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1.
Blood Purif ; : 1-4, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34500449

RESUMO

Anemia is a common complication of chronic kidney disease (CKD). Recombinant human erythropoietin (rHu-EPO) is used extensively in patients with CKD. However, anti-erythropoietin (anti-EPO) antibody has been reported during rHu-EPO treatment, which causes pure red cell aplasia (PRCA). We presented a case of 75-year-old man, who underwent hemodialysis for 2 years. He developed PRCA during rHu-EPO treatment. The rHu-EPO was immediately discontinued, and the patient was given roxadustat treatment. After 6 months of roxadustat treatment, the anti-EPO antibody was disappeared, and hemoglobin recovered normal range. The results suggest that roxadustat can be used to treat patients with anti-EPO antibody-mediated PRCA without immunosuppressive therapy.

2.
Br J Pharmacol ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34553378

RESUMO

BACKGROUND AND PURPOSE: Duchenne muscular dystrophy (DMD) is a degenerative muscle disease with no effective drug treatment. This study investigated the positive effects of fenofibrate on dystrophic muscles. EXPERIMENTAL APPROACH: Myostatin expression in serum and muscle tissue of DMD patients and mdx mice were tested. Primary myoblasts isolated from mdx mice were challenged with an inflammatory stimulus and treated with fenofibrate. In animal experiments, 6-week-old male mdx mice were treated with fenofibrate (100 mg/kg) administered orally once per day for 6 weeks. Tests of muscle function plus histology and biochemical analyses of serum were conducted to evaluate the effects of fenofibrate. The expressions of myostatin, MuRF1, and atrogin-1 in skeletal muscle were evaluated by Western blotting and real-time PCR. Total and oxidative myosin heavy chain (MHC) were assessed via immunofluorescence. KEY RESULTS: Increased expression of myostatin protein was found in dystrophic muscle of DMD patients and mdx mice. Fenofibrate enhanced myofibre differentiation by downregulating the expression of myostatin protein but not mRNA in primary myoblasts of mdx mice. Fenofibrate significantly improved muscle function while ameliorating muscle damage in mdx mice. These benefits are accompanied by an anti-inflammatory effect. Fenofibrate treatment returned myofibre function by inhibiting the expressions of myostatin, MuRF1, and atrogin-1 protein in the gastrocnemius muscle and diaphragm, while leaving the mRNA level of myostatin unaffected. CONCLUSIONS AND IMPLICATIONS: Fenofibrate substantially slows muscle dystrophy by promoting the degradation of myostatin protein, which may indicate a new therapeutic focus for DMD patients.

3.
Eur J Pharmacol ; 910: 174470, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34478691

RESUMO

Myocardial fibrosis in post-myocardial infarction is a self-healing process of the myocardium, making ventricular remodelling difficult to reverse and develop continuously. Fibroblast growth factor 21 (FGF21) plays an essential role in cardiovascular and metabolic diseases. However, the effect and mechanism of FGF21 action on cardiac inflammation and fibrosis caused by myocardial injury have rarely been reported. Adult male Sprague-Dawley rats administered with or without recombinant human basic FGF21 (rhbFGF21) were assessed using echocardiography and haematoxylin-eosin and Masson's trichrome staining to determine the cardiac function and cardiac inflammation and fibrosis levels. FGF21 might improve cardiac remodelling, as characterised by a decrease in the expression of a series of inflammatory and fibrosis-related factors. Moreover, when FGF receptors (FGFRs) were blocked, the effects of FGF21 disappeared. Mechanistically, we found that oxidative stress induced the downregulation of early growth response protein 1 (EGR1), which contributed to inflammatory factors and fibrosis reduction in cardiomyocytes treated with H2O2. Collectively, FGF21 effectively suppressed the inflammation and fibrosis in post-infarcted hearts by regulating FGFR-EGR1.

