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PURPOSE: Colorectal cancer (CRC) is one of the top five cancer-related causes of mortality globally. Acquired resistance has hindered the effectiveness of 5-fluorouracil (5-FU), the main chemotherapeutic drug used to treat CRC. Sphingosine kinase 2 (SphK2) may be a cancer treatment target and involved in 5-FU resistance. METHODS: Cell growth was examined using MTT and clone formation assays for SphK2 expression. To identify immune cells in mice, flow cytometry was performed. West blotting demonstrated alterations in cell division and inflammation-related proteins. SphK2 levels and inflammation-related variables were studied using Elisa. RESULTS: Due to SphK2 overexpression, immunosuppression, and 5-FU resistance are caused by the development of myeloid-derived suppressor cells (MDSCs) subsequent to IL-6/STAT3 activation and alterations in the arginase (ARG-1) protein. After therapy, the combination of SphK2 inhibitors and 5-FU can effectively suppress MDSCs while increasing CD4+ and CD8+ T cell infiltration into the tumor microenvironment, lowering tumor burden, and exhibiting a therapeutic impact on CRC. CONCLUSIONS: Our findings suggest that 5-FU treatment combined with simultaneous Spkh2 inhibition by ABC294640 has anti-tumor synergistic effects by influencing multiple effects on tumor cells, T cells, and MDSCs, potentially improving the poor prognosis of colorectal cancer patients.
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Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Fluoruracila , Células Supressoras Mieloides , Fosfotransferases (Aceptor do Grupo Álcool) , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Animais , Camundongos , Humanos , Linhagem Celular Tumoral , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Current hemostatic materials have many shortcomings, such as biotoxicity or poor degradability, and do not effectively promote wound healing after hemostasis. To address these limitations, a hemostasis-promoting wound-healing hydrogel, polyglutamic acid/polyethyleneimine/montmorillonite (PPM), comprising polyglutamic acid, 3,4-dihydroxybenzaldehyde-modified polyethyleneimine, and amino-modified montmorillonite (montmorillonite-NH2) was constructed in this study. Due to the excellent water absorption abilities of γ-polyglutamic acid, the PPM and polyglutamic acid/polyethyleneimine hydrogels could rapidly absorb the blood and tissue fluid exuded from the wound to keep the wound clean and accelerate the blood coagulation. The homogeneous distribution of montmorillonite-NH2 enhanced not only the mechanical properties of the hydrogel but also its hemostatic properties. In addition, the modification of polyethylenimine with 3,4-dihydroxybenzaldehyde provided anti-inflammatory effects and endorsed the wound healing. Cellular and blood safety experiments demonstrated the biocompatibility of the PPM hydrogel, and animal studies demonstrated that the PPM hydrogel effectively stopped bleeding and promoted wound healing. The concept design of clay-based hydrogel may create diverse opportunities for constructing hemostasis and wound-healing dressings.
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INTRODUCTION: Antimicrobial peptides (AMPs) are polypeptides with potent antimicrobial activity against a broad range of pathogenic microorganisms. Unlike conventional antibiotics, AMPs have rapid bactericidal activity, a low capacity for inducing resistance, and compatibility with the host immune system. A large body of data supports the antimicrobial activities of a large body of data supports the antimicrobial activities of the class of AMPs known as ß-defensins. This review provides a comprehensive analysis of the effects of ß-defensins against various pathogenic microorganism: bacteria, fungi, viruses, Mycoplasmas and Chlamydiae. The primary mechanisms of ß-defensins against pathogenic microorganisms include inhibition of biofilms formations, dissolution of membranes, disruption of cell walls, and inhibition of adhesion and receptor binding. Although further study and structural modifications are needed, ß-defensins are promising candidates for antimicrobial therapy. AREAS COVERED: This review describes the inhibitory effects of ß-defensins on various pathogenic microorganisms. Additionally, we focus on elucidating the mechanisms underlying their actions to provide, providing valuable references for the further study of ß-defensins. EXPERT OPINION: The biological activities and modes of action of ß-defensins provide powerful resources for clinical microbial infection management. Addressing the salt sensitivity and toxicity of ß-defensins may further enhance their potential applications.
