RESUMO
BACKGROUND: Although it is traditionally believed that ATP binding cassette subfamily C member 2 (ABCC2) is a multidrug resistance-associated protein correlated with a worse prognosis, our previous and several other studies demonstrated the contrary to be true in gastric cancer (GC). We aim to explore the underlying mechanism of this discovery. METHODS: Our study utilized whole-exome sequencing (WES), RNA sequencing, and droplet digital PCR (ddPCR) analysis of 80 gastric cancer samples, along with comprehensive immunohistochemical (IHC) analysis of 1044 human GC tissue samples.By utilizing CRISPRCas9 to genetically modify cell lines with the ABCC2-24C > T (rs717620) point mutation and conducting dual-luciferase reporter assays, we identified that transcription factors SOX9 and ETS1 serve as negative regulators of ABCC2 expression. Seahorse assay and mass spectrometry were used to discover altered metabolic patterns. Gain and loss-of-function experiments in GC cell lines and preclinical models were carried out to validate ABCC2 biological function. RESULTS: ABCC2 high expression correlated with better prognosis, and rs717620 can influence ABCC2 expression by disrupting the binding of ETS1 and SOX9. Gain and loss-of-function experiments in GC cell lines demonstrated amino acid deprivation reduces proliferation, migration, and drug resistance in ABCC2-high GC cells. ABCC2 leads to reduced intracellular amino acid pools and disruption of cellular energy metabolism. This phenomenon depended on ABCC2-mediated GSH extrusion, resulting in alterations in redox status, thereby increasing the cell's susceptibility to ferroptosis. Furthermore, patient-derived organoids and patient-derived tumor-like cell clusters were used to observe impact of ABCC2 on therapeutic effect. In the xenograft model with high ABCC2 expression, we observed that constricting amino acid intake in conjunction with GPX4 inactivation resulted in notable tumor regression. CONCLUSIONS: Our findings demonstrate a significant role of ABCC2 in amino acid metabolism and ferroptosis by mediating GSH efflux in GC. This discovery underlines the potential of combining multiple ferroptosis targets as a promising therapeutic strategy for GC with high ABCC2 expression. HIGHLIGHTS: ABCC2 plays a crucial role in inducing metabolic vulnerability and ferroptosis in gastric cancer through enhanced glutathione efflux. The ABCC2 24C > T polymorphism is a key factor influencing its expression. These results highlight the potential of ABCC2 as a predictive biomarker and therapeutic target in gastric cancer.
Assuntos
Ferroptose , Glutationa , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ferroptose/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Glutationa/metabolismo , Animais , Camundongos , Linhagem Celular Tumoral , Masculino , FemininoRESUMO
Acinetobacter baumannii (A. baumannii) poses a serious public health challenge due to its notorious antimicrobial resistance, particularly carbapenem-resistant A. baumannii (CRAB). In this study, we isolated a virulent phage, named P1068, from medical wastewater capable of lysing CRAB, primarily targeting the K3 capsule type. Basic characterization showed that P1068 infected the A. baumannii ZWAb014 with an optimal MOI of 1, experienced a latent period of ten minutes and maintained stability over a temperature range of 4 °C to 37 °C and pH range of 3-10. Phylogenetic and average nucleotide identity analyses indicate that P1068 can be classified as a novel species within the genus Obolenskvirus of the Caudoviricetes class as per the most recent virus classification released by the International Committee on Taxonomy of Viruses (ICTV). Additionally, according to classical morphological classification, P1068 is identified as a T4-like phage (Myoviridae). Interestingly, we found that the tail fibre protein (TFP) of P1068 shares 74% coverage and 88.99% identity with the TFP of a T7-like phage (Podoviridae), AbKT21phiIII (NC_048142.1). This finding suggests that the TFP gene of phages may undergo horizontal transfer across different genera and morphologies. In vitro antimicrobial assays showed that P1068 exhibited antimicrobial activity against A. baumannii in both biofilm and planktonic states. In mouse models of intraperitoneal infection, P1068 phage protected mice from A. baumannii infection and significantly reduced bacterial loads in various tissues such as the brain, blood, lung, spleen, and liver compared to controls. In conclusion, this study demonstrates that phage P1068 might be a potential candidate for the treatment of carbapenem-resistant and biofilm-forming A. baumannii infections, and expands the understanding of horizontal transfer of phage TFP genes.
