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Sensing biogenic amine (BAs) content is very important for assessing food freshness. To address the limitations such as small color difference values (ΔE) and complex preparation of probes for visualizing the freshness of seafood, a pH-responsive ratiometric fluorescent probe (EnEB) was prepared by Eu(NO3)3, trimeric acid (BTC), and hydrochloric acid norepinephrine (Enr). EnEB emitted blue (446 nm) and red fluorescence (616 nm) originating from Enr and Eu3+, respectively, and exhibiting a fluorescence wavelength difference up to 170 nm. The ratiometric fluorescent signals of EnEB showed a linear correlation with pH in the range of 5.5-8.0. Thus, EnEB can rapidly and precisely detect BAs, such as histamine, tyramine, and spermine, with detection limits and response times of 1.14 µmol/L (3 s), 1.04 µmol/L (8 s), and 0.41 µmol/L (2 s), respectively. Furthermore, an EnEB aerogel was prepared by loading EnEB in a matrix formed by polyvinyl alcohol (PVA) and agarose (AG). EnEB aerogel exhibited excellent acid-base gas-sensing properties. The fluorescence color of EnEB aerogel can change significantly with the deterioration of seafood. When seafood changed from fresh to decayed, the ΔE value of EnEB aerogel was as high as 80.9. Importantly, the results of seafood freshness by naked eye using EnEB aerogel was consistent well with the TVB-N content and the freshness standard stipulated by national food standard, indicating EnEB aerogel can accurately visually and real-time monitor seafood freshness. Furthermore, the strategy for sensing food freshness based on EnEB aerogel also offered multiple color variations to indicate fine freshness levels of seafood. This work provided a convenient, efficient, and accurate approach to assessing the freshness of seafood. Additionally, EnEB also has promising applications in security and anti-counterfeiting.
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Age-related hearing loss (ARHL) is a disease that impacts human quality of life and contributes to the progression of other neuronal problems. Various stressors induce an increase in free radicals, destroy mitochondria to further contribute to cellular malfunction, and compromise cell viability, ultimately leading to functional decline. Cisd2, a master gene for Marfan syndrome, plays an essential role in maintaining mitochondrial integrity and functions. As shown by our data, specific deletion of Cisd2 in the cochlea exacerbated the hearing impairment of ARHL in C57BL/6 mice. Increased defects in mitochondrial function, potassium homeostasis and synapse activity were observed in the Cisd2-deleted mouse models. These mechanistic phenotypes combined with oxidative stress contribute to cell death in the whole cochlea. Human patients with obviously deteriorated ARHL had low Cisd2 expression; therefore, Cisd2 may be a potential target for designing therapeutic methods to attenuate the disease progression of ARHL.
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Microbes are involved in a wide range of biological processes and are closely associated with disease. Inferring potential disease-associated microbes as the biomarkers or drug targets may help prevent, diagnose and treat complex human diseases. However, biological experiments are time-consuming and expensive. In this study, we introduced a new method called iPALM-GLMF, which modelled microbe-disease association prediction as a problem of non-negative matrix factorization with graph dual regularization terms and L 2 , 1 $$ {L}_{2,1} $$ norm regularization terms. The graph dual regularization terms were used to capture potential features in the microbe and disease space, and the L 2 , 1 $$ {L}_{2,1} $$ norm regularization terms were used to ensure the sparsity of the feature matrices obtained from the non-negative matrix factorization and to improve the interpretability. To solve the model, iPALM-GLMF used a non-negative double singular value decomposition to initialize the matrix factorization and adopted an inertial Proximal Alternating Linear Minimization iterative process to obtain the final matrix factorization results. As a result, iPALM-GLMF performed better than other existing methods in leave-one-out cross-validation and fivefold cross-validation. In addition, case studies of different diseases demonstrated that iPALM-GLMF could effectively predict potential microbial-disease associations. iPALM-GLMF is publicly available at https://github.com/LiangzheZhang/iPALM-GLMF.