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BACKGROUND: We sought to evaluate renal stiffness in children with hematuria and/or proteinuria using shear wave elastography (SWE) and to investigate the clinical value of renal stiffness in children with hematuria and/or proteinuria. METHODS: According to the results of urinary occult blood and urinary protein tests, 349 pediatric patients were categorized into one of four groups: pure hematuria (HU), pure proteinuria (PU), concomitant hematuria and proteinuria (HUPU), or control (non-HUPU). Patient demographic data, laboratory test results, and renal ultrasound data were collected. RESULTS: There were significant differences in cortical/medullary elasticity among the four groups (the most sensitive cutoff value between HU and PU was 1.72) (P < 0.05). We found that hematuria and proteinuria interacted with renal cortical elasticity (P < 0.05) but that hematuria and proteinuria did not interact with renal medullary elasticity or cortical/medullary elasticity (P > 0.05). Renal elasticity values correlated with sex, age, body surface area, body mass index, qualitative urinary protein, urine N-acetyl-ß-D-glucosaminidase, 24-hour urinary protein quantity, renal volume, and renal cortical thickness (P < 0.05). CONCLUSIONS: SWE can be used to detect changes in renal stiffness in children with hematuria and/or proteinuria. SWE is beneficial for the early detection of glomerular disease in children with abnormal urine test results. IMPACT: This study evaluated the utility of shear wave elastography for the assessment of renal elasticity in pediatric patients presenting with hematuria and/or proteinuria. Children with pure proteinuria had significantly higher renal cortical/medullary elasticity values than those with pure hematuria. An interaction effect between hematuria and proteinuria on renal cortical stiffness was observed. Shear wave elastography can be used as a tool to assess early renal injury in children with urinalysis abnormalities.
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A Gram-stain-negative, aerobic, non-motile, catalase- and oxidase-positive, pale orange, rod-shaped strain EF6T, was isolated from a natural wetland reserve in Hebei province, China. The strain grew at 25-37 °C (optimum, 30 °C), pH 5-9 (optimum, pH 7), and in the presence of 1.0-4.0% (w/v) NaCl (optimum, 2%). A phylogenetic analysis based on 16S rRNA gene sequence revealed that strain EF6T belongs to the genus Paracoccus, and the closest members were Paracoccus shandongensis wg2T with 98.1% similarity, Paracoccus fontiphilus MVW-1 T (97.9%), Paracoccus everestensis S8-55 T (97.7%), Paracoccus subflavus GY0581T (97.6%), Paracoccus sediminis CMB17T (97.3%), Paracoccus caeni MJ17T (97.0%), and Paracoccus angustae E6T (97.0%). The genome size of strain EF6T was 4.88 Mb, and the DNA G + C content was 65.3%. The digital DNA-DNA hybridization, average nucleotide identity, and average amino acid identity values between strain EF6T and the reference strains were all below the threshold limit for species delineation (< 32.8%, < 88.0%, and < 86.7%, respectively). The major fatty acids (≥ 5.0%) were summed feature 8 (86.3%, C18:1 ω6c and/or C18:1 ω7c) and C18:1 (5.0%) and the only isoprenoid quinone was Q-10. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, two unidentified glycolipids, five unidentified phospholipids, and an unidentified aminolipid. Strain EF6T displays notable resistance to benzoate and selenite, with higher tolerance levels (25 g/L for benzoate and 150 mM for selenite) compared to the closely related species. Genomic analysis identified six benzoate resistance genes (acdA, pcaF, fadA, pcaC, purB, and catA) and twenty selenite resistance and reduction-related genes (iscR, ssuB, ssuD, selA, selD and so on). Additionally, EF6T possesses unique genes (catA, ssuB, and ssuC) absent in the closely related species for benzoate and selenite resistance. Its robust resistance to benzoate and selenite, coupled with its genomic makeup, make EF6T a promising candidate for the remediation of both organic and inorganic pollutants. It is worth noting that the specific resistance phenotypes described above were not reported in other novel species in Paracoccus. Based on the results of biochemical, physiological, phylogenetic, and chemotaxonomic analyses, combined with comparisons of the 16S rRNA gene sequence and the whole genome sequence, strain EF6T is considered to represent a novel species of the genus Paracoccus within the family Rhodobacteraceae, for which the name Paracoccus benzoatiresistens sp. nov. is proposed. The type strain is EF6T (= GDMCC 1.3400 T = JCM 35642 T = MCCC 1K08702T).
