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1.
Intern Emerg Med ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886268

RESUMO

Previous studies have reported a high occurrence of contrast-associated acute kidney injury (CA-AKI) in myocardial infarction (MI) patients undergoing primary percutaneous coronary intervention (PCI). However, the data on CA-AKI in MI patients who underwent elective PCI are limited. To evaluate the incidence of CA-AKI in MI patients undergoing elective PCI. The data were sourced from the Iodixanol-AKI Registry of MI patients scheduled to undergo elective PCI in 8 medical centers from May 2020 to November 2021. The participants were divided into three groups: acute, prior, and multiple MI. The outcomes measured were CA-AKI and the composite endpoint of major adverse renal and cardiovascular events (MARCE). The incidence of CA-AKI was 4.46% (37/830) in the MI patients, 4.40% (7/159) in the acute MI patients, 4.41% (22/499) in the prior MI patients, and 4.65% (8/172) in the multiple MI patients. Of note, 36 patients (97.30%) at AKI stage 1, and only 1 patient at AKI stage 2. There was no difference in the incidence of CA-AKI (P = 0.991) among the three groups. Multivariate regression analysis revealed that the independent risk factors for CA-AKI were diabetes and an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. MARCE occurred in 3.4% (28/830) of the total patients and was not associated with either any subgroup of patients with MI or AKI. The incidence of CA-AKI was low and mainly limited to mildly impaired renal function in MI patients undergoing elective PCI.

2.
mSystems ; : e0026224, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38904378

RESUMO

Hypermucoviscosity (HMV) is a phenotype that is commonly associated with hypervirulence in Klebsiella pneumoniae. The factors that contribute to the emergence of HMV subpopulations remain unclear. In this study, eight K. pneumoniae strains were recovered from an inpatient who had been hospitalized for 20 days. Three of the isolates exhibited a non-HMV phenotype, which was concomitant with higher biofilm formation than the other five HMV isolates. All eight isolates were highly susceptible to serum killing, albeit HMV strains were remarkably more infective than non-HMV counterparts in a mouse model of infection. Whole genome sequencing (WGS) showed that the eight isolates belonged to the K57-ST412 lineage. Average nucleotide identity (FastANIb) analysis indicated that eight isolates share 99.96% to 99.99% similarity and were confirmed to be the same clone. Through comparative genomics analysis, 12 non-synonymous mutations were found among these isolates, eight of which in the non-HMV variants, including rmpA (c.285delG) and wbaP (c.1305T > A), which are assumed to be associated with the non-HMV phenotype. Mutations in manB (c.1318G > A), dmsB (c.577C > T) and tkt (c.1928C > A) occurred in HMV isolates only. RNA-Seq revealed transcripts of genes involved in energy metabolism, carbohydrate metabolism and membrane transport, including cysP, cydA, narK, tktA, pduQ, aceB, metN, and lsrA, to be significantly dysregulated in the non-HMV strains, suggesting a contribution to HMV phenotype development. This study suggests that co-occurrence of HMV and non-HMV phenotypes in the same clonal population may be mediated by mutational mechanisms as well as by certain genes involved in membrane transport and central metabolism. IMPORTANCE: K. pneumoniae with a hypermucoviscosity (HMV) phenotype is a community-acquired pathogen that is associated with increased invasiveness and pathogenicity, and underlying diseases are the most common comorbid risk factors inducing metastatic complications. HMV was earlier attributed to the overproduction of capsular polysaccharide, and more data point to the possibility of several causes contributing to this bacterial phenotype. Here, we describe a unique event in which the same clonal population showed both HMV and non-HMV characteristics. Studies have demonstrated that this process is influenced by mutational processes and genes related to transport and central metabolism. These findings provide fresh insight into the mechanisms behind co-occurrence of HMV and non-HMV phenotypes in monoclonal populations as well as potentially being critical in developing strategies to control the further spread of HMV K. pneumoniae.

