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1.
Eur J Pharmacol ; 897: 173958, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33610598

RESUMO

Hepcidin is the only known hormone negatively regulates systemic iron availability, its excess contributes to anemia of chronic disease (ACD).Heparin has been shown to be an efficient hepcidin inhibitor both in vitro and in vivo, but its powerful anticoagulant activity limits this therapeutic application. To this end, heparin-iron complex was prepared by electrostatic interaction and/or coordination between heparin and dihydroxy iron solution ([Fe(OH)2]+) under the condition of ultrasonic assisted. We assessed the anticoagulant activity of heparin-iron in vitro and vivo by sheep plasma, chromogenic substrate method and tail-bleeding in mice, respectively. Anti-hepcidin effect of heparin-iron was detected in HepG2 cell and LPS induced acute inflammation mice by qRT-PCR and ELISA. Turpentine-induced anemia mice were established to evaluate the effect of heparin-iron in ACD. Mice were treated with heparin-iron for 4 weeks. The results indicated that heparin-iron has significantly reduced anticoagulant activity in vitro and in vivo, strongly decreases hepcidin mRNA and IL-6 induced high level of secreted hepcidin in HepG2 cell. Heparin-iron was also found to cause a reduction on hepcidin expression through BMP/SMAD and JAK/STAT3 pathways in LPS induced acute inflammation model in mice. In ACD mice, heparin-iron could lower elevated serum hepcidin and improve anemia. These findings demonstrated low anticoagulant heparin-iron has potential applications for the treatment of ACD with high hepcidin levels.

2.
Proc Natl Acad Sci U S A ; 118(4)2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33483419

RESUMO

Toxin-antitoxin (TA) loci were initially identified on conjugative plasmids, and one function of plasmid-encoded TA systems is to stabilize plasmids or increase plasmid competition via postsegregational killing. Here, we discovered that the type II TA system, Pseudoalteromonas rubra plasmid toxin-antitoxin PrpT/PrpA, on a low-copy-number conjugative plasmid, directly controls plasmid replication. Toxin PrpT resembles ParE of plasmid RK2 while antitoxin PrpA (PF03693) shares no similarity with previously characterized antitoxins. Surprisingly, deleting this prpA-prpT operon from the plasmid does not result in plasmid segregational loss, but greatly increases plasmid copy number. Mechanistically, the antitoxin PrpA functions as a negative regulator of plasmid replication, by binding to the iterons in the plasmid origin that inhibits the binding of the replication initiator to the iterons. We also demonstrated that PrpA is produced at a higher level than PrpT to prevent the plasmid from overreplicating, while partial or complete degradation of labile PrpA derepresses plasmid replication. Importantly, the PrpT/PrpA TA system is conserved and is widespread on many conjugative plasmids. Altogether, we discovered a function of a plasmid-encoded TA system that provides new insights into the physiological significance of TA systems.

3.
Xenobiotica ; 51(1): 24-30, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32686977

RESUMO

Partial or complete deficiency in the dihydropyrimidine dehydrogenase (DPD) has been observed in 3%-5% and 0.1% of the general population, respectively. It causes severe toxicity in the context of 5-fluorouracil (5-FU) therapy. However, the current tests for determination of DPD deficiency have limitations in routine clinical usage. Therefore, an in vitro approach for simulating 5-FU degradation was established by mixing 5-FU with blank whole blood matrix in this study. The effects of initial 5-FU concentrations and temperatures on DPD activities were investigated as well. The degradation process followed the first-order kinetic reaction (r2 > 0.98). The degradation rates were determined by temperature and individually different. The DPD inhibitor, gimeracil, could block this degradation, which indicated that DPD was the main factor. The degradation process of 5-FU in patients' whole blood in vitro was consistent with it after mixing 5-FU with blank whole blood matrix. In conclusion, mixing 5-FU with blank matrix can simulate the process of 5-FU degradation with DPD.


