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Immune-mediated acute hepatic injury is characterized by the destruction of a large number of hepatocytes and severe liver function damage. Interleukin-28A (IL-28A), a member of the IL-10 family, is notable for its antiviral properties. However, despite advances in our understanding of IL-28A, its role in immune-mediated acute injury remains unclear. The present study investigated the role of IL-28A in concanavalin A (Con A)-induced acute immune liver injury. After Con A injection in mice, IL-28A level significantly increased. IL-28A deficiency was found to protect mice from acute liver injury, prolong survival time, and reduce serum aspartate aminotransferase and alanine aminotransferase levels. In contrast, recombinant IL-28A aggravated liver injury in mice. The proportion of activated M1 macrophages was significantly lower in the IL-28A-deficiency group than in the wild-type mouse group. In adoptive transfer experiments, M1 macrophages from WT could exacerbate mice acute liver injury symptoms in the IL-28A deficiency group. Furthermore, the expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), IL-12, IL-6, and IL-1ß, by M1 macrophages decreased significantly in the IL-28A-deficiency group. Western blotting demonstrated that IL-28A deficiency could limit M1 macrophage polarization by modulating the nuclear factor (NF)-κB, mitogen-activated protein kinase (MAPK), and interferon regulatory factor (IRF) signaling pathways. In summary, IL-28A deletion plays an important protective role in the Con A-induced acute liver injury model and IL-28A deficiency inhibits the activation of M1 macrophages by inhibiting the NF-κB, MAPK, and IRF signaling pathways. These results provide a potential new target for the treatment of immune-related hepatic injury.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Citocinas , Interferón lambda , Interleucinas , Animales , Ratones , Concanavalina A , Factores Reguladores del Interferón , Hígado , Macrófagos , Proteínas Quinasas Activadas por Mitógenos , Interferón lambda/genética , Interleucinas/genéticaRESUMEN
AIMS: Lactate accumulation is reported to be a biomarker for diabetic nephropathy progression. Lactate drives lysine lactylation, a newly discovered post-translational modification that is involved in the pathogenesis of cancers and metabolic and inflammatory disease. Here, we aimed to determine whether lysine lactylation is involved in the pathogenesis of diabetic nephropathy. METHODS: Renal biopsy samples from individuals with diabetic nephropathy (n=22) and control samples from individuals without diabetes and kidney disease (n=9) were obtained from the First Affiliated Hospital of Zhengzhou University for immunohistochemical staining. In addition, we carried out global lactylome profiling of kidney tissues from db/m and db/db mice using LC-MS/MS. Furthermore, we assessed the role of lysine lactylation and acyl-CoA synthetase family member 2 (ACSF2) in mitochondrial function in human proximal tubular epithelial cells (HK-2). RESULTS: The expression level of lysine lactylation was significantly increased in the kidneys of individuals with diabetes as well as in kidneys from db/db mice. Integrative lactylome analysis of the kidneys of db/db and db/m mice identified 165 upregulated proteins and 17 downregulated proteins, with an increase in 356 lysine lactylation sites and a decrease in 22 lysine lactylation sites decreased. Subcellular localisation analysis revealed that most lactylated proteins were found in the mitochondria (115 proteins, 269 sites). We further found that lactylation of the K182 site in ACSF2 contributes to mitochondrial dysfunction. Finally, the expression of ACSF2 was notably increased in the kidneys of db/db mice and individuals with diabetic nephropathy. CONCLUSIONS: Our study strongly suggests that lysine lactylation and ACSF2 are mediators of mitochondrial dysfunction and may contribute to the progression of diabetic nephropathy. DATA AVAILABILITY: The LC-MS/MS proteomics data have been deposited in the ProteomeXchange Consortium database ( https://proteomecentral.proteomexchange.org ) via the iProX partner repository with the dataset identifier PXD050070.
