RESUMO
BACKGROUND: Adipose tissue affects not only the meat quality of domestic animals, but also human health. Adipocyte differentiation is regulated by a series of regulatory genes and cyclins. Four and half-LIM protein (FHL2) is positively correlated with the hypertrophy of adipocytes and can cause symptoms such as obesity and diabetes. RESULT: In the transcriptome sequencing analysis of intramuscular adipocytes after three days of differentiation, the differentially expressed gene FHL2 was found. To further explore the biological significance of the differentially expressed gene FHL2, which was downregulated in the mature adipocytes. We revealed the function of FHL2 in adipogenesis through the acquisition and loss of function of FHL2. The results showed that the overexpression of FHL2 significantly increased the expression of adipogenic genes (PPARγ, C/EBPß) and the differentiation of intramuscular and subcutaneous adipocytes. However, silencing FHL2 significantly inhibited adipocyte differentiation. The overexpression of FHL2 increased the number of adipocytes stained with crystal violet and increased the mRNA expression of proliferation marker genes such as CCNE, PCNA, CCND and CDK2. In addition, it significantly increased the rate of EdU positive cells. In terms of apoptosis, overexpression of FHL2 significantly inhibited the expression of P53 and BAX in both intramuscular and subcutaneous adipocytes, which are involved in cell apoptosis. However, overexpression of FHL2 promoted the expression of BCL, but was rescued by the silencing of FHL2. CONCLUSIONS: In summary, FHL2 may be a positive regulator of intramuscular and subcutaneous adipocyte differentiation and proliferation, and acts as a negative regulator of intramuscular and subcutaneous adipocyte apoptosis. These findings provide a theoretical basis for the subsequent elucidation of FHL2 in adipocytes.
Assuntos
Adipócitos , Adipogenia , Cabras , Proteínas com Homeodomínio LIM , Proteínas Musculares , Animais , Cabras/genética , Adipócitos/metabolismo , Adipócitos/citologia , Adipogenia/genética , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Apoptose/genética , Diferenciação Celular/genética , Proliferação de Células , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Gordura Subcutânea/metabolismo , Gordura Subcutânea/citologia , Perfilação da Expressão GênicaRESUMO
BACKGROUND: The effect of proprotein convertase subtilisin kexin type (PCSK9) inhibitors on blood lipids and major adverse cardiovascular events (MACEs) is still controversial for acute coronary syndrome (ACS) patients. This study aimed to evaluate the efficacy and safety of PCSK9 inhibitors for ACS patients. METHODS: We searched the following databases until March 2023: PubMed, Embase, Cochrane, Web of Science, CNKI, Chongqing VIP Database and Wan Fang Database. Finally, all randomized controlled trials, retrospective studies and prospective studies were included in the analysis. RESULTS: A total of 20 studies involving 48,621 patients were included in this meta-analysis. The results demonstrated that PCSK9 inhibitors group was more beneficial for ACS patients compared to control group (receiving statins alone or placebo). The meta-analysis showed: there was no significant difference in high density lipoprotein cholesterol between PCSK9 inhibitors group and control group (standard mean differenceâ =â 0.17, 95% confidence interval [CI]: -0.02 to 0.36, Pâ =â .08), while the level of low density lipoprotein cholesterol in PCSK9 inhibitors group was lower than that in control group (standard mean differenceâ =â -2.32, 95% CI: -2.81 to -1.83, Pâ <â .00001). Compared with the control group, the PCSK9 inhibitors group also decreased the levels of total cholesterol and triglycerides (mean differenceâ =â -1.24, 95% CI: -1.40 to -1.09, Pâ <â .00001, mean differenceâ =â -0.36, 95% CI: -0.56 to -0.16, Pâ =â .0004). Moreover, compared with the control group, PCSK9 inhibitors group could reduce the incidence of MACEs (relative risk [RR]â =â 0.87, 95% CI: 0.83-0.91; Pâ <â .00001). However, this study showed that the incidence of drug-induced adverse events in PCSK9 inhibitors group was higher than that in the control group (RRâ =â 1.15, 95% CI: 1.05-1.25, Pâ <â .0001). CONCLUSION: Although this study demonstrates that PCSK9 inhibitors have higher drug-induced adverse events, they can not only reduce low-density lipoprotein cholesterol levels but also reduce the incidence of MACEs simultaneously. However, these findings needed to be further verified through large sample, multicenter, double-blind randomized controlled trials.
