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1.
Biomed Pharmacother ; 176: 116844, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38823279

RESUMO

In contemporary times, tumors have emerged as the primary cause of mortality in the global population. Ongoing research has shed light on the significance of neurotransmitters in the regulation of tumors. It has been established that neurotransmitters play a pivotal role in tumor cell angiogenesis by triggering the transformation of stromal cells into tumor cells, modulating receptors on tumor stem cells, and even inducing immunosuppression. These actions ultimately foster the proliferation and metastasis of tumor cells. Several major neurotransmitters have been found to exert modulatory effects on tumor cells, including the ability to restrict emergency hematopoiesis and bind to receptors on the postsynaptic membrane, thereby inhibiting malignant progression. The abnormal secretion of neurotransmitters is closely associated with tumor progression, suggesting that focusing on neurotransmitters may yield unexpected breakthroughs in tumor therapy. This article presents an analysis and outlook on the potential of targeting neurotransmitters in tumor therapy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38855856

RESUMO

Thyroid hormones (THs) play important roles in growth, development, morphogenesis, reproduction, and so on. They are mainly meditated by binding to thyroid hormone receptors (TRs) in vertebrates. As important members of the nuclear receptor superfamily, TRs and their ligands are involved in many biological processes. To investigate the potential roles of TRs in the gonadal differentiation and sex change, we cloned and characterized the TRs genes in protogynous rice field eel (Monopterus albus). In this study, three types of TRs were obtained, which were TRαA, TRαB and TRß, encoding preproproteins of 336-, 409- and 415-amino acids, respectively. Multiple alignments of the three putative TRs protein sequences showed they had a higher similarity. Tissue expression analysis showed that TRαA mainly expressed in the gonad, while TRαB and TRß in the brain. During female-to-male sex reversal, the expression levels of all the three TRs showed a similar trend of increase followed by a decrease in the gonad. Intraperitoneal injection of triiodothyronine (T3) stimulated the expression of TRαA and TRαB, while it had no significant change on the expression of TRß in the ovary. Gonadotropin-releasing hormone analogue (GnRHa) injection also significantly upregulated the expression levels of TRαA and TRαB after 6 h, while it had no significant effect on TRß. These results demonstrated that TRs were involved in the gonadal differentiation and sex reversal, and TRα may play more important roles than TRß in reproduction by the regulation of GnRHa in rice field eel.

3.
Phytomedicine ; 131: 155784, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38878325

RESUMO

BACKGROUND: Currently, SARS-CoV-2 has not disappeared and continues to prevail worldwide, with the ongoing risk of mutations and the potential for severe COVID-19. The impairment of monocyte mitochondrial function caused by SARS-CoV-2, leading to a metabolic and immune dysregulation, is a crucial factor in the development of severe COVID-19. PURPOSE: Discover effective phytomedicines based on mitochondrial-related biomarkers in severe SARS-CoV-2 infection. METHODS: Firstly, differential gene analysis and gene set enrichment analysis (GSEA) were conducted on monocytes datasets to identify genes and pathways distinguishing severe patients from uninfected individuals. Then, GO and KEGG enrichment analysis on the differentially expressed genes (DEGs) obtained. Take the DEGs and intersect them with the MitoCarta 3.0 gene set to obtain the differentially expressed mitochondrial-related genes (DE-MRGs). Subsequently, machine learning algorithms were employed to screen potential mitochondrial dysfunction biomarkers for severe COVID-19 based on score values. ROC curves were then plotted to assess the distinguish capability of the biomarkers, followed by validation using two additional independent datasets. Next, the effects of the identified biomarkers on metabolic pathways and immune cells were explored through Gene Set Variation Analysis (GSVA) and CIBERSORT. Finally, potential nature products for severe COVID-19 were screened from the expression profile dataset based on dysregulated mitochondrial-related genes, followed by in vitro experimental validation. RESULTS: There are 1812 DEGs and 17 dysregulated mitochondrial processes between severe COVID-19 patients and uninfected individuals. A total of 77 DE-MRGs were identified, and the potential biomarkers were identified as RECQL4, PYCR1, PIF1, POLQ, and GLDC. In both the training and validation sets, the area under the ROC curve (AUC) for these five biomarkers was greater than 0.9. And they did not show significant changes in mild to moderate patients (p > 0.05), indicating their ability to effectively distinguish severe COVID-19. These biomarkers exhibit a highly significant correlation with the dysregulated metabolic processes (p < 0.05) and immune cell imbalance (p < 0.05) in severe patients, as demonstrated by GSVA and CIBERSORT algorithms. Curcumin has the highest score in the predictive model based on transcriptomic data from 496 natural compounds (p = 0.02; ES = 0.90). Pre-treatment with curcumin for 8 h has been shown to alleviate mitochondrial membrane potential damage caused by the SARS-CoV-2 S1 protein (p < 0.05) and reduce elevated levels of reactive oxygen species (ROS) (p < 0.01). CONCLUSION: The results of this study indicate a significant correlation between severe SARS-CoV-2 infection and mitochondrial dysfunction. The proposed mitochondrial dysfunction biomarkers identified in this study are associated with the disease progression, metabolic and immune changes in severe SARS-CoV-2 infected patients. Curcumin has a potential role in preventing severe COVID-19 by protecting mitochondrial function. Our findings provide new strategies for predicting the prognosis and enabling early intervention in SARS-CoV-2 infection.

