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Lipid metabolism, particularly triglyceride (TG) metabolism, is crucial for liver regeneration. During the early phase of liver regeneration, the liver temporarily accumulates a substantial amount of TG-dominated lipids. However, the specific composition of the TG profile during this phase is not yet fully understood. Here, we showed that the TG molecular composition in the liver was significantly altered during liver regeneration following carbon tetrachloride (CCl4)-induced liver injury. Lipid accumulation in livers was observed as early as 12 hours after CCl4 treatment, with transient regeneration-associated steatosis (TRAS) lasting until 24 hours. Hepatocyte proliferation began only after liver lipid levels returned to baseline at 48 hours. Furthermore, the profile of TG species changed significantly during liver regeneration. During the TRAS period, the accumulated TGs in the liver were mainly long-chain triglycerides, with most of the fatty acids constituting these triglycerides having fewer than 20 carbon atoms. In the proliferation phase, the fatty acid composition of these triglycerides shifted from long-chain to ultra-long-chain fatty acids. Our results suggest a significant TRAS-related change in the TG lipid profile of the liver during liver regeneration.
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Macrophages are multifunctional innate immune cells that play indispensable roles in homeostasis, tissue repair, and immune regulation. However, dysregulated activation of macrophages is implicated in the pathogenesis of various human disorders, making them a potential target for treatment. Through the expression of pattern recognition and scavenger receptors, macrophages exhibit selective uptake of pathogens and apoptotic cells. Consequently, the utilization of drug carriers that mimic pathogenic or apoptotic signals shows potential for targeted delivery to macrophages. In this study, a series of mannosylated or/and phosphatidylserine (PS) -presenting liposomes were developed to target macrophages via the design of experiment (DoE) strategy and the trial-and-error (TaE) approach. The optimal molar ratio for the liposome formulation was DOPC: DSPS: Chol: PEG-PE = 20:60:20:2 based on the results of cellular uptake and cytotoxicity evaluation on RAW 264.7 and THP-1 in vitro. Results from in vivo distribution showed that, in the DSS-induced colitis model and collagen II-induced rheumatoid arthritis model, PS-presenting liposomes (PS-Lipo) showed the highest accumulation in intestine and paws respectively, which holds promising potential for macrophage target therapy since macrophages are abundant at inflammatory sites and contribute to the progression of corresponding diseases. Organs such as the heart, liver, spleen, lung, and kidney did not exhibit histological alterations such as inflammation or necrosis when exposed to PC-presenting liposomes (PC-Lipo) or PS-Lipo. In addition, liposomes demonstrated hemobiocompatibility and no toxicity to liver or kidney for circulation and did not induce metabolic injury in the animals. Thus, the well-designed PS-Lipo demonstrated the most potential for macrophage target therapy.
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Apoptosis , Liposomas , Macrófagos , Fosfatidilserinas , Liposomas/química , Animales , Ratones , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Humanos , Células RAW 264.7 , Fosfatidilserinas/metabolismo , Fosfatidilserinas/química , Células THP-1 , Masculino , Ratones Endogámicos C57BL , Sistemas de Liberación de Medicamentos/métodos , Distribución TisularRESUMEN
Acute kidney injury (AKI) is a critical medical condition characterized by high morbidity and mortality rates. The pathogenesis of AKI potentially involves bursts of reactive oxygen species (ROS) bursts and elevated levels of inflammatory mediators. Developing nanoparticles (NPs) that downregulate ROS and inflammatory mediators is a promising approach to treat AKI. However, such NPs would be affected by the glomerular filtration barrier (GFB). Typically, NPs are too large to penetrate the glomerular system and reach the renal tubulesâthe primary site of AKI injury. Herein, we report the development of ultrasmall carbon dots-gallic acid (CDs-GA) NPs (â¼5 nm). These NPs exhibited outstanding biocompatibility and were shown not only to efficiently eliminate ROS and alleviate oxidative stress but also to suppress the activation of the NF-κB signaling pathway, leading to a reduction in the release of inflammatory factors. Importantly, CDs-GA NPs were shown to be able to rapidly accumulate rapidly in the renal tissues without the need for intricate targeting strategies. In vivo studies demonstrated that CDs-GA NPs significantly reduced the incidence of cisplatin (CDDP)-induced AKI in mice, surpassing the efficacy of the small molecular drug, N-acetylcysteine. This research provides an innovative strategy for the treatment of AKI.