Assuntos
Síndrome Coronariana Aguda , Inibidores de PCSK9 , Humanos , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/tratamento farmacológico , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de PCSK9/administração & dosagem , Inibidores de PCSK9/efeitos adversos , Pró-Proteína Convertase 9/metabolismoRESUMO
Zearalenone (ZEN), a mycotoxin from Fusarium fungi, impairs fertility and milk production in female animals, however, the mechanisms remain poorly understood. Using the bovine mammary epithelial cells (MAC-T) as the model, this study investigated the impacts of ZEN on programmed cell death (PCD) and milk fat synthesis, and explored the underlying mechanism. We found that 10 ng/mL prolactin (PRL) notably enhanced the differentiation of MAC-T cells, promoting the expression of genes related to the synthesis of milk fat, protein, and lactose. Next, the toxic effects of different doses of ZEN on the differentiated MAC-T with PRL treatment were determined. 10 µM and 20 µM ZEN significantly reduced cell viability, induced oxidative stress, and triggered PCD (e.g. apoptosis and necrosis). Notably, ZEN exposure downregulated the mRNA/protein levels of critical factors involving in milk fat synthesis by disrupting the AKT-mTOR-PPARγ-ACSL4 pathway. Interestingly, melatonin (MT), known for its antioxidant properties, protected against the above ZEN-induced effects by enhancing the binding of PPARγ to the promoter regions of ACSL4, which led to the upregulated expression of ACSL4 gene. These results underscored the potential of MT to mitigate the adverse effects of ZEN on mammary cells, highlighting a way for potential therapeutic intervention.
RESUMO
OBJECTIVES: The type of ligamentous tear and the degree of knee laxity have important guiding significance for the diagnosis and management of anterior cruciate ligament (ACL) tears. Instrumental measurement is necessary for ACL tears since physical examination and magnetic resonance imaging (MRI) cannot provide an objective and quantitative assessment of knee laxity. This study aimed to compare the application of a novel knee arthrometer and simultaneous stress radiography in differentiating between complete and partial acute ACL tears, and further assess the correlation between the two measurements. METHODS: A total of 106 patients with complete acute ACL tears and 52 patients with partial acute ACL tears were included in the study. Preoperative arthrometry and simultaneous stress radiography were performed using the Ligs arthrometer at 90, 120, and 150 N to assess side-to-side difference (SSD) in anterior knee laxity. The optimal threshold was determined using the receiver operating characteristic (ROC) curve. The area under the ROC curve (AUC) was used to assess the diagnostic value of the measurement. Pearson's correlation coefficient was used to assess the correlation between the two measurements. RESULTS: The optimal differential SSD thresholds in the Ligs arthrometer were 2.7 mm at 90 N, 3.8 mm at 120 N, and 4.6 mm at 150 N. Similarly, the optimal differential SSD thresholds in simultaneous stress radiography were 3.8 mm at 90 N, 5.1 mm at 120 N, and 5.6 mm at 150 N. The AUC analysis revealed that the Ligs arthrometer was fairly informative at 90 N (AUC = 0.851), 120 N (AUC = 0.878), and 150 N (AUC = 0.884), and simultaneous stress radiography was highly informative at 90 N (AUC = 0.910), 120 N (AUC = 0.925), and 150 N (AUC = 0.948). Moreover, the AUC of the combined measurements was 0.914 at 90 N, 0.931 at 120 N, and 0.951 at 150 N. A significantly strong correlation was found between the two measurements at 90 N (r = 0.743, p < 0.001), 120 N (r = 0.802, p < 0.001), and 150 N (r = 0.823, p < 0.001). CONCLUSIONS: The Ligs arthrometer and simultaneous stress radiography proved to be valid diagnostic tools to differentiate between complete and partial acute ACL tears, with a strong correlation between the two measurements in SSD values. Compared with single instrumental measurement, the combination of the two measurements can further improve the diagnostic value in this regard.
