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1.
EMBO Mol Med ; 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565805

RESUMO

The emergence of drug-resistant Enterobacteriaceae carrying plasmid-mediated ß-lactamase genes has become a significant threat to public health. Organisms in the Enterobacteriaceae family containing New Delhi metallo-ß-lactamase­1 (NDM-1) and its variants, which are capable of hydrolyzing nearly all ß-lactam antibacterial agents, including carbapenems, are referred to as superbugs and distributed worldwide. Despite efforts over the past decade, the discovery of an NDM-1 inhibitor that can reach the clinic remains a challenge. Here, we identified oxidized glutathione (GSSG) as a metabolic biomarker for blaNDM-1 using a non-targeted metabolomics approach and demonstrated that GSSG supplementation could restore carbapenem susceptibility in Escherichia coli carrying blaNDM-1 in vitro and in vivo. We showed that exogenous GSSG promotes the bactericidal effects of carbapenems by interfering with intracellular redox homeostasis and inhibiting the expression of NDM-1 in drug-resistant E. coli. This study establishes a metabolomics-based strategy to potentiate metabolism-dependent antibiotic efficacy for the treatment of antibiotic-resistant bacteria.

2.
Small ; : e2401589, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38567494

RESUMO

Despite possessing substantial benefits of enhanced safety and cost-effectiveness, the aqueous zinc ion batteries (AZIBs) still suffers with the critical challenges induced by inherent instability of Zn metal in aqueous electrolytes. Zn dendrites, surface passivation, and corrosion are some of the key challenges governed by water-driven side reactions in Zn anodes. Herein, a highly reversible Zn anode is demonstrated via interfacial engineering of Zn/electrolyte driven by amino acid D-Phenylalanine (DPA) additions. The preferential adsorption of DPA and the development of compact SEI on the Zn anode suppressed the side reactions, leading to controlled and uniform Zn deposition. As a result, DPA added aqueous electrolyte stabilized Zn anode under severe test environments of 20.0 mA cm-2 and 10.0 mAh cm-2 along with an average plating/stripping Coulombic efficiency of 99.37%. Under multiple testing conditions, the DPA-incorporated electrolyte outperforms the control group electrolyte, revealing the critical additive impact on Zn anode stability. This study advances interfacial engineering through versatile electrolyte additive(s) toward development of stable Zn anode, which may lead to its practical implementation in aqueous rechargeable zinc batteries.

3.
Biomaterials ; 308: 122563, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38574456

RESUMO

A vascular anastomosis is a critical surgical skill that involves connecting blood vessels. Traditional handsewn techniques can be challenging and resource intensive. To address these issues, we have developed a unique sutureless anastomotic device called Vaso-Lock. This intraluminal device connects free vascular ends using anchors to maintain traction and enable a rapid anastomosis. We tested the anastomotic capability of Vaso-Locks in a pig common carotid-internal jugular arteriovenous model. The use of Vaso-Lock allowed us to accomplish this procedure in less than 10 min, in contrast to the approximately 40 min required for a handsewn anastomosis. The Vaso-Lock effectively maintained patency for at least 6 weeks without causing significant tissue damage. Histological analysis revealed that the device was successfully incorporated into the arterial wall, promoting a natural healing process. Additionally, organ evaluations indicated no adverse effects from using the Vaso-Lock. Our findings support the safety and effectiveness of the Vaso-Lock for arteriovenous anastomosis in pigs, with potential applicability for translation to humans. Our novel sutureless device has the potential to advance surgical practice and improve patient outcomes.

4.
J Mol Cell Biol ; 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578631

RESUMO

The recognition of cytosolic nucleic acid triggers the DNA/RNA sensor-IRF3 axis-mediated production of type I interferons (IFNs), which are essential for antiviral immune responses. However, the inappropriate activation of these signaling pathways is implicated in autoimmune conditions. Here, we report that indomethacin, a widely used nonsteroidal anti-inflammatory drug, inhibits nucleic acid-triggered IFN production. We found that both DNA- and RNA-stimulated IFN expression can be effectively blocked by indomethacin. Interestingly, indomethacin also prohibits the nuclear translocation of IRF3 following cytosolic nucleic acid recognition. Importantly, in cell lines and a mouse model of Aicardi-Goutières syndrome, indomethacin administration blunts self-DNA-induced autoimmune responses. Thus, our study reveals a previously unknown function of indomethacin and provides a potential treatment for cytosolic nucleic acid-stimulated autoimmunity.

