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Symmetry engineering is explicitly effective to manipulate and even create phases and orderings in strongly correlated materials. Flexural stress is universally practical to break the space-inversion or time-reversal symmetry. Here, by introducing strain gradient in a centrosymmetric antiferromagnet Sr_{2}IrO_{4}, the space-inversion symmetry is broken accompanying a nonequivalent O p-Ir d orbital hybridization along the z axis. Thus, an emergent polar phase and out-of-plane magnetic moment have been simultaneously observed in these asymmetric Sr_{2}IrO_{4} thin films, which both are absent in its ground state. Furthermore, upon the application of a magnetic field, such polarization can be controlled by modifying the occupied d orbitals through spin-orbit interaction, giving rise to a flexomagnetoelectric effect. This Letter provides a general strategy to artificially design multiple symmetries and ferroic orderings in strongly correlated systems.
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Background: Psoriasis is a chronic inflammatory skin disease. A strong association between the AhR/ NFκB axis and the inflammatory response in psoriasis. Indigo (IDG) has demonstrated significant anti-inflammatory properties. This study aimed to assess the anti-psoriatic efficacy of IDG while investigating the underlying mechanisms involved. Methods: In the in vitro experiments, cell viability was assessed using the CCK-8. qRT-PCR was employed to measure the mRNA levels of NF-κB, TNF-α, IL-1ß, AhR, and CYP1A1. Western blotting was conducted to examine alterations in cytoplasmic and nuclear AhR protein levels. Additionally, an IDG nanoemulsion (NE) cream was prepared for the in vivo experiments. A psoriasis-like skin lesion mice model was induced using IMQ (62.5 mg/day for 7 days). The severity of psoriasis was evaluated using PASI, and skin lesions were scored while epidermal thickness was assessed via HE staining. The expression of inflammatory markers, including IL-6, IL-13, IL-17A, MCP-1, and TNF-α, was detected in skin lesions using Luminex. The levels of CYP1A1, p65, and p-p65 proteins were determined by Western blotting. Results: LPS stimulation significantly elevated TNF-α, IL-6, and NF-κB mRNA levels, which were notably reduced by IDG treatment. Additionally, IDG significantly enhanced the expression of AhR and CYP1A1 mRNA. Further investigation revealed that IDG facilitated AhR translocation from the cytoplasm to the nucleus. In the IMQ-induced psoriasis-like mouse model, IDG NE substantially ameliorated the severity of skin lesions. Moreover, IDG NE treatment reduced the upregulation of inflammatory cytokines such as IL-6, IL-17A, MCP-1, and TNF-α in IMQ-induced skin lesions. It was also observed that IDG NE treatment increased CYP1A1 protein expression while inhibiting p65 and p-p65 protein expression. Conclusion: IDG emerges as a promising treatment for psoriasis, demonstrating effective therapeutic outcomes. Its mechanism of action is likely linked to the modulation of the AhR/NFκB signaling pathway.
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Citocromo P-450 CYP1A1 , Modelos Animais de Doenças , NF-kappa B , Psoríase , Receptores de Hidrocarboneto Arílico , Transdução de Sinais , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Psoríase/patologia , Psoríase/metabolismo , Animais , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismo , Camundongos , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Humanos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Anti-Inflamatórios/farmacologia , Imiquimode , Masculino , Citocinas/metabolismo , Citocinas/genética , Camundongos Endogâmicos BALB CRESUMO
Epigenetic mechanisms play a critical role in the pathogenesis of human diseases including kidney disorders. As the erasers of DNA methylation, Ten-eleven translocation (TET) family proteins can oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), thus leading to passive or active DNA demethylation. Similarly, TET family proteins can also catalyze the same reaction on RNA. In addition, TET family proteins can also regulate chromatin structure and gene expression in a catalytic activity-independent manner through recruiting the SIN3A/HDAC co-repressor complex. In 2012, we reported for the first time that the genomic 5-hydroxymethylcytosine level and the mRNA levels of Tet1 and Tet2 were significantly downregulated in murine kidneys upon ischemia and reperfusion injury. Since then, accumulating evidences have eventually established an indispensable role of TET family proteins in not only acute kidney injury but also chronic kidney disease. In this review, we summarize the upstream regulatory mechanisms and the pathophysiological role of TET family proteins in major types of kidney diseases and discuss their potential values in clinical diagnosis and treatment.
