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Planar π-conjugated groups, like CO3, NO3, and BO3 triangles, are ideal functional units for designing birefringent materials due to their large optical anisotropy and wide band gap. The key point for designing birefringent crystals is to select appropriate functional building blocks (FBBs) and the proper arrangement mode. It is well known that the substitution strategy has proven to be a promising and accessible approach. In this work, alkali metals were chosen to regulate and control two different π-conjugated groups, CO3 and NO3, to build new compounds with large birefringence. Subsequently, three new compounds, Na3K6(CO3)3(NO3)2X·6H2O (X = NO3, Cl, Br), were successfully synthesized using the hydrothermal method. The aliovalent substitution between the [NO3]- anionic group and halogen anions [Cl]-/[Br]- has been achieved in these compounds. Na3K6(CO3)3(NO3)2X·6H2O feature the well-coplanar CO3 and NO3 groups in their crystal structure. This coplanar arrangement mode may effectively enhance the anisotropic polarizability of Na3K6(CO3)3(NO3)2X·6H2O. And their experimental birefringence can reach 0.094-0.131 at 546 nm. Diffuse reflectance spectra demonstrate that these compounds exhibit short ultraviolet (UV) absorption edges of â¼235 nm. Meanwhile, Na3K6(CO3)3(NO3)2X·6H2O also have an easily grown capacity under facile conditions. This work not only reports three new potential UV birefringent crystals but also provides a strategy to make the π-conjugated MO3 group coplanar.
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Isoquinoline alkaloids are an important class of natural products that are abundant in the plant kingdom and exhibit a wide range of structural diversity and biological activities. With the deepening of research in recent years, more and more isoquinoline alkaloids have been isolated and identified and proved to contain a variety of biological activities and pharmacological effects. In this review, we introduce the research progress of isoquinoline alkaloids from 2019 to 2022, mainly in the part of biological activities, including antitumor, antimicrobial, antidiabetic, antiviral, anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, analgesic, and other activities. This study provides a clear direction for the rational development and utilization of isoquinoline alkaloids, suggesting that these alkaloids have great potential in the field of drug research.
Assuntos
Alcaloides , Anti-Infecciosos , Alcaloides/química , Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Isoquinolinas/farmacologia , Isoquinolinas/químicaRESUMO
During vertebrate embryogenesis, fetal hematopoietic stem and progenitor cells (HSPCs) exhibit expansion and differentiation properties in a supportive hematopoietic niche. To profile the developmental landscape of fetal HSPCs and their local niche, here, using single-cell RNA-sequencing, we deciphered a dynamic atlas covering 28,777 cells and 9 major cell types (23 clusters) of zebrafish caudal hematopoietic tissue (CHT). We characterized four heterogeneous HSPCs with distinct lineage priming and metabolic gene signatures. Furthermore, we investigated the regulatory mechanism of CHT niche components for HSPC development, with a focus on the transcription factors and ligand-receptor networks involved in HSPC expansion. Importantly, we identified an endothelial cell-specific G protein-coupled receptor 182, followed by in vivo and in vitro functional validation of its evolutionally conserved role in supporting HSPC expansion in zebrafish and mice. Finally, comparison between zebrafish CHT and human fetal liver highlighted the conservation and divergence across evolution. These findings enhance our understanding of the regulatory mechanism underlying hematopoietic niche for HSPC expansion in vivo and provide insights into improving protocols for HSPC expansion in vitro.