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Lesión Renal Aguda , Carbono , Cisplatino , Especies Reactivas de Oxígeno , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Animales , Carbono/química , Carbono/uso terapéutico , Ratones , Especies Reactivas de Oxígeno/metabolismo , Cisplatino/uso terapéutico , Cisplatino/farmacología , Ácido Gálico/farmacología , Ácido Gálico/química , Ácido Gálico/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Nanopartículas/química , Nanopartículas/uso terapéutico , FN-kappa B/metabolismo , Masculino , Puntos Cuánticos/química , Puntos Cuánticos/uso terapéutico , Puntos Cuánticos/toxicidad , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Transducción de Señal/efectos de los fármacosRESUMEN
Glucose oxidase (GOx) is often used to starvation therapy. However, only consuming glucose cannot completely block the energy metabolism of tumor cells. Lactate can support tumor cell survival in the absence of glucose. Here, we constructed a nanoplatform (Met@HMnO2-GOx/HA) that can deplete glucose while inhibiting the compensatory use of lactate by cells to enhance the effect of tumor starvation therapy. GOx can catalyze glucose into gluconic acid and H2O2, and then HMnO2 catalyzes H2O2 into O2 to compensate for the oxygen consumed by GOx, allowing the reaction to proceed sustainably. Furthermore, metformin (Met) can inhibit the conversion of lactate to pyruvate in a redox-dependent manner and reduce the utilization of lactate by tumor cells. Met@HMnO2-GOx/HA nanoparticles maximize the efficacy of tumor starvation therapy by simultaneously inhibiting cellular utilization of two carbon sources. Therefore, this platform is expected to provide new strategies for tumor treatment.
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Cadmium ion (Cd2+) stress is a major abiotic stressor affecting plant photosynthesis. However, the impact of sustained high-concentration Cd stress on the photosynthetic electron transport chain of aquatic plants is currently unclear. Here, prompt fluorescence (PF), delayed fluorescence (DF), and P700 signals were simultaneously measured to investigate the effect of Cd stress on photosynthesis in water dropwort [Oenanthe javanica (Blume) DC.]. We aimed to elucidate how Cd stress continuously affects the electron transport chain in this species. The PF analysis showed that with prolonged Cd stress, the FJ, FI and FP steadily decreased, accompanied by a positive shift in the K-band and L-band. Moreover, JIP-test parameters, including TRO/ABS, ABS/CSO, TRO/CSO and PIABS, were significantly reduced. The P700 signals showed that exposure to Cd stress hindered both the fast decrease and slow increase phases of the MR transient, ultimately resulting in a gradual reduction in both VPSI and VPSII-PSI. The DF analysis showed a gradual decrease in the I1 and I2 values as the duration of stress from Cd increased. The above results suggested that Cd stress affected the photosynthetic electron transport in water dropwort by influencing the amount of active PSII and PSI, primarily affecting PSII RCs in the early to mid-stages and PSI reductive activity in the later stage.
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OBJECTIVES: To investigate the effectiveness of belimumab on active lupus nephritis (LN) and explore the predictors, including serological biomarkers, of renal response to belimumab in a real-world setting. METHODS: This multicentre, real-world observational study enrolled patients with active LN receiving intravenous belimumab as an add-on therapy with 24-hour urine protein≥1 g and estimated glomerular filtration rate≥30 mL/min/1.73 m2 at baseline. Complete renal response (CRR), partial renal response (PRR), no renal response (NRR) and primary efficacy renal response (PERR) were evaluated. Multivariable logistic regression was used to identify risk factors for NRR to belimumab at 6 months. RESULTS: Among the 122 patients enrolled, the proportions of patients achieving CRR, PRR, NRR and PERR were 35.9%, 17.1%, 47.0% and 44.4% at 6 months (n=117) and 55.6%, 19.4%, 26.4% and 58.3% at 12 months (n=72), respectively. Proteinuria, daily prednisone dosage and Systemic Lupus Erythematosus Disease Activity Index 2000 scores significantly decreased at 6 and 12 months (p<0.0001). NRR at 6 months (NRR6) was the strongest negative predictor of CRR at 12 months. Baseline anti-dsDNA positivity inversely predicted NRR6 (OR=0.32,95% CI=0.10 to 0.98, p=0.049), while anti-SSA/Ro60 positively predicted NRR6 (OR=3.16, 95% CI=1.14 to 8.74, p=0.027). The combination of anti-SSA/Ro60 and anti-dsDNA serotype quantitatively predicted belimumab renal response. CONCLUSION: The effectiveness of belimumab was reproducible in Chinese patients with active LN. The simple yet interesting serotype predictive model needs further validation and its possible underlying mechanistic relevance deserves further exploration.
