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Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1-7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation. We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.
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Dermatitis Atópica , PPAR gamma , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamación/metabolismo , Ratones , Obesidad/metabolismo , PPAR gamma/agonistas , PPAR gamma/metabolismo , Medicina de Precisión , Análisis de Secuencia de ARN , Células Th2/metabolismoRESUMEN
Controlling multimetallic ensembles at the atomic level is significantly challenging, particularly for high-entropy alloys with more than five elements. Herein, we report an innovative ultrasmall (â¼2 nm) PtFeCoNiCuZn high-entropy intermetallic (PFCNCZ-HEI) with a well-ordered structure synthesized by using the space-confined strategy. By exploiting these combined metals, the PFCNCZ-HEI nanoparticles achieve an ultrahigh mass activity of 2.403 A mgPt-1 at 0.90 V vs reversible hydrogen electrode for the oxygen reduction reaction, which is up to 19-fold higher than that of state-of-the-art commercial Pt/C. A proton exchange membrane fuel cell assembled with PFCNCZ-HEI as the cathode (0.03 mgPt cm-2) exhibits a power density of 1.4 W cm-2 and a high mass-normalized rated power of 45 W mgPt-1. Furthermore, theoretical calculations reveal that the outer electrons of the non-noble-metal atoms on the surface of the PFCNCZ-HEI nanoparticle are modulated to show characteristics of multiple active centers. This work offers a promising catalyst design direction for developing highly ordered HEI nanoparticles for electrocatalysis.
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PURPOSE: To improve reproducibility and predictive performance of PET radiomic features in multicentric studies by cycle-consistent generative adversarial network (GAN) harmonization approaches. METHODS: GAN-harmonization was developed to harmonize whole-body PET scans to perform image style and texture translation between different centers and scanners. GAN-harmonization was evaluated by application to two retrospectively collected open datasets and different tasks. First, GAN-harmonization was performed on a dual-center lung cancer cohort (127 female, 138 male) where the reproducibility of radiomic features in healthy liver tissue was evaluated. Second, GAN-harmonization was applied to a head and neck cancer cohort (43 female, 154 male) acquired from three centers. Here, the clinical impact of GAN-harmonization was analyzed by predicting the development of distant metastases using a logistic regression model incorporating first-order statistics and texture features from baseline 18F-FDG PET before and after harmonization. RESULTS: Image quality remained high (structural similarity: left kidney ≥ 0.800, right kidney ≥ 0.806, liver ≥ 0.780, lung ≥ 0.838, spleen ≥ 0.793, whole-body ≥ 0.832) after image harmonization across all utilized datasets. Using GAN-harmonization, inter-site reproducibility of radiomic features in healthy liver tissue increased at least by ≥ 5 ± 14% (first-order), ≥ 16 ± 7% (GLCM), ≥ 19 ± 5% (GLRLM), ≥ 16 ± 8% (GLSZM), ≥ 17 ± 6% (GLDM), and ≥ 23 ± 14% (NGTDM). In the head and neck cancer cohort, the outcome prediction improved from AUC 0.68 (95% CI 0.66-0.71) to AUC 0.73 (0.71-0.75) by application of GAN-harmonization. CONCLUSIONS: GANs are capable of performing image harmonization and increase reproducibility and predictive performance of radiomic features derived from different centers and scanners.
