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Background: Observational studies and clinical trials have implicated polyunsaturated fatty acids (PUFAs) in potentially safeguarding against diabetic microvascular complication. Nonetheless, the causal nature of these relationships remains ambiguous due to conflicting findings across studies. This research employs Mendelian randomization (MR) to assess the causal impact of PUFAs on diabetic microvascular complications. Methods: We identified instrumental variables for PUFAs, specifically omega-3 and omega-6 fatty acids, using the UK Biobank data. Outcome data regarding diabetic microvascular complications were sourced from the FinnGen Study. Our analysis covered microvascular outcomes in both type 1 and type 2 diabetes, namely diabetic neuropathy (DN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). An inverse MR analysis was conducted to examine the effect of diabetic microvascular complications on PUFAs. Sensitivity analyses were performed to validate the robustness of the results. Finally, a multivariable MR (MVMR) analysis was conducted to determine whether PUFAs have a direct influence on diabetic microvascular complications. Results: The study indicates that elevated levels of genetically predicted omega-6 fatty acids substantially reduce the risk of DN in type 2 diabetes (odds ratio (OR): 0.62, 95% confidence interval (CI): 0.47-0.82, p = 0.001). A protective effect against DR in type 2 diabetes is also suggested (OR: 0.75, 95% CI: 0.62-0.92, p = 0.005). MVMR analysis confirmed the stability of these results after adjusting for potential confounding factors. No significant effects of omega-6 fatty acids were observed on DKD in type 2 diabetes or on any complications in type 1 diabetes. By contrast, omega-3 fatty acids showed no significant causal links with any of the diabetic microvascular complications assessed. Conclusions: Our MR analysis reveals a causal link between omega-6 fatty acids and certain diabetic microvascular complications in type 2 diabetes, potentially providing novel insights for further mechanistic and clinical investigations into diabetic microvascular complications.
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Diabetes Mellitus Tipo 2 , Angiopatías Diabéticas , Análisis de la Aleatorización Mendeliana , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Angiopatías Diabéticas/genética , Angiopatías Diabéticas/epidemiología , Masculino , Ácidos Grasos Insaturados , Ácidos Grasos Omega-3 , Ácidos Grasos Omega-6 , Retinopatía Diabética/genética , Retinopatía Diabética/epidemiología , Femenino , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/genética , Nefropatías Diabéticas/genética , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/genética , Persona de Mediana EdadRESUMEN
Background: The number of prediction models for diabetic foot ulcer (DFU) risk is increasing, but their methodological quality and clinical applicability are uncertain. We conducted a systematic review to assess their performance. Methods: We searched PubMed, Cochrane Library, and Embase databases up to 10 February 2024 and extracted relevant information from selected prediction models. The Prediction model Risk Of Bias ASsessment Tool (PROBAST) checklist was used to assess bias risk and applicability. All statistical analyses were conducted in Stata 14.0. Results: Initially, 13,562 studies were retrieved, leading to the inclusion of five development and five validation models from eight studies. DFU incidence ranged from 6% to 16.8%, with age and hemoglobin A1C (HbA1c) commonly used as predictive factors. All included studies had a high risk of bias, mainly due to disparities in population characteristics and methodology. In the meta-analysis, we observed area under the curve (AUC) values of 0.78 (95% CI [0.69-0.89]) for development models and 0.84 (95% CI [0.79-0.90]) for validation models. Conclusion: DFU risk prediction models show good overall accuracy, but there is a risk of bias. Adherence to the PROBAST checklist is crucial for improving their clinical applicability.
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Pie Diabético , Pie Diabético/epidemiología , Pie Diabético/diagnóstico , Humanos , Medición de Riesgo/métodos , Factores de Riesgo , Hemoglobina Glucada/análisis , Modelos EstadísticosRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) poses significant diagnostic challenges due to its asymptomatic nature in its early stages, low specificity of conventional in vitro assays, and limited efficacy of surgical interventions. However, clinical specificity of the current serum biomarkers is suboptimal, leading to diagnostic inaccuracies and oversights. Therefore, this study introduced a novel dual-target electrochemiluminescence (ECL) biosensor to address these critical issues. The ECL biosensor synergistically employs the serum biomarker MUC1 and microRNA-196a to detect early-stage PDAC precisely. While MUC1 is a differential marker between normal and cancerous pancreatic cells, its standalone diagnostic performance is limited. However, integrating miRNA-196a as a complementary marker substantially enhances the specificity of the assay. This biosensor exhibits distinct ECL signal modulation-"on-off" in the presence of MUC1 and "off-on" upon concurrent detection of MUC1 and miRNA-196a. The biosensor achieves remarkably low limits of detection (LODs) at 0.63 fg mL-1 and 4.57 aM for MUC1 and miRNA-196a, respectively. Thus, it facilitates the real-time differentiation between human normal pancreatic (hTERT-HPNE) and pancreatic cancer (PANC-1) cells in authentic biological matrices. This innovative approach heralds a significant advancement in the early and specific detection of PDAC, offering promising prospects for clinical translation and the broader landscape of cancer diagnostics.
