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1.
Diabetol Metab Syndr ; 16(1): 187, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39090745

RESUMEN

BACKGROUND: Limited research has explored the potential association between the Triglyceride-Glucose (TyG) and mortality, especially in individuals with Helicobacter pylori (H. pylori) infection. This study seeks to investigate the correlation between the TyG index and H. pylori infection and investigate whether the associations between the TyG index exposure and all-cause mortality are mediated by H. pylori infection. METHODS: The study utilized data from the National Health and Nutrition Examination Survey (NHANES) 1999-2018, incorporating a final sample size of 2,187 participants. Both univariable and multivariable-adjusted logistic regression analyses were employed to examine the relationship between H. pylori infection and relevant covariates. To assess the association between TyG index, and all-cause mortality in individuals with or without H. pylori infection, Cox regression analysis, and restricted regression cubic spline analysis were implemented. RESULTS: A significant positive correlation was observed between the TyG index and an elevated risk of H. pylori infection [OR 1.157, 95% CI (1.383 ~ 1.664)]. This correlation persisted even after adjusting for confounding factors [OR 1.189, 95% CI (1.003, 1.411), P < 0.05]. Furthermore, in patients with positive H. pylori infection, a noteworthy nonlinear correlation between the TyG index and all-cause mortality was identified (P = 0.0361). With an increase in the TyG index, all-cause mortality exhibited a corresponding rise, particularly following adjustment for all potential confounding factors. Conversely, in patients with negative H. pylori infection, no significant association was observed between the TyG index and all-cause mortality after adjusting for potential confounding factors. CONCLUSION: A higher TyG index was linked to increased H. pylori infection risks. Participants in the higher quantile group of the TyG index are positively associated with higher all-cause mortality compared to the higher quantile group of the TyG index in H. pylori-positive participants instead of H. pylori-negative participants.

2.
Acta Diabetol ; 2024 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-39096328

RESUMEN

AIMS: The relationship between frailty and mortality among individuals with varying diabetic statuses represents a burgeoning area of concern and scholarly interest within the medical community. However, there are limited studies that explore the relationship between frailty and mortality, as well as cause-specific mortality among individuals with non-diabetes, prediabetes, and diabetes patients. Hence, this study aims to investigate the relationship between the frailty statues and all-cause mortality, as well as cause-specific mortality in individuals with varying diabetic statuses using the data in the NHANES database. METHODS: The study utilized data from the National Health and Nutrition Examination Survey (NHANES) 1999-2018, incorporating a final sample size of 57, 098 participants. Both univariable and multivariable-adjusted logistic regression analyses, as well as Cox regression analysis were employed to examine the relationship between frailty index (FI) and mortality. RESULTS: This study, found a significant positive correlation between the frailty and the increased risk of all-cause mortality non-diabetic [OR 4.277, 95%CI (3.982, 4.594), P < 0.001], prediabetic [OR 2.312, 95%CI (2.133, 2.506), P < 0.001], and diabetic patients [OR 3.947, 95%CI (3.378, 4.611), P < 0.001]. This correlation still existed even after adjusting for confounding factors including age, sex, BMI, poverty, fasting insulin, education, smoke, alcohol drink, waist, hypertension, hyperlipidemia, fasting glucose, HbA1c, eGFR, creatinine and total bilirubin. Our result also suggested a significant positive correlation between the frailty index and the increased risk of CVD mortality among non-diabetic [OR 3.095, 95%CI (2.858, 3.352), P < 0.001] and prediabetic [OR 5.985, 95%CI (5.188, 6.904), P < 0.001] individuals. However, in patients with diabetes, the correlation between frailty and CVD mortality lost significance after adjusting for possible confounding factors [OR 1.139, 95%CI (0.794, 1.634), P > 0.05]. CONCLUSION: A nonlinear relationship has been identified between the FI and all-cause mortality, as well as CVD mortality in non-diabetic and pre-diabetic population. In diabetic patients, there was a significant positive correlation between the frailty and the increased risk of all-cause mortality, but not with CVD mortality. Renal function and liver function might potentially acted as an intermediary factor that elevated the risk of CVD mortality in frail patients with diabetes.