Assuntos
Antimetabólitos Antineoplásicos/metabolismo , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Fluoruracila/metabolismo , Humanos , Cinética , Piridinas
4.
Trends Microbiol ; 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33342606

RESUMO

Toxin/antitoxin (TA) systems are present in nearly all bacterial and archaeal strains and consist of a toxin that reduces growth and an antitoxin that masks toxin activity. Currently there are six primary classes for TA systems based on the nature of the antitoxin and the way that the antitoxin inactivates the toxin. Here we show that there now are at least three additional and distinct TA systems in which the antitoxin is an enzyme and the cognate toxin is the direct target of the antitoxin: Hha/TomB (antitoxin oxidizes Cys18 of the toxin), TglT/TakA (antitoxin phosphorylates Ser78 of the toxin), and HepT/MntA (antitoxin adds three AMPs to Tyr104 of the toxin). Thus, we suggest the type VII TA system should be used to designate those TA systems in which the enzyme antitoxin chemically modifies the toxin post-translationally to neutralize it. Defining the type VII TA system using this specific criterion will aid researchers in classifying newly discovered TA systems as well as refine the framework for recognizing the diverse biochemical functions in TA systems.

5.
Complement Ther Med ; 55: 102583, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33220623

RESUMO

AIMS: The effect of DHEA supplementation on fasting plasma glucose (FPG), insulin levels (IN) and the homeostasis model assessment-estimated insulin resistance (HOMA-IR) index in humans has not been assessed so far. Thus, we aimed to conduct a systematic review and meta-analysis of the randomized controlled trials (RCT) which assessed the effects of DHEA supplementation on FPG, IN and the HOMA-IR index in humans. METHODS: An extensive search was performed in Scopus, PubMed/MEDLINE, and Web of Science from inception to June 2020. Data was combined using the random effects model. RESULTS: 14 publications were included in this study. Overall results demonstrated that FPG was significantly altered after DHEA consumption (WMD: -2.185 mg/dl, P = 0.029). DHEA administration did not result in any significant changes in IN (WMD: 0.057 µU/mL, P = 0.067), and the HOMA - IR index (WMD: 0.174, P = 0.060). In the subgroup analyses, FPG significantly decreased in the subgroup who received DHEA supplementation in dosages of ≤50 mg/day (WMD: -2.29 mg/dl), when the treatment duration was <12 weeks (WMD: -5.25 mg/dl), and in subjects aged ≥60 years (WMD: -2.94 mg/dl). CONCLUSION: This systematic review evaluated the association between FPG and DHEA, revealing that the administration of DHEA reduces FPG levels. However, we found no association between DHEA administration and IN levels or insulin resistance.

6.
Inquiry ; 57: 46958020968777, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33124506

RESUMO

In this pilot, single-blind, randomized controlled trial, we investigated the effects of intensified oral hygiene care (IOHC) on reducing stroke-associated pneumonia (SAP) incidence. Patients admitted within 24 hours of stroke onset were recruited and randomized to receive IOHC or routine oral hygiene care. The occurrence of SAP was checked and oral swabs were obtained during the 7-day follow-up. The SAP incidence was lower, though not significantly, in the IOHC group than in the control group. IOHC successfully decreased SAP incidence among patients who were male, had higher National Institutes of Health Stroke Scale and Debris Index scores, and lower Glasgow Coma Scale and Gugging Swallowing Screen scores. Furthermore, IOHC significantly decreased the prevalence of oral suspected SAP pathogens. These results suggest that IOHC can decrease the incidence of SAP in the most vulnerable patient groups and lower the prevalence of suspected oral SAP pathogens.

