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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.
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Adipocitos , Adipogénesis , Cabras , Proteínas con Homeodominio LIM , Proteínas Musculares , Animales , Cabras/genética , Adipocitos/metabolismo , Adipocitos/citología , Adipogénesis/genética , Proteínas con Homeodominio LIM/genética , Proteínas con Homeodominio LIM/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Apoptosis/genética , Diferenciación Celular/genética , Proliferación Celular , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Grasa Subcutánea/metabolismo , Grasa Subcutánea/citología , Perfilación de la Expresión GénicaRESUMEN
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.
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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.
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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.
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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.
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Síndrome Coronario Agudo , Inhibidores de PCSK9 , Humanos , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/sangre , LDL-Colesterol/sangre , LDL-Colesterol/efectos de los fármacos , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Proproteína Convertasa 9RESUMEN
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.
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Destreza Motora , Humanos , Destreza Motora/fisiología , Niño , Reproducibilidad de los Resultados , Femenino , Masculino , Técnica Delphi , China , Desarrollo Infantil/fisiologíaRESUMEN
Although the impact of interest rates, repayment periods, and loan scales on loan consequences has been extensively studied, little attention has been paid to the geographical distance involved in loan transactions. This study collects the addresses of borrowing companies, listed companies, and banks. Nonlocal loans can be distinguished because the regional segmentations in the lending industry reflect the features of provincial boundaries. Using data from Chinese A-share listed companies from 2007 to 2022, this research explores the causes of nonlocal loans and their impact on company innovation. Nonlocal loans are found to address the lack of local credit resources rather than financial constraints, supplementing disposable capital. This interregional circulation of credit resources facilitates innovation, particularly in financially undeveloped areas. This study does not detect research and development manipulation and recognizes the increase in innovation output. The findings have implications for credit resource allocation and balanced regional development.
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Industrias , China , Humanos , Industrias/economía , Invenciones/economía , Comercio/economíaRESUMEN
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.
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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.
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Background: Linezolid (LZD) is a cornerstone medication in the treatment of drug-resistant tuberculosis (DR-TB). However, it frequently triggers adverse effects such as bone marrow suppression, optic neuropathy, and peripheral neuropathy, all of which can impact treatment outcomes and prognosis. Contezolid (CZD), a novel oxazolidinone antibiotic, exhibits comparable antimicrobial efficacy against Mycobacterium tuberculosis as LZD, but with potentially enhanced safety profiles. Case Presentation: This report presents five cases (Cases 1-5) of LZD intolerance, wherein CZD served as an effective alternative treatment. In Cases 1-3, LZD administration resulted in bone marrow suppression, primarily manifested as anemia. Transitioning to CZD therapy led to a rise and stabilization of hemoglobin (HGB) levels in Cases 1-2, and a return to baseline values in Case 3. In Case 4, CZD treatment alleviated symptoms of LZD-induced peripheral neuritis, although complete resolution was not achieved, hinting at potential irreversibility of this type of peripheral neuropathy. In Case 5, direct CZD anti-TB therapy was initiated for recurrent leukopenia and neutropenia, resulting in no further severe myelosuppression and successful recovery. Conclusion: These case studies suggest that CZD could represent an effective and safe option for anti-TB therapy, especially for patients intolerant to LZD.
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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.
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Antibacterianos , Complejos de Coordinación , Pruebas de Sensibilidad Microbiana , Piridinas , Rutenio , Staphylococcus aureus , Tiazoles , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Animales , Ratones , Rutenio/química , Rutenio/farmacología , Piridinas/química , Piridinas/farmacología , Piridinas/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Conejos , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología , Tiazoles/síntesis química , Estructura Molecular , Células RAW 264.7 , Descubrimiento de Drogas , Relación Dosis-Respuesta a Droga , Infecciones Estafilocócicas/tratamiento farmacológico , Hemólisis/efectos de los fármacosRESUMEN
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.