RESUMO
BACKGROUND: Temperature prediction is crucial in the clinical ablation treatment of liver cancer, as it can be used to estimate the coagulation zone of microwave ablation. METHODS: Experiments were conducted on 83 fresh ex vivo porcine liver tissues at two ablation powers of 15 W and 20 W. Ultrasound grayscale images and temperature data from multiple sampling points were collected. The machine learning method of random forests was used to train the selected texture features, obtaining temperature prediction models for sampling points and the entire ultrasound imaging area. The accuracy of the algorithm was assessed by measuring the area of the hyperechoic area in the porcine liver tissue cross-section and ultrasound grayscale images. RESULTS: The model exhibited a high degree of accuracy in temperature prediction and the identification of coagulation zone. Within the test sets for the 15 W and 20 W power groups, the average absolute error for temperature prediction was 1.14°C and 4.73°C, respectively. Notably, the model's accuracy in measuring the area of coagulation was higher than that of traditional ultrasonic grey-scale imaging, with error ratios of 0.402 and 0.182 for the respective power groups. Additionally, the model can filter out texture features with a high correlation to temperature, providing a certain degree of interpretability. CONCLUSION: The temperature prediction model proposed in this study can be applied to temperature monitoring and coagulation zone range assessment in microwave ablation.
Assuntos
Fígado , Aprendizado de Máquina , Micro-Ondas , Temperatura , Ultrassonografia , Animais , Suínos , Ultrassonografia/métodos , Fígado/diagnóstico por imagem , Fígado/cirurgia , Algoritmos , Técnicas de Ablação/métodos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/diagnóstico por imagemRESUMO
RATIONALE: The use of transvenous pacing leads is associated with the risk of tricuspid valve dysfunction, mainly due to the continuous presence of the leads can have an impact on subsequent tricuspid function and possible operation injury of the tricuspid valve during implantation or operation. PATIENT CONCERNS: A 69-year-old female with a history of syncope for 9 months was admitted to the hospital. The electrocardiogram showed sinus bradycardia, junctional escape rhythm, and a heart rate of 44â bpm. Echocardiography suggested a downward displacement and severe insufficiency of the tricuspid valve and atrial septal defect. DIAGNOSES: The cause of syncope was considered to be sick sinus syndrome. The patient was diagnosed with Ebstein anomaly and is considered a candidate for surgical intervention. INTERVENTIONS: To avoid aggravating tricuspid insufficiency by pacing leads crossing the tricuspid valve and hindering subsequent tricuspid valve surgery, a single-chamber pacing mode with atrial pacing (AAI) lead and Micra AV was chosen for maintaining atrioventricular synchrony after multidisciplinary discussion. OUTCOMES: The patient had stable parameters and was in good general condition at 1- and 3-month outpatient follow-ups after discharge. LESSONS: This is the first case of new implantation of single-chamber atrial pacing + leadless ventricular pacing with Micra AV, an alternative strategy to epicardial or coronary sinus system for tricuspid valve displacement and severe tricuspid regurgitation.
Assuntos
Síndrome do Nó Sinusal , Insuficiência da Valva Tricúspide , Humanos , Feminino , Idoso , Síndrome do Nó Sinusal/terapia , Estimulação Cardíaca Artificial/métodos , Anomalia de Ebstein/cirurgia , Marca-Passo Artificial , Síncope/etiologia , Síncope/terapia , Eletrocardiografia , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/fisiopatologiaRESUMO
The aim of this study was to elucidate the effect of FAM13A on the differentiation of goat intramuscular precursor adipocytes and its mechanism of action. Here, we cloned the CDS region 2094 bp of the goat FAM13A gene, encoding a total of 697 amino acid residues. Functionally, overexpression of FAM13A inhibited the differentiation of goat intramuscular adipocytes with a concomitant reduction in lipid droplets, whereas interference with FAM13A expression promoted the differentiation of goat intramuscular adipocytes. To further investigate the mechanism of FAM13A inhibiting adipocyte differentiation, 104 differentially expressed genes were screened by RNA-seq, including 95 up-regulated genes and 9 down-regulated genes. KEGG analysis found that the RIG-I receptor signaling pathway, NOD receptor signaling pathway and toll-like receptor signaling pathway may affect adipogenesis. We selected the RIG-I receptor signaling pathway enriched with more differential genes as a potential adipocyte differentiation signaling pathway for verification. Convincingly, the RIG-I like receptor signaling pathway inhibitor (HY-P1934A) blocked this pathway to save the phenotype observed in intramuscular adipocyte with FAM13A overexpression. Finally, the upstream miRNA of FAM13A was predicted, and the targeted inhibition of miR-21-5p on the expression of FAM13A gene was confirmed. In this study, it was found that FAM13A inhibited the differentiation of goat intramuscular adipocytes through the RIG-I receptor signaling pathway, and the upstream miRNA of FAM13A (miR-21-5p) promoted the differentiation of goat intramuscular adipocytes. This work extends the genetic regulatory network of IMF deposits and provides theoretical support for improving human health and meat quality from the perspective of IMF deposits.