4.
Spectrochim Acta A Mol Biomol Spectrosc ; 322: 124805, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-39003827

RESUMEN

A novel fluorimetric ratiometric probe of green and eco-friendily nitrogen-enriched, oxygen-doped carbon nanodots (Cnanodots) was prepared for the quantitative analysis of mercury(II) (HgII) and nitrofurantoin (Nit) in the environmental sewage. The Cnanodots exhibits dual-emission peaks respectively at 345 and 445 nm under 285 nm excitation, with excitation-independent properties. Unexpectedly, this Cnanodots displays two obvious ratiometric responses to HgII and Nit through decreasing the signal at 345 nm and remaining invariable at 445 nm. Experimental results confirm that the highly sensitive analysis of HgII and Nit are achieved respectively based on matching energy-level electron transfer and inner filter effect mechanisms. The fluorescence (FL) ratiometric intensity of [FL345nm/FL445nm] expresses a good linear relationship with the concentration of HgII in the scope of 0.01-20 µM, while the logarithm of [Log(FL0345nm-FL345nm)] on the quenching degree of the probe by Nit also shows a good linear correlation within the range of 0.01-100 µM. The detection limits were calculated to be 4.14 nM for HgII, and 7.84 nM for Nit. Moreover, recovery experiments of Cnanodots for HgII and Nit sensing in real sewage samples obtained satisfactory results, comfirming the feasibility of practical application.

5.
Front Plant Sci ; 15: 1374431, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39006956

RESUMEN

Plant-parasitic nematodes (PPNs) are among the most damaging pathogens to host plants. Plants can modulate their associated bacteria to cope with nematode infections. The tritrophic plant-nematode-microbe interactions are highly taxa-dependent, resulting in the effectiveness of nematode agents being variable among different host plants. Ficus tikoua is a versatile plant with high application potential for fruits or medicines. In recent years, a few farmers have attempted to cultivate this species in Sichuan, China, where parasitic nematodes are present. We used 16S rRNA genes to explore the effects of nematode parasitism on root-associated bacteria in this species. Our results revealed that nematode infection had effects on both endophytic bacterial communities and rhizosphere communities in F. tikoua roots, but on different levels. The species richness increased in the rhizosphere bacterial communities of infected individuals, but the community composition remained similar as compared with that of healthy individuals. Nematode infection induces a deterministic assembly process in the endophytic bacterial communities of parasitized organs. Significant taxonomic and functional changes were observed in the endophytic communities of root knots. These changes were characterized by the enrichment of nitrogen-fixing bacteria, including Bradyrhizobium, Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium, and nematode-antagonistic bacteria, such as Pseudonocardia, Pseudomonas, Steroidobacter, Rhizobacter, and Ferrovibrio. Our results would help the understanding of the tritrophic plant-nematode-bacterium interactions in host plants other than dominant crops and vegetables and would provide essential information for successful nematode management when F. tikoua were cultivated on large scales.

6.
Ultrason Sonochem ; 109: 106997, 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-39032370

RESUMEN

This study aimed to investigate the effect of ultrasound treatment times (30 min and 60 min) and levels of quinoa protein (QPE) addition (1 % and 2 %) on the quality of Chinese style reduced-salt pork meatballs, commonly known as lion's head. The water-holding capacity (WHC), gel and rheology characteristics, and protein conformation were assessed. The results indicated that extending the ultrasound treatment time and elevating the quinoa protein content caused conspicuous improvements (P<0.05) in the cooking yield, WHC, textural characteristics, color difference, and salt-soluble protein (SSP) solubility of the meatballs. Furthermore, the structural alterations induced by the ultrasound treatment combined with quinoa protein addition included enhancement in ß-sheet, ß-turn, and random coil structure contents, along with a red-shift in the intrinsic fluorescence peak. Additionally, the storage (G') and loss modulus (G'') of the raw meatballs significantly enhanced (P<0.05), indicating a denser gel structure in parallel with the microstructure. In conclusion, the findings demonstrated that ultrasound combined with quinoa protein enhanced the WHC and texture properties of Chinese style reduced-salt pork meatballs by improving SSP solubility.