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Técnicas Biosensibles , Carcinoma Ductal Pancreático , MicroARNs , Neoplasias Pancreáticas , Humanos , MicroARNs/genética , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Biomarcadores , Mucina-1RESUMEN
BACKGROUND: In recent years, mounting evidence has indicated a co-morbid relationship between hypothyroidism and rheumatoid arthritis (RA), however, the shared genetic factors underlying this association remain unclear. This study aims to investigate the common genetic architecture between hypothyroidism and RA. METHODS: Genome-wide association study (GWAS) summary statistics from recently published studies were utilized to examine the genetic correlation, shared genetic loci, and potential causal relationship between hypothyroidism and RA. Statistical methods included linkage disequilibrium score regression (LDSC), high-definition likelihood (HDL), cross-trait meta-analyses, colocalization analysis, multi-marker analysis of genomic annotation (MAGMA), tissue-specific enrichment analysis (TSEA), functional enrichment analysis, and latent causal variable method (LCV). RESULTS: Our study demonstrated a significant genetic correlation between hypothyroidism and RA(LDSC:rg=0.3803,p=7.23e-11;HDL:rg=0.3849,p=1.02e-21). Through cross-trait meta-analysis, we identified 1035 loci, including 43 novel genetic loci. By integrating colocalization analysis and the MAGMA algorithm, we found a substantial number of genes, such as PTPN22, TYK2, and CTLA-4, shared between the two diseases, which showed significant enrichment across 14 tissues. These genes were primarily associated with the regulation of alpha-beta T cell proliferation, positive regulation of T cell activation, positive regulation of leukocyte cell-cell adhesion, T cell receptor signaling pathway, and JAK-STAT signaling pathway. However, our study did not reveal a significant causal association between the two diseases using the LCV approach. CONCLUSION: Based on these findings, there is a significant genetic correlation between hypothyroidism and RA, suggesting a shared genetic basis for these conditions.
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Artritis Reumatoide , Hipotiroidismo , Humanos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Sitios Genéticos , Hipotiroidismo/genética , Polimorfismo de Nucleótido Simple , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genéticaRESUMEN
Breast cancer remains the most frequently diagnosed cancer globally, and the metastasis of this malignancy is the primary cause of mortality in breast cancer patients. Hence, prompt diagnosis and timely detection of metastatic breast cancer are critical for effective therapeutic intervention. Both progression and metastasis of this malignancy are closely associated with aberrant expression of specific microRNAs (miRNAs) and enzymes. To facilitate breast cancer diagnosis and concomitant identification of metastatic breast cancer, we have engineered an innovative electrochemiluminescence (ECL)-based sensing platform integrated with enzyme-free DNA amplification circuits for dual functionality. Specifically, microRNA-21 (miR-21) is employed as a biomarker for breast cancer, and miR-21 induces the quenching of the ECL signal from luminophores via a strategically designed catalytic three-hairpin assembly (CTHA) circuit. Subsequently, miR-105 levels are measured via toehold-mediated strand displacement reactions (TSDR). Here, miR-105 restores the initially quenched ECL signal, enabling the assessment of the metastatic propensity. Our experimental data demonstrate that the devised ECL biosensor offers broad linear detection ranges and low detection limits for both miR-21 and miR-105. Importantly, our novel platform was also successfully validated by using cellular and serum samples. This biosensor not only discriminates breast cancer cell lines MCF-7 and MDA-MB-231 from nonbreast cancer cells like HepG2, TPC-1, and HeLa, but it also distinguishes between malignant MCF-7 and metastatic MDA-MB-231 cells. Consequently, our novel approach holds significant promise for clinical applications and precise cancer screening.