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Procesamiento de Imagen Asistido por Computador , Tomografía de Emisión de Positrones , Humanos , Femenino , Masculino , Procesamiento de Imagen Asistido por Computador/métodos , Tomografía de Emisión de Positrones/normas , Tomografía de Emisión de Positrones/métodos , Neoplasias Pulmonares/diagnóstico por imagen , Persona de Mediana Edad , Reproducibilidad de los Resultados , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Estudios Retrospectivos , Fluorodesoxiglucosa F18 , AncianoRESUMEN
PURPOSE: This study aimed to assess the diagnostic performance of [18F]FAPI-42 PET/CT and compare it with that of 2-[18F]FDG PET/CT in patients with differentiated thyroid cancer (DTC) with biochemical elevations in Tg or anti-Tg antibodies. METHODS: A total of 42 patients with DTC with biochemical elevations in Tg or anti-Tg antibodies underwent [18F]FAPI-42 PET/CT as part of this study; of which, 11 additionally underwent 2-[18F]FDG PET/CT within 7 days. Images were semi-quantitatively and visually interpreted, and the quantity, location, and uptake values of lesions were noted. The diagnostic capacity of [18F]FAPI-42 PET/CT and biomarkers affecting the uptake of [18F]FAPI-42 were evaluated. In addition, the diagnostic performance and uptake of [18F]FAPI-42 and 2-[18F]FDG were compared, and the correlation between lesion diameter and quantitative parameters was investigated. RESULTS: A total of 161 lesions were detected in 27 (64%) patients on [18F]FAPI-42 PET/CT. FAPI-positive local recurrence showed the highest uptake intensity, followed by lymphatic, other site-associated (bone and pleura), and pulmonary lesions (mean SUVmax, 4.7 versus 3.7 versus 3.0 versus 2.2, respectively; P < 0.0001). The levels of TSH, Tg, and Tg-Ab did not affect the uptake value of lesions (median SUVmax: 2.4 versus 3.2, P = 0.56; 2.9 versus 2.4, P = 0.0935; 2.8 versus 2.6, P = 0.0525, respectively). A total of 90 positive lesions were detected in 7 patients using both modalities. All positive lesions showed statistically higher uptake of 2-[18F]FDG than that of [18F]FAPI-42 (SUVmax, 2.6 versus 2.1; P = 0.026). However, the SUVmax of [18F]FAPI-42 was higher than that of 2-[18F]FDG in local recurrences and lymphatic lesions (SUVmax, 4.2 versus 2.9 and 3.9 versus 3.4, respectively; P > 0.05). CONCLUSION: [18F]FAPI-42 can be used for detecting lesions and reflecting FAP expression during local recurrence and metastasis in patients with DTC with biochemical elevations in Tg or anti-Tg antibodies. The diagnostic performance of [18F]FAPI-42 PET/CT is comparable with that of 2-[18F]FDG PET/CT in such patients.
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Adenocarcinoma , Neoplasias de la Tiroides , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Fluorodesoxiglucosa F18 , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/patología , Tomografía de Emisión de Positrones , Radioisótopos de GalioRESUMEN
Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the aging population. Particularly, long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in PD, while the role of lncRNA SNHG8 in PD remains to be further explored. C57BL/6 mice were induced by rotenone to establish a PD model in vivo, and then the dopaminergic (DA) neuronal damage and locomotor dysfunction in rotenone-treated mice were evaluated. Murine DA cell line MN9D was treated with rotenone to establish a cellular PD model in vitro. Then, the viability, apoptosis, mitochondrial dysfunction, endoplasmic reticulum stress, and autophagy in rotenone-treated MN9D cells were assessed. Expression levels of SNHG8, microRNA-421-3p (miR-421-3p), and sorting nexin 8 (SNX8) in the substantia nigra (SN) of PD mice and rotenone-treated MN9D cells were detected. The interaction between SNHG8 and miR-421-3p, and the targeting relationship between SNX8 and miR-421-3p were confirmed. SNHG8 and SNX8 expression levels were decreased while miR-421-3p expression level was increased in the SN of PD mice and rotenone-treated MN9D cells. Upregulated SNHG8 ameliorated dopaminergic neuron damage and locomotor dysfunction in PD mice. Meanwhile, upregulated SNHG8 enhanced viability, diminished apoptosis, and alleviated mitochondrial dysfunction, endoplasmic reticulum stress, and autophagy in rotenone-treated MN9D cells. Mechanistically, SNHG8 bound to miR-421-3p, and miR-421-3p targeted SNX8. Overexpressed SNHG8 downregulates miR-421-3p to alleviate rotenone-induced dopaminergic neuron injury in PD via upregulating SNX8.