RESUMO
Chemodynamic therapy (CDT) alone cannot achieve sufficient therapeutic effects due to the excessive glutathione (GSH) and hypoxia in the tumor microenvironment (TME). Developing a novel strategy to improve efficiency is urgently needed. Herein, we prepared a copper silicate nanoplatform (CSNP) derived from colloidal silica. The Cu(II) in CSNP can be reduced to Cu(I), which cascades to induce a subsequent CDT process. Additionally, benefiting from GSH depletion and oxygen (O2) generation under 660 nm laser irradiation, CSNP exhibits both Fenton-like and hypoxia-alleviating activities, contributing to the effective generation of superoxide anion radical (â¢O2-) and hydroxyl radical (â¢OH) in the TME. Furthermore, given the suitable band-gap characteristic and excellent photochemical properties, CSNP can also serve as an efficient type-I photosensitizer for photodynamic therapy (PDT). The synergistic CDT/PDT activity of CSNP presents an efficient antitumor effect and biosecurity in both in vitro and in vivo experiments. The development of an all-in-one nanoplatform that integrates Fenton-like and photosensing properties could improve ROS production within tumors. This study highlights the potential of silicate nanomaterials in cancer treatment.
RESUMO
Background: The green alga Chlamydomonas reinhardtii can grow photoautotrophically utilizing light and CO2, and heterotrophically utilizing acetate. The physiological and biochemical responses of autotrophy and heterotrophy are different in C. reinhardtii. However, there is no complete understanding of the molecular physiology between autotrophy and heterotrophy. Therefore, we performed biochemical, molecular and transcriptome analysis of C. reinhardtii between autotrophy and heterotrophy. Results: The cell growth characterization demonstrated that heterotrophic cell had enhanced growth rates, and autotrophic cell accumulated more chlorophyll. The transcriptome data showed that a total of 2,970 differentially expressed genes (DEGs) were identified from photoautotrophy 12h (P12h) to heterotrophy 12h (H12h). The DEGs were involved in photosynthesis, the tricarboxylic acid cycle (TCA), pyruvate and oxidative phosphorylation metabolisms. Moreover, the results of qRT-PCR revealed that the relative expression levels of malate dehydrogenase (MDH), succinate dehydrogenase (SDH), ATP synthase (ATPase), and starch synthase (SSS) were increased significantly from P12h and H12h. The protein activity of NAD-malate dehydrogenase (NAD-MDH) and succinate dehydrogenase (SDH) were significantly higher in the H12h group. Conclusion: The above results indicated that the high growth rate observed in heterotrophic cell may be the effects of environmental or genetic regulation of photosynthesis. Therefore, the identification of novel candidate genes in heterotrophy will contribute to the development of microalga strains with higher growth capacity and better performance for biomass production.
RESUMO
Biodiversity losses along with the exponential growth of global human population and human-provoked over-exploitation of natural resources. Genetic factors played an important role in the conservation of endangered species. Conservation genetics is a cross-field disciplinary of genetics and conservation biology. The course of conservation genetics is not available in colleges and universities, and the course of genetics does not directly reflect the content of biological conservation. We have taught genetics with integrative thoughts of conservation biology. In the form of case studies, we have integrated recent advances of research and technology in the relevant fields into the genetics classroom. As a result, we improved the undergraduates' motivation and interest in active learning, provoked the mutual promotion of "basic knowledge of genetics, awareness of ecological protection, and cultivate interdisciplinary thinking", and set up the groundwork for cultivating interdisciplinary talents who not only master solid basic knowledge, but also have the concept of ecological civilization.