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Técnicas Biosensibles , Neoplasias de la Mama , MicroARNs , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , MicroARNs/genética , Fotometría , Células HeLa , Mediciones Luminiscentes , Técnicas ElectroquímicasRESUMEN
Inspired by the mussel, tannic acid (TA) was modified onto the surface of self-made cellulose nanofibrils (CNFs) to prepare TA@CNFs, which was introduced into borax crosslinked polyvinyl alcohol (PVA) to prepare PTC double-network hydrogel with self-healing properties. Through the comparative observation of TEM images and infrared spectra before and after tannic acid modification, the formation of TA@CNFs was proved. The introduction of TA@CNFs greatly increases the fracture stress of PTC hydrogel, which is more than 10 times higher than that of PVA hydrogel without TA@CNFs, and has high fracture strain (1723 %). Moreover, PTC hydrogel has the ability of rapid self-healing, which can heal to the original form within two minutes. In addition, the temperature response ability of PTC hydrogel makes it capable of reshaping. The self-adhesion ability of PTC hydrogel enables it to adhere to the human epidermis to detect motion signals, as sensitive and as stable as a flexible sensor.
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Celulosa , Hidrogeles , Polifenoles , Humanos , Adhesivos , Cementos de ResinaRESUMEN
In this study, ceria nanoparticle (CNP) was used as a capping agent to investigate the efficiency and mechanism of simultaneously controlling the release of sediment internal Arsenic (As) and tungsten (W). The results of incubation experiment demonstrated that CNP capping reduced soluble As and W by 81.80% and 97.97% in overlying water, respectively; soluble As and W by 65.64% and 60.13% in pore water, respectively; and labile As and W in sediment by 45.20% and 53.20%, respectively. The main mechanism of CNP controlling sediment internal As and W was through adsorption via ligand exchange and inner-sphere complexation, as determined through adsorption experiments, XPS and FIRT spectra analysis. Besides, CNP also acted as an oxidant, facilitating the oxidation of Asâ ¢ to AsV and thereby enhancing the adsorption of soluble As. Additionally, sediment As and W fractions experiments demonstrated that the immobilization of As and W with CNP treatment via transforming mobile to stable fractions was another mechanism inhibiting sediment As and W release. The obtained significant positive correlation between soluble As/W and Fe/Mn, labile As/W and Fe/Mn indicated that iron (Fe) and manganese (Mn) oxidation, influenced by CNP, serve as additional mechanisms. Moreover, Fe redox plays a crucial role in controlling internal As and W, while Mn redox plays a more significant role in controlling As compared to W. Meanwhile, CNP capping effectively prevented the release of As and W by reducing the activity of microorganisms that degrade Fe-bound As and W and reduced the release risk of V, Cr, Co, Ni, and Zn from sediments. Overall, this study proved that CNP was a suitable capping agent for simultaneously controlling the release of As and W from sediment.
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Arsénico , Metales Pesados , Contaminantes Químicos del Agua , Arsénico/análisis , Tungsteno , Sedimentos Geológicos , Metales Pesados/análisis , Manganeso/análisis , Agua , Contaminantes Químicos del Agua/análisis , FósforoRESUMEN
BACKGROUND: The Asian Working Group for Sarcopenia (AWGS) introduced the concept of "possible sarcopenia" in 2019. However, the association between possible sarcopenia and hip fracture is not well characterized. Hence, we conducted a study to explore this association in older Chinese adults. METHODS: This was a population-based cohort study based on nationally representative data from the China Health and Retirement Longitudinal Study. Individuals aged ≥60 years with no history of hip fracture at baseline (2011-2012) were included and followed up until September 2018. Possible sarcopenia was defined based on the AWGS 2019 criteria during the study period, and the occurrence of hip fractures was monitored. The association between possible sarcopenia and hip fractures was assessed using Cox proportional hazards regression models. RESULTS: A total of 4,011 participants were included, of whom 44.8 % had possible sarcopenia. During the 7-year follow-up, 197 individuals experienced hip fractures. Individuals with possible sarcopenia had a significantly higher risk of hip fractures than those without possible sarcopenia (hazard ratio: 2.00, 95 % confidence interval: 1.46-2.75; P < 0.001). The association was consistently observed across various subgroups based on age, sex, and overweight status. CONCLUSIONS: This study identified possible sarcopenia as a significant risk factor for hip fractures in older Chinese adults. These findings underscore the importance of addressing possible sarcopenia as a preventive measure to reduce the incidence of hip fractures.