Assuntos
Adipócitos , Diferenciação Celular , Cabras , Transdução de Sinais , Animais , Cabras/genética , Cabras/metabolismo , Adipócitos/metabolismo , Adipócitos/citologia , Diferenciação Celular/genética , MicroRNAs/genética , Adipogenia/genética , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/metabolismoRESUMO
Objective: The goal of this study was to further validate the effect of multimorbidity on cognitive performance in older adults after controlling for confounders using propensity score matching (PSM). Methods: A cross-sectional survey of older adult people aged 60 years or older selected by convenience sampling was conducted in seven medical institutions, three communities, and five nursing homes in Zunyi City, Guizhou Province. The data collected included general information, health-related information, and Mini-Mental State Examination (MMSE) scores. Variables were controlled for confounders by PSM to analyze differences in cognitive ability between multimorbidity and nonmultimorbidity older adults. Logistic regression and multivariate-adjusted restricted cubic spline (RCS) curves for matched samples were used to assess the relationship between multimorbidity and cognitive decline. Results: A total of 14,175 respondents were enrolled, and the mean age of the participants included in this study was 71.26 ± 7.1 years, including 7,170 (50. 58%) of the participants were males, 7,005 (49.42%) were females, and 5,482 participants (38.67%) were screened for cognitive decline. After PSM, logistic regression analysis revealed that multimorbidity was a risk factor for cognitive decline (OR = 1.392, 95% CI = 1.271-1.525, p < 0.001). The RCS show that the risk of cognitive decline is always greater in older adults with multimorbidity than in older adults without multimorbidity at the same age. Age, sex, marital status, educational level, monthly income, drinking status, participation in social activities, and exercise were influential factors for cognitive decline in older adults (p < 0.05). The incidence of cognitive decline in older adults with multimorbidity was also greater than that in older adults with one chronic disease (p < 0.001). Conclusion: The risk of cognitive decline in older adults with multimorbidity is greater than that in older adults without multimorbidity; therefore, the government should strengthen the prevention and treatment of multimorbidity in older adults to further protect their cognitive abilities.
Assuntos
Disfunção Cognitiva , Multimorbidade , Pontuação de Propensão , Humanos , Masculino , Feminino , Idoso , Estudos Transversais , China/epidemiologia , Disfunção Cognitiva/epidemiologia , Pessoa de Meia-Idade , Fatores de Risco , Cognição/fisiologia , Idoso de 80 Anos ou mais , Modelos Logísticos , Testes de Estado Mental e Demência/estatística & dados numéricos , População do Leste AsiáticoRESUMO
Deoxynojirimycin (DNJ) is an α-glucosidase inhibitor with high food values. However, the complex and costly enrichment processes have greatly prevented its application. Herein, this study aimed to propose a simple and efficient enrichment process for DNJ from Morus alba L. extracts using cation exchange resins. The LSI and D113 resins were chosen due to their excellent adsorption and desorption properties. The adsorption characteristics agreed with the pseudo-first-order kinetic model and the Langmuir isotherm model. This adsorption was chemisorption, spontaneous, endothermic and entropy-driven. Furthermore, the concentration and pH of the extracts, desorption solvent, breakthrough and elution curves, sample loading and elution rate were investigated to optimize the enrichment process by resin column chromatography. The results also showed that the purity of DNJ was improved to 44.00 % with a total recovery of 78.21 % using the LSI-D113 combination strategy. This research demonstrated the industrial feasibility of DNJ enrichment using cation exchange resins.