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MicroARNs , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Ratones , Animales , Enfermedad de Parkinson/metabolismo , Neuronas Dopaminérgicas/metabolismo , Rotenona/toxicidad , Enfermedades Neurodegenerativas/metabolismo , Nexinas de Clasificación/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , MicroARNs/genética , MicroARNs/metabolismo , Sustancia Negra/metabolismoRESUMEN
The primary barrier to nutrient absorption in fish is the intestinal epithelium, followed by a community of microorganisms known as the gut microbiota, which can be thought of as a hidden organ. The gastrointestinal microbiota of fish plays a key role in the upholding of overall health by maintaining the homeostasis and disease resistance of the host. However, emerging contaminants as the result of anthropogenic activities have significantly led to disruptions and intestinal dysbiosis in fish. Which probably results in fish mortalities and disrupts the balance of an ecosystem. Therefore, we comprehensively seek to compile the effects and consequences of emerging contaminations on fish intestinal microbiota. Additionally, the mitigation strategies including prebiotics, probiotics, plant-based diet, and Biofloc technology are being outlined. Biofloc technology (BFT) can treat toxic materials, i.e., nitrogen components, and convert them into a useful product such as proteins and demonstrated promising elevating technique for the fish intestinal bacterial composition. However, it remains unclear whether the bacterial isolate is primarily responsible for the BFT's removal of nitrate and ammonia and the corresponding removal mechanism. To answer this, real time polymerase chain reaction (RT-PCR) with metagenomics, transcriptomics, and proteomics techniques probably provides a possible solution.
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The biological synthesis of nanoparticles is an emerging field of study that seeks to synthesize nanoparticles using non-chemical mechanisms such as microorganisms, plants, and animal blood serum. Among these, plants have gained particular attention due to their ease of handling, availability, and ability to synthesize a wide range of nanoparticles. Therefore, the current study aimed to fabricate the silver nanoparticles (AgNPs) using Chinese medicinal plants (CMP) for their possible toxicity in common carp fish (Cyprinus carpio). For this purpose, CMP was dried, ground, and used as a bio-reductive agent. The fabricated AgNPs were characterized and a well dispersed AgNPs were obtained. Moreover, the C. carpio was exposed to the AgNPs for bioaccumulation and histological alterations. The obtained findings revealed that the AgNPs were mostly accumulated in the intestines followed by the gills, muscles, liver, and brain. The accumulated AgNPs caused histological alterations in gills and intestines at the highest concentration (0.08 mg/L). However, very less alterations were caused by the lowest concentration, especially in the intestine. In conclusion, further in-depth research is needed to determine the risks associated with the usage of nanoparticles to reveal their harmful impacts on fish and the aquatic environment. HIGHLIGHTS: The biological fabrication of AgNPs is considered eco-friendly. Chinese medicinal plants play a significant role in AgNPs synthesis. AgNPs have excellent antibacterial activity. AgNPs are bioaccumulated in various organs of fish.