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Composição de Bases , DNA Bacteriano , Ácidos Graxos , Paracoccus , Filogenia , RNA Ribossômico 16S , Áreas Alagadas , Paracoccus/genética , Paracoccus/classificação , Paracoccus/isolamento & purificação , Paracoccus/metabolismo , Paracoccus/efeitos dos fármacos , RNA Ribossômico 16S/genética , Ácidos Graxos/metabolismo , Ácidos Graxos/química , DNA Bacteriano/genética , China , Selenito de Sódio/metabolismo , Técnicas de Tipagem Bacteriana , Fosfolipídeos/análise , Análise de Sequência de DNA , Hibridização de Ácido Nucleico , Oxirredução , Farmacorresistência BacterianaRESUMO
Establishing a physical barrier between the peritoneum and the cecum is an effective method to reduce the risk of postoperative abdominal adhesions. Meloxicam (MX), a nonsteroidal anti-inflammatory drug has also been applied to prevent postoperative adhesions. However, its poor water solubility has led to low bioavailability. Herein, we developed an injectable hydrogel as a barrier and drug carrier for simultaneous postoperative adhesion prevention and treatment. A third-generation polyamide-amine dendrimer (G3) was exploited to dynamically combine with MX to increase the solubility and the bioavailability. The formed G3@MX was further used to crosslink with poly-γ-glutamic acid (γ-PGA) to prepare a hydrogel (GP@MX hydrogel) through the amide bonding. In vitro and in vivo experiments evidenced that the hydrogel had good biosafety and biodegradability. More importantly, the prepared hydrogel could control the release of MX, and the released MX is able to inhibit inflammatory responses and balance the fibrinolytic system in the injury tissues in vivo. The tunable rheological and mechanical properties (compressive moduli: from ⼠57.31 kPa to ⼠98.68 kPa;) and high anti-oxidant capacity (total free radical scavenging rate of ⼠94.56 %), in conjunction with their syringeability and biocompatibility, indicate possible opportunities for the development of advanced hydrogels for postoperative tissue adhesions management.
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Dendrímeros , Hidrogéis , Meloxicam , Nylons , Ácido Poliglutâmico , Hidrogéis/química , Hidrogéis/farmacologia , Animais , Ácido Poliglutâmico/química , Ácido Poliglutâmico/farmacologia , Ácido Poliglutâmico/análogos & derivados , Nylons/química , Aderências Teciduais/prevenção & controle , Dendrímeros/química , Dendrímeros/farmacologia , Meloxicam/química , Meloxicam/farmacologia , Meloxicam/administração & dosagem , Camundongos , Inflamação/prevenção & controle , Inflamação/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/administração & dosagem , Ratos , Ratos Sprague-Dawley , Fibrinólise/efeitos dos fármacos , Complicações Pós-Operatórias/prevenção & controle , Tamanho da Partícula , Injeções , Portadores de Fármacos/químicaRESUMO
OBJECTIVE: The association between obesity, metabolic dysregulation, and the aggressive pathological traits of papillary thyroid carcinoma (PTC) continues to be a contentious issue. To date, no investigations have examined the impact of metabolic status on the malignant pathological features of PTC in relation to obesity. METHODS: This research involved 855 adult patients with PTC from Shandong Provincial Hospital, classified into 4 groups based on metabolic and obesity status: metabolically healthy nonobese, metabolically unhealthy nonobese (MUNO), metabolically healthy obese, and metabolically unhealthy obese. We employed logistic regression to investigate the relationship between these metabolic obesity phenotypes and PTC's pathological characteristics. Mediation analysis was also performed to determine metabolic abnormalities' mediating role in the nexus between obesity and these characteristics. RESULTS: Relative to metabolically healthy nonobese individuals, the metabolically unhealthy obese group was significantly associated with an elevated risk of larger tumor sizes and a greater number of tumor foci in PTC. Mediation analysis indicated that obesity directly influences tumor size, whereas its effect on tumor multifocality is mediated through metabolic dysfunctions. Specifically, high-density lipoprotein cholesterol levels were notably associated with tumor multifocality within obese subjects, serving as a mediator in obesity's impact on this trait. CONCLUSION: The concurrent presence of obesity and metabolic dysregulation is often connected to more aggressive pathological features in PTC. The mediation analysis suggests obesity directly affects tumor size and indirectly influences tumor multifocality via low high-density lipoprotein cholesterol levels.