4.
Int J Equity Health ; 23(1): 115, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840102

RESUMO

BACKGROUND: Since 2020, China has implemented an innovative payment method called Diagnosis-Intervention Packet (DIP) in 71 cities nationwide. This study aims to assess the impact of DIP on medical expenditure, efficiency, and quality for inpatients covered by the Urban Employee Basic Medical Insurance (UEBMI) and Urban and Rural Residents Basic Medical Insurance (URRBMI). It seeks to explore whether there are differences in these effects among inpatients of the two insurance types, thereby further understanding its implications for health equity. MATERIALS AND METHODS: We conducted interrupted time series analyses on outcome variables reflecting medical expenditure, efficiency, and quality for both UEBMI and URRBMI inpatients, based on a dataset comprising 621,125 inpatient reimbursement records spanning from June 2019 to June 2023 in City A. This dataset included 110,656 records for UEBMI inpatients and 510,469 records for URRBMI inpatients. RESULTS: After the reform, the average expenditure per hospital admission for UEBMI inpatients did not significantly differ but continued to follow an upward pattern. In contrast, for URRBMI inpatients, the trend shifted from increasing before the reform to decreasing after the reform, with a decline of 0.5%. The average length of stay for UEBMI showed no significant changes after the reform, whereas there was a noticeable downward trend in the average length of stay for URRBMI. The out-of-pocket expenditure (OOP) per hospital admission, 7-day all-cause readmission rate and 30-day all-cause readmission rate for both UEBMI and URRBMI inpatients showed a downward trend after the reform. CONCLUSION: The DIP reform implemented different upper limits on budgets based on the type of medical insurance, leading to varying post-treatment prices for UEBMI and URRBMI inpatients within the same DIP group. After the DIP reform, the average expenditure per hospital admission and the average length of stay remained unchanged for UEBMI inpatients, whereas URRBMI inpatients experienced a decrease. This trend has sparked concerns about hospitals potentially favoring UEBMI inpatients. Encouragingly, both UEBMI and URRBMI inpatients have seen positive outcomes in terms of alleviating patient financial burdens and enhancing the quality of care.


Assuntos
Gastos em Saúde , Pacientes Internados , Seguro Saúde , Humanos , Gastos em Saúde/estatística & dados numéricos , China , Seguro Saúde/economia , Pacientes Internados/estatística & dados numéricos , Qualidade da Assistência à Saúde/normas , Projetos Piloto , Análise de Séries Temporais Interrompida , Masculino , Feminino
5.
Comput Biol Med ; 178: 108775, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38941901

RESUMO

BACKGROUND: CDD-2103 is an herbal prescription used to treat ulcerative colitis (UC). This study aimed to uncover its mechanism by integrating metabolomics and serum-feces pharmacochemistry-based network pharmacology. METHODS: A DSS-induced chronic colitis mice model was used to evaluate the anti-colitis effect of CDD-2103. Serum and feces metabolomics were conducted to identify differential metabolites and pathways. In the serum-feces pharmacochemistry study, biological samples were collected from rats treated with CDD-2103. Then, network pharmacology was utilized to predict the targets of the identified compounds. Critical genes were extracted through the above-integrated analysis. The interactions between targets, CDD-2103, and its compounds were validated through molecular docking, immunoblotting, and enzyme activity assays. RESULTS: CDD-2103 alleviated ulcerous symptoms and colonic injuries in colitis mice. Metabolomics study identified differential metabolites associated with tryptophan, glycerophospholipid, and linoleic acid metabolisms. The serum-feces pharmacochemistry study revealed twenty-three compounds, which were subjected to network pharmacology analysis. Integration of these results identified three key targets (AHR, PLA2, and PTGS2). Molecular docking showed strong affinities between the compounds and targets. PTGS2 was identified as a hub gene targeted by most CDD-2103 compounds. Immunoblotting and enzyme activity assays provided further evidence that CDD-2103 alleviates UC, potentially through its inhibitory effect on cyclooxygenase-2 (COX-2, encoded by PTGS2), with alkaloids and curcuminoids speculated as crucial anti-inflammatory compounds. CONCLUSION: This integrated strategy reveals the mechanism of CDD-2103 and provides insights for developing herbal medicine-based therapies for UC.