Assuntos
Conservação dos Recursos Naturais , Genética , Conservação dos Recursos Naturais/métodos , Humanos , Genética/educação , Ensino , Biologia/educaçãoRESUMO
AIMS/HYPOTHESIS: The relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus, insulin resistance and the metabolic syndrome is well established. While zinc finger BED-type containing 3 (ZBED3) has been linked to type 2 diabetes mellitus and the metabolic syndrome, its role in MASLD remains unclear. In this study, we aimed to investigate the function of ZBED3 in the context of MASLD. METHODS: Expression levels of ZBED3 were assessed in individuals with MASLD, as well as in cellular and animal models of MASLD. In vitro and in vivo analyses were conducted using a cellular model of MASLD induced by NEFA and an animal model of MASLD induced by a high-fat diet (HFD), respectively, to investigate the role of ZBED3 in MASLD. ZBED3 expression was increased by lentiviral infection or tail-vein injection of adeno-associated virus. RNA-seq and bioinformatics analysis were employed to examine the pathways through which ZBED3 modulates lipid accumulation. Findings from these next-generation transcriptome sequencing studies indicated that ZBED3 controls SREBP1c (also known as SREBF1; a gene involved in fatty acid de novo synthesis); thus, co-immunoprecipitation and LC-MS/MS were utilised to investigate the molecular mechanisms by which ZBED3 regulates the sterol regulatory element binding protein 1c (SREBP1c). RESULTS: In this study, we found that ZBED3 was significantly upregulated in the liver of individuals with MASLD and in MASLD animal models. ZBED3 overexpression promoted NEFA-induced triglyceride accumulation in hepatocytes in vitro. Furthermore, the hepatocyte-specific overexpression of Zbed3 promoted hepatic steatosis. Conversely, the hepatocyte-specific knockout of Zbed3 resulted in resistance of HFD-induced hepatic steatosis. Mechanistically, ZBED3 interacts directly with polypyrimidine tract-binding protein 1 (PTBP1) and affects its binding to the SREBP1c mRNA precursor to regulate SREBP1c mRNA stability and alternative splicing. CONCLUSIONS/INTERPRETATION: This study indicates that ZBED3 promotes hepatic steatosis and serves as a critical regulator of the progression of MASLD. DATA AVAILABILITY: RNA-seq data have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231875 ). MS proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository ( https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041743 ).
RESUMO
BACKGROUND: Investigating the impact of race on the clinicopathologic characteristics and prognosis of hepatic malignant tumors represents a complex and significant area of research. Notably, distinct differences exist among various racial groups in terms of the clinical manifestations, pathologic features, and prognosis of hepatic malignant tumors. AIM: To explore the effect of race on clinicopathologic features and prognosis of hepatic malignancies. METHODS: Data from patients with hepatic malignancies diagnosed between 2000 and 2019 were collected from the Surveillance, Epidemiology, and End Results database and statistically analyzed. RESULTS: This study included 123558 patients with hepatic malignant tumors, among whom 21078 (17.06%) were Asian, 14810 (11.99%) were Black, and 87670 (70.95%) were white. The median survival times for patients with hepatic malignant tumors of different races were 12.56, 7.70, and 9.35 months for Asian patients, Black patients, and white patients, respectively. The 3-year survival rates for Asian, Black, and white patients were 29%, 19%, and 21%, respectively, and the 5-year survival rates were 22%, 13%, and 15%, respectively. The Kruskal-Wallis test indicated a significant difference in the survival time of patients with hepatic malignant tumors between different races (P < 0.001). Univariate analysis revealed gender disparities in the prognosis among different ethnic groups (Asian: P > 0.05; Black: P < 0.001; White: P < 0.05). Among Black patients, the prognosis was less affected by the degree of hepatic fibrosis than among Asian patients and white patients (Black patients: P < 0.05; Asian patients: P < 0.001; White patients: P < 0.001). Significant differences were observed in the median survival time among patients with hepatic neuroendocrine tumors and hepatoblastomas during pathologic staging between races. Tumor number was inversely related to the prognosis. Cox regression analyses revealed that T stage, M stage, surgery, chemotherapy, alpha-fetoprotein, and tumor size independently influenced prognosis. Age was a specific independent prognostic factor for white patients. Among the tumor stages, N stage is a self-reliant prognostic element specific to white patients. Conversely, radiotherapy and liver fibrosis were not self-reliant prognostic factors for Black patients. Income alone did not independently influence the prognosis of Asian patients. CONCLUSION: The prognosis of hepatic malignant tumors is better among Asian patients than among Black patients. The prognosis of hepatic malignant tumors among white patients is affected by multiple factors, including age and N stage.