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Obesidade , Fenótipo , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/metabolismo , Adulto , Obesidade/metabolismo , Obesidade/complicações , Obesidade/patologia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/epidemiologia , IdosoRESUMO
Ferroptosis is a new form of cell death characterized by iron-dependent lipid peroxidation. Whether ferroptosis is involved in retinal microvascular dysfunction under diabetic condition is not known. Herein, the expression of ferroptosis-related genes in patients with proliferative diabetic retinopathy and in diabetic mice was determined with quantitative RT-PCR. Reactive oxygen species, iron content, lipid peroxidation products, and ferroptosis-associated proteins in the cultured human retinal microvascular endothelial cells (HRMECs) and in the retina of diabetic mice were examined. The association of ferroptosis with the functions of endothelial cells in vitro was evaluated. After administration of ferroptosis-specific inhibitor, Fer-1, the retinal microvasculature in diabetic mice was assessed. Characteristic changes of ferroptosis-associated markers, including glutathione peroxidase 4, ferritin heavy chain 1, long-chain acyl-CoA synthetase 4, transferrin receptor protein 1, and cyclooxygenase-2, were detected in the retinal fibrovascular membrane of patients with proliferative diabetic retinopathy, cultured HRMECs, and the retina of diabetic mice. Elevated levels of reactive oxygen species, lipid peroxidation, and iron content were found in the retina of diabetic mice and in cultured HRMECs. Ferroptosis was found to be associated with HRMEC dysfunction under high-glucose condition. Inhibition of ferroptosis with specific inhibitor Fer-1 in diabetic mice significantly reduced the severity of retinal microvasculopathy. Ferroptosis contributes to microvascular dysfunction in diabetic retinopathy, and inhibition of ferroptosis might be a promising strategy for the therapy of early-stage diabetic retinopathy.
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Retinopatia Diabética , Ferroptose , Espécies Reativas de Oxigênio , Retinopatia Diabética/patologia , Retinopatia Diabética/metabolismo , Animais , Humanos , Camundongos , Masculino , Espécies Reativas de Oxigênio/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Peroxidação de Lipídeos , Camundongos Endogâmicos C57BL , Microvasos/patologia , Microvasos/metabolismo , Ferro/metabolismo , Vasos Retinianos/metabolismo , Vasos Retinianos/patologiaRESUMO
Infertility is a major reproductive health problem. Approximately 50% of all documented cases of infertility are attributable to male factors, such as poor testicular function and semen quality. The recent significant global decline in sperm counts has serious implications for male fertility, but the armamentarium for improving testicular function and semen quality is limited. Natural products have a wide range of activities and are a major source of drugs for disease prevention and treatment. To provide ideas and a theoretical basis for the research and development of therapeutic drugs for male infertility, this review summarizes natural products (mostly monomers) that have been shown to improve testicular function and semen quality and their possible mechanisms of action. These natural products primarily improve testicular function and semen quality via antioxidant, antiapoptotic, and anti-inflammatory effects, in addition to increasing serum testosterone and reducing DNA damage in spermatozoa and testicular cells. Prospects for the application of natural products in the treatment of male infertility are discussed.