6.
Redox Biol ; 74: 103229, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38870781

RESUMO

BACKGROUND: Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of endothelial Nrf2 in atherogenesis has yet to be defined. In addition, how endothelial Nrf2 is activated and whether Nrf2 can be targeted for the prevention and treatment of atherosclerosis is not explored. METHODS: RNA-sequencing and single-cell RNA sequencing analysis of mouse atherosclerotic aortas were used to identify the differentially expressed genes. In vivo endothelial cell (EC)-specific activation of Nrf2 was achieved by injecting adeno-associated viruses into ApoE-/- mice, while EC-specific knockdown of Nrf2 was generated in Cdh5CreCas9floxed-stopApoE-/- mice. RESULTS: Endothelial inflammation appeared as early as on day 3 after feeding of a high cholesterol diet (HCD) in ApoE-/- mice, as reflected by mRNA levels, immunostaining and global mRNA profiling, while the immunosignal of the end-product of lipid peroxidation (LPO), 4-hydroxynonenal (4-HNE), started to increase on day 10. TNF-α, 4-HNE, and erastin (LPO inducer), activated Nrf2 signaling in human ECs by increasing the mRNA and protein expression of Nrf2 target genes. Knockdown of endothelial Nrf2 resulted in augmented endothelial inflammation and LPO, and accelerated atherosclerosis in Cdh5CreCas9floxed-stopApoE-/- mice. By contrast, both EC-specific and pharmacological activation of Nrf2 inhibited endothelial inflammation, LPO, and atherogenesis. CONCLUSIONS: Upon HCD feeding in ApoE-/- mice, endothelial inflammation is an earliest event, followed by the appearance of LPO. EC-specific activation of Nrf2 inhibits atherosclerosis while EC-specific knockdown of Nrf2 results in the opposite effect. Pharmacological activators of endothelial Nrf2 may represent a novel therapeutic strategy for the treatment of atherosclerosis.


Assuntos
Apolipoproteínas E , Aterosclerose , Células Endoteliais , Inflamação , Peroxidação de Lipídeos , Fator 2 Relacionado a NF-E2 , Animais , Humanos , Masculino , Camundongos , Apolipoproteínas E/genética , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Aterosclerose/genética , Aterosclerose/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Inflamação/metabolismo , Inflamação/genética , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo
8.
Mediators Inflamm ; 2024: 7524314, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725539

RESUMO

Objective: Microfold cells (M cells) are specific intestinal epithelial cells for monitoring and transcytosis of antigens, microorganisms, and pathogens in the intestine. However, the mechanism for M-cell development remained elusive. Materials and Methods: Real-time polymerase chain reaction, immunofluorescence, and western blotting were performed to analyze the effect of sorbitol-regulated M-cell differentiation in vivo and in vitro, and luciferase and chromatin Immunoprecipitation were used to reveal the mechanism through which sorbitol-modulated M-cell differentiation. Results: Herein, in comparison to the mannitol group (control group), we found that intestinal M-cell development was inhibited in response to sorbitol treatment as evidenced by impaired enteroids accompanying with decreased early differentiation marker Annexin 5, Marcksl1, Spib, sox8, and mature M-cell marker glycoprotein 2 expression, which was attributed to downregulation of receptor activator of nuclear factor kappa-В ligand (RANKL) expression in vivo and in vitro. Mechanically, in the M-cell model, sorbitol stimulation caused a significant upregulation of phosphodiesterase 4 (PDE4) phosphorylation, leading to decreased protein kinase A (PKA)/cAMP-response element binding protein (CREB) activation, which further resulted in CREB retention in cytosolic and attenuated CREB binds to RANKL promoter to inhibit RANKL expression. Interestingly, endogenous PKA interacted with CREB, and this interaction was destroyed by sorbitol stimulation. Most importantly, inhibition of PDE4 by dipyridamole could rescue the inhibitory effect of sorbitol on intestinal enteroids and M-cell differentiation and mature in vivo and in vitro. Conclusion: These findings suggested that sorbitol suppressed intestinal enteroids and M-cell differentiation and matured through PDE4-mediated RANKL expression; targeting to inhibit PDE4 was sufficient to induce M-cell development.