RESUMO
BACKGROUND: The literature is replete with favorable face-lift results, yet the objective facial rejuvenation outcome measures in Chinese women have remained poorly understood. OBJECTIVE: The purpose of the study is to objectively evaluate the apparent age (AA) reduction in Chinese women following face-lift by artificial intelligence (AI) and objective observers. METHODS: Standardized pre- and postoperative (1-year) images of 48 patients undergoing face-lift procedures were analyzed by AI to estimate AA. Additionally, 10 blinded, naive observers viewed each patient's images and assessed AA. The accuracy of AA and reduction in AA were evaluated and compared between the two methods. FACE-Q surveys were employed to measure patient-reported facial esthetic outcomes. RESULTS: The AI demonstrated higher precision than the observers in age estimation, with a mean absolute error of 3.34 years and 90% Pearson correlation. AA reduction generated by AI was significantly lower than that by observers, with a mean reduction of 3.75 ± 3.93 and 4.51 ± 1.20, respectively (p < 0.05). However, both methods showed less AA reduction than patient self-appraisal (- 7.3 years). Improvements in facial rejuvenation following face-lift surgery is relevant to the patient's preoperative aging status. Patients whose pre-AA was greater than chronological age (CA) became "back to normal," while those whose pre-AA was less than CA became "turning back the clock." CONCLUSION: The utilization of AI could provide objective, evidence-based data in the field of face-lift surgery. As a simple, complete, and time-sparing method, AI is expected to be routinely used in clinical trials and practice. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
RESUMO
Objective: To explore the effect of clopidogrel combined with aspirin in the treatment of acute progressive cerebral infarction (APCI). Methods: We retrospectively analyzed the records of 190 patients with APCI admitted to Chengdu First People's Hospital from September 2020 to April 2023. The records were divided into an aspirin group (76 cases), a clopidogrel group (72 cases), and a clopidogrel plus aspirin group (42 cases) according to the treatment records. We compared the efficacy of the three treatment outcomes by analyzing the National Institutes of Health Stroke Scale (NIHSS) scores, and the levels of serum inflammatory factors (IL-8, TNF-α, and IL-1ß), cone like protein-1 (VILIP-1), and caveolin-1 (Cav-1). Results: The total efficacy of the combination group (97.62%) was significantly higher than those of the aspirin group (73.68%) or the clopidogrel group (79.17%) (p<0.05). After treatment, the NIHSS scores, inflammatory factor levels, serum VILIP-1 and Cav-1 levels were significantly lower than those before treatment in the three groups, but all the levels were significantly lower in the combination group (all p<0.05). Conclusions: Our results indicate that compared with aspirin alone or clopidogrel alone, the combination of aspirin and clopidogrel is more effective for the treatment of APCI. The combination regimen effectively lowers serum inflammatory factors (IL-8, TNF-α, and IL-1ß), as well as the VILIP-1 and Cav-1 levels.
RESUMO
Background: There is limited evidence regarding the correlation between prostate-specific antigen (PSA) kinetics and clinical outcomes. Therefore, after regulating other covariates, we studied patients with castration-resistant prostate cancer who received abiraterone acetate as the first-line treatment. In this study, we investigated whether time to PSA nadir was independently associated with PSA progression-free survival (PFS). Methods: As a retrospective cohort study, this study contained a total of 77 castration-resistant prostate cancer patients who received abiraterone acetate from October 2015 to April 2021 in a Chinese hospital. The dependent variable was PSA-PFS. The objective independent variable was time to PSA nadir (TTPN). Covariates involved in this study included age, duration of androgen deprivation therapy (ADT), PSA level at baseline, time of 50% PSA decline, time of PSA decline to nadir, Gleason score, bone metastasis, previous treatment, PSA decline <50% in 3 months, PSA to nadir in 3 months, PSA decline <90%, PSA decline <0.2 ng/mL, and PSA flare. Results: For the 77 subjects, their mean age was 72.70 ± 8.08 years. Fully calibrated linear regression findings indicated that PSA decline and kinetics were positively associated with PFS (months) after adjusting confounders (ß = 0.77, 95% CI: 0.11-1.44). A non-linear relationship was not detected between PSA decline or PSA kinetics and progression-free survival. Conclusion: According to the data of this study, there was a correlation between early PSA changes and patients treated with abiraterone acetate.