7.
World J Clin Cases ; 12(18): 3321-3331, 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38983415

RESUMEN

BACKGROUND: Sudden sensorineural hearing loss (SSNHL), characterized by a rapid and unexplained loss of hearing, particularly at moderate to high frequencies, presents a significant clinical challenge. The therapeutic use of methylprednisolone sodium succinate (MPSS) via different administration routes, in combination with conventional medications, remains a topic of interest. AIM: To compare the therapeutic efficacy of MPSS administered via different routes in combination with conventional drugs for the treatment of mid- to high-frequency SSNHL. METHODS: The medical records of 109 patients with mid- to high-frequency SSNHL were analyzed. The patients were divided into three groups based on the route of administration: Group A [intratympanic (IT) injection of MPSS combined with mecobalamin and Ginkgo biloba leaf extract injection], Group B (intravenous injection of MPSS combined with mecobalamin and Ginkgo biloba leaf extract injection), and Group C (single IT injection of MPSS). The intervention effects were compared and analyzed. RESULTS: The posttreatment auditory thresholds in Group A (21.23 ± 3 .34) were significantly lower than those in Groups B (28.52 ± 3.36) and C (30.23 ± 4.21; P < 0.05). Group A also exhibited a significantly greater speech recognition rate (92.23 ± 5.34) than Groups B and C. The disappearance time of tinnitus, time to hearing recovery, and disappearance time of vertigo in Group A were significantly shorter than those in Groups B and C (P < 0.05). The total effective rate in Group A (97.56%) was significantly greater than that in Groups B and C (77.14% and 78.79%, χ 2 = 7.898, P = 0.019). Moreover, the incidence of adverse reactions in Groups A and C was significantly lower than that in Group B (4.88%, 3.03% vs 2.57%, χ 2 = 11.443, P = 0.003), and the recurrence rate in Group A was significantly lower than that in Groups B and C (2.44% vs 20.00% vs 21.21%, χ 2 = 7.120, P = 0.028). CONCLUSION: IT injection of MPSS combined with conventional treatment demonstrates superior efficacy and safety compared to systemic administration via intravenous infusion and a single IT injection of MPSS. This approach effectively improves patients' hearing and reduces the risk of disease recurrence.

8.
J Ultrasound Med ; 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38975721

RESUMEN

OBJECTIVES: To establish a reliable ultrasound (US) method of evaluating dynamic extrusion of lateral meniscus in healthy population, and to investigate the pattern of dynamic meniscus extrusion (ME) in lateral meniscus under loading conditions. METHODS: The lateral ME was examined via US method in unloaded, double-leg standing, and single-leg standing positions. Two different US measurement methods were compared to the magnetic resonance imaging (MRI) results to determine the optimal measurement methods. The US results obtained by different researchers were tested for interobserver consistency and the results obtained by the same researcher on two separate days were tested for intraobserver consistency. The patterns of dynamic extrusion were compared between medial and lateral sides. RESULTS: A total of healthy 44 volunteers were included in the study, with 86 knees assessed by US, and 25 knees evaluated by MRI. The US evaluation of dynamic lateral ME demonstrated excellent interobserver and intraobserver reliability. The US measurements using method A were consistent with the MRI results with no significant difference (P = .861, intraclass correlation coefficient [ICC] = 0.868), while method B underestimated the lateral ME compared to MRI (P = .001, ICC = 0.649). Lateral ME decreased slightly from unloaded (1.0 ± 0.8 mm) to single-leg standing position (0.8 ± 0.8 mm), whereas medial ME increased significantly in both double-leg and single-leg standing positions (2.4 ± 0.7 mm, 2.6 ± 0.7 mm). CONCLUSION: A novel US evaluation method of lateral ME was established with reliable and accurate results compared to the MRI. Lateral ME in healthy populations decreased slightly as the loadings increased, which was different from the pattern of dynamic extrusion in medial meniscus.