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Produtos Biológicos , Infertilidade Masculina , Masculino , Humanos , Infertilidade Masculina/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Testículo/efeitos dos fármacos , Testículo/metabolismo , Animais , Análise do Sêmen , Espermatozoides/efeitos dos fármacosRESUMO
Fungal infections due to Apiotrichum mycotoxinivorans are clinically rare. Here, we report a case of invasive blood and cerebrospinal fluid infection by Apiotrichum mycotoxinivorans in a girl with B-cell acute lymphoblastic leukemia. This is the first report of the isolation of Apiotrichum mycotoxinivorans from human cerebrospinal fluid. MRI features of meningitis caused by this fungus are presented. Three small isoquinoline alkaloids inhibited the growth of this rare fungus in vitro, providing a starting point for the application of natural products to treat this highly fatal fungal infection. Our case presentation confirms Apiotrichum mycotoxinivorans as a potential emerging pathogen in patients with hematological malignancy undergoing chemotherapy.
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Basidiomycota , Micoses , Trichosporon , Feminino , Humanos , Micoses/microbiologia , Líquido CefalorraquidianoRESUMO
BACKGROUND: The limited availability of antifungal drugs for candidiasis and the persistent problem of drug resistance, necessitates the urgent development of new antifungal drugs and alternative treatment options. RESEARCH DESIGN AND METHODS: This study examined the synergistic antifungal activity of the combination of eravacycline (ERV) and fluconazole (FLC) both in vitro by microdilution checkerboard assay and in vivo by Galleria mellonella model. The underlying synergistic mechanisms of this drug combination was investigated using RNA-sequencing and qPCR. RESULTS: ERV (2 µg/mL) + FLC (0.25-0.5 µg/mL) had strong synergistic antifungal activity against resistant Candida albicans (C. albicans) in vitro, as evidenced by a fractional inhibitory concentration index of 0.0044-0.0088. In vivo experiments in Galleria mellonella larvae infected with resistant C. albicans revealed that ERV (2 µg/larva) + FLC (1 µg/larva) improved survival rates and reduced fungal burden. The results of RNA-sequencing and qPCR showed that the mechanism of synergistic inhibition on resistant C. albicans was related to the inhibition of DNA replication and cell meiosis. CONCLUSIONS: These results indicate that the combination of ERV and FLC effectively inhibits resistant C. albicans both in vitro and in vivo and lay the foundation for a potential novel treatment option for candidiasis.
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Candidíase , Fluconazol , Humanos , Fluconazol/farmacologia , Candida albicans , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana , Farmacorresistência Fúngica , Candidíase/tratamento farmacológico , Candidíase/microbiologia , RNA/farmacologia , RNA/uso terapêuticoRESUMO
Icariin, a Chinese medicinal herb with significant effects on Alzheimer's disease, lacks pharmacokinetic data in mice. To address this, a UPLC-MS/MS method was developed and validated for quantifying Icariin and its metabolites, Icariside I and Icariside II, in the whole blood of mice. The method processed micro-whole blood from serial collections of the same C57 mouse, with well-fitted linearity (0.25-800 ng mL-1) and intra- and inter-day precision and accuracy within 15%. Short-time and autosampler stability were verified, with acceptable extraction recoveries and matrix effects over 74.55%. After intravenous administration (15 mg kg-1) of Icariin in C57 mice, Icariside I and Icariside II were detected within 2 min. However, after the intragastric administration (30, 90, and 150 mg kg-1) of Icariin in C57 mice, Icariin and Icariside I were not detected, and Icariin was rapidly converted into Icariside II. Furthermore, the Cmax and AUC0-t of three doses (30, 90, and 150 mg kg-1) of Icariside II increased as the dose increased. In conclusion, this method improves the traditional method of collecting only one blood sample from each mouse, detecting Icariin and its metabolites in the whole blood of mice, especially for serial collection of micro-whole blood.