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Anticuerpos Antinucleares , Anticuerpos Monoclonales Humanizados , Tasa de Filtración Glomerular , Inmunosupresores , Nefritis Lúpica , Humanos , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/inmunología , Femenino , Masculino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Adulto , Anticuerpos Antinucleares/sangre , Inmunosupresores/uso terapéutico , Persona de Mediana Edad , Tasa de Filtración Glomerular/efectos de los fármacos , Resultado del Tratamiento , Riñón/fisiopatología , Riñón/efectos de los fármacos , Riñón/inmunología , Biomarcadores/sangre , Adulto Joven , Proteinuria/tratamiento farmacológico , ADNRESUMEN
BACKGROUND: Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a pivotal role in modulating mitochondrial homeostasis. However, their involvement in HF remains unclear. METHODS: Experimental HF models were established through continuous angiotensin II and phenylephrine (AngII/PE) infusion or prolonged myocardial ischemia/reperfusion injury. The landscape of N6-methyladenine (6mA) methylation within failing cardiomyocyte mtDNA was characterized using high-resolution mass spectrometry and methylated DNA immunoprecipitation sequencing. A tamoxifen-inducible cardiomyocyte-specific Mettl4 knockout mouse model and adeno-associated virus vectors designed for cardiomyocyte-targeted manipulation of METTL4 (methyltransferase-like protein 4) expression were used to ascertain the role of mtDNA 6mA and its methyltransferase METTL4 in HF. RESULTS: METTL4 was predominantly localized within adult cardiomyocyte mitochondria. 6mA modifications were significantly more abundant in mtDNA than in nuclear DNA. Postnatal cardiomyocyte maturation presented with a reduction in 6mA levels within mtDNA, coinciding with a decrease in METTL4 expression. However, an increase in both mtDNA 6mA level and METTL4 expression was observed in failing adult cardiomyocytes, suggesting a shift toward a neonatal-like state. METTL4 preferentially targeted mtDNA promoter regions, which resulted in interference with transcription initiation complex assembly, mtDNA transcriptional stalling, and ultimately mitochondrial dysfunction. Amplifying cardiomyocyte mtDNA 6mA through METTL4 overexpression led to spontaneous mitochondrial dysfunction and HF phenotypes. The transcription factor p53 was identified as a direct regulator of METTL4 transcription in response to HF-provoking stress, thereby revealing a stress-responsive mechanism that controls METTL4 expression and mtDNA 6mA. Cardiomyocyte-specific deletion of the Mettl4 gene eliminated mtDNA 6mA excess, preserved mitochondrial function, and mitigated the development of HF upon continuous infusion of AngII/PE. In addition, specific silencing of METTL4 in cardiomyocytes restored mitochondrial function and offered therapeutic relief in mice with preexisting HF, irrespective of whether the condition was induced by AngII/PE infusion or myocardial ischemia/reperfusion injury. CONCLUSIONS: Our findings identify a pivotal role of cardiomyocyte mtDNA 6mA and the corresponding methyltransferase, METTL4, in the pathogenesis of mitochondrial dysfunction and HF. Targeted suppression of METTL4 to rectify mtDNA 6mA excess emerges as a promising strategy for developing mitochondria-focused HF interventions.