Assuntos
Hematopoese , Células-Tronco Hematopoéticas/fisiologia , Nicho de Células-Tronco , Animais , Linhagem da Célula , Feto/metabolismo , Perfilação da Expressão Gênica , Humanos , Fígado/metabolismo , Camundongos , Análise de Célula Única , Peixe-ZebraRESUMO
Nascent hematopoietic stem and progenitor cells (HSPCs) acquire definitive hematopoietic characteristics only when they develop into fetal HSPCs; however, the mechanisms underlying fetal HSPC development are poorly understood. Here, we profiled the chromatin accessibility and transcriptional features of zebrafish nascent and fetal HSPCs using ATAC-seq and RNA-seq and revealed dynamic changes during HSPC transition. Functional assays demonstrated that chromatin remodeler-mediated epigenetic programming facilitates fetal HSPC development in vertebrates. Systematical screening of chromatin remodeler-related genes identified that smarca5 is responsible for the maintenance of chromatin accessibility at promoters of hematopoiesis-related genes in fetal HSPCs. Mechanistically, Smarca5 interacts with nucleolin to promote chromatin remodeling, thereby facilitating genomic binding of transcription factors to regulate expression of hematopoietic regulators such as bcl11ab. Our results unravel a new role of epigenetic regulation and reveal that Smarca5-mediated epigenetic programming is responsible for fetal HSPC development, which will provide new insights into the generation of functional HSPCs both in vivo and in vitro.
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Adenosina Trifosfatases/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Epigênese Genética/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Proteínas de Peixe-Zebra/metabolismo , Adenosina Trifosfatases/genética , Animais , Proteínas Cromossômicas não Histona/genética , Camundongos , Camundongos Endogâmicos C57BL , Peixe-Zebra , Proteínas de Peixe-Zebra/genéticaRESUMO
N6-methyladenosine (m6A) has been identified as the most abundant modification on eukaryote messenger RNA (mRNA). Although the rapid development of high-throughput sequencing technologies has enabled insight into the biological functions of m6A modification, the function of m6A during vertebrate embryogenesis remains poorly understood. Here we show that m6A determines cell fate during the endothelial-to-haematopoietic transition (EHT) to specify the earliest haematopoietic stem/progenitor cells (HSPCs) during zebrafish embryogenesis. m6A-specific methylated RNA immunoprecipitation combined with high-throughput sequencing (MeRIP-seq) and m6A individual-nucleotide-resolution cross-linking and immunoprecipitation with sequencing (miCLIP-seq) analyses reveal conserved features on zebrafish m6A methylome and preferential distribution of m6A peaks near the stop codon with a consensus RRACH motif. In mettl3-deficient embryos, levels of m6A are significantly decreased and emergence of HSPCs is blocked. Mechanistically, we identify that the delayed YTHDF2-mediated mRNA decay of the arterial endothelial genes notch1a and rhoca contributes to this deleterious effect. The continuous activation of Notch signalling in arterial endothelial cells of mettl3-deficient embryos blocks EHT, thereby repressing the generation of the earliest HSPCs. Furthermore, knockdown of Mettl3 in mice confers a similar phenotype. Collectively, our findings demonstrate the critical function of m6A modification in the fate determination of HSPCs during vertebrate embryogenesis.
Assuntos
Adenosina/análogos & derivados , Diferenciação Celular , Células Endoteliais/citologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , RNA Mensageiro/metabolismo , Peixe-Zebra/embriologia , Adenosina/metabolismo , Animais , Diferenciação Celular/genética , Códon de Terminação/genética , Sequência Consenso , Células Endoteliais/metabolismo , Técnicas de Silenciamento de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/genética , Imunoprecipitação , Metilação , Metiltransferases/deficiência , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Estabilidade de RNA , RNA Mensageiro/química , RNA Mensageiro/genética , Receptor Notch1/genética , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
Glomerular diseases afflict millions of people and impose an enormous burden on public healthcare costs worldwide. Identification of potential therapeutic targets for preventing glomerular diseases is of considerable clinical importance. CHILKBP is a focal adhesion protein and modulates a wide array of biological functions. However, little is known about the role of CHILKBP in glomerular diseases. To investigate the function of CHILKBP in maintaining the structure and function of podocytes in a physiologic setting, a mouse model (CHILKBP cKO) was generated in which CHILKBP gene was conditionally deleted in podocytes using the Cre-LoxP system. Ablation of CHILKBP in podocytes resulted in massive proteinuria and kidney failure in mice. Histologically, typical podocyte injury including podocyte loss, foot process effacement, and glomerulosclerosis was observed in CHILKBP cKO mice. Mechanistically, we identified ZO-1 as a key junctional protein that interacted with CHILKBP. Loss of CHILKBP in podocytes exhibited a significant reduction of ZO-1 expression, leading to abnormal actin organization, aberrant slit diaphragm protein expression and compromised podocyte filtration capacity. Restoration of CHILKBP or ZO-1 in CHILKBP-deficient podocytes effectively alleviated podocyte injury induced by the loss of CHILKBP in vitro and in vivo. Finally, we showed the glomerular expression of CHILKBP and ZO-1 was decreased in patients with proteinuric kidney diseases. Our findings reveal a novel signaling pathway consisting of CHILKBP and ZO-1 that plays an essential role in maintaining podocyte homeostasis and suggest novel therapeutic approaches to alleviate glomerular diseases.