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Objective: The global rise in the resistance of Candida albicans to conventional antifungals makes Candida albicans infections harder to treat. The main objective of this study was to investigate the antifungal effects and underlying mechanisms of leflunomide in combination with triazoles against resistant Candida albicans. Methods: In this study, the microdilution method was used to determine the antifungal effects of leflunomide in combination with three triazoles on planktonic cells in vitro. The morphological transition from yeast to hyphae was observed under a microscope. The effects on ROS, metacaspase, efflux pumps, and intracellular calcium concentration were investigated, respectively. Results: Our findings suggested that leflunomide + triazoles showed a synergistic effect against resistant Candida albicans in vitro. Further study concluded that the synergistic mechanisms were resulted from multiple factors, including the inhibited efflux of triazoles, the inhibition of yeast-to-hyphae transition, ROS increasing, metacaspase activation, and [Ca2+]i disturbance. Discussion: Leflunomide appears to be a potential enhancer of current antifungal agents for treating candidiasis caused by resistant Candida albicans. This study can also serve as an example to inspire the exploration of new approaches to treating resistant Candida albicans.
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BACKGROUND: Childhood asthma is a major global health concern. ADP-ribosylation factor 6 (ARF6) is a low-molecular-weight GTPase; however, its role in childhood asthma remains unclear. METHODS: Ovalbumin (OVA)-challenged neonatal mice and transforming growth factor-ß1 (TGF-ß1)-induced BEAS-2B cells were used as in vivo and in vitro models of childhood asthma, respectively. RESULTS: Upon OVA stimulation, ARF6 expression was upregulated in the lung tissue. Neonatal mice administered SehinH3 (an ARF6 inhibitor) exhibited improved pulmonary pathological injury, along with reduced inflammatory cell infiltration in the lungs and cytokine release in bronchial alveolar lavage fluid and serum (interleukin [IL]-3, IL-5, IL-13, IgE, and OVA-specific IgE). SehinH3 treatment restrained epithelial - mesenchymal transition (EMT) in the lungs of asthmatic mice, as evidenced by increased E-cadherin and decreased N-cadherin and α-smooth muscle actin expression. Different TGF-ß1 exposures to BEAS-2B cells induced a time- and dose-dependent increase in ARF6 expression in vitro. Upon TGF-ß1 stimulation, ARF6 knockdown repressed EMT and SehinH3 treatment caused similar results in BEAS-2B cells. The transcription factor E2F8 is involved in diverse biological functions and its increased expression was confirmed in vivo and in vitro. Dual-luciferase assays confirmed that E2F8 binds to the ARF6 promoter and promotes its transcriptional activity. In vitro results revealed that E2F8 silencing suppressed EMT, whereas rescue experiments showed that ARF6 overexpression partly reversed these phenomena. CONCLUSION: Our study showed that ARF6 is associated with childhood asthma progression and may be positively regulated by E2F8. These results provide insight into the pathogenesis and treatment of childhood asthma.
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Asma , Fator de Crescimento Transformador beta1 , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Ovalbumina , Fator 6 de Ribosilação do ADP , Transição Epitelial-Mesenquimal , Asma/metabolismo , Inflamação , Imunoglobulina E , Fatores de Transcrição E2F/metabolismo , Camundongos Endogâmicos BALB C , Modelos Animais de DoençasRESUMO
Understanding the formation mechanisms of the nanostructures and their designs has important implications for both the fundamental science and application prospects. In this study, we proposed a strategy for femtosecond laser-induced high regularity concentric rings within silicon microcavity. The morphology of the concentric rings can be flexibly modulated by the pre-fabricated structures and the laser parameters. The physics involved is deeply explored by the Finite-Difference-Time-Domain simulations, which reveals that the formation mechanism can be attributed to the near-field interference of the incident laser and the scattering light from the pre-fabricated structures. Our results provide a new method for creating the designable periodic surface structures.