10.
Gut ; 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38955401

RESUMEN

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5 (STAT5) is a transcription factor implicated in the progression of various cancer types. However, its role in KRAS-driven pancreatic tumourigenesis remains unclear. DESIGN: We performed studies with LSL-Kras G12D; Ptf1a-Cre ERT (KCERT) mice or LSL-KrasG12D; LSL-Trp53R172H ; Pdx1-Cre (KPC) mice crossed with conditional disruption of STAT5 or completed deficiency interleukin (IL)-22. Pancreatitis was induced in mice by administration of cerulein. Pharmacological inhibition of STAT5 on PDAC prevention was studied in the orthotopic transplantation and patient-derived xenografts PDAC model, and KPC mice. RESULTS: The expression and phosphorylation of STAT5 were higher in human PDAC samples than control samples and high levels of STAT5 in tumour cells were associated with a poorer prognosis. The loss of STAT5 in pancreatic cells substantially reduces the KRAS mutation and pancreatitis-derived acinar-to-ductal metaplasia (ADM) and PDAC lesions. Mechanistically, we discovered that STAT5 binds directly to the promoters of ADM mediators, hepatocyte nuclear factor (HNF) 1ß and HNF4α. Furthermore, STAT5 plays a crucial role in maintaining energy metabolism in tumour cells during PDAC progression. IL-22 signalling induced by chronic inflammation enhances KRAS-mutant-mediated STAT5 phosphorylation. Deficiency of IL-22 signalling slowed the progression of PDAC and ablated STAT5 activation. CONCLUSION: Collectively, our findings identified pancreatic STAT5 activation as a key downstream effector of oncogenic KRAS signalling that is critical for ADM initiation and PDAC progression, highlighting its potential therapeutic vulnerability.

11.
BMC Cancer ; 24(1): 912, 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39075397

RESUMEN

In oncology anti-PD1 / PDL1 therapy development for solid tumors, objective response rate (ORR) is commonly used clinical endpoint for early phase study decision making, while progression free survival (PFS) and overall survival (OS) are widely used for late phase study decision making. Developing predictive models to late phase outcomes such as median PFS (mPFS) and median OS (mOS) based on early phase clinical outcome ORR could inform late phase study design optimization and probability of success (POS) evaluation. In existing literature, there are ORR / mPFS / mOS association and surrogacy investigations with limited number of included clinical trials. In this paper, without establishing surrogacy, we attempt to predict late phase survival (mPFS and mOS) based on early efficacy ORR and optimize late phase trial design for anti-PD1 / PDL1 therapy development. In order to include adequate number of eligible clinical trials, we built a comprehensive quantitative clinical trial landscape database (QLD) by combining information from different sources such as clinicaltrial.gov, publications, company press releases for relevant indications and therapies. We developed a generalizable algorithm to systematically extract structured data for scientific accuracy and completeness. Finally, more than 150 late phase clinical trials were identified for ORR / mPFS (ORR / mOS) predictive model development while existing literature included at most 50 trials. A tree-based machine learning regression model has been derived to account for ORR / mPFS (ORR / mOS) relationship heterogeneity across tumor type, stage, line of therapy, treatment class and borrow strength simultaneously when homogeneity persists. The proposed method ensures that the predictive model is robust and have explicit structure for clinical interpretation. Through cross validation, the average predictive mean square error of the proposed model is competitive to random forest and extreme gradient boosting methods and outperforms commonly used additive or interaction linear regression models. An example application of the proposed ORR / mPFS (ORR / mOS) predictive model on late phase trial POS evaluation for anti-PD1 / PDL1 combination therapy was illustrated.