Assuntos
Diferenciação Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Ligante RANK , Sorbitol , Sorbitol/farmacologia , Ligante RANK/metabolismo , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Diferenciação Celular/efeitos dos fármacos , Camundongos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Mucosa Intestinal/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Células M
9.
Int J Pharm ; 658: 124194, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38703929

RESUMO

As a vital energy source for cellular metabolism and tissue survival, the mitochondrion can undergo morphological or positional change and even shuttle between cells in response to various stimuli and energy demands. Multiple human diseases are originated from mitochondrial dysfunction, but the curative succusses by traditional treatments are limited. Mitochondrial transplantation therapy (MTT) is an innovative therapeutic approach that is to deliver the healthy mitochondria either derived from normal cells or reassembled through synthetic biology into the cells and tissues suffering from mitochondrial damages and finally replace their defective mitochondria and restore their function. MTT has already been under investigation in clinical trials for cardiac ischemia-reperfusion injury and given an encouraging performance in animal models of numerous fatal critical diseases including central nervous system disorders, cardiovascular diseases, inflammatory conditions, cancer, renal injury, and pulmonary damage. This review article summarizes the mechanisms and strategies of mitochondrial transfer and the MTT application for types of mitochondrial diseases, and discusses the potential challenge in MTT clinical application, aiming to exhibit the good therapeutic prospects of MTTs in clinics.


Assuntos
Mitocôndrias , Doenças Mitocondriais , Humanos , Animais , Doenças Mitocondriais/terapia , Mitocôndrias/metabolismo , Mitocôndrias/transplante , Terapia de Substituição Mitocondrial/métodos
10.
J Med Chem ; 67(11): 8730-8756, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38817193

RESUMO

The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes "anchor" interactions with the active site zinc ion and catalytic triad. Structure-guided design and optimization led to a series of new benzimidazole derivatives exhibiting nanomolar inhibition for both sQC and gQC. In a MPTP-induced Parkinson's disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment.


Assuntos
Aminoaciltransferases , Benzimidazóis , Inibidores Enzimáticos , Animais , Aminoaciltransferases/antagonistas & inibidores , Aminoaciltransferases/metabolismo , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/síntese química , Cristalografia por Raios X , Camundongos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Relação Estrutura-Atividade , Modelos Animais de Doenças , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Descoberta de Drogas , Masculino , Modelos Moleculares
13.
Sci Rep ; 14(1): 12234, 2024 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-38806556

RESUMO

Prolyl 4-hydroxylases (P4Hs) are a family of key modifying enzymes in collagen synthesis. P4Hs have been confirmed to be closely associated with tumor occurrence and development. However, the expression of P4Hs in head and neck cancer (HNSC) as well as its relationship with prognosis and tumor immunity infiltration has not yet been analyzed. We investigated the transcriptional expression, survival data, and immune infiltration of P4Hs in patients with HNSC from multiple databases. P4H1-3 expression was significantly higher in HNSC tumor tissues than in normal tissues. Moreover, P4HA1 and P4HA2 were associated with tumor stage, patient prognosis, and immune cell infiltration. P4HA3 was related to patient prognosis and immune cell infiltration. Correlation experiments confirmed that P4HA1 may serve as a prognosis biomarker and plays a role in the progression of nasopharyngeal carcinoma. These findings suggest that P4HA1-3 may be a novel biomarker for the prognosis and treatment of HNSC, which is expected to support the development of new therapies for patients with head and neck tumors and improve patient outcomes.


Assuntos
Biomarcadores Tumorais , Neoplasias de Cabeça e Pescoço , Imunoterapia , Pró-Colágeno-Prolina Dioxigenase , Humanos , Biomarcadores Tumorais/metabolismo , Prognóstico , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Imunoterapia/métodos , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Pró-Colágeno-Prolina Dioxigenase/genética , Regulação Neoplásica da Expressão Gênica , Feminino , Masculino , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/mortalidade
14.
Phytomedicine ; 129: 155706, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38723528