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Algoritmos , Humanos , Biologia Computacional/métodos , MicrobiotaRESUMO
In urine drug testing, a cut-off value is often imposed to determine whether the sample is negative or positive. A matrix containing a reference substance helps counteract the adverse effects of the urine matrix across different laboratories to improve the consistency of final results. However, as a biological matrix, urine is prone to corruption and other problems that make it difficult to use as a reference sample. In this study, morphine, nitrazepam, lorazepam, buprenorphine, zolpidem, midazolam, diazepam, and clozapine commonly used in clinical practice were selected as target analytes, and the preparation process was further optimized to repeated lyophilization, in order to obtain more effective, stable, and accurate urine matrix reference materials (mRMs). The appropriate urine density (1.010-1.017â¯kg/m3) for preparing lyophilized samples was investigated through density determination. Conducting repeated lyophilizations resulted in a denser powder with reduced susceptibility to collapse and improved the quality of lyophilized urine samples. Lyophilized urine mRMs could be stored at room temperature for one month or under refrigeration conditions (4 â) for six months.
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Obesity-related metabolic diseases are associated with a chronic inflammatory state. Calenduloside E (CE) is a triterpene saponin from sugar beet. In mouse models, CE reduced pro-inflammatory cytokines in white adipose tissue (WAT) and decreased macrophage infiltration of WAT. And CE inhibited pyroptosis in J774A.1 cells and WAT by inhibiting the activation of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome. Moreover, CE could trigger the activation of Sirtuin 2 (SIRT2), leading to a decrease in the acetylation of NLRP3, particularly at the K24 site. In addition, it has been shown that CE can reduce inflammation in adipocytes that have been induced by macrophage-conditioned medium. However, the selective SIRT2 inhibitor AGK2 hindered the beneficial effects of CE. In summary, CE has the capacity to impede NLRP3-mediated pyroptosis by triggering SIRT2 activity, thus positioning CE as a promising therapeutic avenue for combating obesity-related metabolic disorders.
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Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sirtuína 2 , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Animais , Camundongos , Sirtuína 2/metabolismo , Sirtuína 2/genética , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/imunologia , Saponinas/farmacologia , Saponinas/química , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/imunologiaRESUMO
Exploration of efficient molecular water oxidation catalysts for long-term application remains a key challenge for the conversion of renewable energy sources into fuels. Cuboidal {Co4O4} complexes keep attracting interest as molecular water oxidation catalysts as they combine features of both heterogeneous and homogeneous catalysis with bio-inspired motifs. However, the application of many cluster-based catalysts for the oxygen evolution reaction still requires new stabilization strategies. Drawing inspiration from the stabilizing effects of natural polymers, we introduce a conductive polymer-hybrid approach to covalently immobilize {Co4O4} cubane oxo clusters as oxygen evolution catalysts. Polypyrrole is applied as an efficient p-type conducting polymer that promotes hole transfer during the oxygen evolution reaction, resulting in higher turnover frequency compared to the pristine {Co4O4} oxo cluster and heterogeneous Co-oxide benchmarks. The asymmetric coordination of {Co4O4} not only mitigates catalyst decomposition pathways, but also increases the catalytic efficiency by exposing a directed cofacial dihydroxide motif during catalysis.
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A novel non-volatile photonic-electronic memory, 3D integrating an Al-doped HfO2 ferroelectric thin film onto a silicon photonic platform using fully compatible electronic and photonic fabrication processes, enables electrically/optically programmable, non-destructively readable, and multi-level storage functions.
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Photovoltaic development has played a crucial role in mitigating the energy crisis and addressing global climate change. However, it has also had significant impacts on the ecological environment. To ensure the sustainable growth of the photovoltaic industry, it is essential to establish an indicator system to assess the ecological and environmental effects of photovoltaic development. This study utilizes the Driving-Pressure-Status-Impact-Response (DPSIR) framework to create an indicator system for evaluating the ecological and environmental effects of desert photovoltaic development. The study evaluates the ecological and environmental effects at the on-site (WPS), transitional zone (TPS), and off-site (OPS) areas of the Qinghai Gonghe Photovoltaic Park in China. The entropy weight method was utilized to calculate indicator weights, while the evaluation model and indicators were transformed uniformly to obtain standardized scores for ecological and environmental effects. and conducting a thorough analysis of the distribution characteristics and factors influencing the evaluation indicators' scores. Overall, the large-scale development of desert photovoltaics in Gonghe County has had a positive impact on the ecological environment. The WPS had better ecological and environmental conditions than did the TPS and OPS, and the ecological and environmental evaluation levels of the WPS were categorized as "general" (0.439), while the ecological and environmental effect evaluation levels of the TPS (0.286) and OPS (0.28) were both "poor", indicating significant room for improvement. Moreover, all indicators in the scheme layer, which are used to evaluate ecological and environmental quality, yielded higher scores for the WPS than for the TPS and OPS, demonstrating that photovoltaic development has a positive effect on desert area ecology and the environment.