Asunto(s)
Antígeno B7-H1 , Neoplasias , Receptor de Muerte Celular Programada 1 , Supervivencia sin Progresión , Humanos , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Ensayos Clínicos como Asunto
12.
World J Gastrointest Oncol ; 16(7): 3097-3117, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-39072176

RESUMEN

BACKGROUND: Gastric cancer (GC) is one of the most common malignancies worldwide. Glycolysis has been demonstrated to be pivotal for the carcinogenesis of GC. AIM: To develop a glycolysis-based gene signature for prognostic evaluation in GC patients. METHODS: Differentially expressed genes correlated with glycolysis were identified in stomach adenocarcinoma data (STAD). A risk score was established through a univariate Cox and least absolute shrinkage and selection operator analysis. The model was evaluated using the area under the receiver operating characteristic curves. RNA-sequencing data from high- and low-glycolysis groups of STAD patients were analyzed using Cibersort algorithm and Spearman correlation to analyze the interaction of immune cell infiltration and glycolysis. Multiomics characteristics in different glycolysis status were also analyzed. RESULTS: A five-gene signature comprising syndecan 2, versican, malic enzyme 1, pyruvate carboxylase and SRY-box transcription factor 9 was constructed. Patients were separated to high- or low-glycolysis groups according to risk scores. Overall survival of patients with high glycolysis was poorer. The sensitivity and specificity of the model in prediction of survival of GC patients were also observed by receiver operating characteristic curves. A nomogram including clinicopathological characteristics and the risk score also showed good prediction for 3- and 5-year overall survival. Gene set variation analysis showed that high-glycolysis patients were related to dysregulation of pancreas beta cells and estrogen late pathways, and low-glycolysis patients were related to Myc targets, oxidative phosphorylation, mechanistic target of rapamycin complex 1 signaling and G2M checkpoint pathways. Tumor-infiltrating immune cells and multiomics analysis suggested that the different glycolysis status was significantly correlated with multiple immune cell infiltration. The patients with high glycolysis had lower tumor mutational burden and neoantigen load, higher incidence of microsatellite instability and lower chemosensitivity. High glycolysis status was often found among patients with grade 2/3 cancer or poor prognosis. CONCLUSION: The genetic characteristics revealed by glycolysis could predict the prognosis of GC. High glycolysis significantly affects GC phenotype, but the detailed mechanism needs to be further studied.

13.
Cell Biochem Biophys ; 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39078538

RESUMEN

Systemic lupus erythematosus (SLE) is a classic autoimmune disease characterized by abnormal autoantibodies, immune complex deposition, and tissue inflammation. Despite extensive research, the exact etiology and progression of SLE remain elusive. Cytidine/uridine monophosphate kinase 2 (CMPK2), a mitochondrial nucleoside monophosphate kinase, has garnered attention for its potential involvement in the development of various diseases, including SLE, where it has been observed to be dysregulated in affected individuals. However, the specific involvement of CMPK2 in the pathogenesis of SLE remains unclear. This study aims to clarify the expression level of CMPK2 in SLE CD4+ T cells and explore its impact on CD4+ T cells. The expression levels of the CMPK2 gene and the corresponding CMPK2 protein in CD4+ T cells of SLE patients were quantified using RT-qPCR and Western blot, respectively. Immunofluorescence and RT-qPCR were used to assess the mitochondrial function of SLE CD4+ T cells. Flow cytometry was used to assess CD4+ T cell activation and apoptosis levels. The impact of CMPK2 on CD4+ T cells was investigated by gene transfection experiment. We found that CMPK2 was significantly upregulated in SLE CD4+ T cells at both gene and protein levels. These cells demonstrated aberrant mitochondrial function, as evidenced by elevated mitochondrial reactive oxygen species (mtROS) levels, mitochondrial membrane potential, and mitochondrial DNA (mtDNA) copy number. Flow cytometry revealed a notable increase in both apoptosis and activation levels of CD4+ T cells in SLE patients. Gene transfection experiments showed that suppressing CMPK2 led to a significant improvement in these conditions. These findings suggest that CMPK2 may be involved in the pathogenesis of SLE by regulating mitochondrial dysfunction in CD4+ T cells and thus affecting CD4+ T cell activation and apoptosis. Our study may provide a new target for the treatment of SLE.