5.
Water Sci Technol ; 89(7): 1630-1646, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38619894

RESUMO

Due to the colloidal stability, the high compressibility and the high hydration of extracellular polymeric substances (EPS), it is difficult to efficiently dehydrate sludge. In order to enhance sludge dewatering, the process of ultrasonic (US) cracking, chitosan (CTS) re-flocculation and sludge-based biochar (SBB) skeleton adsorption of water-holding substances to regulate sludge dewaterability was proposed. Based on the response surface method, the prediction model of the specific resistance to filtration (SRF) and sludge cake moisture content (MC) was established. The US cracking time and the dosage of CTS and SBB were optimized. The results showed that the optimal parameters of the three were 5.08 s, 10.1 mg/g dry solids (DS) and 0.477 g/g DS, respectively. Meantime, the SRF and MC were 5.4125 × 1011 m/kg and 76.8123%, which significantly improved the sludge dewaterability. According to the variance analysis, it is found that the fitting degree of SRF and MC model is good, which also confirms that there is significant interaction and synergy between US, CTS and SBB, and the contribution of CTS and SBB is greater. Moreover, the process significantly improves the sludge's calorific value and makes its combustion more durable.


Assuntos
Quitosana , Esgotos , Ultrassom , Carvão Vegetal , Filtração , Água , Eliminação de Resíduos Líquidos/métodos
6.
Biochem Biophys Res Commun ; 710: 149910, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38593619

RESUMO

Ginsenoside Rb1 (Rb1), an active component isolated from traditional Chinese medicine Ginseng, is beneficial to many cardiovascular diseases. However, whether it can protect against doxorubicin induced cardiotoxicity (DIC) is not clear yet. In this study, we aimed to investigate the role of Rb1 in DIC. Mice were injected with a single dose of doxorubicin (20 mg/kg) to induce acute cardiotoxicity. Rb1 was given daily gavage to mice for 7 days. Changes in cardiac function, myocardium histopathology, oxidative stress, cardiomyocyte mitochondrion morphology were studied to evaluate Rb1's function on DIC. Meanwhile, RNA-seq analysis was performed to explore the potential underline molecular mechanism involved in Rb1's function on DIC. We found that Rb1 treatment can improve survival rate and body weight in Dox treated mice group. Rb1 can attenuate Dox induced cardiac dysfunction and myocardium hypertrophy and interstitial fibrosis. The oxidative stress increase and cardiomyocyte mitochondrion injury were improved by Rb1 treatment. Mechanism study found that Rb1's beneficial role in DIC is through suppressing of autophagy and ferroptosis. This study shown that Ginsenoside Rb1 can protect against DIC by regulating autophagy and ferroptosis.


Assuntos
Cardiotoxicidade , Ferroptose , Ginsenosídeos , Camundongos , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/metabolismo , Miócitos Cardíacos/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/metabolismo , Autofagia , Estresse Oxidativo , Apoptose
7.
Org Lett ; 26(15): 2913-2917, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38569099

RESUMO

C-C σ-bond cleavage and reconstruction is a significant tool for structural modification in synthetic chemistry but it remains a formidable challenge to perform on unstrained skeletons. Herein, we describe a radical addition-enabled C-C σ-bond cleavage/reconstruction reaction of unstrained allyl ketones to access various functional indanones bearing a benzylic quaternary center. The synthetic utility of this method has been showcased by the first total synthesis of carexane L, an indanone-based natural product.