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Carpas , Nanopartículas del Metal , Animales , Plata/toxicidad , Plata/química , Nanopartículas del Metal/toxicidad , Nanopartículas del Metal/química , Antibacterianos/toxicidadRESUMEN
Objective: Correct diagnosis and prognostic evaluation of medullary thyroid cancer (MTC) are crucial to treat patients. The purpose of this study was to evaluate the diagnostic and prognostic value of [18F]F-DOPA PET/CT in patients with MTC. Methods: We reviewed MTC patients who underwent [18F]F-DOPA PET/CT from June 2008 to November 2023. Clinical characteristics, follow-up data, and the following [18F]F-DOPA PET/CT parameters were recorded: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and SUVmean of multiple organs. The diagnostic value of PET/CT for the detection of tumor lesions was calculated. Serum basal calcitonin (bCt) and stimulated calcitonin (sCt) were determined. Receiver operating characteristics, Kaplan-Meier, and Cox regression analyses were performed. Results: In total, 109 patients (50 women, 59 men; average age, 55 ± 14 years) were included in the analysis. The patient-related sensitivity, specificity, and accuracy of [18F]F-DOPA PET/CT were 95%, 93%, and 94%, respectively. The lesion-related sensitivity, specificity, and accuracy were 65%, 99%, and 72%, respectively. The optimal cutoff values of bCt, sCt, and CEA to obtain positive [18F]F-DOPA PET/CT results were 64 pg/mL, 1808 pg/mL, and 4 µg/L, respectively. Patients with negative [18F]F-DOPA PET/CT had longer overall survival than patients with positive [18F]F-DOPA PET/CT results (P = 0.017). Significant positive correlations were found between bCt, sCt, and CEA with SUVmax, SUVmean, and MTV of [18F]F-DOPA PET/CT (P < 0.001). [18F]F-DOPA PET/CT results and MTV may be useful for the evaluation of the prognosis of patients with recurrent MTC, while age and MTV were independent prognostic factors in patients with primary MTC. For all patients, SUVmean of the left kidney, liver, aorta, and pancreas might be used to independently predict OS. Conclusion: [18F]F-DOPA PET/CT had great value for diagnosis and prognostic assessment in patients with MTC. The DOPA PET/CT parameter SUVmean and MTV showed significant association with OS.
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Carcinoma Neuroendocrino , Dihidroxifenilalanina , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Tiroides , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Femenino , Masculino , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/mortalidad , Persona de Mediana Edad , Pronóstico , Adulto , Anciano , Carcinoma Neuroendocrino/diagnóstico por imagen , Carcinoma Neuroendocrino/mortalidad , Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/patología , Dihidroxifenilalanina/análogos & derivados , Estudios Retrospectivos , Radiofármacos , Sensibilidad y EspecificidadRESUMEN
Lithium-rich Mn-based oxides have gained significant attention worldwide as potential cathode materials for the next generation of high-energy density lithium-ion batteries. Nonetheless, the inferior rate capability and voltage decay issues present formidable challenges. Here, a Li-rich material equipped with quasi-three-dimensional (quasi-3D) Li-ion diffusion channels is initially synthesized by introducing twin structures with high Li-ion diffusion coefficients into the crystal and constructing a "bridge" between different Li-ion diffusion tunnels. The as-prepared material exhibits monodispersed micron-sized primary particles (MP), delivering a specific capacity of 303 mAh g-1 at 0.1 C and an impressive capacity of 253 mAh g-1 at 1 C. More importantly, the twin structure also serves as a "breakwater" to inhibit the migration of Mn ions and improve the overall structural stability, leading to cycling stability with 85% capacity retention at 1 C after 200 cycles. The proposed strategy of constructing quasi-3D channels in the layered Li-rich cathodes will open up new avenues for the research and development of other layered oxide cathodes, with potential applications in industry.
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Layered Li-rich cathode materials with high reversible energy densities are becoming prevalent. However, owing to the activation of low-potential redox couples and the progressively irreversible structural transformation caused by the local adjustment of transition-metal ions in the intra/interlayer driven by anionic redox, continuous capacity degradation, and voltage decay emerge, thus greatly reducing the energy density and increasing the difficulty of battery system management. Herein, layered Li-rich cathode materials with higher intralayer configuration entropy have more local structural diversity and higher distortion energy, resulting in superior local structural adaptability with no drastic redox couple evolution, major local structural adjustment, or obvious layered-to-spinel phase transition. Consequently, the energy retention of the entropy-stabilization-strategy-enhanced Li-rich cathode materials is almost twice that of a typical Li-rich cathode material (Li1.20 Mn0.54 Ni0.13 Co0.13 O2 , T-LRM) after 3 months of cyclic testing. Moreover, when cycled at 1 C, the voltage degradation per cycle is less than 0.02%, that is, it results in a voltage loss of only 0.8 mV per cycle, which is excellent performance. This study paves the way for the development of Li-rich cathode materials with stabilized intralayer atomic arrangements and high local structural adaptability.