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Aqueous supercapacitors have occupied a significant position among various types of stationary energy storage equipment, while their widespread application is hindered by the relatively low energy density. Herein, N/F co-doped carbon materials activated by manganese clusters (NCM) are constructed by the straightforward experimental routine. Benefiting from the elevated conductivity structure at the microscopic level, the optimized NCM-0.5 electrodes exhibited a remarkable specific capacitance of 653 F g-1 at 0.4 A g-1 and exceptional cycling stability (97.39% capacity retention even after 40,000 cycles at the scanning rate of 100 mV s-1) in a neutral 5 M LiCl electrolyte. Moreover, we assembled an asymmetric device pairing with a VOx anode (NCM-0.5//VOx), which delivered a durable life span of 95% capacity retention over 30,000 cycles and an impressive energy density of 77.9 Wh kg-1. This study provides inspiration for transition metal element doping engineering in high-energy storage equipment.
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Therapeutic cancer vaccines fail to produce satisfactory outcomes against solid tumors since vaccine-induced anti-tumor immunity is significantly hampered by immunosuppression. Generating an in situ cancer vaccine targeting immunological cold tumor microenvironment (TME) appears attractive. Here, a type of free-field based whole-body ultrasound (US)-driven nanovaccines are constructed, named G5-CHC-R, by conjugating the sonosensitizer, Chenghai chlorin (CHC) and the immunomodulator, resiquimod (R848) on top of a super small-sized dendrimeric nanoscaffold. Once entering tumors, R848 can be cleaved from a hypoxia-sensitive linker, thus modifying the TME via converting macrophage phenotypes. The animals bearing orthotopic pancreatic cancer with intestinal metastasis and breast cancer with lung metastasis are treated with G5-CHC-R under a free-field based whole-body US system. Benefit from the deep penetration capacity and highly spatiotemporal selectiveness, G5-CHC-R triggered by US represented a superior alternative for noninvasive irradiation of deep-seated tumors and magnification of local immune responses via driving mass release of tumor antigens and "cold-warm-hot" three-state transformation of TME. In addition to irradiating primary tumors, a robust adaptive anti-tumor immunity is potentiated, leading to successful induction of systemic tumor suppression. The sono-nanovaccines with good biocompatibility posed wide applicability to a broad spectrum of tumors, revealing immeasurable potential for translational research in oncology.
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Vacunas contra el Cáncer , Neoplasias , Animales , Nanovacunas , Ultrasonografía , Inmunidad Adaptativa , Adyuvantes Inmunológicos , Neoplasias/diagnóstico por imagen , Neoplasias/terapiaRESUMEN
BACKGROUND: Indeterminate readout of the quantitative interferon-γ release test (QFT) for Mycobacterium tuberculosis screening is a specific laboratory finding for systemic lupus erythematosus (SLE), which may be due to T-cell exhaustion and abnormal programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) signalling. METHODS: We enrolled 104 patients with SLE and 225 with other rheumatic musculoskeletal diseases (RMDs) who presented to the outpatient clinic between 2020 and 2023. Twenty healthy donors served as the controls. The QFT was performed in all participants, and those with indeterminate results were compared among the groups. Immunophenotyping and functional assays were performed using blood mononuclear cells. Interferon (IFN)-γ was detected in vitro and ex vivo in patients with SLE with indeterminate or negative QFT results, before or after rituximab therapy. RESULTS: 104 patients with SLE had a significantly higher rate of indeterminate QFT results was significantly higher (17.31%) than that of 225 patients with RMD (3.56%). Patients with SLE with indeterminate QFT had more active disease (SLEDAI-2K, mean 10.94 vs 4.02, p<0.0001), including a higher incidence of active nephritis (55.56% vs 29.07%). Indeterminate QFT in SLE is mainly caused by an insufficient IFN-γ response in CD8+T cells with exhausted immunophenotypes. The abnormal interaction between exhausted PD-1 high CD8+ T cells and activated PD-L1 low memory B cells in SLE can be reversed with a PD-1 agonist or increased PD-L1 expression. Rituximab treatment indirectly reversed this IFN-γ response. CONCLUSION: The PD-1/PD-L1 signalling pathway, which governs the crosstalk between exhausted CD8+ T cells and activated memory B cells, is a mechanistic explanation for insufficient interferon-γ response in patients with SLE.