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Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly becoming a prevalent cause of hepatocellular carcinoma (HCC). Our study examines the burden of MASH-related HCC globally, regionally, and nationally, along with associated risk factors from 1990 to 2019, considering variables such as age, sex, and socioeconomic status. Objective: We aimed to report the global, regional, and national burden of liver cancer due to MASH and its attributable risk factors between 1990 and 2019, by age, sex, and sociodemographic index (SDI). Methods: Utilizing the Global Burden of Disease 2019 project, we analyzed data on prevalence, mortality, and disability-adjusted life years (DALYs) for liver cancer attributable to MASH across 204 countries. We provided counts and rates per 100,000 population, including 95% uncertainty intervals. Results: In 2019, there were 46.8 thousand cases of MASH-related HCC, leading to 34.7 thousand deaths, and 795.8 thousand DALYs globally. While the prevalence increased by 19.8% since 1990, the death and DALY rates decreased by 5.3% and 15.1%, respectively. The highest prevalence was in High-income Asia Pacific, with the greatest increases observed in Australasia, Central Asia, and High-income North America. Southern Sub-Saharan Africa reported the highest death rate, while the lowest rates were in parts of Latin America, Central Sub-Saharan Africa, and Eastern Europe. DALY rates were the highest in Southern Sub-Saharan Africa and the lowest in Tropical Latin America. Discussion: The burden of MASH-related HCC is expected to rise slightly over the next decade. This disease, which is not associated with the SDI, remains a major public health problem. In addition, the escalating rates of obesity, demographic shifts, and an aging population could position MASH as a leading factor in liver cancer cases, surpassing viral hepatitis. It is imperative, therefore, that the forthcoming years see the implementation of strategic interventions aimed at the early detection and prevention of liver cancer associated with MASH.
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Candidatus Accumulibacter, a prominent polyphosphate-accumulating organism (PAO) in wastewater treatment, plays a crucial role in enhanced biological phosphorus removal (EBPR). The genetic underpinnings of its polyphosphate accumulation capabilities, however, remain largely unknown. Here, we conducted a comprehensive genomic analysis of Ca. Accumulibacter-PAOs and their relatives within the Rhodocyclaceae family, identifying 124 core genes acquired via horizontal gene transfer (HGT) at its least common ancestor. Metatranscriptomic analysis of an enrichment culture of Ca. Accumulibacter revealed active transcription of 44 of these genes during an EBPR cycle, notably including the polyphosphate kinase 2 (PPK2) gene instead of the commonly recognized polyphosphate kinase 1 (PPK1) gene. Intriguingly, the phosphate regulon (Pho) genes showed minimal transcriptions, pointing to a distinctive fact of Pho dysregulation, where PhoU, the phosphate signaling complex protein, was not regulating the high-affinity phosphate transport (Pst) system, resulting in continuous phosphate uptake. To prevent phosphate toxicity, Ca. Accumulibacter utilized the laterally acquired PPK2 to condense phosphate into polyphosphate, resulting in the polyphosphate-accumulating feature. This study provides novel insights into the evolutionary emergence of the polyphosphate-accumulating trait in Ca. Accumulibacter, offering potential advancements in understanding the PAO phenotype in the EBPR process.