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Nefropatías Diabéticas , Túbulos Renales , Lisina , Animales , Ratones , Humanos , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Lisina/metabolismo , Túbulos Renales/metabolismo , Túbulos Renales/patología , Masculino , Coenzima A Ligasas/metabolismo , Procesamiento Proteico-Postraduccional , Lipoilación , Ratones Endogámicos C57BL , FemeninoRESUMEN
Podocyte apoptosis exerts a crucial role in the pathogenesis of DN. Recently, long noncoding RNAs (lncRNAs) have been gradually identified to be functional in a variety of different mechanisms associated with podocyte apoptosis. This study aimed to investigate whether lncRNA Glis2 could regulate podocyte apoptosis in DN and uncover the underlying mechanism. The apoptosis rate was detected by flow cytometry. Mitochondrial membrane potential (ΔΨM) was measured using JC-1 staining. Mitochondrial morphology was detected by MitoTracker Deep Red staining. Then, the histopathological and ultrastructure changes of renal tissues in diabetic mice were observed using periodic acid-Schiff (PAS) staining and transmission electron microscopy. We found that lncRNA Glis2 was significantly downregulated in high-glucose cultured podocytes and renal tissues of db/db mice. LncRNA Glis2 overexpression was found to alleviate podocyte mitochondrial dysfunction and apoptosis. The direct interaction between lncRNA Glis2 and miR-328-5p was confirmed by dual luciferase reporter assay. Furthermore, lncRNA Glis2 overexpression alleviated podocyte apoptosis in diabetic mice. Taken together, this study demonstrated that lncRNA Glis2, acting as a competing endogenous RNA (ceRNA) of miRNA-328-5p, regulated Sirt1-mediated mitochondrial dysfunction and podocyte apoptosis in DN.
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Diabetes Mellitus Experimental , Nefropatías Diabéticas , MicroARNs , Enfermedades Mitocondriales , Podocitos , ARN Largo no Codificante , Ratones , Animales , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/patología , ARN Largo no Codificante/genética , MicroARNs/genética , Podocitos/patología , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Factores de Transcripción , Apoptosis/genética , Enfermedades Mitocondriales/patología , GlucosaRESUMEN
Herein, we report a versatile reaction platform for tracelessly cleavable cysteine-selective peptide/protein modification. This platform offers highly tunable and predictable conjugation and cleavage by rationally estimating the electron effect on the nucleophilic halopyridiniums. Cleavable peptide stapling, antibody conjugation, enzyme masking/de-masking, and proteome labeling were achieved based on this facile pyridinium-thiol-exchange protocol.
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Péptidos , Proteoma , Cisteína/metabolismoRESUMEN
The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases was published in 2021. Since then, the pace of drug development for glomerular diseases has accelerated, due in large part to rapidly accumulating insights into disease pathogenesis from genetic and molecular studies of afflicted patients. To keep the Glomerular Diseases Guideline as current as possible, KDIGO made a commitment to the nephrology community to provide periodic updates, based on new developments for each disease. After the 2021 guideline was published, two novel drugs received regulatory approval for the management of lupus nephritis, leading to the first KDIGO guideline update. Herein, an executive summary of the most important guideline changes from the Lupus Nephritis chapter is provided as a quick reference.
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Nefritis Lúpica , Nefrología , Humanos , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/tratamiento farmacológico , Riñón , Desarrollo de MedicamentosRESUMEN
The pediatric International IgA Nephropathy (IgAN) Prediction Tool comprises two models with and without ethnicity and is the first method to predict the risk of a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure in children at the time of biopsy using clinical risk factors and Oxford MEST histology scores. However, it is unknown if the Prediction Tool can be applied after a period of observation post-biopsy. Using an international multi-ethnic cohort of 947 children with IgAN, 38% of whom were followed into adulthood, the Prediction Tool was updated for use one year after biopsy. Compared to the original pediatric Prediction Tool, the updated post-biopsy Prediction Tool had a better model fit with higher R2D (51%/50% vs 20%), significant increase in 4-year C-statistics (0.83 vs 0.73/0.69, ΔC 0.09 [95% confidence interval 0.07-0.10] and ΔC 0.14 [0.12-0.15]) and better 4-year calibration with lower integrated calibration indices (0.74/0.54 vs 2.45/1.01). Results were similar after internal validation and when the models were applied two years after biopsy. Trajectories of eGFR after a baseline one year post-biopsy were non-linear and those at higher predicted risk started with a lower eGFR and experienced a more rapid decline over time. In children, eGFR had a variable rate of increase until 15-18 years old and then decreased linearly with a more rapid decline in higher risk groups that was similar to young adults of comparable risk. Thus, the original pediatric Prediction Tool should be used in children at the time of biopsy, and the updated pediatric Prediction Tool should be used to re-evaluate risk one or two years after biopsy.