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BACKGROUND: Polycystic ovary syndrome (PCOS) is a unity of endocrine and metabolic disorders, associated with PI3K/AKT/mTOR, autophagy, and gut microbiota. Quinoa is a valuable food source, which contains rich minerals, unsaturated fatty acids, and has a positive modulating effect on metabolic diseases. However, its effects and potential mechanisms on PCOS have not been reported yet. Therefore, the purpose of this study is to investigate the effect of quinoa on PCOS rats by regulating PI3K/AKT/mTOR, autophagy, and gut microbiota. METHODS: Ten-week-old female Sprague-Dawley (SD) rats have received letrozole for 24 days for induction of PCOS and subsequently were treated with a quinoa diet for 8 weeks. Vaginal smears were used to analyze the estrous cycle of rats. Hormone and biochemical indexes were analyzed by kit assays and glucometer. The pathological changes of ovary, pancreas, duodenum and colon were observed by HE staining. PI3K, AKT, mTOR and autophagy-related proteins in the ovary and colon were measured by western blot and immunohistochemistry staining. Tight junction proteins in colon were measured by immunohistochemistry staining. 16 s rDNA sequencing was used to detect the changes of intestinal microbiota in rats. Network pharmacology and molecular docking were used to study the possible targets and mechanisms of quinoa on PCOS. Spearman correlation analysis was used to study the relationship between intestinal microbial abundance and hormone levels of PCOS rats at the phylum and genus level. RESULTS: Quinoa significantly improved estrous cycle and biochemical parameters of PCOS-like rats, and the pathological state of ovary, pancreas, duodenum and colon tissues. Especially, quinoa significantly regulated the expression of PI3K, AKT, mTOR and autophagy-related proteins in the ovary. Quinoa may repair the intestinal barrier by upregulating the expression of tight junction proteins in the colon, and regulate autophagy-related factors in colon. Additionally, quinoa increased the abundance of Lactobacillu, Bacteroides and Oscillospira, and decreased the Firmicutes/Bacteroidetes ratio and the Blautia, and Prevotella, reversing the dysregulation of the gut microbiota. Correlation analysis showed that there is a strong correlation between gut microbiota with significant changes in abundance and hormone related to PCOS. CONCLUSION: Our result indicated that effect of quinoa on PCOS maybe associated with activation of the PI3K/AKT/mTOR signaling pathway, inhibition of autophagy, and regulation of intestinal flora.
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BACKGROUND: The burgeoning recognition of the nexus between renal functionality and the prevalence of dementia has precipitated a surge in research endeavors. This study aims to substantiate the causal relationship between kidney functionality and dementia. METHODS: We utilized clinical renal function metrics from the Chronic Kidney Disease Genetics (CKDGen) Consortium and diverse dementia types (Alzheimer's disease [AD] and vascular dementia) from the FinnGen Biobank by using Mendelian randomization analysis. At the stratum of genetic susceptibility, we tested the causal relationship between variations index in renal function and the occurrence of dementia. Inverse-variance weighted (IVW) method was the main analysis, and several supplementary analyses and sensitivity analyses were performed to test the causal estimates. RESULTS: The findings indicate a significant correlation between each unit increase in cystatin C-based estimated glomerular filtration rate (eGFR-cys) levels was significantly associated with a reduction in the incidence of late-onset Alzheimer's disease (LOAD) (IVW: OR = 0.35, 95% CI: 0.13-0.91, p = 0.031). After adjusting for creatinine-based eGFR (eGFR-cre) and urinary albumin-to-creatinine ratio (UACR), a causal relationship was still identified between elevated levels of eGFR-cys and decreased risk of LOAD (IVW: OR: 0.08; 95% CI: 0.01-0.97, p = 0.047). Sensitivity tests demonstrated the reliability of causal estimates. CONCLUSIONS: The association between renal function based on cystatin C and the augmented risk of developing AD lends support to the perspective that regular monitoring of cystatin C may be a valuable investigative biomarker.