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Diabetic wounds are serious clinical complications which manifest wet condition due to the mass exudate, along with disturbed regulation of inflammation, severe oxidative stress and repetitive bacterial infection. Existing treatments for diabetic wounds remain unsatisfactory due to the lack of ideal dressings that encompass mechanical performance, adherence to moist tissue surfaces, quick repair, and diverse therapeutic benefits. Herein, we fabricated a wet adhesive, self-healing, glucose-responsive drug releasing hydrogel with efficient antimicrobial and pro-healing properties for diabetic wound treatment. PAE hydrogel was constructed with poly(acrylic acid-co-acrylamide) (AA-Am) integrated with a dynamic E-F crosslinker, which consisted of epigallocatechin gallate (EGCG) and 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AFPBA). Due to the dynamic crosslinking nature of boronate esters, abundant catechol groups and hydrogen bonding, PAE hydrogel demonstrated excellent mechanical properties with about 1000 % elongation, robust adhesion to moist tissues, fast self-healing, and absorption of biofluids of 10 times of its own weight. Importantly, PAE hydrogel exhibited sustained and glucose-responsive release of EGCG. Together, the bioactive PAE hydrogel had effective antibacterial, antioxidative, and anti-inflammatory properties in vitro, and accelerated diabetic wound healing in rats via reducing tissue-inflammatory response, enhancing angiogenesis, and reprogramming of macrophages. Overall, this versatile hydrogel provides a straightforward solution for the treatment of diabetic wound, and shows potential for other wound-related application scenarios.
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Hydrogel dressings with multiple functions are ideal options for wound repair. This study developed hydrogel dressings by interpenetrating the physically crosslinked xanthan gum (XG)/carboxylated chitosan (CCS) network and the chemically crosslinked polyacrylamide (PAAm) network via a one-pot method. The XG-CCS/PAAm hydrogels were found to display tunable mechanical properties, due to the formation of strong network structure. The hydrogels exhibited the strongest tensile strength of 0.6 MPa at an XG/CCS ratio of 40/60, while the largest compressive strength of 4.5 MPa is achieved at an XG/CCS ratio of 60/40. Moreover, the hydrogel with an XG/CCS ratio of 60/40 exhibited desirable adhesion strength on porcine skin, which was 3.7 kPa. It also had a swelling ratio, as high as 1200 %. After loading with cephalexin, the XG-CCS/PAAm hydrogels can deliver the antibacterial drugs following a first-order kinetic. As a result, both E. coli and S. aureus can be completely inactivated by the cefalexin-loaded hydrogels after 12 h. Furthermore, the XG-CCS/PAAm hydrogels were found to exhibit excellent biocompatibility as well as effective wound healing ability, as proven by the in vitro and in vivo tests. In this regard, XG-CCS/PAAm hydrogels can act as promising multifunctional wound dressings.
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Sevoflurane is a volatile anesthetic that can tolerate inhalation induction and is widely used for inducing anesthesia due to its pleasant odor. As a drug that has been on the market for nearly 30 years, the vast majority of adverse reactions have been documented. This study aims to improve the adverse reactions related to Sevoflurane through the mining, organizing and analysis of Food and Drug Administration Adverse Event Reporting System database data. We collected, organized, and analyzed reports from the first quarter of 2004 to the fourth quarter of 2022. We performed disproportionality analysis algorithms, including reporting odds ratio, the proportional reporting ratio values, to quantify the signal values of different adverse events (AEs). A total of 1126 AEs and 27 system organ classes were identified by performing statistics analysis system software. By combining algorithm calculations, we create a forest map of the top 30 AEs of the reporting odds ratio signal. Based on the reviewing relevant literature, we found that the vast majority of AEs have been reported in relevant studies. However, there is currently no study revealing the correlation between atrial fibrillation and Sevoflurane, which means that atrial fibrillation may be an unreported AE of Sevoflurane. In the present study, we found that atrial fibrillation may be a new adverse reaction of Sevoflurane through the Food and Drug Administration Adverse Event Reporting System database, which can function as a novel guideline to guide us in the more standardized use of Sevoflurane in clinical practice.