RESUMO

BACKGROUND: The pathogenesis of lower respiratory tract infections (LRTIs) has been demonstrated to be strongly associated with dysbiosis of respiratory microbiota. Scutellaria baicalensis, a traditional Chinese medicine, is widely used to treat respiratory infections. However, whether the therapeutic effect of S. baicalensis on LRTIs depends upon respiratory microbiota regulation is largely unclear. PURPOSE: To investigate the potential effect and mechanism of S. baicalensis on the respiratory microbiota of LRTI mice. METHODS: A mouse model of LRTI was established using Klebsiella pneumoniae or Streptococcus pneumoniae. Antibiotic treatment was administered, and transplantation of respiratory microbiota was performed to deplete the respiratory microbiota of mice and recover the destroyed microbial community, respectively. High-performance liquid chromatography (HPLC) was used to determine and quantify the chemical components of S. baicalensis water decoction (SBWD). Pathological changes in lung tissues and the expressions of serum inflammatory cytokines, including interleukin-17A (IL-17A), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), were determined by hematoxylin and eosin (H&E) staining and enzyme-linked immunosorbent assay (ELISA), respectively. Quantitative real-time PCR (qRT-PCR) analysis was performed to detect the mRNA expression of GM-CSF. Metagenomic sequencing was performed to evaluate the effect of SBWD on the composition and function of the respiratory microbiota in LRTI mice. RESULTS: Seven main components, including scutellarin, baicalin, oroxylin A-7-O-ß-d-glucuronide, wogonoside, baicalein, wogonin, and oroxylin A, were identified and their levels in SBWD were quantified. SBWD ameliorated pulmonary pathological injury and inflammatory responses in K. pneumoniae and S. pneumoniae-induced LRTI mice, as evidenced by the dose-dependent reductions in the levels of serum inflammatory cytokines, IL-6 and TNF-α. SBWD may exert a bidirectional regulatory effect on the host innate immune responses in LRTI mice and regulate the expressions of IL-17A and GM-CSF in a microbiota-dependent manner. K. pneumoniae infection but not S. pneumoniae infection led to dysbiosis in the respiratory microbiota, evident through disturbances in the taxonomic composition characterized by bacterial enrichment, including Proteobacteria, Enterobacteriaceae, and Klebsiella. K. pneumoniae and S. pneumoniae infection altered the bacterial functional profile of the respiratory microbiota, as indicated by increases in lipopolysaccharide biosynthesis, metabolic pathways, and carbohydrate metabolism. SBWD had a certain trend on the regulation of compositional disorders in the respiratory flora and modulated partial microbial functions embracing carbohydrate metabolism in K. pneumoniae-induced LRTI mice. CONCLUSION: SBWD may exert an anti-infection effect on LRTI by targeting IL-17A and GM-CSF through respiratory microbiota regulation. The mechanism of S. baicalensis action on respiratory microbiota in LRTI treatment merits further investigation.


Assuntos
Pulmão , Scutellaria baicalensis , Animais , Scutellaria baicalensis/química , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Camundongos , Klebsiella pneumoniae/efeitos dos fármacos , Microbiota/efeitos dos fármacos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Extratos Vegetais/farmacologia , Masculino , Streptococcus pneumoniae/efeitos dos fármacos , Citocinas/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/farmacologia , Camundongos Endogâmicos C57BL , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Flavonoides/farmacologia , Infecções Pneumocócicas/tratamento farmacológico , Infecções Pneumocócicas/microbiologia , Apigenina/farmacologia , Disbiose/tratamento farmacológico , Disbiose/microbiologia
15.
Physiol Plant ; 176(3): e14355, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38783519