4.
Eur J Pharmacol ; 909: 174435, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34416239

RESUMO

Hypertension is one of the most common complications of chronic kidney disease (CKD). Some research has indicated that changes in large artery function especially caused by thromboxane A2 (TXA2) may be a novel factor acting to induce hypertension in CKD. We studied the 5/6 nephrectomy rat model and measured serum levels of creatinine (Cr), calcium (Ca), phosphorus (P), TXA2-stable metabolites (thromboxane B2, TXB2), and caudal artery pressure after nephrectomy. The tension variations in thoracic aortas were measured after stimulating by vasoconstrictor/vasodilator using the cumulative concentration administration method and then tested the expression of TXA2 receptors in the thoracic aortas through western blots. The CKD rats developed uremia, electrolyte imbalances,and hypertension. They also exhibited a significant increase in TXB2 concentration. The aortic rings of CKD rats showed an increased contraction response to U46619 (a TXA2 analogue) and the expression of TXA2 receptors also enhanced. In the meanwhile, the diastolic function decreased in the CKD group. Our results demonstrate that the impairment of artery contractile function caused by the increase of TXA2 receptors on the wall of aortic rings may be involved in hypertension in CKD rats.

5.
Healthcare (Basel) ; 9(7)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34356211

RESUMO

During the COVID-19 pandemic, every day, updated case numbers and the lasting time of the pandemic became major concerns of people. We collected the online data (28 January to 7 March 2020 during the COVID-19 outbreak) of 16,453 social media users living in mainland China. Computerized machine learning models were developed to estimate their daily scores of the nine dimensions of the Symptom Checklist-90 (SCL-90). Repeated measures analysis of variance (ANOVA) was used to compare the SCL-90 dimension scores between Wuhan and non-Wuhan residents. Fixed effect models were used to analyze the relation of the estimated SCL-90 scores with the daily reported cumulative case numbers and lasting time of the epidemic among Wuhan and non-Wuhan users. In non-Wuhan users, the estimated scores for all the SCL-90 dimensions significantly increased with the lasting time of the epidemic and the accumulation of cases, except for the interpersonal sensitivity dimension. In Wuhan users, although the estimated scores for all nine SCL-90 dimensions significantly increased with the cumulative case numbers, the magnitude of the changes was generally smaller than that in non-Wuhan users. The mental health of Chinese Weibo users was affected by the daily updated information on case numbers and the lasting time of the COVID-19 outbreak.

6.
J Pediatr ; 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34400207

RESUMO

OBJECTIVE: To describe the parental experience of recruitment and assess differences between parents who participated and those who declined to enroll in a neonatal clinical trial. STUDY DESIGN: This was a survey conducted at 12 US neonatal intensive care units of parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who were eligible but declined enrollment. Questions assessed 6 factors of the parental experience of recruitment: (1) interactions with research staff; (2) the consent experience; (3) perceptions of the study; (4) decisional conflict; (5) reasons for/against participation; and (6) timing of making the enrollment decision. RESULTS: In total, 269 of 387 eligible parents, including 183 of 242 (75.6%) of those who enrolled their children in HEAL and 86 of 145 (59.3%) parents who declined to enroll their children in HEAL, were included in analysis. Parents who declined to enroll more preferred to be approached by clinical team members rather than by research team members (72.9% vs 49.2%, P = .005). Enrolled parents more frequently reported positive initial impressions (54.9% vs 10.5%, P < .001). Many parents in both groups made their decision early in the recruitment process. Considerations of reasons for/against participation differed by enrollment status. CONCLUSIONS: Understanding how parents experience recruitment, and how this differs by enrollment status, may help researchers improve recruitment processes for families and increase enrollment. The parental experience of recruitment varied by enrollment status. These findings can guide future work aiming to inform optimal recruitment strategies for neonatal clinical trials.

7.
J Immunol Res ; 2021: 9117805, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34195297

RESUMO

Although the strain-dependent effects of Bacteroides vulgatus on alleviating intestinal inflammatory diseases have been demonstrated, the literature has rarely focused on the underlying causes of this effect. In this study, we selected four B. vulgatus strains (FTJS5K1, FTJS7K1, FSDTA11B14, and FSDLZ51K1) with different genomic characteristics and evaluated their protective roles against dextran sulfate sodium- (DSS-) induced colitis. Compared to the other three tested strains, B. vulgatus 7K1 more strongly ameliorated the DSS-induced weight loss, shortening of the colon length, increased disease activity index scores, colonic tissue injury, and immunomodulatory disorder. In contrast, B. vulgatus 51K1 significantly worsened the DSS-induced alterations in the tumor necrosis factor-alpha (TNF-α) concentration and colonic histopathology. A comparative genomic analysis of B. vulgatus 7K1 and 51K1 showed that the beneficial effects of B. vulgatus 7K1 may be associated with some of its specific genes involved in the production of short-chain fatty acids or capsular polysaccharides and enhancement of its survivability in the gut. In conclusion, these findings indicate that the supplementation of B. vulgatus 7K1 is a potentially efficacious intervention for alleviating colitis and provides scientific support for the screening of probiotics with anticolitis effect.