Assuntos
Nefropatias , Podócitos , Camundongos , Animais , Podócitos/metabolismo , Glomérulos Renais/metabolismo , Nefropatias/metabolismo , Transdução de Sinais , Proteinúria/metabolismoRESUMO
Based on the research strategy of "drug repurposing", a series of derivatives and marketed drugs that containing salicylic acid skeleton were tested for their antibacterial activities against phytopathogens. Salicylic acid can not only regulate some important growth metabolism of plants, but also induce plant disease resistance. The bioassay results showed that the salicylamides exhibited excellent antibacterial activity. Especially, oxyclozanide showed the best antibacterial effect against Xanthomonas oryzae, Xanthomonas axonopodis pv. citri and Pectobacterium atroseptica with MICs of 0.78, 3.12 and 12.5â µg.mL-1, respectively. In vivo experiments with rice bacterial leaf blight had further demonstrated that oxyclozanide exhibited stronger antibacterial activity than the commercial bactericide, thiodiazole copper. Oxyclozanide could induce plant defense responses through the determination of salicylic acid content and the activities of defense-related enzymes including CAT, POD, and SOD in rice. The preliminarily antibacterial mechanism study indicated that oxyclozanide exhibited the antibacterial activity by disrupting cell integrity and reducing bacterial pathogenicity. Additionally, oxyclozanide could induce plant defense responses through the determination of salicylic acid content.
Assuntos
Oryza , Xanthomonas , Salicilamidas/farmacologia , Reposicionamento de Medicamentos , Oxiclozanida/farmacologia , Antibacterianos/farmacologia , Oryza/microbiologia , Testes de Sensibilidade Microbiana , Ácido Salicílico/farmacologia , Doenças das Plantas/prevenção & controle , Doenças das Plantas/microbiologia , Oxidiazóis/farmacologiaRESUMO
Hematopoietic stem cells (HSCs) are the foundation of adult hematopoiesis that produce all types of mature blood lineages. In vertebrates, HSC development is a stepwise process, coordinately regulated by chromatin architectures and a group of transcriptional and epigenetic regulators. A deeper understanding of the molecular mechanisms governing the generation, expansion, and function of HSCs holds great promise in the generation and expansion of engraftable HSCs in vitro for clinical applications. This study reviewed recent advances in transcriptional and epigenetic control of hematopoietic stem cell fate decisions in vertebrates.
Assuntos
Linhagem da Célula/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Vertebrados/fisiologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Cromatina/metabolismo , DNA/metabolismo , Epigênese Genética/genética , Epigenômica , Hematopoese/genética , Células-Tronco Hematopoéticas/fisiologia , Humanos , Transcrição Gênica/genética , Vertebrados/metabolismoRESUMO
Nephrotic syndrome (NS) is a common kidney disorder caused by dysfunction of the glomerular filtration barrier. Some genetic mutations identified in NS patients cause amino acid substitutions of kidney ankyrin repeat-containing (KANK) proteins, which are scaffold proteins that regulate actin polymerization, microtubule targeting, and cell adhesion via binding to various molecules, including the kinesin motor protein KIF21A. However, the mechanisms by which these mutations lead to NS are unclear. Here, we unexpectedly found that the eukaryotic translation initiation factor 4A1 (eIF4A1) interacts with an NS-associated KANK2 mutant (S684F) but not the wild-type protein. Biochemical and structural analyses revealed that the pathological mutation induces abnormal binding of eIF4A1 to KANK2 at the physiological KIF21A-binding site. Competitive binding assays further indicated that eIF4A1 can compete with KIF21A to interact with the S684F mutant of KANK2. In cultured mouse podocytes, this S684F mutant interfered with the KANK2/KIF21A interaction by binding to eIF4A1, and failed to rescue the focal adhesion or cell adhesion that had been reduced or morphologically changed by KANK2 knockout. These structural, biochemical, and cellular results not only provide mechanistic explanations for the podocyte defects caused by the S684F mutation, but also show how a gain-of-binding mutation can lead to a loss-of-function effect.