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Tumor-derived extracellular vesicle (T-EV) microRNAs have been investigated as promising biomarkers in clinical diagnosis as well as disease progression monitoring. However, the expression profiles of microRNA in different tissues vary widely, the precise monitoring of microRNA levels in EVs originating from diseased tissues is susceptible to background interference, thus remains a challenge. Conventional assays require extensive processing, such as EV isolation and even sample lysis, which is both slow and laborious, and the cumbersome pretreatment could spoil the downstream analysis. To address this issue, we developed a generalizable strategy for T-EVs-selective activation and therefore specific amplified microRNA imaging. The conditional signal amplification is established by integrating a traditional DNA walker system with endogenously activated motif to achieve sensitized microRNA imaging in T-EVs. The preorganized endogenous activation with additional sensing criteria narrowed the scope against the complex specimens, and the amplified sensing with reduced off-target signals was supposed to be sensitive to monitor the tiny changes of microRNA expression during the disease course, which holds great potential for accurate diagnosis and prognosis.
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Vesículas Extracelulares , MicroARNs , MicroARNs/análisis , ADN/metabolismo , Vesículas Extracelulares/química , Pronóstico , Biomarcadores de Tumor/metabolismoRESUMEN
Metal ion homeostasis is imperative for normal functioning of the brain. Considering the close association between brain metal ions and various pathological processes in brain diseases, it becomes essential to track their dynamics in awake animals for accurate physiological insights. Although ion-selective microelectrodes (ISMEs) have demonstrated great advantage in recording ion signals in awake animals, their intrinsic potential drift impairs their accuracy in long-term in vivo analysis. This study addresses the challenge by integrating ISMEs with photoelectrochemical (PEC) sensing, presenting an excitation-detection separated PEC platform based on potential regulation of ISMEs. A flexible indium tin oxide (Flex-ITO) electrode, modified with MoS2 nanosheets and Au NPs, serves as the photoelectrode and is integrated with a micro-LED. The integrated photoelectrode is placed on the rat skull to remain unaffected by animal activity. The potential of ISME dependent on the concentration of target K+ serves as the modulator of the photocurrent signal of the photoelectrode. The proposed design allows deep brain detection while minimizing interference with neurons, thus enabling real-time monitoring of neurochemical signals in awake animals. It successfully monitors changes in extracellular K+ levels in the rat brain after exposure to PM2.5, presenting a valuable analytical tool for understanding the impact of environmental factors on the nervous system.
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Técnicas Biosensibles , Vigilia , Animales , Ratas , Encéfalo , Microelectrodos , Técnicas ElectroquímicasRESUMEN
OBJECTIVE: To explore the feasibility of screening potential drugs for the treatment of diabetic kidney disease (DKD) using a single-cell transcriptome sequencing dataset and Connectivity Map (CMap) database screening. METHODS: A DKD single-nucleus transcriptome sequencing dataset was analyzed using Seurat 4.0 to obtain specific podocyte subclusters and differentially expressed genes (DEGs) related to DKD. These DEGs were subsequently subjected to a search against the CMap database to screen for drug candidates. Cell and animal experiments were conducted to evaluate the efficacy of the top 3 drug candidates. RESULTS: Initially, we analyzed the DKD single-nucleus transcriptome sequencing dataset to obtain intrinsic renal cells such as podocytes, endothelial cells, mesangial cells, proximal tubular cells, collecting duct cells and immune cells. Podocytes were further divided into four subclusters, among which the proportion of POD_1 podcytes was significantly greater in DKD kidneys than in control kidneys (34.0 % vs. 3.4 %). The CMap database was searched using the identified DEGs in the POD_1 subcluster, and the drugs, including tozasertib, paroxetine, and xylazine, were obtained. Cell-based experiments showed that tozasertib, paroxetine and xylazine had no significant podocyte toxicity in the concentration range of 0.01-50 µM. Tozasertib, paroxetine, and xylazine all reversed the advanced glycation end products (AGEs)-induced decrease in podocyte marker levels, but the effect of paroxetine was more prominent. Animal experiments showed that paroxetine decreased urine ALB/Cr levels in DKD model mice by approximately 51.5 % (115.7 mg/g vs. 238.8 mg/g, P < 0.05). Histopathological assessment revealed that paroxetine attenuated basement membrane thickening, restored the number of foot processes of podocytes, and reduced foot process fusion. In addition, paroxetine also attenuated renal tubular-interstitial fibrosis. Mechanistically, paroxetine inhibited the expression of GRK2 and NLRP3, decreased the phosphorylation level of p65, restored NRF2 expression, and relieved inflammation and oxidative stress. CONCLUSION: This strategy based on single-cell transcriptome sequencing and CMap data can facilitate the identification and aid the rapid development of clinical DKD drugs. Paroxetine, screened by this strategy, has excellent renoprotective effects.