8.
Food Funct ; 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34308455

RESUMO

The role of supplementation with different Bacteroides fragilis (B. fragilis) strains in alleviating ulcerative colitis (UC) is unclear due to the controversial results from animal experiments. In this study, three B. fragilis strains were evaluated for their ability to alleviate dextran sulfate sodium (DSS)-induced UC in C57BL/6J mice. We analyzed the anti-inflammatory effects of different B. fragilis strains and the changes they caused in the intestinal microbiota composition, intestinal epithelial permeability, cytokine concentrations, protein expression of nuclear factor kappa-B (NF-κB) and the underlying specific genes. The results showed that when orally administered, the different B. fragilis strains exerted different effects on the assessed parameters of the mice. The results of real-time quantitative polymerase chain reaction and immunofluorescence staining showed that the supplementation of B. fragilis FSHCM14E1, but not FJSWX11BF, enhanced the expression of the tight-junction proteins ZO-1, occludin and claudin-1. Western blot analysis showed that the anti-inflammatory effects of B. fragilis FSHCM14E1 were related to the NF-κB pathway. Genomic analysis suggested that the anti-inflammatory effects of FSHCM14E1 may be mediated through specific genes associated with defense mechanisms and the secretion of SCFAs. Overall, this study indicates the therapeutic potential of B. fragilis FSHCM14E1 for the prevention of UC.

9.
JAMA Netw Open ; 4(7): e2115998, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34232302

RESUMO

Importance: Extremely preterm (EP) infants frequently receive opioids and/or benzodiazepines, but these drugs' association with neurodevelopmental outcomes is poorly understood. Objectives: To describe the use of opioids and benzodiazepines in EP infants during neonatal intensive care unit (NICU) hospitalization and to explore these drugs' association with neurodevelopmental outcomes at 2 years' corrected age. Design, Setting, and Participants: This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial, which was conducted among infants born between gestational ages of 24 weeks, 0 days, and 27 weeks, 6 days. Infants received care at 19 sites in the United States, and data were collected from December 2013 to September 2016. Data analysis for this study was conducted from March to December 2020. Exposures: Short (ie, ≤7 days) and prolonged (ie, >7 days) exposure to opioids and/or benzodiazepines during NICU stay. Main Outcomes and Measures: Cognitive, language, and motor development scores were assessed using the Bayley Scales of Infant Development-Third Edition (BSID-III). Results: There were 936 EP infants (448 [48%] female infants; 611 [65%] White infants; mean [SD] gestational age, 181 [8] days) included in the study, and 692 (74%) had neurodevelopmental outcome data available. Overall, 158 infants (17%) were not exposed to any drugs of interest, 297 (32%) received either opioids or benzodiazepines, and 481 (51%) received both. Infants exposed to both had adjusted odds ratios of 9.7 (95% CI, 2.9 to 32.2) for necrotizing enterocolitis and 1.7 (95% CI, 1.1 to 2.7) for severe bronchopulmonary dysplasia; they also had a longer estimated adjusted mean difference in length of stay of 34.2 (95% CI, 26.2 to 42.2) days compared with those who received neither drug. After adjusting for site and propensity scores derived for each exposure category, infants exposed to opioids and benzodiazepines had lower BSID-III cognitive, motor, and language scores compared with infants with no exposure (eg, estimated difference in mean scores on cognitive scale: -5.72; 95% CI, -8.88 to -2.57). Prolonged exposure to morphine, fentanyl, midazolam, or lorazepam was associated with lower BSID-III scores compared with infants without exposure (median [interquartile range] motor score, 85 [73-97] vs 97 [91-107]). In contrast, BSID-III scores for infants with short exposure to both opioids and benzodiazepines were not different than those of infants without exposure. Conclusions and Relevance: In this study, prolonged combined use of opioids and benzodiazepines was associated with a risk of poorer neurodevelopmental outcomes as measured by BSID-III at 2 years' corrected age.