7.
Phytother Res ; 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33118665

RESUMO

The rhizome of Belamcanda chinensis possesses antiinflammatory and antioxidant activities. However, the effect of irigenin, isolated from the rhizome of B. chinensis, on 1-methyl-4-phenylpyridinium (MPP+ )-induced neurotoxicity is unknown. MTT assay showed that MPP+ exposure dose dependently inhibited the viability of mouse microglia BV-2 cells, whereas irigenin suppressed MPP+ -induced viability reduction. The production of nitric oxide, prostaglandin E2, tumor necrosis factor-α and interleukin-6 were increased by MPP+ treatment, which were abolished by irigenin treatment. Irigenin-attenuated MPP+ -induced increase of malondialdehyde content and activities of superoxide dismutase, catalase and glutathione peroxidase in BV-2 cells. Irigenin treatment also repressed apoptosis, caspase-3/7 activity and Cytochrome C expression in MPP+ -challenged BV-2 cells. Interestingly, irigenin activated the Keap1/Nrf2 pathway in MPP+ -induced BV-2 cells. Nrf2 knockdown attenuated the effects of irigenin on MPP+ -induced viability reduction, inflammation, oxidative stress and apoptosis in BV-2 cells. In conclusion, irigenin alleviated MPP+ -induced neurotoxicity in BV-2 cells through regulating the Keap1/Nrf2 pathway.

9.
Nat Commun ; 11(1): 5092, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037193

RESUMO

The combination of inorganic semiconductors with organic thin films promises new strategies for the realization of complex hybrid optoelectronic devices. Oxidative chemical vapor deposition (oCVD) of conductive polymers offers a flexible and scalable path towards high-quality three-dimensional inorganic/organic optoelectronic structures. Here, hole-conductive poly(3,4-ethylenedioxythiophene) (PEDOT) grown by oxidative chemical vapor deposition is used to fabricate transparent and conformal wrap-around p-type contacts on three-dimensional microLEDs with large aspect ratios, a yet unsolved challenge in three-dimensional gallium nitride technology. The electrical characteristics of two-dimensional reference structures confirm the quasi-metallic state of the polymer, show high rectification ratios, and exhibit excellent thermal and temporal stability. We analyze the electroluminescence from a three-dimensional hybrid microrod/polymer LED array and demonstrate its improved optical properties compared with a purely inorganic microrod LED. The findings highlight a way towards the fabrication of hybrid three-dimensional optoelectronics on the sub-micron scale.

10.
Plant Cell Physiol ; 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33067639

RESUMO

Tiller angle is a key factor determining rice plant architecture, planting density, light interception, photosynthetic efficiency, disease resistance, and grain yield. However, the mechanisms underlying tiller angle control are far from clear. In this study, we identified a mutant, termed bta1-1, with an enlarged tiller angle throughout its life cycle. A detailed analysis reveals that BTA1 has multiple functions because tiller angle, shoot gravitropism, and tolerance to drought stress are changed in bta1-1 plants. Moreover, BTA1 is a positive regulator of shoot gravitropism in rice. Shoot responses to gravistimulation are disrupted in bta1-1 under both light and dark conditions. Gene cloning reveals that bta1-1 is a novel mutant allele of LA1 renamed la1-SN. LA1 is able to rescue the tiller angle and shoot gravitropism defects observed in la1-SN. The nuclear localization signal of LA1 is disrupted by la1-SN, causing changes of its subcellular localization. LA1 is required to regulate the expression of auxin transporters and signaling factors that control shoot gravitropism and tiller angle. High-throughput mRNA sequencing is performed to elucidate the molecular and cellular functions of LA1. The results show that LA1 may be involved in the nucleosome and chromatin assembly, and protein-DNA interactions to control gene expression, shoot gravitropism, and tiller angle. Our results provide new insight into the mechanisms whereby LA1 controls shoot gravitropism and tiller angle in rice.