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Linfocitos T CD8-positivos , Lupus Eritematoso Sistémico , Humanos , Linfocitos T CD8-positivos/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Células B de Memoria , Antígeno B7-H1/fisiología , Ligandos , Rituximab , Lupus Eritematoso Sistémico/complicacionesRESUMEN
PURPOSE: To characterize the in vivo corneal epithelial thickness (CET) remodeling profile in a population of eyes after small incision lenticule intrastromal keratoplasty (SMI-LIKE) for hyperopia. METHODS: The CET profile was measured by RTVue-100 Fourier-domain OCT system across the central 6-mm diameter of the cornea of 17 eyes from 12 subjects (five males and seven females) who accepted corneal stromal lens implantation surgery for correcting hyperopia. The CET were measured at positions with a radius of 0-1.0 mm, 1.0-2.5 mm (divided into eight quadrants) and 2.5-3.0 mm (divided into eight quadrants) from the corneal center. Corneal maximum simulated keratometry (Km) was measured by Pentacam HR anterior segment analyzer to analyze CET changes. The examination data of subjects were collected in four time periods, which were preoperative, short-term postoperative (one week after surgery), mid-term postoperative (the last review within 3-6 months after surgery), and long-term postoperative (the last review over 1-2.5 years after surgery). The changes of CET were compared and analyzed in the four time periods. RESULTS: Mean CET in 0-1.0 mm, 1.0-2.5 mm and 2.5-3.0 mm of the cornea decreased in one week after surgery, respectively, as compared to CET in the preoperative period, which turned from 55.06 ± 0.82 µmã54.42 ± 0.75 µmã53.46 ± 0.60 µm to 51.18 ± 1.05 µm (P = 0.005), 49.38 ± 0.70 µm (P = 0.000), 51.29 ± 0.59 µm (P = 0.025). In the mid-term postoperative period, mean CET in 0-1.0 mm and 1.0-2.5 mm areas kept thinner than mean CET in the preoperative period, CET in 0-1.0 mm is 50.59 ± 0.76 µm (P = 0.000),CET in 1.0-2.5 mm is 50.23 ± 0.57 µm (P = 0.000), while mean CET in 2.5-3.0 mm area recovered to the same thickness as the preoperative level, which is 54.36 ± 0.66 µm (P = 1.000), until the long-term period, CET stabilized in the above doughnut pattern. CONCLUSIONS: After stromal lenticule implantation for hyperopia, CET showed a remodeled form of thinning in the 0-2.5 mm area and thickening in the 2.5-3.0 mm area, and remained stable within one year after surgery.
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Trasplante de Córnea , Hiperopía , Femenino , Masculino , Humanos , Hiperopía/cirugía , Tomografía de Coherencia Óptica , Córnea , Sustancia Propia/cirugíaRESUMEN
Background: MicroFlow imaging (MFI) is a novel noninvasive ultrasound (US) technique that depicts microcirculatory blood vessels in the kidney while filtering out tissue motion and enhancing blood flow signals. We aimed to investigate the value of MFI for the detection of renal microvascular perfusion in chronic kidney disease caused by stage I-II membranous nephropathy (MN). Methods: Seventy-six participants including biopsy-proven MN (n=38) and healthy volunteers (n=38) were prospectively examined using MFI from March 2020 to December 2020. In addition, patients with MN were subdivided into a mild group, a moderate group, and a severe group based on the results of vascular pathology evaluation. All MFI images were analyzed by Image Pro Plus to obtain a cortical vascular index (VI). Basic patient information, relative US parameters and laboratory results were then acquired for each participant. Finally, after the univariate analysis among multiple groups, binary logistic regression (forward LR) and ordered logistic regression were used for multivariate analysis. Significance was set at P<0.05. Results: VI was significantly lower in MN patients compared with that of healthy controls (0.65±0.09 vs. 0.35±0.18, P<0.001). After multivariate analysis, we found that the exploratory diagnostic performance of VI [area under the curve (AUC): 0.94; 95% confidence interval (CI): 0.89-0.99] outperformed that of serum creatinine (Scr) (AUC: 0.87; 95% CI: 0.79-0.95) in identifying MN. We also observed considerable differences among MN groups in parameters including VI (P=0.006), estimated glomerular filtration rate (eGFR) (P=0.037), shape (P=0.013), and impression (P=0.007). In addition, in the group with mild vascular damage, the exploratory diagnostic performance of VI (AUC: 0.79; 95% CI: 0.64-0.94) was better than other parameters, such as eGFR (AUC: 0.63; 95% CI: 0.43-0.84). Conclusions: MFI detected abnormal renal microvascular perfusion in patients with MN (particularly in those with early vascular damage or preserved renal function) without the use of a contrast agent. Combining MFI with B-mode US can improve the predictive performance of traditional kidney US.