RESUMO
Objectives: This study aimed to develop an efficient tool for assessing children's fundamental motor skills, the "Track style" Children's Fundamental Movement Skills Test (TCFMST), based on theories of motor development integrated with Chinese cultural context and physical education teaching situations. Methods: Starting from a literature analysis, the study selected items from existing fundamental movement skill (FMS) assessments, textbooks, physical education and health standards, and children's movement guidelines to construct a pool of test items. Subsequently, the items were screened and optimized using the Delphi method. Finally, the feasibility, discrimination, difficulty, reliability, and validity of the constructed test were examined using testing methods. Results: The TCFMST includes three dimensions: locomotive skills, body control skills, and manipulative skills, with a total of 10 items. The difficulty and discrimination of each item are appropriate; the correlation coefficients for retest reliability range from 0.789 to 0.943 (p < 0.01). The results of exploratory factor analysis indicate that the common factors align with the hypothesized three dimensions, indicating good structural validity of the test. The concurrent validity results show a correlation coefficient of -0.510 (p < 0.01) between the TCFMST and the total score of TGMD-3, indicating a moderate correlation between the two tests. Conclusion: The TCFMST developed in this study has good difficulty, discrimination, reliability, and validity. It also features strong operability, a short duration, and high interest. It can serve as an important tool for monitoring children's fundamental motor skill levels.
Assuntos
Destreza Motora , Humanos , Destreza Motora/fisiologia , Criança , Reprodutibilidade dos Testes , Feminino , Masculino , Técnica Delphi , China , Desenvolvimento Infantil/fisiologiaRESUMO
Valvular heart disease (VHD) is a major cause of loss of physical function, quality of life and longevity, and its prevalence is growing worldwide due to increased survival rates and an aging population. The most common treatment for VHD is surgical heart valve replacement with mechanical heart valves (MHVs) and bioprosthetic heart valves (BHVs), but with different limitations. Polymeric heart valves (PHVs) exhibit promising material properties, valve dynamics and biocompatibility, representing the most feasible alternative to existing artificial heart valves. However, inadequate fatigue performance remains a critical obstacle to their clinical translation. In this case, geometry and material design are essential to obtain the best mechanical properties of the PHV. In this study, we summarized the effects of optimal design of PHVs from geometrical configuration optimization (valve height, thickness and design curve) and structural material optimization (anisotropy, fiber reinforcement, variable thickness, microstructure and asymmetric optimization), and selected the parameters including Effective Orifice Area (EOA), Regurgitant fraction (RF), and Stress Distribution to compare the performance of valves. It would provide the theoretical support for the optimal design of PHVs.
RESUMO
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) typically present with a complex anatomical distribution, often accompanied by insidious symptoms. This combination contributes to its high incidence and poor prognosis. It is now understood that the immune features of cellular components within the tumor ecosystem and their complex interactions are critical factors influencing both tumor progression and the effective immune response. METHODS: We obtained single-cell RNA sequencing data of 26,496 cells from three tumor tissues and five normal tissues and performed subsequent analyses. Immunohistochemical staining on tumor sections was used to validate the presence of malignant cells. Additionally, we included bulk RNA sequencing data from 502 HNSCC patients. Kaplan-Meier analysis and the log-rank test were employed to assess predictors of patient outcomes. RESULTS: We identified three epithelial subclusters exhibiting immune-related features. These subclusters promoted the infiltration of T cells, dendritic cells, and monocytes into the tumor microenvironment. Additionally, cancer-associated fibroblasts displayed tumor-promoting and angiogenesis characteristics, contrasting with the predominant antigen-presenting and inflammatory roles observed in fibroblasts from normal tissues. Furthermore, tumor endothelial subsets exhibited a double-sided effect, promoting tumor progression and enhancing the effectiveness of immune response. Finally, follicular helper T cells and T helper 17 cells were found to be significantly correlated with improved outcomes in HNSCC patients. These CD4+ T cell subpopulations could promote the anti-tumor immune response by recruiting and activating B and T cells. CONCLUSION: Our findings provide deeper insights into the immune features of the tumor ecosystem and reveal the prognostic significance of follicular helper T cells and T helper 17 cells. These findings may pave the way for the development of therapeutic approaches.