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Nefropatías Diabéticas , Podocitos , Transcriptoma , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/patología , Animales , Transcriptoma/efectos de los fármacos , Ratones , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Podocitos/patología , Análisis de la Célula Individual/métodos , Masculino , Evaluación Preclínica de Medicamentos/métodos , Ratones Endogámicos C57BL , Perfilación de la Expresión Génica , HumanosRESUMEN
In the field of photocatalytic CO2 reduction, quantum dot (QD) assemblies have emerged as promising candidate photocatalysts due to their superior light absorption and better substrate adsorption. However, the poor contacts within QD assemblies lead to low interfacial charge transfer efficiency, making QD assemblies suffer from unsatisfactory photocatalytic performance. Herein, a novel approach is presented involving the construction of strongly interfacial fused CdS QD assemblies (CdS QD gel) for CO2 reduction. The novel CdS QD gel demonstrates outstanding photocatalytic performance for CO2 methanation, achieving a CH4 generation rate of ≈296 µmol g-1 h-1, with a selectivity surpassing 76% and an apparent quantum yield (AQY) of 1.4%. Further investigations reveal that the robust interfacial fusion in these CdS QDs not only boosts their ability to absorb visible light but also significantly promotes charge separation. The present work paves the way for utilizing QD gel photocatalysts in realizing efficient CO2 reduction and highlights the critical role of interfacial engineering in photocatalysts.
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Polyvinylidene fluoride (PVDF) has unique electrochemical oxidation resistance and is the only binder for high-voltage cathode materials in the battery industry for a long time. However, PVDF still has some drawbacks, such as environmental limitations on fluorine, strict requirements for environmental humidity, weak adhesion, and poor lithium ion conductivity. Herein, the long-standing issues associated with high-voltage lithium cobalt oxide (LiCoO2; LCO) are successfully addressed by incorporating phenolphthalein polyetherketone (PEK-C) and phenolphthalein polyethersulfone (PES-C) as binder materials. These binders have unexpected electrochemical oxidation resistance and robustness adhesion, ensure uniform coverage on the surface of LCO, and establish an effective and fast ion-conductive CEI/binder composite layer. By leveraging these favorable characteristics, electrodes based on polyarylether binders demonstrate significantly better cycling and rate performance than their counterparts using traditional PVDF binders. The fast ion-conductive CEI/binder composite layer effectively mitigates adverse reactions at the cathode-electrolyte interface. As anticipated, batteries utilizing phenolphthalein polyarylether binders exhibit capacity retention rates of 88.92% and 80.4% after 200 and 500 cycles at 4.5 and 4.6 V, respectively. The application of binders, such as polyarylether binders, offers a straightforward and inspiring approach for designing high-energy-density battery materials.
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BACKGROUND: Glomerular lesions are the main injuries of diabetic nephropathy (DN) and are used as a crucial index for pathologic classification. Manual quantification of these morphologic features currently used is semi-quantitative and time-consuming. Automatically quantifying glomerular morphologic features is urgently needed. METHODS: A series of convolutional neural networks (CNN) were designed to identify and classify glomerular morphologic features in DN patients. Associations of these digital features with pathologic classification and prognosis were further analyzed. RESULTS: Our CNN-based model achieved a 0.928 F1-score for global glomerulosclerosis and 0.953 F1-score for Kimmelstiel-Wilson lesion, further obtained a dice of 0.870 for the mesangial area and F1-score beyond 0.839 for three glomerular intrinsic cells. As the pathologic classes increased, mesangial cell numbers and mesangial area increased, and podocyte numbers decreased (p for all < 0.001), while endothelial cell numbers remained stable (p = 0.431). Glomeruli with Kimmelstiel-Wilson lesion showed more severe podocyte deletion compared to those without (p < 0.001). Furthermore, CNN-based classifications showed moderate agreement with pathologists-based classification, the kappa value between the CNN model 3 and pathologists reached 0.624 (ranging from 0.529 to 0.688, p < 0.001). Notably, CNN-based classifications obtained equivalent performance to pathologists-based classifications on predicting baseline and long-term renal function. CONCLUSION: Our CNN-based model is promising in assisting the identification and pathologic classification of glomerular lesions in DN patients.