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Vanadium trioxide (V6 O13 ) cathode has recently aroused intensive interest for aqueous zinc-ion batteries (AZIBs) due to their structural and electrochemical diversities. However, it undergoes sluggish reaction kinetics and significant capacity decay during prolonged cycling. Herein, an oxygen-vacancy-reinforced heterojunction in V6 O13- x /reduced graphene oxide (rGO) cathode is designed through electrostatic assembly and annealing strategy. The abundant oxygen vacancies existing in V6 O13- x weaken the electrostatic attraction with the inserted Zn2+ ; the external electric field constructed by the heterointerfaces between V6 O13- x and rGO provides additional built-in driving force for Zn2+ migration; the oxygen-vacancy-enriched V6 O13- x highly dispersed on rGO fabricates the interconnected conductive network, which achieves rapid Zn2+ migration from heterointerfaces to lattice. Consequently, the obtained 2D heterostructure exhibits a remarkable capacity of 424.5 mAh g-1 at 0.1 A g-1 , and a stable capacity retention (96% after 5800 cycles) at the fast discharge rate of 10 A g-1 . Besides, a flexible pouch-type AZIB with real-life practicability is fabricated, which can successfully power commercial products, and maintain stable zinc-ion storage performances even under bending, heavy strikes, and pressure condition. A series of quantitative investigation of pouch batteries demonstrates the possibility of pushing pouch-type AZIBs to realistic energy storage market.
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AIMS: To analyse spatial and temporal changes in the global burden of diabetes mellitus (DM) attributable to dietary factors from 1990 to 2019. MATERIALS AND METHODS: The burden of DM was analysed in terms of age-standardized disability-adjusted life-year (DALY) rates and age-standardized death rates (ASDRs), which were obtained from the Global Burden of Disease Study 2019, and their corresponding estimated annual percentage changes (EAPCs). RESULTS: The ASDR exhibited a decreasing trend (EAPC = -0.02), while the age-standardized DALY rate exhibited an increasing trend (EAPC = 0.65). Forty-four percent of the burden of DM was attributable to dietary factors, with the three largest contributors being high intake of red meat, high intake of processed meat, and low intake of fruit. Residence in a region with a high sociodemographic index (SDI) was associated with a diet low in whole grains and high in red meat and processed meat, while residence in a low-SDI region was associated with a diet low in whole grains and fruits, and high in red meat. CONCLUSIONS: The age-standardized DALYs of DM attributable to dietary factors increased between 1990 and 2019 but differed among areas. The three largest dietary contributors to the burden of DM were high intake of red meat, high intake of processed meat, and low intake of fruit.