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Doença de Alzheimer , Cistatina C , Taxa de Filtração Glomerular , Análise da Randomização Mendeliana , Insuficiência Renal Crônica , Humanos , Cistatina C/sangue , Doença de Alzheimer/genética , Doença de Alzheimer/epidemiologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/epidemiologia , Creatinina/sangue , Creatinina/urina , Fatores de Risco , Demência/epidemiologia , Demência/genética , Demência/etiologia , Albuminúria/genética , Feminino , Rim/fisiopatologia , Masculino , Incidência , Idoso , Predisposição Genética para Doença , Demência Vascular/genética , Demência Vascular/epidemiologiaRESUMO
In 2023, the U.S. Food and Drug Administration has approved 29 small molecule drugs. These newly approved small molecule drugs possess the distinct scaffolds, thereby exhibiting diverse mechanisms of action and binding modalities. Moreover, the marketed drugs have always been an important source of new drug development and creative inspiration, thereby fostering analogous endeavors in drug discovery that potentially extend to the diverse clinical indications. Therefore, conducting a comprehensive evaluation of drug approval experience and associated information will facilitate the expedited identification of highly potent drug molecules. In this review, we comprehensively summarized the relevant information regarding the clinical applications, mechanisms of action and chemical synthesis of 29 small molecule drugs, with the aim of providing a promising structural basis and design inspiration for pharmaceutical chemists.
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Aprovação de Drogas , United States Food and Drug Administration , Estados Unidos , Humanos , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química , Descoberta de Drogas , Bibliotecas de Moléculas Pequenas/síntese químicaRESUMO
Although mitochondrial aldehyde dehydrogenase 2 (ALDH2) is involved in aging and aging-related diseases, its role in the regulation of human mesenchymal stem cell (MSC) senescence has not been investigated. This study aimed to determine the role of ALDH2 in regulating MSC senescence and illustrate the potential mechanisms. MSCs were isolated from young (YMSCs) and aged donors (AMSCs). Senescence-associated ß-galactosidase (SA-ß-gal) staining and Western blotting were used to assess MSC senescence. Reactive oxygen species (ROS) generation and mitochondrial membrane potential were determined to evaluate mitochondrial function. We showed that the expression of ALDH2 increased alongside cellular senescence of MSCs. Overexpression of ALDH2 accelerated YMSC senescence whereas down-regulation alleviated premature senescent phenotypes of AMSCs. Transcriptome and biochemical analyses revealed that an elevated ROS level and mitochondrial dysfunction contributed to ALDH2 function in MSC senescence. Using molecular docking, we identified interferon regulatory factor 7 (IRF7) as the potential target of ALDH2. Mechanistically, ectopic expression of ALDH2 led to mitochondrial dysfunction and accelerated senescence of MSCs by increasing the stability of IRF7 through a direct physical interaction. These effects were partially reversed by knockdown of IRF7. These findings highlight a crucial role of ALDH2 in driving MSC senescence by regulating mitochondrial homeostasis, providing a novel potential strategy against human aging-related diseases.