Assuntos
Cinesinas , Síndrome Nefrótica , Animais , Adesão Celular , Linhagem Celular , Proteínas do Citoesqueleto/metabolismo , Adesões Focais/metabolismo , Cinesinas/metabolismo , Camundongos , Microtúbulos/metabolismo , Mutação , Podócitos/metabolismoRESUMO
The active sites in Cu/ZnO/Al2O3 industrial catalyst for CO2 hydrogenation to methanol need to be fully clarified. In this work, we reveal two types of active sites at the nano-sized Cu/ZnO interface, of which only one type is efficient. The efficient active site is characterized by isolated and under-coordinated Zn atoms located at the vertices of the supported ZnO island, thus the density of which is so limited. To anchor such Zn atoms onto other islands on Cu with high density is the key to enhancing the catalytic activity. To replace ZnO with Al2O3 islands on Cu is not favored energetically. However, under reduction condition, Zn single atoms can stably decorate the edges of the Al2O3 islands, resulting in the enhancement of the efficient active sites at the Cu/oxide interface. This could be the mechanism of the synergy effects taking place in the Cu/ZnO/Al2O3 catalyst.
RESUMO
Pre-coagulation is commonly used with ultrafiltration (UF) to alleviate the membrane fouling. Compared to conventional coagulation-sedimentation-UF (CSUF) processes, the direct coagulation-UF (CUF) processes are widely believed to perform better due to the formation of a looser cake layer. It is however shown in this study that not only the density of a cake layer, but also its thickness as well, can affect the membrane fouling behavior, which therefore are influenced by both the sedimentation time and flocs characteristics. Herein, the membrane fouling performance of Fe-based coagulation-UF process was systematically investigated with different sedimentation times. A critical threshold of 30 min was observed at the lab-scale: if shorter than that, the membrane fouling depended mainly on the cake layer density, and thus CUF outperformed CSUF; but when the sedimentation time was over 30 min, the cake layer thickness turned to be the dominant factor, thereby resulting in CSUF performing better. Furthermore, it was shown that the critical sedimentation time was decided by flocs characteristics. A lower water temperature induced the formation of irregular flocs with a lower fractal dimension, and the corresponding cake layer exhibited an almost identical density with increasing sedimentation time. In this regard, CSUF processes were constantly superior to CUF as the cake layer thickness decreased. On the other hand, a critical sedimentation time reappeared because of the higher floc fractal dimension under acidic conditions. This work showed for the first time that the membrane fouling of CSUF was up to the sedimentation time, and it was possible to outperform CUF if the sedimentation time exceeded a critical threshold. Such a finding is crucial to the future development of coagulation integrated UF processes.