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Diabetes Mellitus , Carga Global de Enfermedades , Humanos , Diabetes Mellitus/epidemiología , Carne/efectos adversos , Frutas , Años de Vida Ajustados por Calidad de VidaRESUMEN
OBJECTIVES: To explore the differences in clinical characteristics, prognosis, and risk factors between type I and type II endometrial cancer (EC). MATERIALS AND METHODS: We retrospectively collected EC patients diagnosed with type I or type II EC from 2009 to 2021 in the First Affiliated Hospital of Zhengzhou University. RESULTS: In total, 606 eligible EC patients (396 type I, and 210 type II) were included. Baseline analyses revealed that type II patients were older, had more advanced clinical stage, were more likely to receive chemoradiotherapy, and had higher incidence of myometrial infiltration, cervix involvement, lymph node metastasis and positive ascites cytology. Type II significantly favored poorer overall survival (OS) (HR = 9.10, 95%CI 4.79-17.28, P < 0.001) and progression-free survival (PFS) (HR = 6.07, 95%CI 2.75-13.37, P < 0.001) compared to type I. For all included EC, univariate and multivariate COX analyses revealed age, myometrial infiltration and pathological type were independent risk factors for OS and PFS. Subgroup analyses identified age, menopause, clinical stage, and lymph node metastasis as independent risk factors for type I regarding OS. While age, myometrial infiltration and chemoradiotherapy were identified as risk and protective factors for type II regrading OS. Age and cervix involvement were identified as independent risk factors for type I regarding PFS. Myometrial infiltration was identified as independent risk factor for type II regarding PFS. CONCLUSION: Type II patients shared different clinical characteristics and worse prognosis compared to type I, and their independent risk and protective factors also varied.
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Atherosclerosis, which is a vascular pathology characterized by inflammation and plaque build-up within arterial vessel walls, acts as the important cause of most cardiovascular diseases. Except for a lipid-depository and chronic inflammatory, increasing evidences propose that epigenetic modifications are increasingly associated with atherosclerosis and are of interest from both therapeutic and biomarker perspectives. The chronic progressive nature of atherosclerosis has highlighted atherosclerosis heterogeneity and the fact that specific cell types in the complex milieu of the plaque are, by far, not the only initiators and drivers of atherosclerosis. Instead, the ubiquitous effects of cell type are tightly controlled and directed by the epigenetic signature, which, in turn, is affected by many proatherogenic stimuli, including low-density lipoprotein, proinflammatory, and physical forces of blood circulation. In this review, we summarize the role of DNA methylation and histone post-translational modifications in atherosclerosis. The future research directions and potential therapy for the management of atherosclerosis are also discussed. Video Abstract.
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Aterosclerosis , Placa Aterosclerótica , Humanos , Metilación de ADN , Histonas/metabolismo , Aterosclerosis/genética , Aterosclerosis/terapia , Aterosclerosis/metabolismo , Placa Aterosclerótica/genética , Placa Aterosclerótica/terapia , Placa Aterosclerótica/patología , Epigénesis Genética , Procesamiento Proteico-Postraduccional , Inflamación/genéticaRESUMEN
Background: Epidemiological studies emphasize the link between metabolic factors and thyroid cancer. Using Mendelian randomization (MR), we assessed the possible causal impact of metabolic factors on thyroid cancer for the first time. Methods: Summary statistics for metabolic factors and thyroid cancer were obtained from published Genome-wide association studies. The causal relationships were assessed using the inverse-variance weighted (IVW) method as the primary method through a two-sample Mendelian Randomization (MR) analysis. To account for the potential existence of horizontal pleiotropy, four additional methods were employed, including Mendelian Randomization-Egger (MR-Egger), weighted median method (WM), simple mode, and weighted mode method. Given the presence of interactions between metabolic factors, a multivariable MR analysis was subsequently conducted. Results: The results showed there was a genetic link between HDL level and protection effect of thyroid cancer using IVW (OR= 0.75, 95% confidence intervals [CIs] 0.60-0.93, p=0.01) and MR-Egger method (OR= 0.70, 95% confidence intervals [CIs] 0.50- 0.97, p=0.03). The results remained robust in multivariable MR analysis for the genetic link between HDL level and protection effect of thyroid cancer (OR= 0.74, 95% confidence intervals [CIs] 0.55-0.99, p=0.04). Conclusions: This study suggests a protection role for HDL on thyroid cancer. The study findings provide evidence for the public health suggestion for thyroid cancer prevention. HDL's potential as a pharmacological target needs further validation.