RESUMO
By introducing the d0 metal cation Mo6+ into phosphates, two new molybdophosphates, K2MgMoP2O10 and K3Mg2MoP3O14, were synthesized by spontaneous crystallization, and their structures were determined by single-crystal X-ray diffraction. K2MgMoP2O10 shows a two-dimensional layer composed of the uncommon eight-membered ring [Mo2P2O16] formed by [MoO6] and [PO4], while K3Mg2MoP3O14 shows isolated [MoP3O14] clusters composed of [MoO5] and [PO4]. K2MgMoP2O10 and K3Mg2MoP3O14 have UV cut-off wavelengths of 277 and 271 nm, respectively, which are significantly shorter than those of most recently published molybdophosphates. To the best of our acknowledge, K2MgMoP2O10 exhibits the largest birefringence (a calculated value of 0.187 at 546 nm) among reported alkali metal or alkaline earth metal molybdophosphates, which provides a way to explore new birefringent materials. First-principles analysis of the electronic structure shows that the large birefringence of K2MgMoP2O10 mainly originates from the [MoO6] units.
RESUMO
Background: Gout is a nutrition-related, highly prevalent inflammatory arthritis with undesirable effects on the quality of life. The relationships between circulating fatty acids (FAs) and gout remain poorly understood. Method: We included 268 174 participants with plasma FAs measured using nuclear magnetic resonance at the baseline (2006-2010) from the UK Biobank, of which 15 194 participants had repeated measures of FAs between 2012 and 2013. Cox proportional hazards models were used to assess the association of the baseline and longitudinal changes in relative levels of plasma FAs (% total FAs) with incident gout. Mendelian randomization (MR) analyses were conducted to assess the potential causality of the examined association. Results: Over a median follow-up of 12.8 years, 5160 incident cases of gout occurred. Baseline polyunsaturated fatty acids (PUFAs), n-6 PUFAs, and linoleic acids (LAs) were inversely associated with incident gout (all P-trend values < 0.0001). Baseline monounsaturated fatty acids (MUFAs), n-3 PUFAs, and docosahexaenoic acids (DHAs) were positively associated with incident gout (all P-trend values < 0.0001). Longitudinal increments of n-6 PUFAs and LAs were associated with a lower risk of subsequent gout, whereas an increment of n-3 PUFAs was associated with a higher risk. In two-sample MR analyses, genetically determined higher levels of PUFAs, n-6 PUFAs, and LAs were associated with a decreased risk of gout (all P values < 0.05). Conclusions: Our findings consistently indicate a causal relationship of elevated levels of n-6 PUFAs, especially LAs, with a reduced risk of gout.
Assuntos
Gota , Ácido Linoleico , Humanos , Gota/epidemiologia , Gota/sangue , Gota/genética , Masculino , Feminino , Pessoa de Meia-Idade , Fatores de Risco , Idoso , Ácido Linoleico/sangue , Adulto , Estudos de Coortes , Análise da Randomização Mendeliana , Reino Unido/epidemiologia , Ácidos Graxos Insaturados/sangueRESUMO
Eleven previously undescribed sesquiterpenoids (8-18), one undescribed jasmonic acid derivative (35) and 28 known compounds were isolated from the leaves of Artemisia stolonifera. Undescribed compounds with their absolute configurations were determined by extensive spectroscopic analysis, single-crystal X-ray diffraction and ECD calculation. Compound 8 was identified as a rare sesquiterpenoid featuring a rearranged 5/8 bicyclic ring system, whereas compound 17 was found to be an unprecedented monocyclic sesquiterpenoid with methyl rearrangement. Evaluation of biological activity showed that compounds 1-5 and 7 displayed cytotoxicity against six tumor cells. In the meantime, compounds 11, 12, 18 and 35 exhibited inhibitory effects against LPS-stimulated NO production in RAW 264.7 macrophage cells and reduced the transcription of IL-6 and IL-1ß in a dose-dependent manner at 25, 50 and 100 µM. Moreover, the anti-inflammatory-based network pharmacology and molecular docking analyses revealed potential target proteins of 11, 12, 18 and 35.