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Rationale: Understanding the molecular mechanisms of deleterious cardiac remodeling is important for the development of treatments for heart failure. Recent studies have highlighted a role of deubiquitinating enzymes in cardiac pathophysiology. In the present study, we screened for alteration of deubiquitinating enzymes in experimental models of cardiac remodeling, which indicated a potential role of OTU Domain-Containing Protein 1 (OTUD1). Methods: Wide-type or OTUD1 knockout mice with chronic angiotensin II infusion and transverse aortic constriction (TAC) were utilized to develop cardiac remodeling and heart failure. We also overexpressed OTUD1 in mouse heart with AAV9 vector to validate the function of OTUD1. LC-MS/MS analysis combined with Co-IP was used to identify the interacting proteins and substrates of OTUD1. Results: We found that OTUD1 is elevated in mouse heart tissues following chronic angiotensin II administration. OTUD1 knockout mice were significantly protected against angiotensin II-induced cardiac dysfunction, hypertrophy, fibrosis and inflammatory response. Similar results were obtained in the TAC model. Mechanistically, OTUD1 bounds to the SH2 domain of STAT3 and causes deubiquitination of STAT3. Cysteine at position 320 of OTUD1 exerts K63 deubiquitination to promote STAT3 phosphorylation and nuclear translocation, thereby increasing STAT3 activity to induce inflammatory responses, fibrosis, and hypertrophy in cardiomyocytes. Finally, OTUD1 overexpression by AAV9 vector increases Ang II-induced cardiac remodeling in mice and OTUD1-regulated responses can be inhibited by blocking STAT3. Conclusion: Cardiomyocyte OTUD1 promotes pathological cardiac remodeling and dysfunction by deubiquitinating STAT3. These studies have highlighted a novel role of OTUD1 in hypertensive heart failure and identified STAT3 as a target of OTUD1 in mediating these actions.
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Insuficiência Cardíaca , Miócitos Cardíacos , Animais , Camundongos , Angiotensina II/farmacologia , Cromatografia Líquida , Enzimas Desubiquitinantes/metabolismo , Fibrose , Insuficiência Cardíaca/metabolismo , Hipertrofia/metabolismo , Hipertrofia/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Espectrometria de Massas em Tandem , Remodelação Ventricular/fisiologia , Fator de Transcrição STAT3RESUMO
Iron is an essential micronutrient for human biology and health, but high iron levels can be dangerous. Both iron deficiency and iron overload have been linked to reproductive health. This review summarizes the effects of iron deficiency and overload on omen of reproductive age (including pregnant women) and adult men. In addition, appropriate iron levels and the need for iron and nutritional supplements at different stages of life and pregnancy are discussed. In general, men should be aware of the risk of iron overload at any stage of life; women should take appropriate iron supplements before menopause; postmenopausal women should pay attention to the risk of iron overload; and pregnant women should receive reasonable iron supplementation in middle and late pregnancy. By summarizing evidence on the relationship between iron and reproductive health, this review aims to promote the development of strategies to optimize reproductive capacity from the perspective of nutrition. However, additional detailed experimental investigations and clinical studies are needed to assess the underlying causes and mechanisms of the observed associations between iron and reproductive health.
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Deficiências de Ferro , Sobrecarga de Ferro , Adulto , Gravidez , Feminino , Humanos , Gestantes , Reprodução , Ferro , Suplementos NutricionaisRESUMO
Ischemic stroke is one of the major causes of death and long-term disability worldwide. C-reactive protein (CRP) as a potential biomarker for functional outcome after acute ischemic stroke remains controversial. The aim of the present study was to examine the association between the level of CRP and functional outcome of stroke. A total of 218 consecutive patients with acute ischemic stroke within 24 h after onset were recruited for the study. Poor functional outcome was defined as a modified Rankin scale score of >2 at 3 months after stroke. The retrospective analysis was performed to investigate whether CRP within 24 h after stroke is associated with poor functional outcome at 3 months. Multivariate logistic regression analysis indicated that the CRP level (odds ratio=1.146, 95%CI: 1.012-1.297, P=0.031) was an independent risk factor for poor outcome. The receiver operating characteristics curve analysis revealed that the optimal cut-off value of CRP to distinguish favorable from poor outcome was 6.34 (area under the curve=0.829, 95%CI: 0.772-0.887, P<0.001), with 68.2% sensitivity and 85.7% specificity. Spearman correlation analysis indicated that the CRP level was positively related to the baseline National Institutes of Health Stroke Scale (NIHSS) score (r=0.551, P<0.001), fasting glucose (r=0.301, P<0.001) and age (r=0.252, P<0.001). In conclusion, a high level of CRP within 24 h after onset was associated with a poor functional outcome after the acute ischemic event. The elevation of CRP may be correlated with the baseline NIHSS score, fasting glucose and age.