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Fracturas de Cadera , Sarcopenia , Humanos , Persona de Mediana Edad , Anciano , Sarcopenia/complicaciones , Sarcopenia/epidemiología , Estudios Longitudinales , Estudios de Cohortes , Fracturas de Cadera/epidemiología , Factores de Riesgo , China/epidemiologíaRESUMEN
CD226 is an activated receptor on the surface of natural killer (NK) cells. It competes with TIGIT and CD96 to bind to ligands such as CD155 on the surface of tumor cells and mediates the killing function of NK cells. Although TIGIT and CD96 have other binding ligands in the tumor microenvironment, they compete to bind CD115 ligands with higher affinity and inhibit the activity of NK cells, which allows tumor cells to evade killing. Therefore, studying the expression patterns of these three NK cell surface receptors in different tumors and monitoring their binding ability with ligands will help us to explore new tumor treatment strategies. This article reviews the role and mechanism of CD226, TIGIT, CD96 and other NK cell receptor molecules in regulating NK cell function in anti-tumor immune response.
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Células Asesinas Naturales , Receptores Inmunológicos , Ligandos , Receptores de Células Asesinas Naturales , Antígenos CDRESUMEN
It is well known that colorimetric matching of colors on different media does not ensure that their appearance is the same for everyone. One of the reasons is that there are variations in the color matching functions (CMFs) between observers, and that individual CMFs are different from that of the standard observer defined in CIE. If CMFs can be measured easily for each observer, customized color management will be possible. Traditional methods require the adjustment of the intensities of three primary lamps (R, G, B) which is not easy for naïve observers. A simple method is proposed in this research, in which observers select the closest color from multiple candidates to a reference. The candidate colors are composed of 5 x 5 x 5 lattice, whose center is the expected matching color. The average and standard deviation of the CMFs were calculated based on the CMFs of 11 observers. For each CMF, 5 candidate values were produced: average, average +/- 1/2 SD, average +/- SD. In the experiment, the observers were allowed to choose one for each CMF of RGB among 5 candidates to make a best match. Five observers whose CMFs were measured with the adjustment method participated in the experiment. The results of two methods showed good consistencies for the G and R CMFs, while some discrepancies were observed for the B CMFs. The total time of the experiment was reduced to 1/4 to 1/3, and it was also easy for the naïve subjects, which indicate that our method is an effective one.
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BACKGROUND: Previous studies have shown that type 2 diabetes mellitus (T2DM) can cause sarcopenia; however, these conditions may have a bidirectional association. This study aimed to explore the longitudinal association between possible sarcopenia and new-onset T2DM. METHODS: We conducted a population-based cohort study using nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS). This study included participants aged ≥ 60 years who were free of diabetes during the baseline survey of CHARLS (2011 to 2012) and were followed up until 2018. Possible sarcopenia status was defined according to the Asian Working Group for Sarcopenia 2019 criteria. Cox proportional hazards regression models were used to evaluate the effect of possible sarcopenia on new-onset T2DM. RESULTS: In total, 3,707 individuals were enrolled in this study, with a median age of 66 years; the prevalence of possible sarcopenia was 45.1%. During the 7-year follow-up, 575 cases (15.5%) of incident diabetes were identified. Participants with possible sarcopenia were more likely to have new-onset T2DM than those without possible sarcopenia (hazard ratio: 1.27, 95% confidence interval: 1.07-1.50; p = 0.006). In subgroup analysis, we found a significant association between possible sarcopenia and T2DM in individuals aged < 75 years or with a BMI < 24 kg/m². However, this association was not significant in individuals aged ≥ 75 years or with a BMI ≥ 24 kg/m². CONCLUSIONS: Possible sarcopenia is associated with an increased risk of new-onset T2DM in older adults, especially in individuals who are not overweight and aged 75 years or younger.