RESUMO

Fusarium solani exerts detrimental effects on plant growth, which is one of the reasons for the incidence of apple replant disease. Arbuscular mycorrhizal fungi (AMF) enhance plant resistance to Fusarium wilt; however, the mechanism remains poorly understood. Therefore, the present study investigated the symbiosis between apple and AMF and explored the physiology, especially nitrate metabolism, antioxidant defense, and photosynthetic performance, when infected by F. solani. The experiment was carried out with four treatments, namely -AMF - F. solani, -AMF + F. solani, -AMF + F. solani, and + AMF + F. solani. In this study, the -AMF + F. solani treatment increased the activity of enzymes associated with nitrogen metabolism, such as the nitrate and nitrite reductases, in the apple root system. The +AMF + F. solani treatment showed higher antioxidant enzyme activities than the -AMF + F. solani by F. solani infection. The apple seedlings of the +AMF + F. solani treatment decreased reactive oxygen accumulation and reduced the oxidative damages triggered by F. solani infection. The improvement in antioxidant capacity due to the +AMF + F. solani treatment was closely associated with the upregulation of genes related to the antioxidant system. The F. solani infection greatly damaged the photosynthetic process, while the +AMF + F. solani treatment significantly improved it compared to the -AMF + F. solani treatment. In conclusion, the study demonstrated that the apple-AMF symbiosis plays an active role in regulating the resistance against F. solani infection by enhancing defense response and nitrogen metabolism.


Assuntos
Fusarium , Malus , Micorrizas , Nitrogênio , Doenças das Plantas , Simbiose , Fusarium/fisiologia , Fusarium/patogenicidade , Micorrizas/fisiologia , Nitrogênio/metabolismo , Malus/microbiologia , Malus/genética , Malus/metabolismo , Malus/fisiologia , Malus/imunologia , Doenças das Plantas/microbiologia , Doenças das Plantas/imunologia , Resistência à Doença/genética , Antioxidantes/metabolismo , Raízes de Plantas/microbiologia , Raízes de Plantas/genética , Raízes de Plantas/fisiologia , Raízes de Plantas/metabolismo , Fotossíntese , Plântula/microbiologia , Plântula/fisiologia , Plântula/genética
16.
World J Stem Cells ; 16(5): 538-550, 2024 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-38817334

RESUMO

BACKGROUND: Thrombocytopenia 2, an autosomal dominant inherited disease characterized by moderate thrombocytopenia, predisposition to myeloid malignancies and normal platelet size and function, can be caused by 5'-untranslated region (UTR) point mutations in ankyrin repeat domain containing 26 (ANKRD26). Runt related transcription factor 1 (RUNX1) and friend leukemia integration 1 (FLI1) have been identified as negative regulators of ANKRD26. However, the positive regulators of ANKRD26 are still unknown. AIM: To prove the positive regulatory effect of GATA binding protein 2 (GATA2) on ANKRD26 transcription. METHODS: Human induced pluripotent stem cells derived from bone marrow (hiPSC-BM) and urothelium (hiPSC-U) were used to examine the ANKRD26 expression pattern in the early stage of differentiation. Then, transcriptome sequencing of these iPSCs and three public transcription factor (TF) databases (Cistrome DB, animal TFDB and ENCODE) were used to identify potential TF candidates for ANKRD26. Furthermore, overexpression and dual-luciferase reporter experiments were used to verify the regulatory effect of the candidate TFs on ANKRD26. Moreover, using the GENT2 platform, we analyzed the relationship between ANKRD26 expression and overall survival in cancer patients. RESULTS: In hiPSC-BMs and hiPSC-Us, we found that the transcription levels of ANKRD26 varied in the absence of RUNX1 and FLI1. We sequenced hiPSC-BM and hiPSC-U and identified 68 candidate TFs for ANKRD26. Together with three public TF databases, we found that GATA2 was the only candidate gene that could positively regulate ANKRD26. Using dual-luciferase reporter experiments, we showed that GATA2 directly binds to the 5'-UTR of ANKRD26 and promotes its transcription. There are two identified binding sites of GATA2 that are located 2 kb upstream of the TSS of ANKRD26. In addition, we discovered that high ANKRD26 expression is always related to a more favorable prognosis in breast and lung cancer patients. CONCLUSION: We first discovered that the transcription factor GATA2 plays a positive role in ANKRD26 transcription and identified its precise binding sites at the promoter region, and we revealed the importance of ANKRD26 in many tissue-derived cancers.