11.
Nucleic Acids Res ; 48(19): 11054-11067, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33045733

RESUMO

The two-gene module HEPN/MNT is predicted to be the most abundant toxin/antitoxin (TA) system in prokaryotes. However, its physiological function and neutralization mechanism remains obscure. Here, we discovered that the MntA antitoxin (MNT-domain protein) acts as an adenylyltransferase and chemically modifies the HepT toxin (HEPN-domain protein) to block its toxicity as an RNase. Biochemical and structural studies revealed that MntA mediates the transfer of three AMPs to a tyrosine residue next to the RNase domain of HepT in Shewanella oneidensis. Furthermore, in vitro enzymatic assays showed that the three AMPs are transferred to HepT by MntA consecutively with ATP serving as the substrate, and this polyadenylylation is crucial for reducing HepT toxicity. Additionally, the GSX10DXD motif, which is conserved among MntA proteins, is the key active motif for polyadenylylating and neutralizing HepT. Thus, HepT/MntA represents a new type of TA system, and the polyadenylylation-dependent TA neutralization mechanism is prevalent in bacteria and archaea.


Assuntos
Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Shewanella/metabolismo , Sistemas Toxina-Antitoxina
12.
Eur J Clin Pharmacol ; 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32875388

RESUMO

AIMS: The efficacy and toxicity of polymyxin B (PB) are closely related to its pharmacokinetic/pharmacodynamic (PK/PD) index area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) ratio. The purpose of this study was to obtain PK data for PB in Chinese severe pneumonia patients and establish appropriate blood sampling time points for the PB therapeutic drug monitoring (TDM). SUBJECT AND METHOD: After treatment with at least four doses of PB (50 IU, q12h), the blood samples were collected immediately after the end of infusion (C0) and 1.5, 2, 4, 6, 8, and 12 h (C1.5, C2, C4, C6, C8, C12) after PB administration. The PB blood plasma concentrations were determined using an ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). All 42 patients were randomly divided into modeling (n = 24) and validation (n = 18) groups. The relationship between AUCss,24h and PB plasma concentration at each time point in modeling group was analyzed using limited sampling strategy and a PK method based on one-compartment with correction model. RESULTS: C6 scheme was found to provide the most accurate prediction of AUCss,24h values (r2 = 0.984) with the target value of 1.9-4.2 µg/ml at steady state to reach the 50-100 µg h/ml criteria of AUCss,24h. C0 with target value of 1.0-2.8 µg/ml can be considered an alternative sampling scheme (r2 = 0.900) but prediction deviation may exist. C0 and Cmax sampling scheme also demonstrated good predicting ability of AUC values using PK model. CONCLUSION: This study provides a clear plan for the implementation of TDM of PB, which is useful for optimizing the dosing regimen and individualizing treatment in severe pneumonia patients.

13.
Medicine (Baltimore) ; 99(36): e21974, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899036

RESUMO

The present study attempted to analyze the clinical characteristics and pathogenesis of Kawasaki disease (KD) in children with hyperbilirubinemia.A total of 390 children with KD hospitalized in our hospital from September 2018 to July 2019 were selected and divided into control (270 cases) and hyperbilirubinemia (120 cases) groups based on the total, direct, and indirect bilirubin values after admission. Clinical data of the inflammatory index and fever process of the 2 groups were analyzed and compared.The difference in sex and age between the 2 groups was statistically nonsignificant (P > .05). In the hyperbilirubinemia group, the white blood cell count, C-reactive protein, hemoglobin, platelet count, erythrocyte sedimentation rate, alanine aminotransferase, aspartate aminotransferase, albumin, and routine urine leucocyte; and incidence of coronary artery expansion, heart injury, and unreactive gamma globulin treatment were higher than those in the control group and the differences were statistically significant (P < .05). In the hyperbilirubinemia group, the mean fever duration before admission was shorter than that in the control group, whereas the fever duration after gamma globulin treatment was longer than that in the control group; these differences were statistically significant (P < .05).Hyperbilirubinemia incidence in children with KD was approximately 30.77% (120 cases), of which increased direct bilirubin was observed in 70.83% (85 cases) and increased indirect bilirubin in 29.17% (35 cases). Children with KD combined with hyperbilirubinemia exhibited a strong inflammatory reaction, which may be due to liver damage or biliary block.