10.
Antonie Van Leeuwenhoek ; 114(8): 1225-1235, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34129122

RESUMO

A novel strictly anaerobic, Gram-negative bacterium, designated as strain FXJYN30E22T, was isolated from the feces of a healthy woman in Yining county, Xinjiang province, China. This strain was non-spore-forming, bile-resistant, non-motile and rod-shaped. It was found to belong to a single separate group in the Phocaeicola genus based on its 16 S ribosomal RNA (rRNA) gene sequence. Alignments of 16 S rRNA gene sequences showed only a low sequence identity (≤ 95.5 %) between strain FXJYN30E22T and all other Phocaeicola strains in public data bases. The genome (43.0% GC) of strain FXJYN30E22T was sequenced, and used for phylogenetic analysis which showed that strain FXJYN30E22T was most closely related to the type strain Phocaeicola massiliensis JCM 13223T. The average nucleotide identity (ANI) value and digital DNA-DNA hybridization (dDDH) between FXJYN30E22T and P. massiliensis JCM 13223T were 90.4 and 41.9 %, which were lower than the generally accepted species boundaries (94.0 and 70 %, respectively). The major cellular fatty acids and polar lipids were anteiso-branched C15:0 and phosphatidylethanolamine, respectively. The result of genome annotation and KEGG analysis showed that strain FXJYN30E22T contains a number of genes in polysaccharide and fatty acid synthesis that indicated adaptation to the human gut system. Furthermore, a pbpE (penicillin-binding protein) gene was found in the genome of strain FXJYN30E22T but in no other Phocaeicola species, which suggested this gene might be contribute to the adaptive capacity of strain FXJYN30E22T. Based on our data, strain FXJYN30E22T (= CGMCC1.17870T/KCTC25195T) was classified as a novel Phocaeicola species, and the name Phocaeicola faecalis sp. nov., was proposed.


Assuntos
Ecossistema , Ácidos Graxos , Anaerobiose , Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano/genética , Feminino , Humanos , Hibridização de Ácido Nucleico , Fosfolipídeos , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
11.
Crisis ; 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34128719

RESUMO

Background: Coronavirus disease 2019 (COVID-19) threatens people's physical and mental health, globally, and it may even trigger suicide ideation and suicidal behavior. Aims: We aimed to examine the impact of COVID-19 on suicide risk by sampling Chinese Weibo users and analyzing their social media messages. Method: We predicted the probability of suicide (including hopelessness, suicidal ideation, negative self-evaluation, and hostility) of Weibo users in order to assess the changes in suicide probability at different times. Repeated-measures ANOVA was performed to examine the differences in suicide probability in different regions during different periods. Results: There was no significant difference in suicide probability between profoundly infected areas (PIAs) and less infected areas (LIAs) before the outbreak of COVID-19. LIAs had an increase in hopelessness during the COVID-19 growth period, while hopelessness and hostility in PIA increased during the COVID-19 decline period, indicating potential suicide probability. Limitations: Results should be interpreted with caution, and cross-cultural research may be considered in the future. Conclusion: COVID-19 has a dynamic impact on suicide probability. Using data from online social networks may help to understand the impact pattern of COVID-19 on people's suicide probability.

12.
Kidney Int ; 100(2): 377-390, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34051263

RESUMO

Receptor activator of NF-κB (RANK) expression is increased in podocytes of patients with diabetic nephropathy. However, the relevance of RANK to diabetic nephropathy pathobiology remains unclear. Here, to evaluate the role of podocyte RANK in the development of diabetic nephropathy, we generated a mouse model of podocyte-specific RANK depletion (RANK-/-Cre T), and a model of podocyte-specific RANK overexpression (RANK TG), and induced diabetes in these mice with streptozotocin. We found that podocyte RANK depletion alleviated albuminuria, mesangial matrix expansion, and basement membrane thickening, while RANK overexpression aggravated these indices in streptozotocin-treated mice. Moreover, streptozotocin-triggered oxidative stress was increased in RANK overexpression but decreased in the RANK depleted mice. Particularly, the expression of NADPH oxidase 4, and its obligate partner, P22phox, were enhanced in RANK overexpression, but reduced in RANK depleted mice. In parallel, the transcription factor p65 was increased in the podocyte nuclei of RANK overexpressing mice but decreased in the RANK depleted mice. The relevant findings were largely replicated with high glucose-treated podocytes in vitro. Mechanistically, p65 could bind to the promoter regions of NADPH oxidase 4 and P22phox, and increased their respective gene promoter activity in podocytes, dependent on the levels of RANK. Taken together, these findings suggested that high glucose induced RANK in podocytes and caused the increase of NADPH oxidase 4 and P22phox via p65, possibly together with the cytokines TNF- α, MAC-2 and IL-1 ß, resulting in podocyte injury. Thus, we found that podocyte RANK was induced in the diabetic milieu and RANK mediated the development of diabetic nephropathy, likely by promoting glomerular oxidative stress and proinflammatory cytokine production.