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Sistemas de Notificação de Reações Adversas a Medicamentos , Anestésicos Inalatórios , Sevoflurano , United States Food and Drug Administration , Sevoflurano/efeitos adversos , Humanos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Estados Unidos/epidemiologia , Anestésicos Inalatórios/efeitos adversos , Masculino , Feminino , Fibrilação Atrial/tratamento farmacológico , Algoritmos , Adulto , Pessoa de Meia-Idade , Bases de Dados FactuaisRESUMO
Based on the technical methods of GB/T 42430-2023 and GA/T 204-2019, this study established an analytical method for headspace injection double-column dual-detector (hydrogen flame ion detector) gas chromatography for the simultaneous analysis of at least 12 volatile compounds, including ethanol, in human blood using two different equipment platforms and chromatographic columns. A 100 µL blood or urine sample and a 0.04 g/L tert-butanol working solution prepared as an internal standard are introduced into the headspace sample bottle and then sealed, mixed, and placed on the headspace sampler rack. Using different equipment platforms and columns, methodological parameters such as the limit of detection (LOD), limit of quantification (LOQ), precision, and accuracy of the method were systematically evaluated. The chromatographic separation of acetone, alcohols and benzenes using the established method was satisfactory. The linear ranges, linear correlation coefficients (r), and LODs of acetone and six alcohols, including ethanol, were 0.10-3.00 g/L, >0.997, and 0.05 g/L, respectively. The LOQs were 0.10 g/L for all other compounds, excluding n-propanol (0.005 g/L). Additionally, the linear ranges, r values, LODs, and LOQs of benzene and four benzene derivatives were 0.05-50 mg/L, >0.995, 0.02 mg/L, and 0.05 mg/L, respectively (Column J&W DB-BAC1 UI and Column Rtx-BAC-PLUS 2). The average recoveries of compounds on J&W DB-BAC1 UI and Rtx-BAC-PLUS 2 columns ranged from 92.2% to 111.6%, and the relative standard deviations (RSDs, n=6) ranged from 0.4% to 7.4%. The LOD, LOQ, precision, accuracy, and linearity of the established method met the requirements of relevant standards, and no significant differences arose between the methodological parameters of the two platforms. CNAS-GL006 (2019) and JJF 1059.1-2012 were used as guides to evaluate the uncertainty of ethanol on two different sets of equipment platforms and chromatographic columns. The ethanol uncertainty was mainly derived from the calibration curve; however, the confidence probability was 95% (k=2). According to the analysis of the verification samples and real samples, the established method is suitable for the high-precision quantitative analysis of acetone and six alcohols and five benzene derivatives in human blood and other body fluids. It can be used in practical scenarios such as judicial identification and the detection of poisons.
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Etanol , Compostos Orgânicos Voláteis , Humanos , Cromatografia Gasosa/métodos , Compostos Orgânicos Voláteis/análise , Compostos Orgânicos Voláteis/sangue , Limite de DetecçãoRESUMO
Background: Mitochondria have always been considered too be closely related to the occurrence and development of malignant tumors. However, the bioinformatic analysis of mitochondria in lung adenocarcinoma (LUAD) has not been reported yet. Methods: In the present study, we constructed a novel and reliable algorithm, comprising a consensus cluster analysis and risk assessment model, to predict the survival outcomes and tumor immunity for patients with terminal LUAD. Results: Patients with LUAD were classified into three clusters, and patients in cluster 1 exhibited the best survival outcomes. The patients in cluster 3 had the highest expression of PDL1 (encoding programmed cell death 1 ligand 11) and HAVCR2 (encoding Hepatitis A virus cellular receptor 2), and the highest tumor mutation burden (TMB). In the risk assessment model, patients in the low-risk group tended to have a significantly better survival outcome. Furthermore, the risk score combined with stage could act as a reliable independent prognostic indicator for patients with LUAD. The prognostic signature is a novel and effective biomarker to select anti-tumor drugs. Low-risk patients tended to have a higher expression of CTLA4 (encoding cytotoxic T-lymphocyte associated protein 4) and HAVCR2. Moreover, patients in the high-risk group were more sensitive to Cisplatin, Docetaxel, Erlotinib, Gemcitabine, and Paclitaxel, while low-risk patients would probably benefit more from Gefitinib. Conclusion: We constructed a novel and reliable algorithm comprising a consensus cluster analysis and risk assessment model to predict survival outcomes, which functions as a reliable guideline for anti-tumor drug treatment for patients with terminal LUAD.