8.
Nanoscale ; 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38639878

RESUMO

The exploration of powerful, efficient and precious metal-free electrocatalysts for facilitating the sluggish kinetics of the oxygen reduction reaction (ORR) is a crucial endeavor in the development and application of energy conversion and storage devices. Herein, we have rationally designed and synthesized bimetallic CoFe species consisting of CoFe nanoparticles and atomically dispersed dual atoms anchored on an ordered mesoporous carbon matrix (CoFe/NC) as highly efficient ORR electrocatalysts. The pyrolyzation temperature for CoFe/NC plays a vital role in regulating the morphology and composition of both the carbon matrix and CoFe species. The optimized CoFe/NC-750 exhibits a favorable ORR performance in 0.1 M KOH with a high half-wave potential (E1/2) of 0.87 V vs. RHE, excellent tolerance to methanol and remarkable durability (no obvious decrease in E1/2 value after 3000 cycles), all of which are superior to the performance of commercial Pt/C. Experimental measurements and density functional theory (DFT) calculations reveal that the improved ORR performance of CoFe/NC-750 is mainly attributed to the electronic structure of atomically dispersed Fe active sites modulated by the surrounding CoFe alloys and Co single atoms, which accelerates the dissociation and reduction of intermediate OH* species and promotes the ORR process.

9.
Poult Sci ; 103(6): 103730, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38631229

RESUMO

Atrazine (ATR) is widely used worldwide as a commercial herbicide, Diaminochlorotriazine (DACT) is the main metabolite of ATR in the organism. Both of them disrupt the production of steroids and induce abnormal reproductive development. The granulosa cells (GCs) are important for growth and reproduction of animals. However, the toxicity of ATR on the GCs of birds is not well clarified. To evaluate the effect of the environmental pollutant ATR on bird GCs. The quail GCs were allotted into 7 groups, C (The medium of M199), A20 (20 µM ATR), A100 (100 µM ATR), A250 (250 µM ATR), D20 (20 µM DACT), D100 (100 µM DACT) and D200 (200 µM DACT). The results demonstrated that ATR reduced the viability of GCs, disrupted mitochondrial structure (including mitochondrial cristae fragmentation and the mitochondrial morphology disappearance) and decreased mitochondrial membrane potential. Meanwhile, ATR interfered with the expression of key factors in the steroid synthesis pathway, inducing the secretion of the sex hormones E2 and P in GCs. which in turn induced apoptosis. Furthermore, the Nrf2/ARE pathway as a potential target to ameliorate ATR-induced endocrine disruption in GCs for proper reproductive functions. Our research provides a new perspective for understanding the effects of ATR on reproductive functions in birds.

10.
Sci Rep ; 14(1): 8886, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38632476

RESUMO

As one of the three major outdoor components of the railroad signal system, the track circuit plays an important role in ensuring the safety and efficiency of train operation. Therefore, when a fault occurs, the cause of the fault needs to be found quickly and accurately and dealt with in a timely manner to avoid affecting the efficiency of train operation and the occurrence of safety accidents. This article proposes a fault diagnosis method based on multi-scale attention network, which uses Gramian Angular Field (GAF) to transform one-dimensional time series into two-dimensional images, making full use of the advantages of convolutional networks in processing image data. A new feature fusion training structure is designed to effectively train the model, fully extract features at different scales, and fusing spatial feature information through spatial attention mechanisms. Finally, experiments are conducted using real track circuit fault datasets, and the accuracy of fault diagnosis reaches 99.36%, and our model demonstrates better performance compared to classical and state-of-the-art models. And the ablation experiments verified that each module in the designed model plays a key role.

11.
Mater Today Commun ; 392024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38618226

RESUMO

Synthetic polymers are often utilized in the creation of vascular devices, and need to possess specific qualities to prevent thrombosis. Traditional strategies for this include surface modification of vascular devices through covalent attachment of substrates such as heparin, antiplatelet agents, thrombolytic agents, or hydrophilic polymers. One promising prosthetic material is polyether ether ketone (PEEK), which is utilized in various FDA-approved medical devices, including vascular and endovascular prostheses. We hypothesized that surface modification of biologically inert PEEK can help improve its endothelial cell affinity and reduce its thrombogenic potential. To evaluate this, we developed an effective surface-modification approach with unique cyclic peptides, such as CCHGGVRLYC and CCREDVC. We treated the PEEK surface with ammonia plasma, which introduced amine groups onto the PEEK surface. Subsequently, we were able to conjugate these peptides to the plasma-modified PEEKs. We observed that cyclic CCHGGVRLYC conjugated on prosthetic PEEK not only supported endothelialization, but minimized platelet adhesion and activation. This technology can be potentially applied for in vivo vascular and endovascular protheses to enhance their utility and patency.