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The anionic redox reaction (ARR) has attracted extensive attention due to its potential to enhance the reversible capacity of cathode materials in Li/Na-ion batteries (LIBs/SIBs). However, the understanding of its activation mechanism is still limited by the insufficient mastering of the underlying thermodynamics and kinetics. Herein, a series of Mg/Li/Zn-substituted Nax MnO2 and Lix MnO2 cathode materials are designed to investigate their ARR behaviors. It is found that the ARR can be activated in only Li-substituted Lix MnO2 and not for Mg- and Zn-substituted ones, while all Mg/Li/Zn-substituted Nax MnO2 cathode materials exhibit ARR activities. Combining theoretical calculations with experimental results, such a huge difference between Li and Na cathodes is closely related to the migration of substitution ions from the transition metal layer to the alkali metal layer in a kinetic aspect, which generates unique Li(Na)-O-â¡TM and/or â¡Li/ Na -O-â¡TM configurations and reducing reaction activation energy to trigger the ARR. Based on these findings, an ion-migration mechanism is proposed to explain the different ARR behaviors between the Nax MnO2 and Lix MnO2 , which can not only reveal the origin of ARR in the kinetic aspect, but also provide a new insight for the development of high-capacity metal oxide cathode materials for LIBs/SIBs.
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The secreted protein isthmin-1 (Ism1) mitigates diabetes by increasing adipocyte and skeletal muscle glucose uptake by activating the PI3K-Akt pathway. However, while both Ism1 and insulin converge on these common targets, Ism1 has distinct cellular actions suggesting divergence in downstream intracellular signaling pathways. To understand the biological complexity of Ism1 signaling, we performed phosphoproteomic analysis after acute exposure, revealing overlapping and distinct pathways of Ism1 and insulin. We identify a 53% overlap between Ism1 and insulin signaling and Ism1-mediated phosphoproteome-wide alterations in ~450 proteins that are not shared with insulin. Interestingly, we find several unknown phosphorylation sites on proteins related to protein translation, mTOR pathway, and, unexpectedly, muscle function in the Ism1 signaling network. Physiologically, Ism1 ablation in mice results in altered proteostasis, including lower muscle protein levels under fed and fasted conditions, reduced amino acid incorporation into proteins, and reduced phosphorylation of the key protein synthesis effectors Akt and downstream mTORC1 targets. As metabolic disorders such as diabetes are associated with accelerated loss of skeletal muscle protein content, these studies define a non-canonical mechanism by which this antidiabetic circulating protein controls muscle biology.
Cells need energy to survive and carry out their role in the body. They do this by breaking down molecules, like sugar, into substances that can fuel the creation of new compounds, like proteins or lipids. This process, known as metabolism, involves a series of interconnecting chemical reactions which are organized into pathways. Metabolic pathways contain proteins that catalyze each sequential reaction. Hormones can change the activity of these proteins by adding a chemical group called a phosphate. This reversible modification can majorly impact the metabolism of cells, resulting in changes to the body's tissues. The hormone insulin, for instance, alters a well-known metabolic pathway that triggers skeletal muscle cells to produce more proteins, leading to stronger and larger muscles. In 2021, a group of scientists discovered a molecule made by fat cells, called Isthmin-1, also activates components in this pathway. Similar to insulin, Isthmin-1 encourages muscle and fat cells to take up sugar. However, it also prevents the liver from accumulating excess fat, suggesting Isthmin-1 may trigger a different cascade of molecules to insulin. To investigate this possibility, Zhao et al. including some of the researchers involved in the 2021 study exposed cells grown in the laboratory to Isthmin-1 or insulin and looked for phosphates on all their proteins. This revealed that only 53% of the proteins Isthmin-1 modifies are also altered by insulin. Of the proteins unique to Isthmin-1, several had known roles in making and maintaining proteins in muscle cells. To understand more about the role of this newly discovered pathway, Zhao et al. genetically engineered mice to lack the gene that codes for Isthmin-1. This decreased the size and strength of the mice's muscle fibers and reduced the signals that normally lead to skeletal muscle growth. These findings suggest that Isthmin-1 regulates skeletal muscle size via a metabolic pathway that is slightly different to the one activated by insulin. Many metabolic disorders are associated with muscle loss, like diabetes, and this newly discovered network of proteins could further our understanding of how to prevent and treat these diseases.