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Diabetes Mellitus Tipo 2 , Sarcopenia , Humanos , Anciano , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Estudios de Cohortes , Estudios Longitudinales , Sarcopenia/diagnóstico , Sarcopenia/epidemiología , Sarcopenia/complicaciones , Jubilación , China/epidemiología , Factores de RiesgoRESUMEN
Diabetic cardiomyopathy (DCM) is one of the main complications in type I diabetic patients. Activated macrophage is critical for directing the process of inflammation during the development of DCM. The present study focused on the roles of CD226 on macrophage function during the DCM progression. It has been found that the number of cardiac macrophages in the hearts of streptozocin (STZ)-induced diabetes mice was significantly increased compared with that in non-diabetes mice, and the expression level of CD226 on cardiac macrophages in STZ-induced diabetes mice was higher than that in non-diabetes mice. CD226 deficiency attenuated the diabetes-induced cardiac dysfunction and decreased the proportion of CD86+ F4/80+ macrophages in the diabetic hearts. Notably, adoptive transfer of Cd226-/- - bone marrow derived macrophages (BMDMs) alleviated diabetes-induced cardiac dysfunction, which may be due to the attenuated migration capacity of Cd226-/- -BMDM under high glucose stimulation. Furthermore, CD226 deficiency decreased the macrophage glycolysis accompanying by the downregulated hexokinase 2 (HK2) and lactate dehydrogenase A (LDH-A) expression. Taken together, these findings revealed the pathogenic roles of CD226 played in the process of DCM and provided a basis for the treatment of DCM.
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Antígenos de Diferenciación de Linfocitos T , Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Animales , Ratones , Diabetes Mellitus Experimental/complicaciones , Glucólisis , Corazón , Macrófagos , Antígenos de Diferenciación de Linfocitos T/genéticaRESUMEN
The initial formation of the follicular antrum (iFFA) serves as a dividing line between gonadotropin-independent and gonadotropin-dependent folliculogenesis, enabling the follicle to sensitively respond to gonadotropins for its further development. However, the mechanism underlying iFFA remains elusive. Herein, we reported that iFFA is characterized by enhanced fluid absorption, energy consumption, secretion, and proliferation and shares a regulatory mechanism with blastula cavity formation. By use of bioinformatics analysis, follicular culture, RNA interference, and other techniques, we further demonstrated that the tight junction, ion pumps, and aquaporins are essential for follicular fluid accumulation during iFFA, as a deficiency of any one of these negatively impacts fluid accumulation and antrum formation. The intraovarian mammalian target of rapamycin-C-type natriuretic peptide pathway, activated by follicle-stimulating hormone, initiated iFFA by activating tight junction, ion pumps, and aquaporins. Building on this, we promoted iFFA by transiently activating mammalian target of rapamycin in cultured follicles and significantly increased oocyte yield. These findings represent a significant advancement in iFFA research, further enhancing our understanding of folliculogenesis in mammals.
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Acuaporinas , Uniones Estrechas , Animales , Femenino , Acuaporinas/genética , Hormona Folículo Estimulante , Gonadotropinas , Bombas Iónicas , Mamíferos , Serina-Treonina Quinasas TOR/genética , Ratones , Péptido Natriurético Tipo-C/metabolismoRESUMEN
In this study, CaO2 was used as a capping material to control the release of Phosphate (P) and tungsten (W) from the sediment due to its oxygen-releasing and oxidative properties. The results revealed significant decreases in SRP and soluble W concentrations after the addition of CaO2. The mechanisms of P and W adsorption by CaO2 were mainly chemisorption and ligand exchange mechanisms. In addition, the results showed significant increases in HCl-P and amorphous and poorly crystalline(oxyhydr)oxides bound W after the addition of CaO2. The highest reduction rates of sediment SRP and soluble W release were 37 and 43%, respectively. Furthermore, CaO2 can promote the redox of iron (Fe) and manganese (Mn). On the other hand, a significant positive correlation was observed between SRP/soluble W and soluble Fe (II) and between SRP/soluble W and soluble Mn, indicating that the effects of CaO2 on Fe and Mn redox play a crucial role in controlling P and W releases from sediments. However, the redox of Fe plays a key role in controlling sediment P and W release. Therefore, CaO2 addition can simultaneously inhibit sediment internal P and W release.