Assuntos
Nefropatias Diabéticas , Podócitos , Receptor Ativador de Fator Nuclear kappa-B , Albuminúria/genética , Animais , Diabetes Mellitus , Nefropatias Diabéticas/genética , Camundongos , Estreptozocina
13.
Chem Commun (Camb) ; 57(38): 4674-4677, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977976

RESUMO

The highly enantioselective copper-catalyzed propargylic amination of propargylic esters with amine hydrochloride salts has been realized for the first time using copper salts with chiral N,N,P-ligands. This method features a broad substrate scope and wide functional group tolerance, generating propargylic amines in good to excellent yields with high enantioselectivities (up to 99% ee). The utility of the approach was demonstrated by late-stage functionalization of marketed pharmaceuticals.

14.
Nat Chem Biol ; 17(7): 767-775, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33723431

RESUMO

The transcriptional coactivator Yes-associated protein 1 (YAP) orchestrates a proproliferative transcriptional program that controls the fate of somatic stem cells and the regenerative responses of certain tissues. As such, agents that activate YAP may hold therapeutic potential in disease states exacerbated by insufficient proliferative repair. Here we report the discovery of a small molecule, termed PY-60, which robustly activates YAP transcriptional activity in vitro and promotes YAP-dependent expansion of epidermal keratinocytes in mouse following topical drug administration. Chemical proteomics revealed the relevant target of PY-60 to be annexin A2 (ANXA2), a protein that directly associates with YAP at the cell membrane in response to increased cell density. PY-60 treatment liberates ANXA2 from the membrane, ultimately promoting a phosphatase-bound, nonphosphorylated and transcriptionally active form of YAP. This work reveals ANXA2 as a previously undescribed, druggable component of the Hippo pathway and suggests a mechanistic rationale to promote regenerative repair in disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Anexina A2/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/metabolismo , Administração Tópica , Células-Tronco Adultas/efeitos dos fármacos , Células-Tronco Adultas/metabolismo , Animais , Anexina A2/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química
15.
Biomed Pharmacother ; 137: 111401, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33761615

RESUMO

Radiotherapy is one of the three main treatments for tumors. Almost 70% of tumor patients undergo radiotherapy at different periods. Although radiotherapy can enhance the local control rate of tumors and patients' quality of life, normal tissues often show radiation damage following radiotherapy. In recent years, several studies have shown that exosomes could be biomarkers for diseases and be involved in the treatment of radiation damage. Exosomes are nanoscale vesicles containing complex miRNAs and proteins. They can regulate the inflammatory response, enhance the regeneration effect of damaged tissue, and promote the repair of damaged tissues and cells, extending their survival time. In addition, their functions are achieved by paracrine signaling. In this review, we discuss the potential of exosomes as biomarkers and introduce the impact of exosomes on radiation damage in different organs and the hematopoietic system in detail.


Assuntos
Exossomos/fisiologia , Exossomos/efeitos da radiação , Lesões Experimentais por Radiação/terapia , Lesões por Radiação/terapia , Animais , Biomarcadores , Humanos , Qualidade de Vida , Lesões por Radiação/diagnóstico , Lesões Experimentais por Radiação/diagnóstico , Radioterapia/efeitos adversos
16.
Environ Sci Pollut Res Int ; 28(28): 38159-38172, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33725303

RESUMO

The phthalate concentrations in dust from undergraduate dormitories, classrooms, and homes in Beijing, China, were measured in April 2017. We analyzed the characteristics of phthalates in dust from three environments. In addition, we estimated the daily intake of phthalates via three pathways using Monte Carlo simulations. The detection frequency of eight phthalates in dust ranges from 74.5 to 100%. Di (2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DnBP), and di-isobutyl phthalate (DiBP) are the most abundant phthalates. The median proportion of DEHP in dust is the highest, ranging from 67.1 to 72.9%. The PMF results indicated that two, four, and three types of phthalate sources exist in home, dormitory, and classroom, respectively. The differences in the phthalate concentrations between sunny and shaded rooms and urban and suburban classrooms are insignificant, whereas that between male and female dormitories is significant. The total daily intake of DEHP, DnBP, and DiBP ranges from 97.3 to 336 ng/ (kg·day). The oral intake for DEHP in classrooms and the dermal intake of DnBP and DiBP in homes are the highest. The carcinogenic risk of DEHP to university students is the highest in classrooms and the total carcinogenic risk of the three environments is 4.70 × 10-6.