Assuntos
Neoplasias de Cabeça e Pescoço , Linfócitos do Interstício Tumoral , Análise da Expressão Gênica de Célula Única , Carcinoma de Células Escamosas de Cabeça e Pescoço , Células Th17 , Microambiente Tumoral , Feminino , Humanos , Masculino , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Linfócitos do Interstício Tumoral/imunologia , Prognóstico , RNA-Seq/métodos , Análise da Expressão Gênica de Célula Única/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Células T Auxiliares Foliculares/imunologia , Células Th17/imunologia , Microambiente Tumoral/imunologiaRESUMO
Deubiquitinase-targeting chimera (DUBTAC) is a promising technology for inducing targeted protein stabilization (TPS). Despite its therapeutic potential, very few proteins have been stabilized by DUBTACs to date. The limited applicability of this technology is likely due to the modest DUBTAC-induced protein stabilization effect, and the scarcity of effective deubiquitinase ligands that can be harnessed for DUBTAC development. Here, we report the discovery of MS7829 and MS8588, the first-in-class DUBTACs of cGAS, a key component of the cGAS-STING pathway. While these DUBTACs are based on a cGAS inhibitor, they effectively stabilized cGAS and activated the cGAS/STING/IRF3 signaling. To develop these cGAS DUBTACs, we optimized EN523, an OTUB1 covalent ligand, into an improved ligand, MS5105. We validated MS5105 by generating a MS5105-based CFTR DUBTAC, which was approximately 10-fold more effective in stabilizing the ΔF508-CFTR mutant protein than the previously reported EN523-based CFTR DUBTAC. Overall, this work advances the DUBTAC technology for TPS.
RESUMO
This study investigated the underlying function and mechanism of genipin in neuroblastoma (NB). Using flow cytometry analysis and cytotoxicity tests, in vitro studies were conducted to assess the effects of genipin on the SK-N-SH cell line. The mechanism of action of genipin was explored through immunofluorescence staining, Western blotting, and caspase-3 activity assays. In addition, we also created a xenograft tumour model to investigate the effects of genipin in vivo. This research confirmed that genipin suppressed cell viability, induced apoptosis, and promoted autophagy, processes that are likely linked to the inhibition of the PI3K/AKT/mTOR signalling pathway. Autophagy inhibition increases the sensitivity of SK-N-SH cells to genipin. Furthermore, combination treatment with a PI3K inhibitor enhanced the therapeutic efficacy of genipin. These results highlight the potential of genipin as a candidate drug for the treatment of NB.
Assuntos
Apoptose , Autofagia , Iridoides , Neuroblastoma , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Iridoides/farmacologia , Humanos , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Animais , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Sobrevivência Celular/efeitos dos fármacosRESUMO
Fumonisin B1 (FB1), a mycotoxin produced by Fusarium species, is prevalent in crops and animal feed, posing significant health risks to livestock and humans. FB1 induces oxidative stress in Sertoli cells, destroys testicular structure, and affects spermatogenesis. However, methods to mitigate the reproductive toxicity of FB1 in testes remain unknown. Quercetin, a natural flavonoid antioxidant, may offer protective benefits. This study investigated the protective effects and mechanisms of quercetin against FB1-induced reproductive toxicity in TM4 cells (a Sertoli cell line). The results indicated that 40 µM quercetin improved cell viability, reduced apoptosis, and preserved cell functions. Quercetin also decreased reactive oxygen species (ROS) levels in TM4 cells exposed to FB1, enhanced the expression of antioxidant genes, and improved mitochondrial membrane potential. Compared with FB1 alone, the combination of quercetin and FB1 increased ATP levels, as well as pyruvate and lactic acid, the key glycolysis products. Furthermore, this combination elevated the mRNA and protein expression of glycolysis-related genes, including glucose-6-phosphate isomerase 1 (Gpi1), hexokinase 2 (Hk2), aldolase (Aldoa), pyruvate kinase, muscle (Pkm), lactate dehydrogenase A (Ldha) and phosphofructokinase, liver, B-type (Pfkl). Quercetin also boosted the activity of PKM and LDHA, two crucial glycolytic enzymes. In summary, quercetin mitigates FB1-induced toxicity in TM4 cells by reducing ROS levels and enhancing glycolysis. This study offers new insights into preventing and treating FB1-induced toxic damage to the male reproductive system and highlights the potential application of quercetin.