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Aldeído-Desidrogenase Mitocondrial , Senescência Celular , Células-Tronco Mesenquimais , Mitocôndrias , Espécies Reativas de Oxigênio , Células-Tronco Mesenquimais/metabolismo , Humanos , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/genética , Espécies Reativas de Oxigênio/metabolismo , Homeostase , Potencial da Membrana Mitocondrial , Adulto , Envelhecimento/metabolismo , Envelhecimento/genética , Células Cultivadas , Simulação de Acoplamento Molecular , Idoso , Regulação da Expressão GênicaRESUMO
This study aimed to clarify the differences between the previously reported mechanisms of sports-related concussion (SRC) injuries without a loss of consciousness in contact and collision sports and the mechanisms of SRC injuries in our cases. Based on two videos of SRC injuries occurring during a men's rhythmic gymnastics competition (three people were injured), the risk of SRC occurrence was estimated from various parameters using a multibody analysis and eight brain injury evaluation criteria. In the present study, the three SRC impacts that occurred in men's rhythmic gymnastics showed significant characteristics in duration compared to previously reported cases in the contact sports. This suggests that the occurrence of SRC may have been caused by a different type of impact from that which causes SRC in contact sports (e.g., tackling). In addition, calculation of the strain indicating the rate of brain deformation suggested a risk of nerve swelling in all cases involving type 2 axonal injuries. Therefore, when reexamining sports-related head injuries, it is important to recognize the characteristics and mechanisms of SRC that occur in each different sport, as well as the symptoms and course of SRC after injury.
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Background: Diabetic cardiomyopathy (DC), a frequent complication of type 2 diabetes mellitus (T2DM), is mainly associated with severe adverse outcomes. Previous research has highlighted the role of Lysophosphatidylcholine (LPC) in inducing myocardial injury; however, the specific mechanisms through which LPC mediate such injury in DC remain elusive. The existing knowledge gap underscores the need for additional clarification. Consequently, this study aimed to explore the impact and underlying mechanisms of LPC on myocardial injury in DC. Methods: A total of 55 patients diagnosed with T2DM and 62 healthy controls were involved. A combination of 16s rRNA sequencing, metabolomic analysis, transcriptomic RNA-sequencing (RNA-seq), and whole exome sequencing (WES) was performed on fecal and peripheral blood samples collected from the participants. Following this, correlation analysis was carried out, and the results were further validated through the mouse model of T2DM. Results: Four LPC variants distinguishing T2DM patients from healthy controls were identified, all of which were upregulated in T2DM patients. Specifically, Lysopc (16:0, 2 N isoform) and LPC (16:0) exhibited a positive correlation with nuclear factor kappa B subunit 2 (NFKB2) and a negative correlation with Zinc finger protein 480 (ZNF480) Furthermore, the expression levels of Toll-like receptor 4 (TLR4), c-Jun, c-Fos, and NFKB2 were upregulated in the peripheral blood of T2DM patients and in the myocardial tissue of T2DM mice, whereas ZNF480 expression level was downregulated. Lastly, myocardial injury was identified in T2DM mice. Conclusions: The results indicated that LPC could induce myocardial injury in DC through the TLR4/ZNF480/AP-1/NF-kB pathway, providing a precise target for the clinical diagnosis and treatment of DC.
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Mesoporous silica nanoparticles (MSNs) have attracted extensive attention as drug delivery systems because of their unique meso-structural features (high specific surface area, large pore volume, and tunable pore structure), easily modified surface, high drug-loading capacity, and sustained-release profiles. However, the enduring and non-specific enrichment of MSNs in healthy tissues may lead to toxicity due to their slow degradability and hinder their clinical application. The emergence of degradable MSNs provided a solution to this problem. The understanding of strategies to regulate degradation and clearance of these MSNs for promoting clinical trials and expanding their biological applications is essential. Here, a diverse variety of degradable MSNs regarding considerations of physiochemical properties and doping strategies of degradation, the biodistribution of MSNs in vivo, internal clearance mechanism, and adjusting physical parameters of clearance are highlighted. Finally, an overview of these degradable and clearable MSNs strategies for biosafety is provided along with an outlook of the encountered challenges.