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Ultrafiltração , Purificação da Água , Membranas ArtificiaisRESUMO
RATIONALE: Our pilot study suggested that noninvasive ventilation (NIV) reduced the need for intubation compared with conventional administration of oxygen on patients with "early" stage of mild acute respiratory distress syndrome (ARDS, PaO2/FIO2 between 200 and 300). OBJECTIVES: To evaluate whether early NIV can reduce the need for invasive ventilation in patients with pneumonia-induced early mild ARDS. METHODS: Prospective, multicenter, randomized controlled trial (RCT) of NIV compared with conventional administration of oxygen through a Venturi mask. Primary outcome included the numbers of patients who met the intubation criteria. RESULTS: Two hundred subjects were randomized to NIV (n = 102) or control (n = 98) groups from 21 centers. Baseline characteristics were similar in the two groups. In the NIV group, PaO2/FIO2 became significantly higher than in the control group at 2 h after randomization and remained stable for the first 72 h. NIV did not decrease the proportion of patients requiring intubation than in the control group (11/102 vs. 9/98, 10.8% vs. 9.2%, p = 0.706). The ICU mortality was similar in the two groups (7/102 vs. 7/98, 4.9% vs. 3.1%, p = 0.721). Multivariate analysis showed minute ventilation greater than 11 L/min at 48 h was the independent risk factor for NIV failure (OR, 1.176 [95% CI, 1.005-1.379], p = 0.043). CONCLUSIONS: Treatment with NIV did not reduce the need for intubation among patients with pneumonia-induced early mild ARDS, despite the improved PaO2/FIO2 observed with NIV compared with standard oxygen therapy. High minute ventilation may predict NIV failure. TRIAL REGISTRATION: NCT01581229 . Registered 19 April 2012.
Assuntos
Ventilação não Invasiva/efeitos adversos , Síndrome do Desconforto Respiratório/complicações , Lesão Pulmonar Induzida por Ventilação Mecânica/etiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ventilação não Invasiva/métodos , Projetos Piloto , Estudos Prospectivos , Índice de Gravidade de Doença , Lesão Pulmonar Induzida por Ventilação Mecânica/terapiaRESUMO
Presbycusis is a sensorineural hearing loss caused by hearing system aging and degeneration. The clinical manifestations are progressive bilateral symmetrical hearing loss, and the hearing curve is mostly slope-shaped with high-frequency reduction, sometimes flat. The results of the second national sample survey of disabled persons (2006) showed that the total number of hearing and speech disability in China was 27.8 million, accounting for 34% of the total number of disabled people in China. Among them are people over 60 years old. There are 20.4541 million people with hearing disabilities. There are 9.49 million senile deaf patients, accounting for 34.1% of the total number of hearing disabilities. As society gradually becomes aging, the incidence of presbycusis is getting higher and higher. The study of its pathogenesis is of great significance for the diagnosis, treatment, and prevention of presbycusis. The rapid progress of molecular biology experimental technology has provided us with a new opportunity to fully understand and reveal the presbycusis. In the near future, early diagnosis of presbycusis-related genes and early prevention or delay of the occurrence and development of presbycusis will become a reality.
Assuntos
Perda Auditiva Neurossensorial/prevenção & controle , Presbiacusia/prevenção & controle , China , HumanosRESUMO
Protein-like substances always induce severe ultrafiltration (UF) membrane fouling. To systematically understand the effect of proteins, regenerated cellulose UF membrane (commonly used for protein separation) performance was investigated in the presence of bovine serum albumin (BSA) under various water conditions. Results showed that although trypsin enhanced the membrane flux via proteolysis, catalysis took a long time. Membrane fouling was alleviated at high solution pH and low water temperature owing to the strong electrostatic repulsion force among BSA molecules. Both Na+ and Ca2+ could increase membrane flux. However, Ca2+ played a bridging role between adjacent BSA molecules, whereas membrane fouling was alleviated via a hydration repulsion force with Na+. The order of influence on membrane fouling was as follows: Ca2+ concentration > Na+ concentration > pH > temperature > trypsin concentration. Furthermore, a polyvinylidene fluoride UF membrane experiment showed that Ca2+ could reduce the fouling induced by BSA. Thus, the differences in UF membrane performance will have application potential for alleviating UF membrane fouling induced by proteins during water treatment.