Assuntos
Poluentes Ambientais , Ácidos Ftálicos , Pequim , China , Poeira/análise , Exposição Ambiental/análise , Poluentes Ambientais/análise , Feminino , Humanos , Masculino , Ácidos Ftálicos/análise
17.
Mol Med Rep ; 23(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33760166

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease often used as a model in genomics research. The downregulation of microRNA­101­3p (miR­101­3p) participates in the progression of SLE, although the underlying mechanisms remain to be elucidated. The present study aimed to evaluate the specific roles of miR­101­3p in the SLE inflammatory response and its potential mechanisms. Reverse transcription­quantitative (RT­q) PCR was used to profile miR­101­3p expression in the peripheral blood mononuclear cells (PBMCs) from 40 female patients with SLE and 20 female healthy volunteers. The interactions between miR­101­3p and MAPK1 were identified and evaluated using dual­luciferase reporter and RNA pull­down assays. The levels of IL­10 and IFN­Î³ were evaluated by enzyme­linked immunosorbent assay. The expression of NF­κB p65 and phosphorylated IκBα were evaluated using western blotting. miR­101­3p expression was demonstrated to be downregulated in SLE PBMCs. miR­101­3p negatively regulated IL­10 and IFN­Î³ expression in SLE samples and was demonstrated to target MAPK1. Increases in MAPK1 expression eliminated miR­101­3p inhibition of IL­10 and IFN­Î³. MAPK1 activated the NF­κB pathway in SLE PBMCs and this activation was inhibited when miR­101­3p was overexpressed. In addition, treatment with BAY11­7085 (NF­κB activator) was demonstrated to reverse the inhibitory effects of miR­101­3p expression on both IL­10 and IFN­Î³ in SLE PBMCs. BAY11­7082 also markedly reduced MAPK1­induced increases in IL­10 and IFN­Î³ in SLE PBMCs. miR­101­3p overexpression attenuated the inflammatory response in SLE PBMCs by inhibiting the expression of MAPK1 and blocking the NF­κB pathway. The results revealed a novel regulatory mechanism in SLE inflammation and offer a new direction for the development of SLE treatments.


Assuntos
Inflamação/genética , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Fator de Transcrição RelA/genética , Regulação da Expressão Gênica , Humanos , Inflamação/patologia , Interleucina-10/genética , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Lúpus Eritematoso Sistêmico/patologia , NF-kappa B/genética , Fosforilação , Transdução de Sinais/genética
18.
Skelet Muscle ; 11(1): 9, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785075

RESUMO

BACKGROUND: ALAS2 (delta-aminolevulinate synthase 2) is one of the two isoenzymes catalyzing the synthesis of delta-aminolevulinic acid (ALA), which is the first precursor of heme synthesis. ALAS2-overexpressing transgenic mice (Tg mice) showed syndrome of porphyria, a series of diseases related to the heme anabolism deficiency. Tg mice showed an obvious decrease in muscle size. Muscle atrophy results from a decrease in protein synthesis and an increase in protein degradation, which ultimately leads to a decrease in myofiber size due to loss of contractile proteins, organelles, nuclei, and cytoplasm. METHODS: The forelimb muscle grip strength of age-matched ALAS-2 transgenic mice (Tg mice) and wild-type mice (WT mice) were measured with an automated grip strength meter. The activities of serum LDH and CK-MB were measured by Modular DPP. The histology of skeletal muscle (quadriceps femoris and gastrocnemius) was observed by hematoxylin and eosin (HE) staining, immunohistochemistry, and transmission electron microscope. Real-time PCR was used to detect mtDNA content and UCP3 mRNA expression. Evans blue dye staining was used to detect the membrane damage of the muscle fiber. Single skeletal muscle fiber diameter was measured by single-fiber analyses. Muscle adenosine triphosphate (ATP) levels were detected by a luminometric assay with an ATP assay kit. RESULTS: Compared with WT mice, the strength of forelimb muscle and mass of gastrocnemius were decreased in Tg mice. The activities of serum CK-MB and LDH, the number of central nuclei fibers, and Evans blue positive fibers were more than those in WT mice, while the diameter of single fibers was smaller, which were associated with suppressed expression levels of MHC, myoD1, dystrophin, atrogin1, and MuRF1. Re-expression of eMyHC was only showed in the quadriceps of Tg mice, but not in WT mice. Muscle mitochondria in Tg mice showed dysfunction with descented ATP production and mtDNA content, downregulated UCP3 mRNA expression, and swelling of mitochondria. CONCLUSION: ALAS2 overexpressing-transgenic mice (Tg mice) showed muscle dystrophy, which was associated with decreased atrogin-1 and MuRF-1, and closely related to mitochondrial dysfunction.