4.
Biotechnol Bioeng ; 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877732

RESUMO

Natural hydrogels are widely employed in tissue engineering and have excellent biodegradability and biocompatibility. Unfortunately, the utilization of such hydrogels in the field of three-dimensional (3D) printing nasal cartilage is constrained by their subpar mechanical characteristics. In this study, we provide a multicrosslinked network hybrid ink made of photocurable gelatin, hyaluronic acid, and acrylamide (AM). The ink may be processed into intricate 3D hydrogel structures with good biocompatibility and high stiffness properties using 3D printing technology based on digital light processing (DLP), including intricate shapes resembling noses. By varying the AM content, the mechanical behavior and biocompatibility of the hydrogels can be adjusted. In comparison to the gelatin methacryloyl (GelMA)/hyaluronic acid methacryloyl (HAMA) hydrogel, adding AM considerably enhances the hydrogel's mechanical properties while also enhancing printing quality. Meanwhile, the biocompatibility of the multicrosslinked network hydrogels and the development of cartilage were assessed using neonatal Sprague-Dawley (SD) rat chondrocytes (CChons). Cells sown on the hydrogels considerably multiplied after 7 days of culture and kept up the expression of particular proteins. Together, our findings point to GelMA/HAMA/polyacrylamide (PAM) hydrogel as a potential material for nasal cartilage restoration. The photocuring multicrosslinked network ink composed of appropriate proportions of GelMA/HAMA/PAM is very suitable for DLP 3D printing and will play an important role in the construction of nasal cartilage, ear cartilage, articular cartilage, and other tissues and organs in the future. Notably, previous studies have not explored the application of 3D-printed GelMA/HAMA/PAM hydrogels for nasal cartilage regeneration.

5.
Clin Breast Cancer ; 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38871576

RESUMO

BACKGROUND: Mucinous breast carcinoma (MBC) is often misdiagnosed as fibroadenoma (FA),which can lead to inappropriate or delayed treatments. This study aimed to establish an efficient ultrasound (US)-based diagnostic model to distinguish MBC subtypes from FAs. METHODS: Between January 2017 and February 2024, 240 lesions were enrolled, comprising 65 cases of pure mucinous breast carcinoma (PMBC), 47 cases of mixed mucinous breast carcinoma (MMBC), and 128 cases of FAs. Ten US feature variables underwent principal component analysis (PCA). Models were constructed based on components explaining over 75% of the total variation, with varimax rotation applied for interpretability. Comprehensive models were developed to distinguish PMBCs and MMBCs from FAs. RESULTS: Six principal components were selected, achieving a cumulative contribution rate of 77.46% for PMBCs vs. FAs and 78.62% for MMBCs vs. FAs. The principal component of cystic-solid composition and posterior acoustic enhancement demonstrated the highest diagnostic value for distinguishing PMBCs from FAs (AUC: 0.86, ACC: 80.31%). Features including vascularization, irregular shape, ill-defined border, and larger size exhibited the highest diagnostic value for distinguishing MMBCs from FAs (AUC: 0.90, ACC: 87.43%). The comprehensive models showed excellent clinical value in distinguishing PMBCs (AUC = 0.86, SEN = 86.15%, SPE = 73.44%, ACC = 77.72%) and MMBCs (AUC = 0.92, SEN = 80.85%, SPE = 95.31%, ACC = 91.43%) from FAs. CONCLUSION: This diagnostic model holds promise for effectively distinguishing PMBCs and MMBCs from FAs, assisting radiologists in mitigating diagnostic biases and enhancing diagnostic efficiency.