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Apoptosis , Autofagia , Iridoides , Neuroblastoma , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Iridoides/farmacología , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Animales , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Supervivencia Celular/efectos de los fármacosRESUMEN
Sarcopenia is an age-related syndrome characterized by the loss of skeletal muscle mass and function. Community screening, commonly used in early diagnosis, usually lacks features such as real-time monitoring, low cost, and convenience. This study introduces a promising approach to sarcopenia screening by dynamic plantar pressure monitoring. We propose a wearable flexible-printed piezoelectric sensing array incorporating barium titanate thin films. Utilizing a flexible printer, we fabricate the array with enhanced compressive strength and measurement range. Signal conversion circuits convert charge signals of the sensors into voltage signals, which are transmitted to a mobile phone via Bluetooth after processing. Through cyclic loading, we obtain the average voltage sensitivity (4.844 mV/kPa) of the sensing array. During a 6 m walk, the dynamic plantar pressure features of 51 recruited participants are extracted, including peak pressures for both sarcopenic and control participants before and after weight calibration. Statistical analysis discerns feature significance between groups, and five machine learning models are employed to screen for sarcopenia with the collected features. The results show that the features of dynamic plantar pressure have great potential in early screening of sarcopenia, and the Support Vector Machine model after feature selection achieves a high accuracy of 93.65%. By combining wearable sensors with machine learning techniques, this study aims to provide more convenient and effective sarcopenia screening methods for the elderly.
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Presión , Sarcopenia , Caminata , Dispositivos Electrónicos Vestibles , Humanos , Sarcopenia/diagnóstico , Sarcopenia/fisiopatología , Caminata/fisiología , Masculino , Anciano , Femenino , Persona de Mediana Edad , Pie/fisiología , Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodos , Aprendizaje AutomáticoRESUMEN
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.
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Supervivencia Celular , Fumonisinas , Quercetina , Especies Reactivas de Oxígeno , Células de Sertoli , Quercetina/farmacología , Fumonisinas/toxicidad , Masculino , Células de Sertoli/efectos de los fármacos , Células de Sertoli/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular , Ratones , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Glucólisis/efectos de los fármacos , Sustancias Protectoras/farmacologíaRESUMEN
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.
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Ácidos y Sales Biliares , Progresión de la Enfermedad , Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Neoplasias , Humanos , Neoplasias/microbiología , Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Ácidos Grasos Volátiles/metabolismo , Ácidos y Sales Biliares/metabolismo , Sulfuro de Hidrógeno/metabolismo , Poliaminas/metabolismo , Triptófano/metabolismo , Carcinogénesis , Animales , Microambiente TumoralRESUMEN
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.
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Neoplasias de Cabeza y Cuello , Linfocitos Infiltrantes de Tumor , Análisis de Expresión Génica de una Sola Célula , Carcinoma de Células Escamosas de Cabeza y Cuello , Células Th17 , Microambiente Tumoral , Femenino , Humanos , Masculino , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Linfocitos Infiltrantes de Tumor/inmunología , Pronóstico , RNA-Seq/métodos , Análisis de Expresión Génica de una Sola Célula/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Células T Auxiliares Foliculares/inmunología , Células Th17/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
OBJECTIVE: To analyze the differences of clinical features of acute gout flare and postoperative infection under arthroscopy of knee gouty arthritis patients to offer guiding opinions of clinical diagnosis and treatment. METHODS: Between January 2017 and December 2022, 235 patients with gouty knee osteoarthritis were admitted, and underwent arthroscopic debridement combined with synovectomy. Among them, 35 cases had fever with a temperature higher than 38 °C postoperatively while acute inflammatory appears under redness, swelling, heat and pain of the operated joints. There were 29 males and 6 females, with an average age of (41.48±13.90) years old. Among them 23 patients were diagnosed with acute gout attack, and recovered well after being given colchicine and prednisolone;12 