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Estudio de Asociación del Genoma Completo , Neoplasias de la Tiroides , Humanos , Análisis de la Aleatorización Mendeliana , Neoplasias de la Tiroides/etiología , Neoplasias de la Tiroides/genética , Salud PúblicaRESUMEN
Accurate evaluation of patients with disorders of consciousness (DoC) is crucial for personalized treatment. However, misdiagnosis remains a serious issue. Neuroimaging methods could observe the conscious activity in patients who have no evidence of consciousness in behavior, and provide objective and quantitative indexes to assist doctors in their diagnosis. In the review, we discussed the current research based on the evaluation of consciousness rehabilitation after DoC using EEG, fMRI, PET, and fNIRS, as well as the advantages and limitations of each method. Nowadays single-modal neuroimaging can no longer meet the researchers` demand. Considering both spatial and temporal resolution, recent studies have attempted to focus on the multi-modal method which can enhance the capability of neuroimaging methods in the evaluation of DoC. As neuroimaging devices become wireless, integrated, and portable, multi-modal neuroimaging methods will drive new advancements in brain science research.
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BACKGROUND: Individuals with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs) are at risk of developing venous thromboembolism (VTE), a serious complication. There is no established clinical model for predicting VTE in the Chinese population. We develop a new risk assessment model (RAM) for IMiD-associated VTE in Chinese MM patients. METHODS: We retrospectively selected 1334 consecutive MM patients receiving IMiDs from 16 medical centers in China and classified them randomly into the derivation and validation cohorts. A multivariate Cox regression model was used for analysis. RESULTS: The overall incidence of IMiD-related VTE in Chinese MM patients was 6.1%. Independent predictive factors of VTE (diabetes, ECOG performance status, erythropoietin-stimulating agent use, dexamethasone use, and VTE history or family history of thrombosis) were identified and merged to develop the RAM. The model identified approximately 30% of the patients in each cohort at high risk for VTE. The hazard ratios (HRs) were 6.08 (P < 0.001) and 6.23 (P < 0.001) for the high-risk subcohort and the low-risk subcohort, respectively, within both the derivation and validation cohorts. The RAM achieved satisfactory discrimination with a C statistic of 0.64. The stratification approach of the IMWG guidelines yielded respective HRs of 1.77 (P = 0.053) and 1.81 (P = 0.063). The stratification approach of the SAVED score resulted in HRs of 3.23 (P = 0.248) and 1.65 (P = 0.622), respectively. The IMWG guideline and the SAVED score-based method yielded C statistics of 0.58 and 0.51, respectively. CONCLUSIONS: The new RAM outperformed the IMWG guidelines and the SAVED score and could potentially guide the VTE prophylaxis strategy for Chinese MM patients.
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ABSTRACT: Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, accounting for 50% of all heart failure patients, and is associated with significant mortality. Sodium-glucose cotransporter subtype inhibitor (SGLT2i) is recommended in the AHA and ESC guidelines for the treatment of HFpEF, but the mechanism of SGLT2i to prevent and treat cardiac remodeling and dysfunction is currently unknown, hindering the understanding of the pathophysiology of HFpEF and the development of novel therapeutics. HFpEF model was induced by a high-fat diet (60% calories from lard) + N [w] -nitro- l -arginine methyl ester ( l -NAME-0.5 g/L) (2 Hit) in male Sprague Dawley rats to effectively recapture the myriad phenotype of HFpEF. This study's results showed that administration of dapagliflozin (DAPA, SGLT2 inhibitor) significantly limited the 2-Hit-induced cardiomyocyte hypertrophy, apoptosis, inflammation, oxidative stress, and fibrosis. It also improved cardiac diastolic and systolic dysfunction in a late-stage progression of HFpEF. Mechanistically, DAPA influences energy metabolism associated with fatty acid intake and mitochondrial dysfunction in HFpEF by increasing ß-hydroxybutyric acid (ß-OHB) levels, directing the activation of citrate synthase, reducing acetyl coenzyme A (acetyl-CoA) pools, modulating adenosine 5'-triphosphate production, and increasing the expression of mitochondrial oxidative phosphorylation system complexes I-V. In addition, following clinical DAPA therapy, the blood levels of ß-OHB and citrate synthase increased and the levels of acetyl-CoA in the blood of HFpEF patients decreased. SGLT2i plays a beneficial role in the prevention and treatment of cardiac remodeling and dysfunction in HFpEF model by attenuating cardiometabolic dysregulation.