary alcohols with only byproducts H2 and H2O provides a green synthetic strategy to prepare ß-disubstituted ketones. Density functional theory (DFT) calculations were performed with the coupling of 1-phenylethanol and cyclohexanol as a model reaction to gain deeper mechanistic insights herein. The mechanistic details of the main reaction and the key steps of possible side reactions were clarified, and the obtained results are consistent with reported selectivity. Hydrogenation of α,ß-unsaturated ketones and dehydrogenation of ruthenium hydride intermediate are direct chemoselectivity-determining stages. The hydrogenation via 1,4-addition generates more stable intermediates, being favored over that via 1,2-addition, and thus avoids the formation of alkene products. The conjugation and π-π stacking effects of phenyl and the weak electronic effect of alkyls explain the dominance of specific ketone products in the hydrogenation stage. Hydrogenation of ketone products is kinetically operative but not exergonic enough to stop the irreversible dihydrogen release in an open reaction system, and thus alcohol products are absent. Furthermore, water evaporation in aldol condensation is found to be a double-edged sword, as it can accelerate the hydrogenation stage to prevent α,ß-unsaturated ketones from being the main products but decrease the selectivity therein from thermodynamics overall.

20.
Parasit Vectors ; 13(1): 451, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894174

RESUMO

BACKGROUND: Hepatic granuloma formation and fibrosis as the consequence of tissue entrapped eggs produced by female schistosomes characterize the pathology of Schistosoma japonicum infection. It has been proposed that fucoidan, a sulfated polysaccharide existing naturally in brown seaweed Fucus vesiculosus, plays a diversified role to perform immunomodulatory activities. However, whether fucoidan functions in the host hepatic pathology is unknown and identifying the potential mechanism that is responsible for hepatic improvement is still necessary. METHODS: We evaluated the hepatic pathology from S. japonicum-infected mice after treatment with fucoidan. qRT-PCR and immunofluorescence were used to detect the pro- or anti-inflammatory factors and the phosphorylated p65 in the livers. In addition, flow cytometry was also performed to investigate the T cell subsets in the S. japonicum-infected mice after treatment with fucoidan, and functional molecules relatively specific to Treg cells were detected in vitro. Furthermore, macrophages were treated with fucoidan in vitro and to detect the inflammatory cytokines. RESULTS: Treatment with fucoidan significantly reduced the hepatic granuloma size and fibrosis response during S. japonicum infection. The attenuated phospho-p65 protein levels and the mRNA levels of pro-inflammatory cytokines (IL-6, IL-12 and TNF-α) were observed in the livers from fucoidan-treated S. japonicum-infected mice; however, the mRNA levels of anti-inflammatory cytokines (IL-4 and IL-13) were increased. In addition, the infiltration of Treg cells was significantly enhanced both in the livers and spleens from fucoidan-treated S. japonicum-infected mice. Consistent with this, the mRNA levels of IL-10 and TGF-ß were dramatically increased in the livers from S. japonicum-infected mice after fucoidan treatment. Furthermore, in vitro stimulated splenocytes with fucoidan resulted in increasing Treg cells in splenocytes as well as the functional expression of CC chemokine receptor type 4 (CCR4) and CXC chemokine receptor type 5 (CXCR5) in Treg cells. Additionally, fucoidan promoted the mRNA levels of IL-4 and IL-13 in macrophages. CONCLUSIONS: These findings suggest an important role of natural fucoidan in reducing hepatic pathology in the progress of S. japonicum infection with a stronger Treg response, which may reveal a new potential therapeutic strategy for hepatic disease caused by parasitic chronic infection.

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