12.
Sci Adv ; 10(11): eadl4871, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38489356

RESUMO

Noise-enhanced applications in open quantum walk (QW) has recently seen a surge due to their ability to improve performance. However, verifying the success of open QW is challenging, as mixed-state tomography is a resource-intensive process, and implementing all required measurements is almost impossible due to various physical constraints. To address this challenge, we present a neural-network-based method for reconstructing mixed states with a high fidelity (∼97.5%) while costing only 50% of the number of measurements typically required for open discrete-time QW in one dimension. Our method uses a neural density operator that models the system and environment, followed by a generalized natural gradient descent procedure that significantly speeds up the training process. Moreover, we introduce a compact interferometric measurement device, improving the scalability of our photonic QW setup that enables experimental learning of mixed states. Our results demonstrate that highly expressive neural networks can serve as powerful alternatives to traditional state tomography.

13.
J Hazard Mater ; 469: 134032, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38492389

RESUMO

Plant invasions and microplastics (MPs) have significantly altered the structure and function of aquatic habitats worldwide, resulting in severe damage to aquatic ecosystem health. However, the effects of MPs on plant invasion and the underlying mechanisms remain largely unknown. In this study, we conducted mesocosm experiments over a 90-day period to assess the effects of polystyrene microplastics on the invasion of exotic submerged macrophytes, sediment physicochemical properties, and sediment bacterial communities. Our results showed that PS-MPs significantly promoted the performance of functional traits and the invasive ability of exotic submerged macrophytes, while native plants remained unaffected. Moreover, PS-MPs addition significantly decreased sediment pH while increasing sediment carbon and nitrogen content. Additionally, MPs increased the diversity of sediment bacterial community but inhibited its structural stability, thereby impacting sediment bacterial multifunctionality to varying degrees. Importantly, we identified sediment properties, bacterial composition, and bacterial multifunctionality as key mediators that greatly enhance the invasion of exotic submerged macrophytes. These findings provide compelling evidence that the increase in MPs may exacerbate the invasion risk of exotic submerged macrophytes through multiple pathways. Overall, this study enhances our understanding of the ecological impacts of MPs on aquatic plant invasion and the health of aquatic ecosystems.


Assuntos
Microbiota , Microplásticos , Microplásticos/toxicidade , Ecossistema , Plásticos , Poliestirenos , Bactérias
14.
Cell Death Discov ; 10(1): 142, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38490981

RESUMO

Pleckstrin homology domain-containing family M member 2 (PLEKHM2) is an essential adaptor for lysosomal trafficking and its homozygous truncation have been reported to cause early onset dilated cardiomyopathy (DCM). However, the molecular mechanism of PLEKHM2 deficiency in DCM pathogenesis and progression is poorly understood. Here, we generated an in vitro model of PLEKHM2 knockout (KO) induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to elucidate the potential pathogenic mechanism of PLEKHM2-deficient cardiomyopathy. PLEKHM2-KO hiPSC-CMs developed disease phenotypes with reduced contractility and impaired calcium handling. Subsequent RNA sequencing (RNA-seq) analysis revealed altered expression of genes involved in mitochondrial function, autophagy and apoptosis in PLEKHM2-KO hiPSC-CMs. Further molecular experiments confirmed PLEKHM2 deficiency impaired autophagy and resulted in accumulation of damaged mitochondria, which triggered increased reactive oxygen species (ROS) levels and decreased mitochondrial membrane potential (Δψm). Importantly, the elevated ROS levels caused oxidative stress-induced damage to nearby healthy mitochondria, resulting in extensive Δψm destabilization, and ultimately leading to impaired mitochondrial function and myocardial contractility. Moreover, ROS inhibition attenuated oxidative stress-induced mitochondrial damage, thereby partially rescued PLEKHM2 deficiency-induced disease phenotypes. Remarkably, PLEKHM2-WT overexpression restored autophagic flux and rescued mitochondrial function and myocardial contractility in PLEKHM2-KO hiPSC-CMs. Taken together, these results suggested that impaired mitochondrial clearance and increased ROS levels play important roles in PLEKHM2-deficient cardiomyopathy, and PLEKHM2-WT overexpression can improve mitochondrial function and rescue PLEKHM2-deficient cardiomyopathy.