patients were diagnosed with postoperative joint infection, and were cured after being given anti-infective treatments and cleaning and rinsing of the joint cavity. The two groups of patients were compared and analyzed in terms of preoperative general data, surgical conditions, hematology, joint fluid, limb function and other clinical characteristics. RESULTS: There were no significant difference in the preoperative general data between two groups. The onset of fever in the postoperative acute gout flare group occurred mostly within 48 hours, significantly earlier than that in the postoperative infection group(P=0.037). The visual analogue scale score was significantly higher in the acute gout flare group (5.32±1.38) score than in the postoperative infection group (2.45±0.68) score (P=0.000), while 14 patients with acute gout flare were accompanied by severe pain in other joints. Hematologically, indicators such as white blood cell counts and ratios were significantly higher in both groups. In terms of inflammatory indicators, IL-6, erythrocyte sedimentation rate, procalcitonin and other inflammatory indicators were significantly elevated in both groups, but there was no statistical difference between two groups. The C-reactive protein level in the postoperative infection group (220.97±116.30) mg·L-1 was higher than that in the postoperative acute gout attack group(120.67±82.45) mg·L-1(P=0.006). Blood uric acid (316.55±112.84) µmol·L-1 was higher in the acute postoperative gout flare group than in the postoperative infection group (159.14±126.92) µmol·L-1(P=0.001). In the joint fluid examination of the postoperative infection group, the glucose metabolism indicator was significantly lower than that of the acute gout flare group, and five of them had positive bacterial cultures. CONCLUSION: The symptoms of acute gout flare could be mistaken as postoperative infection due to their similarity, therefore requires careful differentiation. Differential diagnosis should be based on a combination of clinical signs, hematology and joint fluid findings, and targeted treatment should be given to avoid serious complications.
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Artritis Gotosa , Artroscopía , Humanos , Femenino , Masculino , Artritis Gotosa/cirugía , Artroscopía/efectos adversos , Adulto , Persona de Mediana Edad , Errores Diagnósticos , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Articulación de la Rodilla/cirugía , Enfermedad Aguda , AncianoRESUMEN
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.
Asunto(s)
Diseño de Fármacos , Proteína p53 Supresora de Tumor , Acetilación , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Humanos , Animales , Relación Estructura-Actividad , Ratones , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Factores de Transcripción p300-CBP/antagonistas & inhibidores , Factores de Transcripción p300-CBP/metabolismo , MutaciónRESUMEN
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.
RESUMEN
BACKGROUND: The causal relationship between childhood adiposity and adult risk of heart diseases has not been clearly demonstrated. This study aims to ascertain whether genetically predicted childhood body mass index (BMI) and childhood obesity are causally associated with adult coronary heart disease, myocardial infarction, heart failure, atrial fibrillation, hypertrophic cardiomyopathy, and pulmonary heart disease. METHODS AND RESULTS: To investigate the causative relationships and underlying mechanisms between childhood adiposity and adult heart diseases, 3 main methods of Mendelian randomization were used: 2-sample Mendelian randomization, multivariable Mendelian randomization with controlling for several cardiometabolic risk variables, and mediation analysis. Every 1-SD rise in genetically predicted childhood body mass index was associated with 24% (odds ratio [OR], 1.24 [95% CI, 1.12-1.37]), 28% (OR, 1.28 [95% CI, 1.14-1.42]), 28% (OR, 1.28 [95% CI, 1.14-1.42]), and 27% (OR, 1.27 [95% CI, 1.04-1.49]) higher risk of coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation, respectively. Every 1-unit increase in log-odds in childhood obesity was associated with 11% (OR, 1.11 [95% CI, 1.06-1.16]), 14% (OR, 1.14 [95% CI, 1.04-1.23]), 10% (OR, 1.10 [95% CI, 1.03-1.18]), and 20% (OR, 1.20 [95% CI, 1.08-1.32]) higher risk of coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation, respectively. The link between childhood adiposity and adult heart diseases was found to be mediated by high-density lipoprotein cholesterol, triglyceride, hypertension, and type 2 diabetes. CONCLUSIONS: Our findings support the causal relationships between childhood adiposity and risk of adult coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation. Blood lipids, hypertension, and type 2 diabetes are factors that mediate the aforementioned associations.