14.
Theranostics ; 14(8): 3104-3126, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38855191

RESUMEN

Background: The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic and epigenetic programs. A comprehensive characterization and mapping of the cell-of-origin of breast cancer using novel technologies to unveil novel subtype-specific therapeutic targets is still absent. Methods: We integrated 195,144 high-quality cells from normal breast tissues and 406,501 high-quality cells from primary breast cancer samples to create a large-scale single-cell atlas of human normal and cancerous breasts. Potential heterogeneous origin of malignant cells was explored by contrasting cancer cells against reference normal epithelial cells. Multi-omics analyses and both in vitro and in vivo experiments were performed to screen and validate potential subtype-specific treatment targets. Novel biomarkers of identified immune and stromal cell subpopulations were validated by immunohistochemistry in our cohort. Results: Tumor stratification based on cancer cell-of-origin patterns correlated with clinical outcomes, genomic aberrations and diverse microenvironment constitutions. We found that the luminal progenitor (LP) subtype was robustly associated with poor prognosis, genomic instability and dysfunctional immune microenvironment. However, the LP subtype patients were sensitive to neoadjuvant chemotherapy (NAC), PARP inhibitors (PARPi) and immunotherapy. The LP subtype-specific target PLK1 was investigated by both in vitro and in vivo experiments. Besides, large-scale single-cell profiling of breast cancer inspired us to identify a range of clinically relevant immune and stromal cell subpopulations, including subsets of innate lymphoid cells (ILCs), macrophages and endothelial cells. Conclusion: The present single-cell study revealed the cellular repertoire and cell-of-origin patterns of breast cancer. Combining single-cell and bulk transcriptome data, we elucidated the evolution mimicry from normal to malignant subtypes and expounded the LP subtype with vital clinical implications. Novel immune and stromal cell subpopulations of breast cancer identified in our study could be potential therapeutic targets. Taken together, Our findings lay the foundation for the precise prognostic and therapeutic stratification of breast cancer.


Asunto(s)
Neoplasias de la Mama , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Análisis de la Célula Individual/métodos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Microambiente Tumoral/inmunología , Animales , Ratones , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Pronóstico
15.
Adv Sci (Weinh) ; : e2308243, 2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38881520

RESUMEN

Cell-free DNA (cfDNA) fragmentation patterns have immense potential for early cancer detection. However, the definition of fragmentation varies, ranging from the entire genome to specific genomic regions. These patterns have not been systematically compared, impeding broader research and practical implementation. Here, 1382 plasma cfDNA sequencing samples from 8 cancer types are collected. Considering that cfDNA within open chromatin regions is more susceptible to fragmentation, 10 fragmentation patterns within open chromatin regions as features and employed machine learning techniques to evaluate their performance are examined. All fragmentation patterns demonstrated discernible classification capabilities, with the end motif showing the highest diagnostic value for cross-validation. Combining cross and independent validation results revealed that fragmentation patterns that incorporated both fragment length and coverage information exhibited robust predictive capacities. Despite their diagnostic potential, the predictive power of these fragmentation patterns is unstable. To address this limitation, an ensemble classifier via integrating all fragmentation patterns is developed, which demonstrated notable improvements in cancer detection and tissue-of-origin determination. Further functional bioinformatics investigations on significant feature intervals in the model revealed its impressive ability to identify critical regulatory regions involved in cancer pathogenesis.

16.
J Med Chem ; 67(11): 9536-9551, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38822802

RESUMEN

The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of ortho-aminophenol derivatives as potential ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these ortho-aminophenol derivatives exhibit unique intra-H bond interactions, compelling ortho-amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of ferroptosis inhibitors, serving as valuable insights for future structural modifications.