Assuntos
Hiperbilirrubinemia/complicações , Síndrome de Linfonodos Mucocutâneos/etiologia , Estudos de Casos e Controles , Pré-Escolar , Feminino , Humanos , Masculino
14.
Commun Biol ; 3(1): 527, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968175

RESUMO

Fungal-bacterial associations are present in nature, playing important roles in ecological, evolutionary and medicinal processes. Here we report a fungus-bacterial symbiont from marine sediment. The bacterium lives inside the fungal mycelium yet is robust enough to survive independent of its host; the independently grown bacterium can infect the fungal host in vitro and continue to grow progenitively. The bacterial symbiont modulates the fungal host to biosynthesize a polyketide antimicrobial, spiromarmycin. Spiromarmycin appears to endow upon the symbiont pair a protective/defensive means of warding off competitor organisms, be they prokaryotic or eukaryotic microorganisms. Genomic analyses revealed the spiromarmycin biosynthetic machinery to be encoded, not by the bacterium, but rather the fungal host. This unique fungal-bacterial symbiotic relationship and the molecule/s resulting from it dramatically expand our knowledge of marine microbial diversity and shed important insights into endosymbionts and fungal-bacterial relationships.

15.
Medicine (Baltimore) ; 99(34): e21900, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846854

RESUMO

BACKGROUND: Gene mutations with important prognostic roles have been identified in patients with myelodysplastic syndrome (MDS). Overall, it is not yet fully clear whether enhancer of zeste homolog 2 (EZH2) is affected and contributes to the disease in MDS patients. Thus, we performed a meta-analysis to investigate the effects of EZH2 mutations on the prognosis of patients with MDS. METHODS: We searched English-language databases (PubMed, Embase, and Cochrane Library) for studies published on the effects of EZH2 mutations in MDS patients. The study had to include at least 1 of the following indices as therapeutic evaluation data: overall survival (OS), transformation time to leukemia, and International Prognostic Scoring System risk. Revman, version 5.2 software was used for all statistical processing. We calculated the risk ratio and the 95% confidence interval (CI) of continuous variables, and determined the hazard ratio and 95% CI of time-to-event data. RESULTS: We included 5 studies with a total enrolment of 994 patients. There was a significant adverse effect on OS in the EZH2-mutation group compared to the unmutated group (hazard ratio = 2.47, 95% CI: 1.37-4.47, P < .00001), while the heterogeneity was relatively high (I = 68%). There was no significant correlation between EZH2 mutations and IPSS risk (low/int-1 vs int-2/high) (odds ratio: 0.69, 95% CI: 0.14-3.39, P = .65), with significant heterogeneity (I = 78%). The analysis did not show significant publication bias in the studies. CONCLUSION: This meta-analysis indicated an adverse effect of EZH2 mutations with regard to OS in patients with MDS. However, larger cohort trials are still needed to better understand the prognostic impacts of EZH2 mutations on MDS patients.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/patologia , Razão de Chances , Prognóstico , Análise de Sobrevida , Adulto Jovem
16.
Int J Mol Sci ; 21(16)2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32824274

RESUMO

Polycomb repressive complex 1 (PRC1) and PRC2 are the major complexes composed of polycomb-group (PcG) proteins in plants. PRC2 catalyzes trimethylation of lysine 27 on histone 3 to silence target genes. Like Heterochromatin Protein 1/Terminal Flower 2 (LHP1/TFL2) recognizes and binds to H3K27me3 generated by PRC2 activities and enrolls PRC1 complex to further silence the chromatin through depositing monoubiquitylation of lysine 119 on H2A. Mutations in PcG genes display diverse developmental defects during shoot apical meristem (SAM) maintenance and differentiation, seed development and germination, floral transition, and so on so forth. PcG proteins play essential roles in regulating plant development through repressing gene expression. In this review, we are focusing on recent discovery about the regulatory roles of PcG proteins in SAM maintenance, root development, embryo development to seedling phase transition, and vegetative to reproductive phase transition.