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Inteligencia Artificial , Nefropatías Diabéticas , Glomérulos Renales , Humanos , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/clasificación , Glomérulos Renales/patología , Masculino , Femenino , Persona de Mediana Edad , Redes Neurales de la ComputaciónRESUMEN
BACKGROUND: Insulin resistance (IR) plays an important role in the pathophysiology of cardiovascular disease. Recent studies have shown that diabetes mellitus and impaired lipid metabolism are associated with the severity and prognosis of idiopathic pulmonary arterial hypertension (IPAH). However, the relationship between IR and pulmonary hypertension is poorly understood. This study explored the association between four IR indices and IPAH using data from a multicenter cohort. METHODS: A total of 602 consecutive participants with IPAH were included in this study between January 2015 and December 2022. The metabolic score for IR (METS-IR), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose (TyG) index, and triglyceride-glucose-body mass index (TyG-BMI) were used to quantify IR levels in patients with IPAH. The correlation between non-insulin-based IR indices and long-term adverse outcomes was determined using multivariate Cox regression models and restricted cubic splines. RESULTS: During a mean of 3.6 years' follow-up, 214 participants experienced all-cause death or worsening condition. Compared with in low to intermediate-low risk patients, the TG/HDL-C ratio (2.9 ± 1.7 vs. 3.3 ± 2.1, P = 0.003) and METS-IR (34.5 ± 6.7 vs. 36.4 ± 7.5, P < 0.001) were significantly increased in high to intermediate-high risk patients. IR indices correlated with well-validated variables that reflected the severity of IPAH, such as the cardiac index and stroke volume index. Multivariate Cox regression analyses indicated that the TyG-BMI index (hazard ratio [HR] 1.179, 95% confidence interval [CI] 1.020, 1.363 per 1.0-standard deviation [SD] increment, P = 0.026) and METS-IR (HR 1.169, 95% CI 1.016, 1.345 per 1.0-SD increment, P = 0.030) independently predicted adverse outcomes. Addition of the TG/HDL-C ratio and METS-IR significantly improved the reclassification and discrimination ability beyond the European Society of Cardiology (ESC) risk score. CONCLUSIONS: IR is associated with the severity and long-term prognosis of IPAH. TyG-BMI and METS-IR can independently predict clinical worsening events, while METS-IR also provide incremental predictive performance beyond the ESC risk stratification.
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Biomarcadores , Glucemia , Resistencia a la Insulina , Índice de Severidad de la Enfermedad , Triglicéridos , Adulto , Femenino , Humanos , Masculino , Biomarcadores/sangre , Glucemia/metabolismo , China/epidemiología , HDL-Colesterol/sangre , Progresión de la Enfermedad , Hipertensión Pulmonar Primaria Familiar/diagnóstico , Hipertensión Pulmonar Primaria Familiar/sangre , Hipertensión Pulmonar Primaria Familiar/fisiopatología , Hipertensión Pulmonar Primaria Familiar/mortalidad , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Triglicéridos/sangreRESUMEN
Coal dust is the main occupational hazard factor during coal mining operations. This study aimed to investigate the role of macrophage polarization and its molecular regulatory network in lung inflammation and fibrosis in Sprague-Dawley rats caused by coal dust exposure. Based on the key exposure parameters (exposure route, dose and duration) of the real working environment of coal miners, the dynamic inhalation exposure method was employed, and a control group and three coal dust groups (4, 10 and 25 mg/m3) were set up. Lung function was measured after 30, 60 and 90 days of coal dust exposure. Meanwhile, the serum, lung tissue and bronchoalveolar lavage fluid were collected after anesthesia for downstream experiments (histopathological analysis, RT-qPCR, ELISA, etc.). The results showed that coal dust exposure caused stunted growth, increased lung organ coefficient and decreased lung function in rats. The expression level of the M1 macrophage marker iNOS was significantly upregulated in the early stage of exposure and was accompanied by higher expression of the inflammatory cytokines TNF-α, IL-1ß, IL-6 and the chemokines IL-8, CCL2 and CCL5, with the most significant trend of CCL5 mRNA in lung tissues. Expression of the M2 macrophage marker Arg1 was significantly upregulated in the mid to late stages of coal dust exposure and was accompanied by higher expression of the anti-inflammatory cytokines IL-10 and TGF-ß. In conclusion, macrophage polarization and its molecular regulatory network (especially CCL5) play an important role in lung inflammation and fibrosis in SD rats exposed to coal dust by dynamic inhalation.