Asunto(s)
Aminofenoles , Ferroptosis , Peroxidación de Lípido , Animales , Aminofenoles/farmacología , Aminofenoles/química , Ferroptosis/efectos de los fármacos , Ratones , Peroxidación de Lípido/efectos de los fármacos , Humanos , Relación Estructura-Actividad , Acetaminofén/farmacología , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Masculino , Descubrimiento de Drogas , Ratones Endogámicos C57BL
17.
Acta Biomater ; 183: 30-49, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38849022

RESUMEN

Bone, an actively metabolic organ, undergoes constant remodeling throughout life. Disturbances in the bone microenvironment can be responsible for pathologically bone diseases such as periodontitis, osteoarthritis, rheumatoid arthritis and osteoporosis. Conventional bone tissue biomaterials are not adequately adapted to complex bone microenvironment. Therefore, there is an urgent clinical need to find an effective strategy to improve the status quo. In recent years, nanotechnology has caused a revolution in biomedicine. Cerium(III, IV) oxide, as an important member of metal oxide nanomaterials, has dual redox properties through reversible binding with oxygen atoms, which continuously cycle between Ce(III) and Ce(IV). Due to its special physicochemical properties, cerium(III, IV) oxide has received widespread attention as a versatile nanomaterial, especially in bone diseases. This review describes the characteristics of bone microenvironment. The enzyme-like properties and biosafety of cerium(III, IV) oxide are also emphasized. Meanwhile, we summarizes controllable synthesis of cerium(III, IV) oxide with different nanostructural morphologies. Following resolution of synthetic principles of cerium(III, IV) oxide, a variety of tailored cerium-based biomaterials have been widely developed, including bioactive glasses, scaffolds, nanomembranes, coatings, and nanocomposites. Furthermore, we highlight the latest advances in cerium-based biomaterials for inflammatory and metabolic bone diseases and bone-related tumors. Tailored cerium-based biomaterials have already demonstrated their value in disease prevention, diagnosis (imaging and biosensors) and treatment. Therefore, it is important to assist in bone disease management by clarifying tailored properties of cerium(III, IV) oxide in order to promote the use of cerium-based biomaterials in the future clinical setting. STATEMENT OF SIGNIFICANCE: In this review, we focused on the promising of cerium-based biomaterials for bone diseases. We reviewed the key role of bone microenvironment in bone diseases and the main biological activities of cerium(III, IV) oxide. By setting different synthesis conditions, cerium(III, IV) oxide nanostructures with different morphologies can be controlled. Meanwhile, tailored cerium-based biomaterials can serve as a versatile toolbox (e.g., bioactive glasses, scaffolds, nanofibrous membranes, coatings, and nanocomposites). Then, the latest research advances based on cerium-based biomaterials for the treatment of bone diseases were also highlighted. Most importantly, we analyzed the perspectives and challenges of cerium-based biomaterials. In future perspectives, this insight has given rise to a cascade of cerium-based biomaterial strategies, including disease prevention, diagnosis (imaging and biosensors) and treatment.


Asunto(s)
Materiales Biocompatibles , Enfermedades Óseas , Cerio , Cerio/química , Cerio/uso terapéutico , Humanos , Materiales Biocompatibles/química , Materiales Biocompatibles/uso terapéutico , Enfermedades Óseas/tratamiento farmacológico , Animales
18.
Nano Lett ; 24(26): 8134-8142, 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38900138

RESUMEN

Developing highly efficient and carbon monoxide (CO)-tolerant platinum (Pt) catalysts for the formic acid oxidation reaction (FAOR) is vital for direct formic acid fuel cells (DFAFCs), yet it is challenging due to the high energy barrier of direct intermediates (HCOO* and COOH*) as well as the CO poisoning issues associated with Pt alloy catalysts. Here we present a versatile biphasic strategy by creating a hexagonal/cubic crystalline-phase-synergistic PtPb/C (h/c-PtPb/C) catalyst to tackle the aforementioned issues. Detailed investigations reveal that h/c-PtPb/C can simultaneously facilitate the adsorption of direct intermediates while inhibiting CO adsorption, thereby significantly improving the activation and CO spillover. As a result, h/c-PtPb/C showcases an outstanding FAOR activity of 8.1 A mgPt-1, which is 64.5 times higher than that of commercial Pt/C and significantly surpasses monophasic PtPb. Moreover, the h/c-PtPb/C-based membrane electrode assembly exhibits an exceptional peak power density of 258.7 mW cm-2 for practical DFAFC applications.