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Fósforo , Contaminantes Químicos del Agua , Tungsteno , Contaminantes Químicos del Agua/análisis , Sedimentos Geológicos , ManganesoRESUMEN
Natural killer cell-based immunotherapy has become a leading-edge tool against cancer, but still faces a variety of challenges, such as phenotype shift and dysfunction of NK cells in tumor microenvironment. Thus, finding potent agents that could inhibit the phenotype shift and incapacity of NK cells in the tumor microenvironment is essential for improving antitumor effects. dl-tetrahydropalmatine (dl-THP), one of the active alkaloids of Chinese herb Corydalis Rhizoma, has been proven to possess antitumor activity. However, whether dl-THP acts on NK cells to enhance antitumor activity remains unknown. In this study, we found that the proportion of blood CD56dimCD16+ NK cells was decreased while the proportion of CD56brightCD16- NK cells was increased when the cells were cultured in conditional medium (CM, medium from the human choriocarcinoma cell lines JEG-3). dl-THP could alter the varied proportion of CD56dimCD16+ NK cells and CD56brightCD16- NK cells in CM respectively. Importantly, the expression level of NKp44 on CD56dimCD16+ NK cells was dramatically reduced when the cells were cultured in CM, which could also be reversed by dl-THP. Furthermore, dl-THP increased the decreased NK-cell cytotoxicity when cells were cultured in CM. In summary, our study demonstrated that dl-THP could recover the decreased NKp44 expression level on CD56dimCD16+ NK cells and restore the cytotoxicity of NK cells in tumor microenvironment.
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Alcaloides de Berberina , Células Asesinas Naturales , Humanos , Línea Celular Tumoral , Antígeno CD56/metabolismo , Células Asesinas Naturales/metabolismo , Receptores de IgG/metabolismoRESUMEN
Myocardial injury as one of the severe complications leads to the increasing morbidity and mortality in patients with sepsis. Recent studies reported that reactive oxygen species (ROS)-mediated ferroptosis plays a critical role in the development of heart diseases. Therefore, we hypothesized that anti-ferroptosis agent might be a novel potential therapeutic strategy for sepsis-induced cardiac injury. Herein, we demonstrated that a small biocompatible and MRI-visible melanin nanoparticles (MMPP) improves myocardial function by inhibiting ROS-related ferroptosis signaling pathway. In LPS-induced murine sepsis model, after a single dose intravenously injection of MMPP treatment, MMPP markedly alleviated the myocardial injury including cardiac function and heart structure disorder through suppressing iron-accumulation induced ferroptosis. In vitro, MMPP inhibited cardiomyocyte death by attenuating oxidative stress, inflammation and maintaining mitochondrial homeostasis. Collectively, our findings demonstrated that MMPP protected heart against sepsis-induced myocardial injury via inhibiting ferroptosis and inflammation, which might be a novel therapeutic approach in future.
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BACKGROUND: The filamentous fungus Trichoderma reesei is a widely used workhorse for cellulase production in industry due to its prominent secretion capacity of extracellular cellulolytic enzymes. However, some key components are not always sufficient in this cellulase cocktail, making the conversion of cellulose-based biomass costly on the industrial scale. Development of strong and efficient promoters would enable cellulase cocktail to be optimized for bioconversion of biomass. RESULTS: In this study, a synthetic hybrid promoter was constructed and applied to optimize the cellulolytic system of T. reesei for efficient saccharification towards corncob residues. Firstly, a series of 5' truncated promoters in different lengths were established based on the strong constitutive promoter Pcdna1. The strongest promoter amongst them was Pcdna1-3 (- 640 to - 1 bp upstream of the translation initiation codon ATG), exhibiting a 1.4-fold higher activity than that of the native cdna1 promoter. Meanwhile, the activation region (- 821 to - 622 bp upstream of the translation initiation codon ATG and devoid of the Cre1-binding sites) of the strong inducible promoter Pcbh1 was cloned and identified to be an amplifier in initiating gene expression. Finally, this activation region was fused to the strongest promoter Pcdna1-3, generating the novel synthetic hybrid promoter Pcc. This engineered promoter Pcc drove strong gene expression by displaying 1.6- and 1.8-fold stronger fluorescence intensity than Pcbh1 and Pcdna1 under the inducible condition using egfp as the reporter gene, respectively. Furthermore, Pcc was applied to overexpress the Aspergillus niger ß-glucosidase BGLA coding gene bglA and the native endoglucanase EG2 coding gene eg2, achieving 43.5-fold BGL activity and 1.2-fold EG activity increase, respectively. Ultimately, to overcome the defects of the native cellulase system in T. reesei, the bglA and eg2 were co-overexpressed under the control of Pcc promoter. The bglA-eg2 double expression strain QPEB70 exhibited a 178% increase in total cellulase activity, whose cellulase system displayed 2.3- and 2.4-fold higher saccharification efficiency towards acid-pretreated and delignified corncob residues than the parental strain, respectively. CONCLUSIONS: The synthetic hybrid promoter Pcc was generated and employed to improve the cellulase system of T. reesei by expressing specific components. Therefore, construction of synthetic hybrid promoters would allow particular cellulase genes to be expressed at desired levels, which is a viable strategy to optimize the cellulolytic enzyme system for efficient biomass bioconversion.