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Incrustação Biológica , Membranas Artificiais , Soroalbumina Bovina/metabolismo , Ultrafiltração , Purificação da Água , Animais , Cálcio/química , Bovinos , Celulose/química , Concentração de Íons de Hidrogênio , Concentração Osmolar , Temperatura , Tripsina/metabolismoRESUMO
Microplastics have caused great concern worldwide recently due to their ubiquitous presence within the marine environment. Up to now, most attention has been paid to their sources, distributions, measurement methods, and especially their eco-toxicological effects. With microplastics being increasingly detected in freshwater, it is urgently necessary to evaluate their behaviors during coagulation and ultrafiltration (UF) processes. Herein, the removal behavior of polyethylene (PE), which is easily suspended in water and is the main component of microplastics, was investigated with commonly used Fe-based salts. Results showed that although higher removal efficiency was induced for smaller PE particles, low PE removal efficiency (below 15%) was observed using the traditional coagulation process, and was little influenced by water characteristics. In comparison to solution pH, PAM addition played a more important role in increasing the removal efficiency, especially anionic PAM at high dosage (with efficiency up to 90.9%). The main reason was ascribed to the dense floc formation and high adsorption ability because of the positively charged Fe-based flocs under neutral conditions. For ultrafiltration, although PE particles could be completely rejected, slight membrane fouling was caused owing to their large particle size. The membrane flux decreased after coagulation; however, the membrane fouling was less severe than that induced by flocs alone due to the heterogeneous nature of the cake layer caused by PE, even at high dosages of Fe-based salts. Based on the behavior exhibited during coagulation and ultrafiltration, we believe these findings will have potential application in drinking water treatment.
Assuntos
Água Potável/química , Plásticos/química , Poluentes Químicos da Água/química , Purificação da Água/métodos , Floculação , Ferro/química , Membranas Artificiais , Plásticos/análise , Ultrafiltração/métodos , Poluentes Químicos da Água/análiseRESUMO
This study investigated the mechanisms of microbial growth and metabolism during biofilm cultivation in the biofilm sequencing batch reactor (BSBR) process for phosphate (P) enrichment. The results showed that the sludge discharge was key to biofilm growth, as it terminated the competition for carbon (C) source between the nascent biofilm and the activated sludge. For the tested reactor, after the sludge discharge on 18 d, P metabolism and C source utilization improved significantly, and the biofilm grew rapidly. The P concentration of the recovery liquid reached up to 157.08 mg/L, which was sufficient for further P recovery via mineralization. Meta-omics methods were used to analyze metabolic pathways and functional genes in microbial growth during biofilm cultivation. It appeared that the sludge discharge activated the key genes of P metabolism and inhibited the key genes of C metabolism, which strengthened the polyphosphate-accumulating metabolism (PAM) as a result. The sludge discharge not only changed the types of polyphosphate-accumulating organisms (PAOs) but also promoted the growth of dominant PAOs. Before the sludge discharge, the necessary metabolic abilities that were spread among different microorganisms gradually concentrated into a small number of PAOs, and after the sludge discharge, they further concentrated into Candidatus_Contendobacter (P3) and Candidatus_Accumulibacter (P17). The messenger molecule C-di-GMP, produced mostly by P3 and P17, facilitated P enrichment by regulating cellular P and C metabolism. The glycogen-accumulating organism (GAO) Candidatus_Competibacter secreted N-Acyl homoserine lactones (AHLs), which stimulated the secretion of protein in extracellular polymeric substances (EPS), thus promoting the adhesion of microorganisms to biofilm and improving P metabolism via EPS-based P adsorption. Under the combined action of the dominant GAOs and PAOs, AHLs and C-di-GMP mediated QS to promote biofilm development and P enrichment. The research provides theoretical support for the cultivation of biofilm and its wider application.