19.
Acta Pharmacol Sin ; 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658706

RESUMO

Continuous docetaxel (DTX) treatment of non-small cell lung cancer induces development of drug resistance, but the mechanism is poorly understood. In this study we performed metabolomics analysis to characterize the metabolic patterns of sensitive and resistant A549 non-small cell lung cancer cells (A549/DTX cells). We showed that the sensitive and resistant A549 cells exhibited distinct metabolic phenotypes: the resistant cells were characterized by an altered microenvironment of redox homeostasis with reduced glutathione and elevated reactive oxygen species (ROS). DTX induction reprogrammed the metabolic phenotype of the sensitive cells, which acquired a phenotype similar to that of the resistant cells: it reduced cystine influx, inhibited glutathione biosynthesis, increased ROS and decreased glutathione/glutathione disulfide (GSH/GSSG); the genes involved in glutathione biosynthesis were dramatically depressed. Addition of the ROS-inducing agent Rosup (25, 50 µg/mL) significantly increased P-glycoprotein expression and reduced intracellular DTX in the sensitive A549 cells, which ultimately acquired a phenotype similar to that of the resistant cells. Supplementation of cystine (1.0 mM) significantly increased GSH synthesis, rebalanced the redox homeostasis of A549/DTX cells, and reversed DTX-induced upregulation of P-glycoprotein, and it markedly improved the effects of DTX and inhibited the growth of A549/DTX in vitro and in vivo. These results suggest that microenvironmental redox homeostasis plays a key role in the acquired resistance of A549 cancer cells to DTX. The enhancement of GSH synthesis by supplementary cystine is a promising strategy to reverse the resistance of tumor cells and has potential for translation in the clinic.

20.
J Hazard Mater ; 415: 125630, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-33774360

RESUMO

The optical signature of chromophoric dissolved organic matter (CDOM) has been related to sources and composition of dissolved organic matter (DOM) in surface waters, but the spatial scope of previous research has been limited to single cities with no studies exploring patterns across gradients of development/industrialization or latitude. Using EEM (excitation emission matrix) techniques, a study was conducted to examine optical properties of CDOM in urban waters along a gradient of urban development (developed and undeveloped cities) and industries (primary, secondary, tertiary). The optical properties of CDOM were measured in 436 water samples collected from urbanized waterbodies spanning 93 cities across China. Results showed marked differences of DOM composition for different level of urban development and for different types of dominant industries. The mean aCDOM(254) for developed cities (14.31 m-1) was significantly lower (p < 0.05) than that of undeveloped cities (18.01 m-1). The intensity of the tryptophan-like component (Q2) of CDOM was significantly higher for developed cities (0.98 ×1010 nm) than for undeveloped cities (4.6 ×109 nm), whereas the humic-like component (Q5) intensity was significantly lower for undeveloped cities (19.80 ×1010 nm) than for developed cities (16.26 ×1010 nm). Regression analysis showed that the Q5 component was mainly (and positively) influenced by secondary industries, while Q2 was mainly affected by both tertiary and secondary industries. The proportion of allochthonous CDOM increased significantly with latitude from south to north with the minimum increased percentage of 67% for humification index (HIX) within different urban development degrees. These findings indicate that changes in urban development, human activities and industrial structure could alter DOM sources and composition in urbanized waterbodies. These findings are relevant to the management of urban water resources in regions experiencing rapid urban and industrial expansion, and add to our understanding of carbon cycling in urbanized freshwater ecosystems.

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