15.
Sci Total Environ ; 922: 171338, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38428608

RESUMO

Wastewater treatment plants (WWTPs) receive large quantities of microplastics (MPs) from raw wastewater, but many MPs are trapped in the sludge. Land application of sludge is a significant source of MP pollution. Existing reviews have summarized the analysis methods of MPs in sludge and the effect of MPs on sludge treatments. However, MP aging and mitigation during sludge treatment processes are not fully reviewed. Treatment processes used to remove water, pathogenic microorganisms, and other pollutants in sewage sludge also cause surface changes and degradation in the sludge MPs, affecting the potential risk of MPs. This study integrates MP abundance and distribution in sludge and their aging and mitigation characteristics during sludge treatment processes. The abundance, composition, and distribution of sludge MPs vary significantly with WWTPs. Furthermore, MPs exhibit variable degrees of aging, including rough surfaces, enhanced adsorption potentials for pollutants, and increased leaching behavior. Various sludge treatment processes further intensify these aging characteristics. Some sludge treatments, such as hydrothermal treatment, have efficiently removed MPs from sewage sludge. It is crucial to understand the potential risk of MP aging in sludge and the degradation properties of the MP-derived products from MP degradation in-depth and develop novel MP mitigation strategies in sludge, such as combining hydrothermal treatment and biological processes.


Assuntos
Poluentes Ambientais , Poluentes Químicos da Água , Esgotos , Microplásticos , Plásticos , Águas Residuárias , Poluentes Químicos da Água/análise , Eliminação de Resíduos Líquidos
16.
J Hazard Mater ; 470: 134126, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38554509

RESUMO

Cadmium (Cd) is a well-known testis toxicant. The blood-testis barrier (BTB) is a crucial component of the testis. Cd can disrupt the integrity of the BTB and reproductive function. However, the mechanism of Cd-induced disruption of BTB and testicular damage has not been fully elucidated. Here, our study investigates the effects of Cd on BTB integrity and testicular dysfunction. 80 (aged 1 day) Hy-Line white variety chickens were randomly designed into 4 groups and treated for 90 days, as follows: control group (essential diet), 35 Cd, 70 Cd and 140 Cd groups (35, 70 and 140 mg/kg Cd). The results found that Cd exposure diminished volume of the testes and induced histopathological lesions in the testes. Exposure to Cd induced an inflammatory response, disrupted the structure and function of the FAK/occludin/ZO-1 protein complex and disrupted the tight junction and adherens junction in the BTB. In addition, Cd exposure reduced the expression of steroid-related proteins and inhibited testosterone synthesis. Taken together, these data elucidate that Cd disrupts the integrity of the BTB and further inhibits spermatogenesis by dissociating the FAK/occludin/ZO-1 complex, which provides a basis for further investigation into the mechanisms of Cd-induced impairment of male reproductive function and pharmacological protection.