Assuntos
Acil-Butirolactonas , Biofilmes , GMP Cíclico , GMP Cíclico/análogos & derivados , Fosfatos , Eliminação de Resíduos Líquidos , Acil-Butirolactonas/metabolismo , Fosfatos/metabolismo , GMP Cíclico/metabolismo , Eliminação de Resíduos Líquidos/métodos , Reatores Biológicos/microbiologia , Esgotos/microbiologiaRESUMO
Aim: Atractylodes macrocephala Rhizome (AM) has been used to treat hyperlipidemia for centuries, but its functional components and mechanisms are not clear. This research aimed to investigate the active components in AM and the mechanisms that underlie its anti-hyperlipidemia effect. Methods: SD rats were fed a high-sucrose high-fat diet in conjunction with alcohol (HSHFDAC) along with different AM extracts (AMW, AMO, AME, and AMP) for 4 weeks. AM's active components were analyzed using multiple databases, and their mechanisms were explored through network pharmacology. The relationship between AM's effect of enhancing serum HDL-c and regulating the expression of reverse cholesterol transport (RCT)-related proteins (Apo-A1, LCAT, and SR-BI) was further validated in the HSHFDAC-induced hyperlipidemic rats. The kidney and liver functions of the rats were measured to evaluate the safety of AM. Results: AMO, mainly comprised of volatile and liposoluble components, contributed the most significant anti-hyperlipidemia effect among the four extracts obtained from AM, significantly improving the blood lipid profile. Network pharmacology analysis also suggested that volatile and liposoluble components, comprise AM's main active components and they might act on signaling pathways associated with elevated HDL-c. Validation experiments found that AMO substantially and dose-dependently increased HDL-c levels, upregulated the expression of Apo-A1, SR-BI, and LCAT, improved the pathological changes in the kidney and liver, and significantly reduced the serum creatinine levels in rats with hyperlipidemia. Conclusion: The main anti-hyperlipidemia active components of AM are its volatile and liposoluble components, which may enhance serum HDL-c by increasing the expression of the RCT-related proteins Apo-A1, LCAT, and SR-BI.
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OBJECTIVES: To elucidate the therapeutic effects and mechanisms of Atractylodes macrocephala extract crystallize (BZEP) and BZEP self-microemulsion (BZEPWR) on metabolic dysfunction-associated fatty liver disease (MAFLD) induced by "high sugar, high fat, and excessive alcohol consumption" based on the gut-liver axis HDL/LPS signaling pathway. METHODS: In this study, BZEP and BZEPWR were obtained via isolation, purification, and microemulsification. Furthermore, an anthropomorphic MAFLD rat model of "high sugar, high fat, and excessive alcohol consumption" was established. The therapeutic effects of BZEPWR and BZEP on the model rats were evaluated in terms of liver function, lipid metabolism (especially HDL-C), serum antioxidant indexes, and liver and intestinal pathophysiology. To determine the lipoproteins in the serum sample, the amplitudes of a plurality of NMR spectra were derived via deconvolution of the composite methyl signal envelope to yield HDL-C subclass concentrations. The changes in intestinal flora were detected via 16â¯S rRNA gene sequencing. In addition, the gut-liver axis HDL/LPS signaling pathway was validated using immunohistochemistry, immunofluorescence, and western blot. RESULTS: The findings established that BZEPWR and BZEP improved animal signs, serum levels of liver enzymes (ALT and AST), lipid metabolism (TC, TG, HDL-C, and LDL-C), and antioxidant indexes (GSH, SOD, and ROS). In addition, pathological damage to the liver, colon, and ileum was ameliorated, and the intestinal barrier function of the model rats was restored. At the genus level, BZEPWR and BZEP exerted positive effects on beneficial bacteria, such as Lactobacillus and norank_f__Muribaculaceae, and inhibitory effects on harmful bacteria, such as unclassified_f__Lachnospiraceae and Blautia. Twenty HDL-C subspecies were detected, and their levels were differentially increased in both BZEPWR and BZEP groups, with BZEPWR exhibiting a stronger elevating effect on specific HDL-C subspecies. Also, the gut-liver axis HDL/LPS signaling pathway was studied, which indicated that BZEPWR and BZEP significantly increased the expressions of ABCA1, LXR, occludin, and claudin-1 proteins in the gut and serum levels of HDL-C. Concomitantly, the levels of LPS in the serum and TLR4, Myd88, and NF-κB proteins in the liver were decreased. CONCLUSION: BZEPWR and BZEP exert restorative and reversal effects on the pathophysiological damage to the gut-liver axis in MAFLD rats, and the therapeutic mechanism may be related to the regulation of the intestinal flora and the HDL/LPS signaling pathway.