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Celulasa/genética , Celulasa/metabolismo , Hypocreales/genética , Hypocreales/metabolismo , Regiones Promotoras Genéticas , Zea mays/metabolismo , Biomasa , Celulosa/metabolismo , Proteínas Fúngicas/genética , Zea mays/microbiologíaRESUMEN
Early folliculogenesis begins with the activation of the follicle and ends with the formation of the follicular antrum, which takes up most of the time of folliculogenesis. In this long process, follicles complete a series of developmental events, including but not limited to granulosa cell (GC) proliferation, theca folliculi formation, and antrum formation. However, the logical or temporal sequence of these events is not entirely clear. This study demonstrated in a mouse model that completion of early folliculogenesis required a minimum of two weeks. The oocyte reached its largest size in the Type 4-5 stage, which was therefore considered as the optimum period for studying oogenesis. Postnatal days (PD) 10-12 were regarded as the crucial stage of theca folliculi formation, as Lhcgr sharply increased during this stage. PD13-15 was the rapid growth period of early follicles, which was characterized by rapid cell proliferation, the sudden emergence of the antrum, and increased Fshr expression. The ovarian morphology remained stable during PD15-21, but antrum follicles accumulated gradually. Atresia occurred at all stages, with the lowest rate in Type 3 follicles and no differences among early Type 4-6 follicles. The earliest vaginal opening was observed at PD24, almost immediately after the first growing follicular wave. Therefore, the period of PD22-23 could be considered as a suitable period for studying puberty initiation. This study objectively revealed the pattern of early folliculogenesis and provided time windows for the study of biological events in this process.
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Regulación del Desarrollo de la Expresión Génica , Células de la Granulosa/citología , Oogénesis , Folículo Ovárico/citología , Maduración Sexual , Animales , Ciclo Celular , Proliferación Celular , Femenino , Células de la Granulosa/metabolismo , Masculino , Ratones , Folículo Ovárico/metabolismoRESUMEN
BACKGROUND: Progranulin (PGRN) and its potential receptor Eph-receptor tyrosine kinase-type A2 (EphA2) are inflammation-related molecules that present on the atherosclerotic plaques. However, the roles of circulating PGRN and EphA2 in coronary artery disease (CAD) remain unclear. OBJECTIVE: To study the clinical significance of circulating PGRN and EphA2 levels in Chinese patients undergoing coronary angiography. METHODS: Levels of circulating EphA2 fragments and PGRN were examined in 201 consecutive individuals who underwent coronary angiography for suspected CAD in our center from Jan 2020 to Oct 2020. Demographic characteristics, results of biochemical and auxiliary examinations, and other relevant information were collected. The coronary atheroma burden was quantified by the Gensini score and the existence of chronic total occlusion (CTO). Univariate analysis and multivariate logistic regression analysis were used to analyze the risk factors for acute coronary syndrome (ACS). In patients with ACS and SAP, a receiver operating characteristic (ROC) curve was generated to detect the accuracy and discriminative ability of levels of EphA2 and PGRN, the Gensini score, and cardiac injury biomarkers as surrogate endpoints for CTO. RESULTS: Circulating EphA2 levels were significantly higher in patients with ACS than in subjects with stable angina pectoris (SAP) or control subjects (p < 0.001). A positive linear correlation was verified between EphA2 levels and the Gensini score (r = 0.306, p < 0.001), and negative correlation was detected with the left ventricular ejection fraction (LVEF) (r = -0.405, p < 0.001). Both PGRN and EphA2 were positively associated with cardiac injury biomarkers (i.e., NT-proBNP, cTnT, and hs-CRP) (p < 0.05). The area under the ROC curve of PGRN and EphA2 was 0.604 and 0.686, respectively (p < 0.01). CONCLUSIONS: Higher circulating EphA2 and PGRN levels were detected in patients with ACS than in patients with SAP. Circulating EphA2 and PGRN levels might be diagnostic factors for predicting the atheroma burden in patients with CAD.