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Exposición por Inhalación , Neumonía , Ratas , Animales , Ratas Sprague-Dawley , Exposición por Inhalación/efectos adversos , Neumonía/inducido químicamente , Fibrosis , Polvo , Citocinas/metabolismo , Macrófagos/metabolismo , Carbón MineralRESUMEN
Background: The cardiotoxicity of doxorubicin (DOX) limits its use in cancer treatment. To address this limitation, we developed a novel animal model that uses beagle dogs to investigate DOX-induced cardiac disorders. Unfortunately, the lack of effective cardioprotection strategies against DOX-induced cardiotoxicity poses a significant challenge. To establish a canine model for low-mortality DOX-induced cardiac dysfunction and explore the relationship between inflammatory reprogramming and DOX-related cardiotoxicity. Methods: Twenty male beagle dogs aged two years were randomly assigned into the DOX (N = 10) and control (CON) (N = 10) groups. DOX was infused (1.5 mg/kg) every two weeks until doses cumulatively reached 12 mg/kg. Serum biomarkers and myocardial pathology were evaluated, while real-time fluorescence-based quantitative polymerase chain reaction (RTFQ-PCR), two- and three-dimensional echocardiography (2DE and RT3DE), functional enrichment, and matrix correlation were also performed. Results: In the DOX group, high-sensitive cardiac troponin T (hs cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were significantly increased. Myocardial pathology indicated early to medium myocardial degeneration via a decreased cardiomyocyte cross-sectional area (CSA). Increased levels of inflammatory gene transcripts (interleukin 6 (IL6), tumor necrosis factor (TNF), transforming growth factor ß (TGF ß ), intercellular adhesion molecule 1 (ICAM1), interleukin 1 (IL1), interleukin 1 ß (IL1 ß ), and interleukin 8 (IL8)), of collagen metabolism and deposition regulatory genes (matrix metalloproteinase (MMP) family and tissue inhibitor of matrix metalloproteinase (TIMP) family), and the natriuretic peptide family (NPS) (natriuretic peptide A, B and C (NPPA, NPPB, and NPPC)) were observed. Strain abnormalities in the right ventricular longitudinal septal strain (RVLSS), right ventricular longitudinal free-wall strain (RVLFS), left ventricular global longitudinal strain (LVGLS), and left ventricular global circumferential strain (LVGCS) were detected at week 28 (vs. week 0 or CON group, p < 0.05, respectively). A significant decline in RVLSS and RVLFS occurred at week 16, which was earlier than in the corresponding left ventricular areas. A significant right ventricular ejection fraction (RVEF) decline was noted at week 16 (vs. week 0, 33.92 ± 3.59% vs. 38.58 ± 3.58%, p < 0.05), which was 12 weeks earlier than for the left ventricular ejection fraction (LVEF), which occurred at week 28 (vs. week 0, 49.02 ± 2.07% vs. 54.26 ± 4.38%, p < 0.01). The right ventricular strain and functional damages correlated stronger with inflammatory reprogramming (most R from 0.60 to 0.90) than the left ones (most R from 0.30 to 0.65), thereby indicating a more pronounced correlation. Conclusions: Inflammatory reprogramming mediated disorders of strain capacity and cardiac function predominantly in the right side of the heart in the newly established DOX-related cardiomyopathy beagle dog model.
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Tunable optical filters at the chip scale play a crucial role in fulfilling the need for reconfigurability in channel routing, optical switching, and wavelength division multiplexing systems. In this Letter, we propose a tunable double notch filter on thin-film lithium niobate using dual microring architecture. This unique integrated filter is essential for complex photonic integrated circuits, along with multiple channels and various frequency spacing. With only one loaded voltage, the device demonstrates a wide frequency spacing tunability from 16.1 to 89.9â GHz by reversely tuning the resonances of the two microrings while the center wavelength between the two resonances remains unaltered. Moreover, by utilizing the pronounced electro-optic properties of lithium niobate associated with the tight light confined nanophotonic waveguides, the device demonstrates a spacing tunability of 0.82â GHz/V and a contrast of 10-16â dB. In addition, the device has an ultracompact footprint of 0.0248â mm2.