Assuntos
Barreira Hematotesticular , Cádmio , Galinhas , Testículo , Testosterona , Proteína da Zônula de Oclusão-1 , Animais , Masculino , Barreira Hematotesticular/efeitos dos fármacos , Cádmio/toxicidade , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Proteína da Zônula de Oclusão-1/metabolismo , Testosterona/sangue , Ocludina/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Espermatogênese/efeitos dos fármacos
17.
Clin Appl Thromb Hemost ; 30: 10760296241234320, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38444211

RESUMO

BACKGROUND AND AIMS: The diagnostic standard of coronary artery disease (CAD) is coronary angiography (CAG). Since CAG is an invasive procedure underscores the need for identifying non-invasive, effective, and innovative biomarkers. Our study aimed to retrospectively analyze hematological markers for predicting the severity of CAD. METHODS AND RESULTS: Case data were collected from 195 CAD patients admitted to the hospital for CAG. According to Gensini score, patients were divided into mild, moderate, and severe CAD groups. Blood indexes and predictive efficacy of the triglyceride-glucose (TyG) index were retrospectively analyzed. Among 195 CAD patients, 81 had mild CAD, 60 had moderate CAD, and 54 had severe CAD. Sex, fast blood glucose (FBG), TyG index, and high-sensitivity C-reactive protein (hs-CRP) significantly differed among the three groups. The TyG index demonstrated higher values in patients with moderate (9.07[8.62-9.44]) and severe (8.98[8.46-9.45]) CAD compared to those with mild CAD (8.75[8.49-9.14]). The AUC of the TyG index was 0.615 (95% confidence interval (CI): 0.536-0.694, P =.004), with a cut-off value of 8.997, specificity of 0.704, and sensitivity of 0.535. Logistics analysis showed the risk of moderate and severe CAD with an odds ratio (OR) value of 2.595 (95% CI: 1.199-5.619, adjusted P = .016) following regrouping by the TyG index optimal cut-off value of 8.997. The TyG index combined with FBG and hs-CRP had an elevated AUC value, significantly higher than other combinations (P = .011 and 0.02, respectively). CONCLUSIONS: The severity of CAD is positively correlated with an increased TyG index value. A combination of TyG, FBG, and hs-CRP has demonstrated improved diagnostic efficiency, suggesting its potential as a novel indicator for predicting and diagnosing CAD progression.


Assuntos
Doença da Artéria Coronariana , Humanos , Doença da Artéria Coronariana/diagnóstico , Estudos Retrospectivos , Proteína C-Reativa , Glucose , Triglicerídeos
18.
J Cell Mol Med ; 28(6): e18186, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38445803

RESUMO

Clear cell renal cell carcinoma (ccRCC) represents a significant challenge in oncology, primarily due to its resistance to conventional therapies. Understanding the tumour microenvironment (TME) is crucial for developing new treatment strategies. This study focuses on the role of amyloid precursor protein (APP) in tumour-associated macrophages (TAMs) within the ccRCC TME, exploring its potential as a prognostic biomarker. Basing TAM-related genes, the prognostic model was important to constructed. Employing advanced single-cell transcriptomic analysis, this research dissects the TME of ccRCC at an unprecedented cellular resolution. By isolating and examining the gene expression profiles of individual cells, particularly focusing on TAMs, the study investigates the expression levels of APP and their association with the clinical outcomes of ccRCC patients. The analysis reveals a significant correlation between the expression of APP in TAMs and patient prognosis in ccRCC. Patients with higher APP expression in TAMs showed differing clinical outcomes compared to those with lower expression. This finding suggests that APP could serve as a novel prognostic biomarker for ccRCC, providing insights into the disease progression and potential therapeutic targets. This study underscores the importance of single-cell transcriptomics in understanding the complex dynamics of the TME in ccRCC. The correlation between APP expression in TAMs and patient prognosis highlights APP as a potential prognostic biomarker. However, further research is needed to validate these findings and explore the regulatory mechanisms and therapeutic implications of APP in ccRCC.


Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Precursor de Proteína beta-Amiloide , Biomarcadores , Carcinoma de Células Renais/genética , Perfilação da Expressão Gênica , Neoplasias Renais/genética , Microambiente Tumoral/genética
19.
Chin Med ; 19(1): 36, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429802

RESUMO

BACKGROUND: Liver cirrhosis is a chronic liver disease with hepatocyte necrosis and lesion. As one of the TCM formulas Wuling Powder (WLP) is widely used in the treatment of liver cirrhosis. However, it's key functional components and action mechanism still remain unclear. We attempted to explore the Key Group of Effective Components (KGEC) of WLP in the treatment of Liver cirrhosis through integrative pharmacology combined with experiments. METHODS: The components and potential target genes of WLP were extracted from published databases. A novel node importance calculation model considering both node control force and node bridging force is designed to construct the Function Response Space (FRS) and obtain key effector proteins. The genetic knapsack algorithm was employed to select KGEC. The effectiveness and reliability of KGEC were evaluated at the functional level by using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, the effectiveness and potential mechanism of KGEC were confirmed by CCK-8, qPCR and Western blot. RESULTS: 940 effective proteins were obtained in FRS. KEGG pathways and GO terms enrichments analysis suggested that effective proteins well reflect liver cirrhosis characteristics at the functional level. 29 components of WLP were defined as KGEC, which covered 100% of the targets of the effective proteins. Additionally, the pathways enriched for the KGEC targets accounted for 83.33% of the shared genes between the targets and the pathogenic genes enrichment pathways. Three components scopoletin, caryophyllene oxide, and hydroxyzinamic acid from KGEC were selected for in vivo verification. The qPCR results demonstrated that all three components significantly reduced the mRNA levels of COL1A1 in TGF-ß1-induced liver cirrhosis model. Furthermore, the Western blot assay indicated that these components acted synergistically to target the NF-κB, AMPK/p38, cAMP, and PI3K/AKT pathways, thus inhibiting the progression of liver cirrhosis. CONCLUSION: In summary, we have developed a new model that reveals the key components and potential mechanisms of WLP for the treatment of liver cirrhosis. This model provides a reference for the secondary development of WLP and offers a methodological strategy for studying TCM formulas.

20.
PLoS One ; 19(3): e0300895, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38527035

RESUMO

Triterpenoid saponins and flavonoids have several pharmacological activities against P. tenuifolia. The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) and chalcone synthase (CHS) are the rate-limiting enzymes of triterpenoid saponin and flavonoid biosynthesis, respectively. In this study, HMGR and CHS genes were cloned from P. tenuifolia, and their bioinformatics analyses and tissue-specific expression were investigated. The results showed that the HMGR and CHS genes were successfully cloned, separately named the PtHMGR gene (NCBI accession: MK424118) and PtCHS gene (NCBI accession: MK424117). The PtHMGR gene is 2323 bp long, has an open reading frame (ORF) of 1782 bp, and encods 593 amino acids. The PtCHS gene is 1633 bp long with an ORF of 1170 bp, encoding 389 amino acids. PtHMGR and PtCHS were both hydrophobic, not signal peptides or secreted proteins, containing 10 conserved motifs. PtHMGR and PtCHS separately showed high homology with HMGR and CHS proteins from other species, and their secondary structures mainly included α-helix and random curl. The tertiary structure of PtHMGR was highly similarity to that the template 7ULI in RCSB PDB with 92.0% coverage rate. The HMG-CoA-binding domain of PtHMGR is located at 173-572 amino acid residues, including five bound sites. The tertiary structure of PtCHS showed high consistency with the template 1I86 in RCSB PDB with 100% coverage rate, contained malonyl CoA and 4-coumaroyl-CoA linkers. The expression of PtHMGR and PtCHS is tissue-specific. PtHMGR transcripts were mainly accumulated in roots, followed by leaves, and least in stems, and were significantly positively correlated with the contents of total saponin and tenuifolin. PtCHS was highly expressed in the stems, followed by the leaves, with low expression in the roots. PtCHS transcripts showed a significant positive correlation with total flavonoids content, however, they were significantly negatively correlated with the content of polygalaxanthone III (a type of flavonoids). This study provided insight for further revealing the roles of PtHMGR and PtCHS.


Assuntos
Aciltransferases , Polygala , Saponinas , Triterpenos , Polygala/metabolismo , Oxirredutases , Clonagem Molecular , Saponinas/genética , Triterpenos/metabolismo , Aminoácidos , Flavonoides , Filogenia
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