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The monoclonal antibody (mAb) manufacturing process comes with high profits and high costs, and thus mAb productivity is of vital importance. However, many factors can impact the cell culture process, and lead to mAb productivity reduction. Nowadays, the biopharma industry is actively employing manufacturing information systems, which enable the integration of both online data and offline data. Although the volume of data is large, related data mining studies for mAb productivity improvement are rare. Therefore, a data-driven approach is proposed in this study to leverage both the inline and offline data of the cell culture process to discover the causes of mAb productivity reduction. The approach consists of four steps, namely data preprocessing, phase division, feature extraction and fusion, and cluster comparing. First, data quality issues are solved during the data preprocessing step. Next, the inline data are divided into several phases based on the moving window k-nearest neighbor method. Then, the inline data features are extracted via functional data analysis and combined with the offline data features. Finally, the causes of mAb productivity reduction are identified using the contrasting clusters via the principal component analysis method. A commercial-scale cell culture process case study is provided in this research to verify the effectiveness of the approach. Data from 35 batches were collected, and each batch contained nine inline variables and seven offline variables. The causes of mAb productivity reduction were identified to be the lack of nutrients, and recommended actions were taken according to the result, which was subsequently proven by six validation batches.
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Non-alcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population and, to date, there is no approved drug therapy for this condition. Individuals with type 2 diabetes mellitus (T2DM) are at a significantly elevated risk of developing NAFLD, underscoring the urgency of identifying effective NAFLD treatments for T2DM patients. Salvianolic acid A (SAA) is a naturally occurring phenolic acid that is an important component of the water-soluble constituents isolated from the roots of Salvia miltiorrhiza Bunge. SAA has been demonstrated to possess anti-inflammatory and antioxidant stress properties. Nevertheless, its potential in ameliorating diabetes-associated NAFLD has not yet been fully elucidated. In this study, diabetic ApoE-/- mice were employed to establish a NAFLD model via a Western diet. Following this, they were treated with different doses of SAA (10 mg/kg, 20 mg/kg) via gavage. The study demonstrated a marked improvement in liver injury, lipid accumulation, inflammation, and the pro-fibrotic phenotype after the administration of SAA. Additionally, RNA-seq analysis indicated that the primary pathway by which SAA alleviates diabetes-induced NAFLD involves the cascade pathways of lipid metabolism. Furthermore, SAA was found to be effective in the inhibition of lipid accumulation, mitochondrial dysfunction and ferroptosis. A functional enrichment analysis of RNA-seq data revealed that SAA treatment modulates the AMPK pathway and IGFBP-1. Further experimental results demonstrated that SAA is capable of inhibiting lipid accumulation through the activation of the AMPK pathway and IGFBP-1.
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Proteínas Quinases Ativadas por AMP , Ácidos Cafeicos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina , Lactatos , Hepatopatia Gordurosa não Alcoólica , Transdução de Sinais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Camundongos , Lactatos/farmacologia , Lactatos/uso terapêutico , Lactatos/química , Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/uso terapêutico , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos KnockoutRESUMO
Gasdermin (GSDM) family proteins, known as the executors of pyroptosis, undergo protease-mediated cleavage before inducing pyroptosis. We here discovered a form of pyroptosis mediated by full-length (FL) GSDME without proteolytic cleavage. Intense ultraviolet-C irradiation-triggered DNA damage activates nuclear PARP1, leading to extensive formation of poly(ADP-ribose) (PAR) polymers. These PAR polymers are released to the cytoplasm, where they activate PARP5 to facilitate GSDME PARylation, resulting in a conformational change in GSDME that relieves autoinhibition. Moreover, ultraviolet-C irradiation promotes cytochrome c-catalysed cardiolipin peroxidation to elevate lipid reactive oxygen species, which is then sensed by PARylated GSDME, leading to oxidative oligomerization and plasma membrane targeting of FL-GSDME for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARylation and oxidation of FL-GSDME, synergistically promoting pyroptotic cell death. Overall, the present findings elucidate an unreported mechanism underlying the cleavage-independent function of GSDME in executing cell death, further enriching the paradigms and understanding of FL-GSDME-mediated pyroptosis.