17.
PLoS One ; 19(5): e0300185, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38820439

RESUMO

Based on the background of urbanization in China, we used the dynamic spatial panel Durbin model to study the driving mechanism of ozone pollution empirically. We also analyzed the spatial distribution of ozone driving factors using the GTWR. The results show that: i) The average annual increase of ozone concentration in ambient air in China from 2015 to 2019 was 1.68µg/m3, and 8.39µg/m3 elevated the year 2019 compared with 2015. ii) The Moran's I value of ozone in ambient air was 0.027 in 2015 and 0.209 in 2019, showing the spatial distribution characteristics of "east heavy and west light" and "south low and north high". iii) Per capita GDP industrial structure, population density, land expansion, and urbanization rate have significant spillover effects on ozone concentration, and the regional spillover effect is greater than the local effect. R&D intensity and education level have a significant negative impact on ozone concentration. iv) There is a decreasing trend in the inhibitory effect of educational attainment and R&D intensity on ozone concentration, and an increasing trend in the promotional effect of population urbanization rate, land expansion, and economic development on ozone concentration. Empirical results suggest a twofold policy meaning: i) to explore the causes behind the distribution of ozone from the new perspective of urbanization, and to further the atmospheric environmental protection system and ii) to eliminate the adverse impacts of ozone pollution on nature and harmonious social development.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Ozônio , Urbanização , Ozônio/análise , China , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Poluição do Ar/efeitos adversos , Humanos , Análise Espaço-Temporal , Monitoramento Ambiental
18.
J Ethnopharmacol ; 331: 118306, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38723920

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Invigorating blood circulation to remove blood stasis is a primary strategy in TCM for treating vascular dementia (VaD). Danggui-Shaoyao San (DSS), as a traditional prescription for neuroprotective activity, has been proved to be effective in VaD treatment. However, its precise molecular mechanisms remain incompletely understood. AIM OF THE STUDY: The specific mechanism underlying the therapeutic effects of DSS on VaD was explored by employing network pharmacology as well as in vivo and in viro experiment validation. MATERIALS AND METHODS: We downloaded components of DSS from the BATMAN-TCM database for target prediction. The intersection between the components of DSS and targets, PPI network, as well as GO and KEGG enrichment analysis were then performed. Subsequently, the potential mechanism of DSS predicted by network pharmacology was assessed and validated through VaD rat model induced by 2VO operation and CoCl2-treated PC12 cells. Briefly, the DSS extract were first quantified by HPLC. Secondly, the effect of DSS on VaD was studied using MWM test, HE staining and TUNEL assay. Finally, the molecular mechanism of DSS against VaD was validated by Western blot and RT-QPCR experiments. RESULTS: Through network analysis, 137 active ingredients were obtained from DSS, and 67 potential targets associated with DSS and VaD were identified. GO and KEGG analysis indicated that the action of DSS on VaD primarily involves hypoxic terms and HIF-1 pathway. In vivo validation, cognitive impairment and neuron mortality were markedly ameliorated by DSS. Additionally, DSS significantly reduced the expression of proteins related to synaptic plasticity and neuron apoptosis including PSD-95, SYP, Caspase-3 and BCL-2. Mechanistically, we confirmed DSS positively modulated the expression of HIF-1α and its downstream proteins including EPO, p-EPOR, STAT5, EPOR, and AKT1 in the hippocampus of VaD rats as well as CoCl2-induced PC12 cells. HIF-1 inhibitor YC-1 significantly diminished the protection of DSS on CoCl2-induced PC12 cell damage, with decreased HIF-1α, EPO, EPOR expression. CONCLUSION: Our results initially demonstrated DSS could exert neuroprotective effects in VaD. The pharmacological mechanism of DSS may be related to its positive regulation on HIF-1α/EPO pathway.


Assuntos
Disfunção Cognitiva , Demência Vascular , Medicamentos de Ervas Chinesas , Eritropoetina , Subunidade alfa do Fator 1 Induzível por Hipóxia , Fármacos Neuroprotetores , Ratos Sprague-Dawley , Animais , Medicamentos de Ervas Chinesas/farmacologia , Demência Vascular/tratamento farmacológico , Demência Vascular/metabolismo , Ratos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células PC12 , Masculino , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Fármacos Neuroprotetores/farmacologia , Eritropoetina/farmacologia , Apoptose/efeitos dos fármacos , Farmacologia em Rede , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Cobalto
19.
Int J Antimicrob Agents ; 64(2): 107221, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38810938