19.
Pharmacol Res ; 205: 107263, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38876442

RESUMEN

Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a challenge in clinical management. Mixed-lineage leukemia 4 (MLL4) is a member of the SET family of histone methyltransferase enzymes, which possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity. However, whether and how MLL4 regulates cardiac function is not reported in adult HF. Here we report that MLL4 is required for endoplasmic reticulum (ER) stress homeostasis of cardiomyocytes and protective against pressure overload-induced cardiac hypertrophy and HF. We observed that MLL4 is increased in the heart tissue of HF mouse model and HF patients. The cardiomyocyte-specific deletion of Mll4 (Mll4-cKO) in mice leads to aggravated ER stress and cardiac dysfunction following pressure overloading. MLL4 knockdown neonatal rat cardiomyocytes (NRCMs) also display accelerated decompensated ER stress and hypertrophy induced by phenylephrine (PE). The combined analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) data reveals that, silencing of Mll4 alters the chromatin landscape for H3K4me1 modification and gene expression patterns in NRCMs. Interestingly, the deficiency of MLL4 results in a marked reduction of H3K4me1 and H3K27ac occupations on Thrombospondin-4 (Thbs4) gene loci, as well as Thbs4 gene expression. Mechanistically, MLL4 acts as a transcriptional activator of Thbs4 through mono-methylation of H3K4 and further regulates THBS4-dependent ER stress response, ultimately plays a role in HF. Our study indicates that pharmacologically targeting MLL4 and ER stress might be a valid therapeutic approach to protect against cardiac hypertrophy and HF.


Asunto(s)
Estrés del Retículo Endoplásmico , Insuficiencia Cardíaca , N-Metiltransferasa de Histona-Lisina , Ratones Endogámicos C57BL , Miocitos Cardíacos , Animales , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/etiología , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Masculino , Humanos , Ratones Noqueados , Ratas , Ratones , Células Cultivadas , Cardiomegalia/metabolismo , Cardiomegalia/genética , Ratas Sprague-Dawley , Trombospondinas
20.
Life Sci ; 352: 122797, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-38917871

RESUMEN

Caries and pulpitis remain a major global disease burden and affect the quality of life of patients. Odontoblasts are key players in the progression of caries and pulpitis, not only secreting and mineralizing to form dentin, but also acting as a wall of defense to initiate immune defenses. Mitochondrion is an information processor for numerous cellular activities, and dysregulation of mitochondrion homeostasis not only affects cellular metabolism but also triggers a wide range of diseases. Elucidating mitochondrial homeostasis in odontoblasts can help deepen scholars' understanding of odontoblast-associated diseases. Articles on mitochondrial homeostasis in odontoblasts were evaluated for information pertinent to include in this narrative review. This narrative review focused on understanding the complex interplay between mitochondrial homeostasis in odontoblasts under physiological and pathological conditions. Furthermore, mitochondria-centered therapeutic strategies (including mitochondrial base editing, targeting platforms, and mitochondrial transplantation) were emphasized by resolving key genes that regulate mitochondrial function. Mitochondria are involved in odontoblast differentiation and function, and act as mitochondrial danger-associated molecular patterns (mtDAMPs) to mediate odontoblast pathological progression. Novel mitochondria-centered therapeutic strategies are particularly attractive as emerging therapeutic approaches for the maintenance of mitochondrial homeostasis. It is expected to probe key events of odontoblast differentiation and advance the clinical resolution of dentin formation and mineralization disorders and odontoblast-related diseases.


Asunto(s)
Homeostasis , Mitocondrias , Odontoblastos , Odontoblastos/metabolismo , Odontoblastos/fisiología , Humanos , Homeostasis/fisiología , Mitocondrias/metabolismo , Mitocondrias/patología , Animales , Caries Dental/patología , Caries Dental/metabolismo , Diferenciación Celular , Pulpitis/metabolismo , Pulpitis/patología
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