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Nanopartículas , Dióxido de Silício , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Porosidade , Nanopartículas/química , Humanos , Distribuição Tecidual , Animais , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodosRESUMO
In this study, to discuss the influence of concussion risk from the long-term use of American football helmets on collegiate teams, accident cases during the game are replicated based on game videos by simulations using whole-body numerical models and helmeted finite element human head models. The concussion risks caused by collisions were estimated using the mechanical parameters inside the skull obtained from finite element analyses. In the analyses, the different material properties of helmets identified by free-fall experiments using headform impactor-embedded helmets were used to represent brand-new and long-term-use helmets. After analyzing the five cases, it was observed that wearing a new helmet instead of a long-term-use one resulted in a reduction in the risk of concussion by 1 to 44%. More energy is attenuated by the deformation of the liners of the brand-new helmet, so the energy transferred to the head is smaller than that when wearing the long-term-use helmet. Thus, the long-term use of the helmet reduces its ability to protect the head.
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Multichannel meta-imaging, inspired by the parallel-processing capability of neuromorphic computing, offers considerable advancements in resolution enhancement and edge discrimination in imaging systems, extending even into the mid- to far-infrared spectrum. Currently typical multichannel infrared imaging systems consist of separating optical gratings or merging multi-cameras, which require complex circuit design and heavy power consumption, hindering the implementation of advanced human-eye-like imagers. Here, we present printable graphene plasmonic photodetector arrays driven by a ferroelectric superdomain for multichannel meta-infrared imaging with enhanced edge discrimination. The fabricated photodetectors exhibited multiple spectral responses with zero-bias operation by directly rescaling the ferroelectric superdomain instead of reconstructing the separated gratings. We also demonstrated enhanced and faster shape classification (98.1%) and edge detection (98.2%) using our multichannel infrared images compared with single-channel detectors. Our proof-of-concept photodetector arrays simplify multichannel infrared imaging systems and offer potential solutions in efficient edge detection in human-brain-type machine vision.
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Salicylic acid (SA) plays a crucial role in plant defense against biotrophic and semibiotrophic pathogens. In Arabidopsis (Arabidopsis thaliana), isochorismate synthase 1 (AtICS1) is a key enzyme for the pathogen-induced biosynthesis of SA via catalytic conversion of chorismate into isochorismate, an essential precursor for SA synthesis. Despite the extensive knowledge of ICS1-related menaquinone, siderophore, and tryptophan (MST) enzymes in bacteria, the structural mechanisms for substrate binding and catalysis in plant isochorismate synthase (ICS) enzymes are unknown. This study reveals that plant ICS enzymes catalyze the isomerization of chorismate through a magnesium-dependent mechanism, with AtICS1 exhibiting the most substantial catalytic activity. Additionally, we present high-resolution crystal structures of apo AtICS1 and its complex with chorismate, offering detailed insights into the mechanisms of substrate recognition and catalysis. Importantly, our investigation indicates the existence of a potential substrate entrance channel and a gating mechanism regulating substrate into the catalytic site. Structural comparisons of AtICS1 with MST enzymes suggest a shared structural framework with conserved gating and catalytic mechanisms. This work provides valuable insights into the structural and regulatory mechanisms governing substrate delivery and catalysis in AtICS1, as well as other plant ICS enzymes.