RESUMO

Phage therapy has shown great promise in the treatment of bacterial infections. However, the effectiveness of phage therapy is compromised by the inevitable emergence of phage-resistant strains. In this study, a phage-resistant carbapenem-resistant Klebsiella pneumoniae strain SWKP1711R, derived from parental carbapenem-resistant K. pneumoniae strain SWKP1711 was identified. The mechanism of bacteriophage resistance in SWKP1711R was investigated and the molecular determinants causing altered growth characteristics, antibiotic resistance, and virulence of SWKP1711R were tested. Compared to SWKP1711, SWKP1711R showed slower growth, smaller colonies, filamentous cells visible under the microscope, reduced production of capsular polysaccharide (CPS) and lipopolysaccharide, and reduced resistance to various antibiotics accompanied by reduced virulence. Adsorption experiments showed that phage vB_kpnM_17-11 lost the ability to adsorb onto SWKP1711R, and the adsorption receptor was identified to be bacterial surface polysaccharides. Genetic variation analysis revealed that, compared to the parental strain, SWKP1711R had only one thymine deletion at position 78 of the open reading frame of the lpcA gene, resulting in a frameshift mutation that caused alteration of the bacterial surface polysaccharide and inhibition of phage adsorption, ultimately leading to phage resistance. Transcriptome analysis and quantitative reverse transcriptase PCR revealed that genes encoding lipopolysaccharide synthesis, ompK35, blaTEM-1, and type II and Hha-TomB toxin-antitoxin systems, were all downregulated in SWKP1711R. Taken together, the evidence presented here indicates that the phenotypic alterations and phage resistance displayed by the mutant may be related to the frameshift mutation of lpcA and altered gene expression. While evolution of phage resistance remains an issue, our study suggests that the reduced antibiotic resistance and virulence of phage-resistant strain derivatives might be beneficial in alleviating the burden caused by multidrug-resistant bacteria.

20.
Heliyon ; 10(9): e30511, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38765139

RESUMO

Objective: To prospectively determine the median effective dose (ED50) of propofol for inhibiting a response to laryngeal mask airway (LMA) insertion when combined with different doses of esketamine in female patients. Methods: A total of 58 female patients (aged 20-60 years, ASAⅠ-Ⅱ) scheduled for elective hysteroscopy were enrolled and randomly divided into 2 groups, one of which was administered 0.2 mg/kg of esketamine (K1 group, n = 28) and the other 0.3 mg/kg of esketamine (K2 group, n = 30). The 2 groups received the corresponding doses of esketamine intravenously, followed by an intravenous injection of propofol (injection time was 30 s). The initial dose of propofol was 2 mg/kg, and the dose ratio of propofol in the adjacent patients was 0.9. If a positive reaction occurred due to LMA insertion, the dose ratio in the next patient was increased by 1 gradient; if not, the dose ratio was decreased by 1 gradient. The ED50, 95 % effective dose (ED95) and 95 % confidence interval (CI) of propofol for inhibiting a response to LMA insertion in the 2 esketamine groups were calculated using probit analysis. Results: The ED50 of propofol for inhibiting a response to LMA insertion in female patients was 1.95 mg/kg (95 % CI, 1.82-2.08 mg/kg) in the K1 group and 1.60 mg/kg (95 % CI, 1.18-1.83 mg/kg) in the K2 group. The ED95 of propofol for inhibiting a response to LMA insertion in female patients was 2.22 mg/kg (95 % CI, 2.09-2.86 mg/kg) in the K1 group and 2.15 mg/kg (95 % CI, 1.88-3.09 mg/kg) in the K2 group. Conclusion: Propofol combined with 0.3 mg/kg of esketamine has low ED50 and ED95 effective doses for inhibiting an LMA insertion response in female patients undergoing hysteroscopy and surgery. There were no significant adverse effects, but the additional dose of propofol and airway pressure were significantly higher than those in the group administered 0.2 mg/kg of esketamine. Based on the results, we recommend the combination of propofol with 0.2 mg/kg esketamine for optimal conditions during LMA insertion in women undergoing hysteroscopy.

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