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Proteínas Musculares , Proteínas Proto-Oncogénicas c-akt , Ratones , Animales , Proteínas Musculares/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Biosíntesis de Proteínas , Serina-Treonina Quinasas TOR/metabolismo , Insulina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Músculo Esquelético/metabolismo , Glucosa/metabolismo , Hipoglucemiantes/metabolismo , Aminoácidos/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismoRESUMEN
BACKGROUND: Anthracycline-induced cardiomyopathy (AIC) is a significant source of morbidity and mortality in cancer survivors. The role of mesenchymal stem cells (MSCs) in treating AIC was evaluated in the SENECA trial, a Phase 1 National Heart, Lung, and Blood Institute-sponsored study, but the mechanisms underpinning efficacy in human tissue need clarification. OBJECTIVES: The purpose of this study was to perform an in vitro clinical trial evaluating the efficacy and putative mechanisms of SENECA trial-specific MSCs in treating doxorubicin (DOX) injury, using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iCMs) generated from SENECA patients. METHODS: Patient-specific iCMs were injured with 1 µmol/L DOX for 24 hours, treated with extracellular vesicles (EVs) from MSCs by either coculture or direct incubation and then assessed for viability and markers of improved cellular physiology. MSC-derived EVs were separated into large extracellular vesicles (L-EVs) (>200 nm) and small EVs (<220nm) using a novel filtration system. RESULTS: iCMs cocultured with MSCs in a transwell system demonstrated improved iCM viability and attenuated apoptosis. L-EVs but not small EVs recapitulated this therapeutic effect. L-EVs were found to be enriched in mitochondria, which were shown to be taken up by iCMs. iCMs treated with L-EVs demonstrated improved contractility, reactive oxygen species production, ATP production, and mitochondrial biogenesis. Inhibiting L-EV mitochondrial function with 1-methyl-4-phenylpyridinium attenuated efficacy. CONCLUSIONS: L-EV-mediated mitochondrial transfer mitigates DOX injury in patient-specific iCMs. Although SENECA was not designed to test MSC efficacy, consistent tendencies toward a positive effect were observed across endpoints. Our results suggest a mechanism by which MSCs may improve cardiovascular performance in AIC independent of regeneration, which could inform future trial design evaluating the therapeutic potential of MSCs.
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With the increasing prevalence of type 2 diabetes and fatty liver disease, there is still an unmet need to better treat hyperglycemia and hyperlipidemia. Here, we identify isthmin-1 (Ism1) as an adipokine and one that has a dual role in increasing adipose glucose uptake while suppressing hepatic lipid synthesis. Ism1 ablation results in impaired glucose tolerance, reduced adipose glucose uptake, and reduced insulin sensitivity, demonstrating an endogenous function for Ism1 in glucose regulation. Mechanistically, Ism1 activates a PI3K-AKT signaling pathway independently of the insulin and insulin-like growth factor receptors. Notably, while the glucoregulatory function is shared with insulin, Ism1 counteracts lipid accumulation in the liver by switching hepatocytes from a lipogenic to a protein synthesis state. Furthermore, therapeutic dosing of recombinant Ism1 improves diabetes in diet-induced obese mice and ameliorates hepatic steatosis in a diet-induced fatty liver mouse model. These findings uncover an unexpected, bioactive protein hormone that might have simultaneous therapeutic potential for diabetes and fatty liver disease.