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Proteínas de Arabidopsis , Arabidopsis , Domínio Catalítico , Ácido Corísmico , Transferases Intramoleculares , Ácido Corísmico/metabolismo , Arabidopsis/enzimologia , Arabidopsis/genética , Transferases Intramoleculares/metabolismo , Transferases Intramoleculares/genética , Transferases Intramoleculares/química , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/química , Magnésio/metabolismo , Cristalografia por Raios X , Isomerismo , Modelos Moleculares , Especificidade por SubstratoRESUMO
Compared with transcription and translation, protein degradation machineries can act faster and be targeted to different subcellular compartments, enabling immediate regulation of signaling events. It is therefore not surprising that proteolysis has been used extensively to control homeostasis of key regulators in different biological processes and pathways. Over the past decades, numerous studies have shown that proteolysis, where proteins are broken down to peptides or amino acids through ubiquitin-mediated degradation systems and proteases, is a key regulatory mechanism to control plant immunity output. Here, we briefly summarize the roles various proteases play during defence activation, focusing on recent findings. We also update the latest progress of ubiquitin-mediated degradation systems in modulating immunity by targeting plant membrane-localized pattern recognition receptors, intracellular nucleotide-binding domain leucine-rich repeat receptors, and downstream signaling components. Additionally, we highlight recent studies showcasing the importance of proteolysis in maintaining broad-spectrum resistance without obvious yield reduction, opening new directions for engineering elite crops that are resistant to a wide range of pathogens with high yield.
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Imunidade Vegetal , Proteínas de Plantas , Proteólise , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Transdução de Sinais , Doenças das Plantas/imunologia , Resistência à Doença/imunologia , Resistência à Doença/genética , Peptídeo Hidrolases/metabolismo , Receptores de Reconhecimento de Padrão/metabolismoRESUMO
BACKGROUND: Drug-eluting bead transarterial chemoembolization (DEB-TACE) has shown efficacy for treating hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). However, whether DEB-TACE is superior to conventional TACE (cTACE) remains unclear. OBJECTIVE: This randomized controlled trial aimed to compare the efficacy and safety of DEB-TACE versus cTACE in treating HCC with PVTT. METHODS: The study was conducted at a tertiary care center in Southeast China. HCC patients with PVTT were randomized at a 1:1 ratio into the DEB-TACE or cTACE groups. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS) and the incidence of adverse events (AEs). An independent review committee assessed the radiologic response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). AEs were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Systemic therapies were not restricted. RESULTS: Between September 2018 and July 2020, 163 patients were randomized to undergo DEB-TACE ( n =82) or cTACE ( n =81). Nine patients were excluded, and 154 patients were included in the final analysis; the median age was 55 years (range, 24-78 years), and 140 (90.9%) were male. The median PFS in the DEB-TACE group was 6.0 months (95% CI, 5.0-10.0) versus 4.0 months (95% CI, 3.0-5.0) in the cTACE group (hazard ratio, 0.63; 95% CI, 0.42-0.95; P =0.027). The DEB-TACE group showed a higher response rate [51 (66.2%) vs. 36 (46.8%); P =0.0015] and a longer median OS [12.0 months (95% CI, 9.0-16.0) vs. 8.0 months (95% CI, 7.0-11.0), P =0.039] than the cTACE group. Multivariate analysis showed that the treatment group, ALBI score, distant metastasis and additional TKIs were the four independent prognostic factors correlated with PFS. In addition, the treatment group, PVTT group and combination with surgery were independently associated with OS. AEs were similar in the two groups, and postembolization syndrome was the most frequent AE. CONCLUSION: DEB-TACE is superior to cTACE in treating HCC patients with PVTT, demonstrating improved PFS and OS with an acceptable safety profile, and may thus emerge as a promising treatment strategy for HCC patients with PVTT. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800018035.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Veia Porta , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/complicações , Quimioembolização Terapêutica/métodos , Masculino , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Pessoa de Meia-Idade , Feminino , Idoso , Adulto , China , Trombose Venosa/terapia , Resultado do TratamentoRESUMO
Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-ß-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment.