Assuntos
Atractylodes , Emulsões , Microbioma Gastrointestinal , Lipopolissacarídeos , Fígado , Extratos Vegetais , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Transdução de Sinais/efeitos dos fármacos , Masculino , Ratos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Atractylodes/química , Extratos Vegetais/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Lipoproteínas HDL/sangue , Modelos Animais de Doenças , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Antioxidantes/farmacologiaRESUMO
BACKGROUND: Currently, transcatheter aortic valve implantation (TAVI) is presently a recognized treatment modality for patients with severe aortic stenosis who are often old, disabled, frail, and have low exercise capacity (ExCap). It is further expected from this therapy to improve quality of life by improving of the cardio function performance. The aim of this study is to evaluate the effect of exercise-based cardiac rehabilitation (CR) on patients after TAVI. METHODS: PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to December 10, 2022 for relevant studies that evaluated the effect of CR on patients after TAVI. The primary outcome was the improvement of 6-minute walked distance and Barthel index score after CR. The secondary outcomes included other parameters such as SF-12 scale, HADS score, Morse Fall Scale, Frailty-Index, ExCap, and FIM score. All statistical analyses were performed using the standard statistical procedures provided in Review Manager 5.2. RESULTS: A total of 12 observational studies were identified, with 2365 participants. Pooled data indicated that CR programmers significantly improved the 6-minute walked distance (SMD 0.65; 95% confidence intervals [CI] 0.51-0.79) and Barthel index score (SMD 0.83; 95% CI 0.61-1.06). In addition, compared with admission, patients experienced significant improvement in SF-12 scale at CR discharge, with a pooled mean differences (MD) of 2.74 (95% CI 0.86-4.61) in physical component score and 2.76 (95% CI 0.59-4.93) in mental component score. Similar results were also observed in ExCap (MD 8.10 W; 95% CI 1.57 W-14.63 W) and FIM score (MD 11.0; 95% CI 6.22-15.78). CONCLUSIONS: Our analysis indicated that exercise-based CR programmers had significant effect on patients after TAVI in improving exercise tolerance and functional independence.
Assuntos
Estenose da Valva Aórtica , Reabilitação Cardíaca , Substituição da Valva Aórtica Transcateter , Humanos , Substituição da Valva Aórtica Transcateter/métodos , Reabilitação Cardíaca/métodos , Estenose da Valva Aórtica/cirurgia , Estenose da Valva Aórtica/etiologia , Qualidade de Vida , Resultado do Tratamento , Valva Aórtica/cirurgiaRESUMO
Cisplatin is widely used in clinical tumor chemotherapy but has severe ototoxic side effects, including tinnitus and hearing damage. This study aimed to determine the molecular mechanism underlying cisplatin-induced ototoxicity. In this study, we used CBA/CaJ mice to establish an ototoxicity model of cisplatin-induced hair cell loss, and our results showed that cisplatin treatment could reduce FOXG1 expression and autophagy levels. Additionally, H3K9me2 levels increased in cochlear hair cells after cisplatin administration. Reduced FOXG1 expression caused decreased microRNA (miRNA) expression and autophagy levels, leading to reactive oxygen species (ROS) accumulation and cochlear hair cell death. Inhibiting miRNA expression decreased the autophagy levels of OC-1 cells and significantly increased cellular ROS levels and the apoptosis ratio in vitro. In vitro, overexpression of FOXG1 and its target miRNAs could rescue the cisplatin-induced decrease in autophagy, thereby reducing apoptosis. BIX01294 is an inhibitor of G9a, the enzyme in charge of H3K9me2, and can reduce hair cell damage and rescue the hearing loss caused by cisplatin in vivo. This study demonstrates that FOXG1-related epigenetics plays a role in cisplatin-induced ototoxicity through the autophagy pathway, providing new ideas and intervention targets for treating ototoxicity.