Assuntos
Sobrevivência Celular , Fumonisinas , Quercetina , Espécies Reativas de Oxigênio , Células de Sertoli , Quercetina/farmacologia , Fumonisinas/toxicidade , Masculino , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Substâncias Protetoras/farmacologiaRESUMO
BACKGROUND: The triglyceride-glucose (TyG) index performs better at reflecting insulin resistance when combined with waist circumference (WC), body mass index (BMI), and waist-to-height ratio (WHtR) than when used alone. This study aimed to prospectively examine the relationships between TyG, TyG-BMI, TyG-WC, and TyG-WHtR with the incidence of myocardial infarction (MI) and its subtypes. METHODS: This cohort study included 370,390 participants from the UK Biobank. The Cox proportional hazards model and restricted cubic spline regression model were used to assess the associations of TyG, TyG-BMI, TyG-WC, and TyG-WHtR with MI, ST-elevation MI (STEMI) and non-ST-elevation MI (NSTEMI). The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were employed to examine the predictive value of four indicators. RESULTS: The hazard ratios (HRs) and 95% confidence intervals (CIs) of MI in the highest quartiles for TyG, TyG-BMI, TyG-WC, and TyG-WHtR were 1.36 (1.28-1.44), 1.47 (1.39-1.56), 1.53 (1.43-1.64), and 1.58 (1.48-1.68) in the fully-adjusted model. Comparable findings were observed when the outcomes were reclassified as STEMI or NSTEMI. However, the associations of TyG-BMI, TyG-WC, and TyG-WHtR with the risk of STEMI were weaker than MI and NSTEMI. A linear dose-response association between TyG and the risk of MI and NSTEMI were demonstrated. TyG-BMI, TyG-WC, and TyG-WHtR all showed nonlinear patterns in their associations with the risk of MI, STEMI, and NSTEMI. TyG-WC was most effective in diagnosing MI (AUC: 0.648, 95% CI: 0.644-0.653), STEMI (AUC: 0.631, 95% CI: 0.622-0.639), and NSTEMI (AUC: 0.647, 95% CI: 0.641-0.654). CONCLUSION: The TyG index was linearly associated with increased risk of MI and NSTEMI, whereas TyG-BMI, TyG-WC, and TyG-WHtR were nonlinearly associated with increased risk of MI and NSTEMI. There were distinct patterns in the relationships between these indicators with STEMI. TyG-WC provided the best diagnostic effectiveness for MI, STEMI, and NSTEMI.
Assuntos
Adiposidade , Glicemia , Infarto do Miocárdio , Triglicerídeos , Humanos , Masculino , Feminino , Triglicerídeos/sangue , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/sangue , Incidência , Glicemia/análise , Glicemia/metabolismo , Adiposidade/fisiologia , Idoso , Índice de Massa Corporal , Estudos de Coortes , Circunferência da Cintura , Fatores de Risco , Estudos Prospectivos , Adulto , Biobanco do Reino UnidoRESUMO
Wastewater contains various organic contaminants that pose great hazards to human health and the environment. A protein/polysaccharide-derived aerogel, namely, ICMA, was developed as a high-performance adsorbent for the simultaneous and efficient removal of diverse contaminants from wastewater, including melanoidin (MLE), Congo red (CR), and diclofenac (DIC). Metal organic framework (UiO-66-NH2), as a regulatory factor, significantly improved the porosity and pore volume of the ICMA to enhance the capture performance of contaminants. The ICMA exhibited outstanding adsorption efficiency owing to the incorporation of ample polyamine functional groups and its well-developed pore structure, large porosity and pore volume, and remarkable heat resistance. The equilibrium capture capacities of the ICMA were 1364, 2031, and 539 mg/g for MLE, CR, and DIC, respectively, with corresponding removal efficiencies all exceeding 90%. Furthermore, the ICMA can capture cationic dyes through MLE/CR/DIC-bridging interactions. After five cycles, the used ICMA can still maintain a high contaminant removal rate/amount, demonstrating good reusability. The classic adsorption model showed that the capture of contaminants by the ICMA is a double-layered and heterogeneous adsorption orientation. A brand new LWAMTM model demonstrated that the adsorption mass-transfer process is jointly determined by the external mass conveyance, pore diffusion, and adsorption on the active site. Multiple characterizations indicated that the contaminant adsorption onto the ICMA was mainly facilitated by charge interactions, with H-bonds playing a secondary role. Quantum chemical theory simulations further provide insights into the atomic-level mechanisms involved in the capture of contaminants. Hirshfeld surface analysis revealed that the ICMA functions as both an H-bond acceptor and a donor during contaminant adsorption. Scale-up and upgrade adsorption were performed to treat actual/simulated wastewater, establishing the groundwork for the industrial implementation of the ICMA.