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BACKGROUND: Malnutrition is common in patients with chronic cardiovascular disease and is associated with significantly higher all-cause mortality. Approximately one-third of patients with heart failure are malnourished. However, the relationship between malnutrition and idiopathic pulmonary arterial hypertension (IPAH) remains unclear. This study aimed to clarify the prognostic value of malnutrition in patients with IPAH. METHODS: A total of 432 consecutive participants with IPAH were included in this study between March 2013 and August 2021. Three common malnutrition assessment tools, including the geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI), and controlling nutritional status (CONUT) score, were used to evaluate the nutritional status of patients with IPAH. The relationships between the malnutrition tools and long-term adverse outcomes were determined using restricted cubic splines and multivariate Cox regression models. RESULTS: During a mean follow-up of 3.1 years, 158 participants experienced clinical worsening or all-cause death. Patients were stratified into the low-, intermediate- and high-risk groups based on the European Society of Cardiology (ESC) risk stratification, and the PNI (55.9 ± 5.7 vs. 54.4 ± 7.2 vs. 51.1 ± 7.1, P = 0.005) and CONUT score (2.1 ± 0.9 vs. 2.5 ± 1.2 vs. 3.3 ± 1.1, P < 0.001) identified these patient groups better than the GNRI. All three malnutrition tools were associated with well-validated variables that reflected IPAH severity, such as the World Health Organization functional class, 6-min walk distance, and N-terminal pro-brain natriuretic peptide level. The CONUT score exhibited better predictive ability than both the GNRI (ΔAUC = 0.059, P < 0.001) and PNI (ΔAUC = 0.095, P < 0.001) for adverse outcomes and significantly improved reclassification and discrimination beyond the ESC risk score. Multivariable Cox regression analysis indicated that only the CONUT score (hazard ratio = 1.363, 95% confidence interval 1.147, 1.619 per 1.0-standard deviation increment, P < 0.001) independently predicted adverse outcomes. CONCLUSIONS: The malnutrition status was associated with disease severity in patients with IPAH. The CONUT score provided additional information regarding the risk of clinically worsening events, making it a meaningful risk stratification tool for these patients.
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Desnutrición , Índice de Severidad de la Enfermedad , Humanos , Femenino , Masculino , Desnutrición/diagnóstico , Desnutrición/epidemiología , Persona de Mediana Edad , Estudios Retrospectivos , Estado Nutricional , Adulto , Hipertensión Pulmonar Primaria Familiar/diagnóstico , Hipertensión Pulmonar Primaria Familiar/fisiopatología , Hipertensión Pulmonar Primaria Familiar/mortalidad , Anciano , Evaluación Nutricional , Estudios de Cohortes , Estudios de Seguimiento , Medición de Riesgo/métodos , Pronóstico , Factores de RiesgoRESUMEN
Glioma, the most common primary brain tumor, is highly invasive and grows rapidly. As such, the survival of glioma patients is relatively short, highlighting the vital importance of timely diagnosis and treatment of glioma. However, the blood brain barrier (BBB) and the non-targeting delivery systems of contrast agents and drugs greatly hinder the effective glioma imaging and therapy. Fortunately, in recent years, investigators have constructed various biomimetic delivery platforms utilizing the exceptional advantages of biomimetic nanocomposites, such as immune evasion, homologous targeting ability, and BBB penetrating ability, to achieve efficient and precise delivery of substances to glioma sites for improved diagnosis and treatment. In this concept, we present the application of these biomimetic nanocomposites in fluorescence imaging (FI), magnetic resonance imaging (MRI), and multi-modal imaging, as well as in chemotherapy, phototherapy, and combined therapy for glioma. Lastly, we provide our perspective on this research field.