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Diabetes Mellitus Tipo 2 , Hígado Graso , Resistencia a la Insulina , Adipoquinas , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa , Hígado Graso/tratamiento farmacológico , Hígado Graso/metabolismo , Glucosa/metabolismo , Péptidos y Proteínas de Señalización Intercelular , Metabolismo de los Lípidos/fisiología , Lipogénesis , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
Metabolic diseases, such as diabetes, obesity, and fatty liver disease, have now reached epidemic proportions. Receptor tyrosine kinases (RTKs) are a family of cell surface receptors responding to growth factors, hormones, and cytokines to mediate a diverse set of fundamental cellular and metabolic signaling pathways. These ligands signal by endocrine, paracrine, or autocrine means in peripheral organs and in the central nervous system to control cellular and tissue-specific metabolic processes. Interestingly, the expression of many RTKs and their ligands are controlled by changes in metabolic demand, for example, during starvation, feeding, or obesity. In addition, studies of RTKs and their ligands in regulating energy homeostasis have revealed unexpected diversity in the mechanisms of action and their specific metabolic functions. Our current understanding of the molecular, biochemical and genetic control of energy homeostasis by the endocrine RTK ligands insulin, FGF21 and FGF19 are now relatively well understood. In addition to these classical endocrine signals, non-endocrine ligands can govern local energy regulation, and the intriguing crosstalk between the RTK family and the TGFß receptor family demonstrates a signaling network that diversifies metabolic process between tissues. Thus, there is a need to increase our molecular and mechanistic understanding of signal diversification of RTK actions in metabolic disease. Here we review the known and emerging molecular mechanisms of RTK signaling that regulate systemic glucose and lipid metabolism, as well as highlighting unexpected roles of non-classical RTK ligands that crosstalk with other receptor pathways.
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To improve the stability and ductility of polylactic acid (PLA), chain extender or crosslinking agent of phosphite functional polysilsesquioxane (PPSQ) was synthesized by the reaction of phosphite group with the amino group of poly(amino-epoxy)silsesquioxane (PSQ). First, the reaction of PPSQ with PLA was characterized by molecular weight (M w) and melt mass flow rate (MFR) of PLA after melting reaction. The results showed a 6.6% increase in the M w of PLA and a 24.5% decrease in MFR value at the PPSQ loading content of 2 wt% in PLA, indicating that PPSQ takes chain extension or crosslinking in PLA. Then, this result was further supported by the thermal stability improvement of PLA, which was testified by the increase of oxidative activation energy and the oxygen onset temperature (OOT) value. PPSQ improved the water resistance and mechanical properties of PLA. The hydrolysis rate decreased by 46.8%, and the tensile strength and impact strength increased by 17.2% and 89.4%. Taken together, these results indicate that the addition of PPSQ can produce the PLA with excellent thermal stability, hydrolytic stability and mechanical properties.
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A novel phosphorus-silicon flame retardant (P5PSQ) was prepared by bonding phosphate to silicon-based polysilsesquioxane (PSQ) and used as flame retardant of poly (lactic acid) (PLA). The results show that PLA with 10 wt % P5PSQ has a limiting oxygen index (LOI) 24.1%, the peak heat release rate (PHRR) and total heat release (THR) of PLA decrease 21.8% and 25.2% compared to neat PLA in cone calorimetric test, indicating that P5PSQ shows better flame retardancy in comparison to PSQ. Furthermore, the study for the morphology and composition of carbon residue after the combustion of PLA and the gas release of PLA during combustion illustrate that P5PSQ has flame retardancy in condensed phase and gas phase simultaneously. In condensed phase, phosphorus from phosphate promotes the formation of more stable and better carbon layer containing Si and P, which inhibits the transfer of heat and oxygen in the combustion. In gas phase, the phosphate in P5PSQ emits phosphorus-containing compound that can restrain the release of C-O containing products, which may have effective flame retardancy for PLA in gas phase to a certain extent. In one word, P5PSQ is denoted as a good phosphorus-silicon synergistic flame-retardant.