RESUMO
The well-known tumor suppressor p53 is mutated in approximately half of all cancers. The Y220C mutation is one of the major p53 hotspot mutations. Several small-molecule stabilizers of p53Y220C have been developed. We recently developed a new technology for inducing targeted protein acetylation, termed acetylation targeting chimera (AceTAC), and the first p53Y220C AceTAC that effectively acetylated p53Y220C at lysine 382. Here, we report structure-activity relationship (SAR) studies of p53Y220C AceTACs, which led to the discovery of a novel p53Y220C AceTAC, compound 11 (MS182). 11 effectively acetylated p53Y220C at lysine 382 in a time- and concentration-dependent manner via inducing the ternary complex formation between p300/CBP acetyltransferase and p53Y220C. 11 was more effective than the parent p53Y220C stabilizer in suppressing the proliferation and clonogenicity in cancer cells harboring the p53Y200C mutation and was bioavailable in mice. Overall, 11 is a potentially valuable chemical tool to investigate the role of p53Y220C acetylation in cancer.
Assuntos
Desenho de Fármacos , Proteína Supressora de Tumor p53 , Acetilação , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/antagonistas & inibidores , Humanos , Animais , Relação Estrutura-Atividade , Camundongos , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Fatores de Transcrição de p300-CBP/metabolismo , MutaçãoRESUMO
The gut microbiota plays a critical role in numerous biochemical processes essential for human health, such as metabolic regulation and immune system modulation. An increasing number of research suggests a strong association between the gut microbiota and carcinogenesis. The diverse metabolites produced by gut microbiota can modulate cellular gene expression, cell cycle dynamics, apoptosis, and immune system functions, thereby exerting a profound influence on cancer development and progression. A healthy gut microbiota promotes substance metabolism, stimulates immune responses, and thereby maintains the long-term homeostasis of the intestinal microenvironment. When the gut microbiota becomes imbalanced and disrupts the homeostasis of the intestinal microenvironment, the risk of various diseases increases. This review aims to elucidate the impact of gut microbial metabolites on cancer initiation and progression, focusing on short-chain fatty acids (SCFAs), polyamines (PAs), hydrogen sulfide (H2S), secondary bile acids (SBAs), and microbial tryptophan catabolites (MTCs). By detailing the roles and molecular mechanisms of these metabolites in cancer pathogenesis and therapy, this article sheds light on dual effects on the host at different concentrations of metabolites and offers new insights into cancer research.
Assuntos
Ácidos e Sais Biliares , Progressão da Doença , Ácidos Graxos Voláteis , Microbioma Gastrointestinal , Neoplasias , Humanos , Neoplasias/microbiologia , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Ácidos Graxos Voláteis/metabolismo , Ácidos e Sais Biliares/metabolismo , Sulfeto de Hidrogênio/metabolismo , Poliaminas/metabolismo , Triptofano/metabolismo , Carcinogênese , Animais , Microambiente TumoralRESUMO
Quaternization of ruthenium complexes may be a promising strategy for the development of new antibiotics. In response to the increasing bacterial resistance, we integrated the quaternary amine structure into the design of ruthenium complexes and evaluated their antibacterial activity. All the ruthenium complexes showed good antibacterial activity against the tested Staphylococcus aureus (S. aureus). Ru-8 was the most effective antibacterial agent that displayed excellent antibacterial activity against S. aureus (MIC = 0.78-1.56 µg/mL). In vitro experiments showed that all nine ruthenium complexes had low hemolytic toxicity to rabbit erythrocytes. Notably, Ru-8 was found to disrupt bacterial cell membranes, alter their permeability, and induce ROS production in bacteria, all the above leading to the death of bacteria without inducing drug resistance. To further explore the antibacterial activity of Ru-8in vivo, we established a mouse skin wound infection model and a G. mellonella larvae infection model. Ru-8 exhibited significant antibacterial efficacy against S. aureus in vivo and low toxicity to mouse tissues. The Ru-8 showed low toxicity to Raw264.7 cells (mouse monocyte macrophage leukemia cells). This study indicates that the ruthenium complex ruthenium quaternary was a promising strategy for the development of new antibacterial agents.