6.
Sci Rep ; 14(1): 13572, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866897

RESUMO

Settlement of roads or railway caused by traffic loading has a serious effect on the safety and service performance of transport infrastructures constructed on soft marine clay. While simple cyclic triaxial test with constant confining pressure (CCP) were used in most of the previous studies, a series of cyclic triaxial tests with variable confining pressure (VCP) were carried out on normally consolidated (NC) and overconsolidated (OC) reconstituted Wenzhou soft clay in this paper to study the undrained behavior of soft marine clay due to surcharge preloading as well as cyclic traffic loading. VCP test is able to approximate the complicated stress path than CCP test caused by traffic loading. The test results indicate that NC specimens show significantly different pore water pressure (u) evolution compared with OC specimens. However, a change in the overconsolidation ratio (OCR) of OC specimens does not have a significant influence on variation of u with identical cyclic stress ratio (CSR) and total stress path (η). The slope of the effective stress path is dependent on the total stress path under which the specimen was loaded cyclically, regardless of the OCR and whether variable confining pressure was applied. The slope of the effective stress path is broadly in line with the slope of corresponding total stress path. In addition, the development of permanent axial strain (εpa) due to one-way cyclic loading was shown to depend significantly on the values of η and OCR. Both the variable confining pressure and OCR limited the strain accumulation of saturated marine clay under undrained one-way cyclic loading. Finally, the effects of η and OCR on the magnitude of εpa after 1000 loading cycles are quantified and incorporated in a power law function for the permanent deformation prediction of soft marine clay due to traffic loading.

7.
Chem Res Toxicol ; 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38837948

RESUMO

Hydroquinone(HQ) is a widely used industrial raw material and is a topical lightening product found in over-the-counter products. However, inappropriate exposure to HQ can pose certain health hazards. This study aims to explore the mechanisms of DNA damage and cell apoptosis caused by HQ, with a focus on whether HQ activates the nuclear factor-κB (NF-κB) pathway to participate in this process and to investigate the correlation between the NF-κB pathway activation and poly(ADP-ribose) polymerase 1(PARP1). Through various experimental techniques, such as DNA damage detection, cell apoptosis assessment, cell survival rate analysis, immunofluorescence, and nuclear-cytoplasmic separation, the cytotoxic effects of HQ were verified, and the activation of the NF-κB pathway was observed. Simultaneously, the relationship between the NF-κB pathway and PARP1 was verified by shRNA interference experiments. The results showed that HQ could significantly activate the NF-κB pathway, leading to a decreased cell survival rate, increased DNA damage, and cell apoptosis. Inhibiting the NF-κB pathway could significantly reduce HQ-induced DNA damage and cell apoptosis and restore cell proliferation and survival rate. shRNA interference experiments further indicated that the activation of the NF-κB pathway was regulated by PARP1. This study confirmed the important role of the NF-κB pathway in HQ-induced DNA damage and cell apoptosis and revealed that the activation of the NF-κB pathway was mediated by PARP1. This research provides important clues for a deeper understanding of the toxic mechanism of HQ.

8.
Surgery ; 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38839433

RESUMO

We aimed to analyze the feasibility of endovascular treatment for brucellosis-related aorta-iliac artery pseudoaneurysm. We did a statistical analysis that among the 11 cases, the thoracic aorta was involved in 3 cases, the abdominal aorta was involved in 6 cases, and the iliac artery was involved in 2 cases. Five patients had a history of contact with cattle and sheep, 3 had a history of drinking raw milk, 10 patients had a fever before the operation, and 11 patients had positive serum agglutination test. Blood culture was positive in 2 patients. All patients were given anti-brucellosis treatment immediately after diagnosis. One died of aortic rupture 5 days after emergency endovascular gastrointestinal bleeding. Endovascular-covered stent implantation and active anti-brucellosis therapy were used to treat 10 patients. The follow-up period was 8 years without aortic complications or death for all patients. We think early diagnosis and a combination of anti-brucellosis drugs and endovascular therapy may be the first choice for treating the pseudoaneurysm caused by Brucella.