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Cardiomiopatias , Células-Tronco Pluripotentes Induzidas , MicroRNAs , Humanos , Camundongos , Animais , Miócitos Cardíacos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Cardiomiopatias/induzido quimicamente , Transdução de Sinais , DoxorrubicinaRESUMO
KIFC2 plays an important role in prostate cancer progression and chemotherapy resistance, but the mechanism of its involvement in other malignancies remains unclear. Therefore, this study aimed to analyze and validate the mechanism of effect of KIFC2 in multiple tumors. Bioinformatic analysis was performed in conjunction with multiple databases (The Cancer Genome Atlas, Genotype-Tissue Expression Project, Human Protein Atlas, etc.) to fully explore the potential role of KIFC2 within individual tumors and to analyze the correlation with major research components such as prognosis, mutations, and the tumor microenvironment. The expression of KIFC2 demonstrates a significant correlation with the prognosis, clinical phenotype, tumor mutational burden, microsatellite instability, and tumor microenvironment across various malignancies and is associated with the modulation of diverse functional and signaling pathways. The differences in the expression of KIFC2 in the bladder cancer tissues (14 pairs) were statistically significant. The pan-cancer analysis in this study revealed the multifunctionality of KIFC2 in a variety of tumors, indicating a possible prognostic predictor and potential therapeutic target for tumors.
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The understanding of the function of perivascular adipose tissue (PVAT) in vascular aging has significantly changed due to the increasing amount of information regarding its biology. Adipose tissue surrounding blood vessels is increasingly recognized as a key regulator of vascular disorders. It has significant endocrine and paracrine effects on the vasculature and is mediated by the production of a variety of bioactive chemicals. It also participates in a number of pathological regulatory processes, including oxidative stress, immunological inflammation, lipid metabolism, vasoconstriction, and dilation. Mechanisms of homeostasis and interactions between cells at the local level tightly regulate the function and secretory repertoire of PVAT, which can become dysregulated during vascular aging. The PVAT secretion group changes from being reducing inflammation and lowering cholesterol to increasing inflammation and increasing cholesterol in response to systemic or local inflammation and insulin resistance. In addition, the interaction between the PVAT and the vasculature is reciprocal, and the biological processes of PVAT are directly influenced by the pertinent indicators of vascular aging. The architectural and biological traits of PVAT, the molecular mechanism of crosstalk between PVAT and vascular aging, and the clinical correlation of vascular age-related disorders are all summarized in this review. In addition, this paper aims to elucidate and evaluate the potential benefits of therapeutically targeting PVAT in the context of mitigating vascular aging. Furthermore, it will discuss the latest advancements in technology used for targeting PVAT.
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Tecido Adiposo , Envelhecimento , Vasos Sanguíneos , Humanos , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiologia , Animais , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Vasos Sanguíneos/fisiologia , Vasos Sanguíneos/metabolismo , Doenças Vasculares/metabolismo , Doenças Vasculares/patologia , Doenças Vasculares/fisiopatologiaRESUMO
Sepsis-induced myocardial dysfunction (SMD) is the major cause of death in sepsis. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)-mediated pyroptosis contributes to the occurrence and development of SMD. Although Apelin confers direct protection against SMD, the potential mechanisms remain unclear. This study aimed to determine whether Apelin protects against SMD via regulation of NLRP3-mediated pyroptosis of cardiomyocytes. Experimental SMD was induced in wild-type (WT) control mice and Apelin knockout (Apelin-/-) mice by cecal ligation and puncture (CLP). Neonatal mouse cardiomyocytes (NMCs) were treated with lipopolysaccharide (LPS) to simulate the physiological environment of SMD in vitro. The expression of Apelin was greatly decreased in the plasma from septic patients and septic mouse heart. Knockout of Apelin aggravated SMD, evidenced by decreased cardiac function, and increased cardiac fibrosis and NLRP3 inflammasome and pyroptosis levels in CLP-treated Apelin-/- mice compared with WT mice. Overexpression of Apelin activated the AMPK pathway and thereby inhibited NLRP3 inflammasome-mediated pyroptosis of NMCs induced by LPS in vitro These protective effects were partially abrogated by AMPK inhibitor. In conclusion, Apelin attenuated SMD by inhibiting NLRP3-mediated pyroptosis via activation of the AMPK pathway. Apelin may serve as a promising therapeutic target for SMD.