Assuntos
Anti-Inflamatórios , Artemisia , Ciclopentanos , Óxido Nítrico , Oxilipinas , Sesquiterpenos , Artemisia/química , Camundongos , Oxilipinas/farmacologia , Oxilipinas/química , Oxilipinas/isolamento & purificação , Animais , Células RAW 264.7 , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Sesquiterpenos/isolamento & purificação , Ciclopentanos/química , Ciclopentanos/farmacologia , Ciclopentanos/isolamento & purificação , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Estrutura Molecular , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Humanos , Relação Dose-Resposta a Droga , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Folhas de Planta/química , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Due to the chemical stability of graphene, synthesis of carboxylated graphene still remains challenging during the electrochemical exfoliation of graphite. In this work, a spatially confined radical addition reaction which occurs in the sub-nanometer scaled interlayers of the expanded graphene sheets for the electrochemical synthesis of highly stable carboxylated graphene is reported. Here, formate anions act as both intercalation ions and co-reactant acid for the confinement of electro-generated carboxylic radical (âCOOH) in the sub-nanometer scaled interlayers, which facilitates the radical addition reaction on graphene sheets. The controllable carboxylation of graphene is realized by tuning the concentration of formate anions in the electrolyte solution. The high crystallinity of the obtained product indicates the occurrence of spatially confined âCOOH addition reaction between the sub-nanometer interlayers of expanded graphite. In addition, the carboxylated graphene have been used for water desalination and hydrogen/oxygen reduction reaction. Therefore, this work provides a new method for the in situ preparation of functionalized graphene through the electrolysis and its applications in water desalination and hydrogen/oxygen reduction reactions.
RESUMO
Liver fibrosis is a key contributor to hepatic disease-related mortality. Exosomes derived from mesenchymal stem cells (MSCs) have been revealed to improve liver fibrosis. To explore the effect and mechanism of MSC-derived exosomal miR-26a on liver fibrosis, exosomes were separated from bone marrow-derived MSCs (BMSCs) and used to treat with LX2 cells. The miR-26a level was decreased in BMSC-derived exosomes. Treatment with exosomes isolated from human BMSCs transfected with miR-26a mimics (miR-26a mimic-Exo) decreased the 5-ethynyl-2'-deoxyuridine-positive cell rate, the protein level of α-SMA and collagen I, and the glutathione (GSH) level but enhanced the apoptosis rate and the reactive oxide species (ROS) level in LX2 cells, which were reversed by the treatment of deferoxamine. Mechanically, miR-26a directly bound SLC7A11 mRNA and negatively modulated the level of SLC7A11 in LX2 cells. Overexpression of SLC7A11 reversed the miR-26a mimic-Exo-induced alterations in the level of ROS, Fe2+, malonaldehyde, and GSH in LX2 cells. In vivo, miR-26a mimic-Exo decreased the level of SLC7A11 and attenuated CCL4-induced liver fibrosis. Collectively, miR-26a mimic-Exo induced ferroptosis to alleviate liver fibrosis by regulating SLC7A11, which may provide new strategies for the treatment of liver fibrosis, and even other relevant diseases.
RESUMO
Testosterone, an important sex hormone, regulates sexual maturation, testicular development, spermatogenesis and the maintenance of secondary sexual characteristics in males. Testicular Leydig cells are the primary source of testosterone production in the body. Hezuo pigs, native to the southern part of Gansu, China, are characterized by early sexual maturity, strong disease resistance and roughage tolerance. This study employed type IV collagenase digestion combined with cell sieve filtration to isolate and purify Leydig cells from the testicular tissue of 1-month-old Hezuo pigs. We also preliminarily investigated the functions of these cells. The results indicated that the purity of the isolated and purified Leydig cells was as high as 95%. Immunofluorescence analysis demonstrated that the isolated cells specifically expressed the 3ß-hydroxysteroid dehydrogenase antibody. Enzyme-linked immunosorbent assay results showed that the testosterone secretion of the Leydig cells cultured in vitro (generations 5-9) ranged between 1.29-1.67 ng/mL. Additionally, the content of the cellular autophagy signature protein microtubule-associated protein 1 light chain 3 was measured at 230-280 pg/mL. Through this study, we established an in vitro system for the isolation, purification and characterization of testicular Leydig cells from 1-month-old Hezuo pigs, providing a reference for exploring the molecular mechanism behind precocious puberty in Hezuo pigs.