17.
Onco Targets Ther ; 13: 7665-7681, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821125

RESUMO

Objective: To investigate the characteristics of hematological malignancies in patients with the SET-CAN fusion gene and provide a literature review. Methods: We retrospectively analyzed the clinical data of three cases of acute leukemia and myeloid neoplasms harboring the SET-CAN fusion gene who were treated at our hospital. Their clinical manifestations, pathological results and treatment strategies were investigated. Results: The three cases were diagnosed with T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML) and myeloid sarcoma (MS), respectively. Karyotype analyses identified a normal result in all three patients. Subsequently, we confirmed del(9q34) utilizing FISH analysis. Mutation of the BRAF gene was detected in case 1, while mutations in PHF6 and BCOR were detected in case 2, which have not been officially reported in patients with SET-CAN fusions. Finally, relevant literature focusing on adult patients with hematological malignancies harboring the SET-CAN fusion gene were summarized. Conclusion: Adult patients with the SET-CAN fusion gene were rare among cases of hematological malignancies. There was a large degree of heterogeneity between different patients. Notably, some patients remained sensitive to chemotherapy. Overall prognosis may be related to the type of disease and other cytogenetic abnormalities. Systemic cytogenetic and molecular studies are needed to make accurate diagnoses. Additional cases need to be accumulated and summarized to better understand these diseases.

19.
Adv Mater ; 32(44): e2002559, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32715511

RESUMO

Porous materials possessing high surface area, large pore volume, tunable pore structure, superior tailorability, and dimensional effect have been widely applied as components of lithium-oxygen (Li-O2 ) batteries. Herein, the theoretical foundation of the porous materials applied in Li-O2 batteries is provided, based on the present understanding of the battery mechanism and the challenges and advantageous qualities of porous materials. Furthermore, recent progress in porous materials applied as the cathode, anode, separator, and electrolyte in Li-O2 batteries is summarized, together with corresponding approaches to address the critical issues that remain at present. Particular emphasis is placed on the importance of the correlation between the function-orientated design of porous materials and key challenges of Li-O2 batteries in accelerating oxygen reduction reaction (ORR)/oxygen evolution reaction (OER) kinetics, improving the electrode stability, controlling lithium deposition, suppressing the shuttle effect of the dissolved redox mediators, and alleviating electrolyte decomposition. Finally, the rational design and innovative directions of porous materials are provided for their development and application in Li-O2 battery systems.

20.
Int Immunopharmacol ; 86: 106741, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32650294

RESUMO

BACKGROUND: Berberine has been established as a potential drug for inflammation and metabolic disorder. Here, we aimed to explore the effects and the underlying mechanisms of berberine on obesity-induced chronic inflammation. METHODS: Mice were fed with high-fat diet to induce obesity. Inflammation in adipocytes were induced with treatment of free fatty acids. The expression of IL-4, CD206, ARG1 and other markers were used to identify M1 and M2 polarization. The expression of GPR78 and CHOP were used to evaluate endoplasmic reticulum stress. H&E staining was used to reveal the adipose tissue macrophage and adipocytes enlargement. RESULTS: Berberine treatment attenuated endoplasmic reticulum stress and inflammation in obese mice and free fatty acids-treated adipocytes. Overexpression of lncRNA Gomafu partially blocked the protective effects of berberine in free fatty acids-treated adipocytes by increasing endoplasmic reticulum stress. Moreover, Gomafu overexpression partly reversed berberine-induced enhancement of M2 polarization in macrophages. Finally, Gomafu overexpression induced ER stress and inflammation in mice, which were improved by berberine administration. CONCLUSIONS: Berberine improves obesity-induced chronic inflammation by alleviating endoplasmic reticulum stress and consequently promoting macrophage M2 polarization. And these protective effects were mediated at least partly by the suppression of lncRNA Gomafu.

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