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A yellow, Gram-stain-positive, strictly aerobic, thermotolerant, non-motile and rod-shaped bacterial strain, designated RY-1T, was isolated from a silt sample of Fuyang River, Wuqiang County, Hengshui City, Hebei Province, PR China. Cells showed oxidase- and catalase-positive activities. Growth occurred at 20-45 °C (optimum, 37 °C) and pH 6.0-8.0 (optimum, pH 7.0), and in the presence of 0-1.5â% (w/v) NaCl (optimum, 0%). A phylogenetic tree based on 16S rRNA gene sequences revealed that strain RY-1T formed a phylogenetic lineage with Flavihumibacter members within the family Chitinophagaceae. A comparison of 16S rRNA gene sequences showed that strain RY-1T was most closely related to Flavihumibacter cheonanensis WS16T (98.6â%), Flavihumibacter sediminis CJ663T (97.7â%) and Flavihumibacter solisilvae 3-3T (97.6â%). The genome size of strain RY-1T was 4.71 Mb, and the DNA G+C content was 44.3ââ%. The average nucleotide identity, digital DNA-DNA hybridization and average amino acid identity values between strain RY-1T and reference strains were all lower than the threshold values for species delineation. Strain RY-1T contained menaquinone-7 and iso-C15â:â0, iso-C17â:â0 3-OH and iso-C15â:â1G as the sole respiratory isoprenoid quinone and major cellular fatty acids (≥5â%), respectively. The major polar lipids consisted of phosphatidylethanolamine, three unidentified aminolipids and four unidentified lipids. According to the results of phenotypic, phylogenetic and chemotaxonomic characteristics, strain RY-1T represents a novel species of the genus Flavihumibacter, for which the name Flavihumibacter fluminis sp. nov. is proposed. The type strain is RY-1T (=GDMCC 1.2775T=JCM 34870T).
Assuntos
Bacteroidetes , Filogenia , Rios , Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano/genética , Ácidos Graxos/química , Rios/microbiologia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2/química , Bacteroidetes/classificação , Bacteroidetes/isolamento & purificação , ChinaRESUMO
Osthole (OST) is a simple coumarin derivative with pharmacological effects in many types of cancer cells. However, its role and its mechanism of action in breast cancer 4T1 cells remain unclear. In this study, we explored the effects and potential mechanisms of action of OST in 4T1 cells. The MTT, PI, and Annexin V-FITC/PI methods were used to evaluate the effects of OST-treated and untreated 4T1 cells on viability, cell cycle, and apoptosis, respectively. UPLC-Q-TOF/MS combined with multivariate data analysis was used to screen potential biomarkers relevant to the therapeutic mechanisms of OST. Additionally, mTOR, SREBP1, and FASN protein levels were detected using western blotting in OST-treated and untreated 4T1 cells. OST inhibited 4T1 cell proliferation, blocked the cells from remaining in S-phase, and induced apoptosis. In 4T1 cells, OST mainly affected the phospholipid biosynthesis, methyl histidine metabolism, pyrimidine metabolism, and ß-oxidation of very long chain fatty acid pathways, suggesting that metabolic changes related to lipid metabolism-mediated signaling systems were the most influential pathways, possibly via inhibition of mTOR/SREBP1/FASN signaling. Our findings reveal biomarkers with potential therapeutic effects in breast cancer and provide insight into the therapeutic and metabolic mechanisms of OST in 4T1 cells.