Assuntos
Células Intersticiais do Testículo , Testosterona , Animais , Masculino , Células Intersticiais do Testículo/metabolismo , Testosterona/metabolismo , Suínos , Testículo/citologia , Células Cultivadas , Técnicas de Cultura de Células/veterinária , Separação Celular/métodos , Separação Celular/veterináriaRESUMO
BACKGROUND: The extent to which educational attainment (EA) influences the risk of varicose veins (VVs), venous thromboembolism (VTE), and phlebitis occurrence, whether this pathway is mediated by obesity-related traits, and the proportion of their mediation is unknown. METHODS: A Mendelian randomization (MR) design was used to genetically investigate the causal effects of EA on the risk of VV, VTE, and phlebitis and to assess the mediating effect of obesity-related traits. Causal effects were estimated using primarily the multiplicative random-effects inverse variance-weighted method. This was supplemented by Cochran's Q-statistic, MR-Egger regression, MR funnel plots, and leave-one-out test to evaluate the reliability of the results. For the individual mediation effect, the coefficient product method was mainly utilized to estimate. RESULTS: An increase in genetically predicted EA was associated with a lower risk of VV, VTE, and phlebitis, as well as lower body mass index, basal metabolic rate, hip circumference, and waist circumference. As genetically predicted body mass index, basal metabolic rate, hip circumference, and waist circumference increased, the risk of developing VV, VTE, and phlebitis increased, respectively. Body mass index, basal metabolic rate, hip circumference, and waist circumference were identified as mediators of the protective effects of EA on VV, VTE, and phlebitis. CONCLUSION: The findings support a causal relationship between higher EA and lower risk of VV, VTE, and phlebitis. Obesity-related traits play a significant mediating role in these pathways, and there are interactions between them, with hip circumference mediating these pathways relatively independently from the other three.
RESUMO
Ionic liquids have been widely used to improve the efficiency and stability of perovskite solar cells (PSCs), and are generally believed to passivate defects on the grain boundaries of perovskites. However, few studies have focused on the relevant effects of ionic liquids on intragrain defects in perovskites which have been shown to be critical for the performance of PSCs. In this work, the effect of ionic liquid 1-hexyl-3-methylimidazolium iodide (HMII) on intragrain defects of formamidinium lead iodide (FAPbI3) perovskite is investigated. Abundant {111}c intragrain planar defects in pure FAPbI3 grains are found to be significantly reduced by the addition of the ionic liquid HMII, shown by using ultra-low-dose selected area electron diffraction. As a result, longer charge carrier lifetimes, higher photoluminescence quantum yield, better charge carrier transport properties, lower Urbach energy, and current-voltage hysteresis are achieved, and the champion power conversion efficiency of 24.09% is demonstrated. These observations suggest that ionic liquids significantly improve device performance resulting from the elimination of {111}c intragrain planar defects.
RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Pueraria lobata (Willd.) Ohwi is a typical medicinal and edible plant with a long application history in China and Southeast Asia. As a widely used traditional medicine, P. lobata exhibits the properties of anti-inflammatory, antipyretic, antioxidant, relieving cough and asthma. Particularly, the increasing evidence indicates that the P. lobata has the therapeutic effect on fibrotic-related diseases in terms of metabolic regulation. However, the mechanisms of P. lobata on pulmonary fibrosis (PF) has not been thoroughly explored. AIM OF THE STUDY: This study aimed to explore the effect of arginine metabolites of P. lobata against PF model by integrating metabolomics and network pharmacology analysis. It might provide a new idea for the target finding of P. lobata anti-pulmonary fibrosis. MATERIALS AND METHODS: In this study, the Sprague Dawley (SD) rats were randomly divided into five experimental groups: saline-treated control group, bleomycin-induced fibrosis group, prednisolone acetate group, P. lobata 3.2 g/kg group and P. lobata 6.4 g/kg group. The therapeutic effect of P. lobata on bleomycin-induced PF in rats was evaluated by clinical symptoms such as lung function, body weight, hematoxylin eosin staining (HE), Masson staining and hydroxyproline assay. Next, the plasma metabolomics analysis was carried out by LC-MS to explore the pathological differences between the group of control, PF and P. lobata-treated rats. Then, the network pharmacology study coupled with experimental validation was conducted to analysis the results of metabolic research. We constructed the "component-target-disease" network of P. lobata in the treatment of PF. In addition, the molecular docking method was used to verify the interaction between potential active ingredients and core targets of P. lobata. Finally, we tested NOS2 and L-OT in arginine-related metabolic pathway in plasma of the rats by enzyme-linked immunosorbent assay (ELISA). Real-time PCR was performed to observe the level of TNF-α mRNA and MMP9 mRNA. And we tested the expression of TNF-α and MMP9 by Western blot analysis. RESULTS: Our findings revealed that P. lobata improved lung function and ameliorated the pathological symptoms, such as pathological damage, collagen deposition, and body weight loss in PF rats. Otherwise, the plasma metabolomics were employed to screen the differential metabolites of amino acids, lipids, flavonoids, arachidonic acid metabolites, glycoside, etc. Finally, we found that the arginine metabolism signaling mainly involved in the regulating of P. lobata on the treatment of PF rats. Furtherly, the network pharmacology predicted that the arginine metabolism pathway was contained in the top 20 pathways. Next, we integrated metabolomics and network pharmacology that identified NOS2, MMP9 and TNF-α as the P. lobata regulated hub genes by molecular docking. Importantly, it indicated a strong affinity between the puerarin and the NOS2. P. lobata attenuated TNF-α, MMP-9 and NOS2 levels, suppressed TNF-α and MMP-9 protein expression, and decreased L-OT and NOS2 content in PF rats. These results indicated that the effects of P. lobata may ameliorated PF via the arginine metabolism pathway in rats. Therefore, P. lobata may be a potential therapeutic agent to ameliorated PF. CONCLUSION: In this work, we used metabolomics and network pharmacology to explore the mechanisms of P. lobata in the treatment of PF. Finally, we confirmed that P. lobata alleviated BLM-induced PF in rats by regulating arginine metabolism pathway based on reducing the L-OT and NOS2-related signal molecular. The search for the biomarkers finding of arginine metabolism pathway revealed a new strategy for P. lobata in the treatment of PF.
Assuntos
Arginina , Metabolômica , Farmacologia em Rede , Pueraria , Fibrose Pulmonar , Ratos Sprague-Dawley , Animais , Pueraria/química , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/induzido quimicamente , Arginina/farmacologia , Masculino , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Bleomicina , Modelos Animais de Doenças , Metaloproteinase 9 da Matriz/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacosRESUMO
Layered materials with kagome lattice have attracted a lot of attention due to the presence of nontrivial topological bands and correlated electronic states with tunability. In this work, we investigate a unique van der Waals (vdW) material system,A2M3X4(A= K, Rb, Cs;M= Ni, Pd;X= S, Se), where transition metal kagome lattices, chalcogen honeycomb lattices and alkali metal triangular lattices coexist simultaneously. A notable feature of this material is that each Ni/Pd atom is positioned in the center of four chalcogen atoms, forming a local square-planar environment. This crystal field environment results in a low spin stateS= 0 of Ni2+/Pd2+. A systematic study of the crystal growth, crystal structure, magnetic and transport properties of two representative compounds, Rb2Ni3S4and Cs2Ni3Se4, has been carried out on powder and single crystal samples. Both compounds exhibit nonmagneticp-type semiconducting behavior, closely related to the particular chemical environment of Ni2+ions and the alkali metal intercalated vdW structure. Additionally, Cs2Ni3Se4undergoes an insulator-metal transition (IMT) in transport measurements under pressure up to 87.1 GPa without any structural phase transition, while Rb2Ni3S4shows the tendency to be metalized.