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Materiales Biomiméticos , Barrera Hematoencefálica , Neoplasias Encefálicas , Glioma , Imagen por Resonancia Magnética , Nanocompuestos , Glioma/diagnóstico por imagen , Glioma/terapia , Humanos , Nanocompuestos/química , Nanocompuestos/uso terapéutico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/terapia , Materiales Biomiméticos/química , Barrera Hematoencefálica/metabolismo , Medios de Contraste/química , Imagen Óptica , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Animales , Sistemas de Liberación de Medicamentos , Fototerapia , Biomimética/métodosRESUMEN
BACKGROUND: Histone deacetylase 6 (HDAC6) inhibitor CAY10603 has been identified as a potential therapeutic agent for the treatment of diabetic kidney disease (DKD). The objective of this study was to investigate the therapeutic effects of CAY10603 in mice with acute kidney injury (AKI) and chronic kidney diseases (CKD). METHODS: Renal immunohistology was performed to assess the expression levels of HDAC6 in both human and mouse kidney samples. C57BL/6J mice were intraperitoneal injected with lipopolysaccharide (LPS) to induce AKI; CD-1 mice were fed with adenine diet to induce adenine-nephropathy as CKD model. Serum creatinine, blood urea nitrogen and uric acid were measured to reflect renal function; renal histology was applied to assess kidney damage. Western blot and immunohistology were used to analyze the unfolded protein response (UPR) level. RESULTS: HDAC6 was significantly upregulated in renal tubular epithelial cells (RTECs) of both AKI and CKD patients as well as mice. In the murine models of AKI induced by LPS and adenine-induced nephropathy, CAY10603 exhibited notable protective effects, including improvement in biochemical indices and pathological changes. In vivo and in vitro studies revealed that CAY10603 effectively suppressed the activation of activating transcription factor 6 (ATF6) branch of UPR triggered by thapsigargin (Tg), a commonly employed endoplasmic reticulum (ER) stressor. Consistent with these findings, CAY10603 also displayed substantial inhibition of ATF6 activation in RTECs from both murine models of LPS-induced AKI and adenine-induced nephropathy. CONCLUSIONS: Collectively, these results suggest that CAY10603 holds promise as a potential therapeutic agent for both acute and chronic kidney injury.
Asunto(s)
Factor de Transcripción Activador 6 , Lesión Renal Aguda , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas , Ratones Endogámicos C57BL , Insuficiencia Renal Crónica , Respuesta de Proteína Desplegada , Animales , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Histona Desacetilasa 6/metabolismo , Histona Desacetilasa 6/antagonistas & inhibidores , Humanos , Factor de Transcripción Activador 6/metabolismo , Ratones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/inducido químicamente , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Masculino , Respuesta de Proteína Desplegada/efectos de los fármacos , LipopolisacáridosRESUMEN
BACKGROUND: Cholestasis is a common yet severe complication that occurs during the advancement of liver metastasis. However, how cholestasis impacts the development, treatment, and tumor microenvironment (TME) of liver metastasis remains to be elucidated. METHODS: Extrahepatic and intrahepatic cholestatic mouse models with liver metastasis were established to detect the differential expression levels of genes, infiltration of immune cells and change in bile acid-associated metabolites by using RNA-Sequencing, flowcytometry, and liquid chromatography and mass spectrometry. Western blot was applied to neutrophils under the stimulation of primary bile acids (BAs) in vitro to study the mechanism of phenotypic alteration. In vitro coculture of BA-treated neutrophils with CD8+ T cells were performed to study the immune-suppressive effect of phenotypic-altered neutrophils. Clinical samples collected from colorectal cancer patients with liver metastasis and cholestasis were applied to RNA-Seq. RESULTS: Compared to non-cholestatic mice, the progression of liver metastasis of cholestatic mice was significantly accelerated, which was associated with increased neutrophil infiltration and T-cell exclusion. Both neutrophils and T cells expressed higher immunosuppressive markers in the cholestatic mouse model, further indicating that an immunosuppressive tumor microenvironment was induced during cholestasis. Although neutrophils deletion via anti-Ly6G antibody partially hindered liver metastasis progression, it reduced the overall survival of mice. Tauro-ß-muricholic acid (Tß-MCA) and Glycocholic acid (GCA), the two most abundant cholestasis-associated primary BAs, remarkably promoted the expression of Arg1 and iNOS on neutrophils via p38 MAPK signaling pathway. In addition, BAs-pretreated neutrophils significantly suppressed the activation and cytotoxic effects of CD8+ T cells, indicating that the immunosuppressive phenotype of neutrophils was directly induced by BAs. Importantly, targeting BA anabolism with Obeticholic acid (OCA) under cholestasis effectively suppressed liver metastasis progression, enhanced the efficacy of immune checkpoint blockade, and prolonged survival of mice. CONCLUSIONS: Our study reveals the TME of cholestasis-associated liver metastasis and proposes a new strategy for such patients by targeting bile acid anabolism.