10.
Artigo em Inglês | MEDLINE | ID: mdl-38862429

RESUMO

DNA sequencers have become increasingly important research and diagnostic tools over the past 20 years. In this study, we developed a single-molecule desktop sequencer, GenoCare 1600 (GenoCare), which utilizes amplification-free library preparation and two-color sequencing-by-synthesis chemistry, making it more user-friendly compared with previous single-molecule sequencing platforms for clinical use. Using the GenoCare platform, we sequenced an Escherichia coli standard sample and achieved a consensus accuracy exceeding 99.99%. We also evaluated the sequencing performance of this platform in microbial mixtures and coronavirus disease 2019 (COVID-19) samples from throat swabs. Our findings indicate that the GenoCare platform allows for microbial quantitation, sensitive identification of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, and accurate detection of virus mutations, as confirmed by Sanger sequencing, demonstrating its remarkable potential in clinical application.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/virologia , COVID-19/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Escherichia coli/genética , Mutação
11.
J Bone Miner Res ; 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38843381

RESUMO

Although the negative association of tobacco smoking with osteoporosis is well-documented, little is known regarding the shared genetic basis underlying these conditions. In this study, we aim to investigate a shared genetic architecture between smoking and heel estimated bone mineral density (eBMD), a reliable proxy for osteoporosis. We conducted a comprehensive genome-wide cross-trait analysis to identify genetic correlation, pleiotropic loci and causal relationship of smoking with eBMD, leveraging summary statistics of the hitherto largest genome-wide association studies conducted in European ancestry for smoking initiation (Nsmoker = 1 175 108, Nnonsmoker = 1 493 921), heaviness (cigarettes per day, N = 618 489), cessation (Ncurrent smoker = 304 244, Nformer smoker = 843 028), and eBMD (N = 426 824). A significant negative global genetic correlation was found for smoking cessation and eBMD (${r}_g$ = -0.051, P = 0.01), while we failed to identify a significant global genetic correlation of smoking initiation or heaviness with eBMD. Partitioning the whole genome into independent blocks, we observed six significant shared local signals for smoking and eBMD, with 22q13.1 showing the strongest regional genetic correlation. Such a genetic overlap was further supported by 71 pleiotropic loci identified in the cross-trait meta-analysis. Mendelian randomization identified no causal effect of smoking initiation (beta = -0.003 g/cm2, 95%CI = -0.033-0.027) or heaviness (beta = -0.017 g/cm2, 95%CI = -0.072-0.038) on eBMD, but a putative causal effect of genetic predisposition to being a current smoker was associated with a lower eBMD compared to former smokers (beta = -0.100 g/cm2, 95%CI = -0.181- - 0.018). Our study demonstrates a pronounced biological pleiotropy as well as a putative causal link between current smoking status and eBMD, providing novel insights into the primary prevention and modifiable intervention of osteoporosis by advocating individuals to avoid, reduce or quit smoking as early as possible.


We conducted a comprehensive genome-wide cross-trait analysis to investigate the shared genetic basis and causal relationship underlying smoking and osteoporosis. Our findings revealed that smoking and eBMD are inherently linked through biological pleiotropy. Importantly, our study discovered that quitting smoking significantly reduced the risk of lower eBMD. We recommend individuals to avoid, reduce, or quit smoking as early as possible to protect bone health.

12.
Nat Commun ; 15(1): 5127, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38879565

RESUMO

The Omicron subvariants BQ.1.1, XBB.1.5, and XBB.1.16 of SARS-CoV-2 are known for their adeptness at evading immune responses. Here, we isolate a neutralizing antibody, 7F3, with the capacity to neutralize all tested SARS-CoV-2 variants, including BQ.1.1, XBB.1.5, and XBB.1.16. 7F3 targets the receptor-binding motif (RBM) region and exhibits broad binding to a panel of 37 RBD mutant proteins. We develop the IgG-like bispecific antibody G7-Fc using 7F3 and the cross-neutralizing antibody GW01. G7-Fc demonstrates robust neutralizing activity against all 28 tested SARS-CoV-2 variants and sarbecoviruses, providing potent prophylaxis and therapeutic efficacy against XBB.1 infection in both K18-ACE and BALB/c female mice. Cryo-EM structure analysis of the G7-Fc in complex with the Omicron XBB spike (S) trimer reveals a trimer-dimer conformation, with G7-Fc synergistically targeting two distinct RBD epitopes and blocking ACE2 binding. Comparative analysis of 7F3 and LY-CoV1404 epitopes highlights a distinct and highly conserved epitope in the RBM region bound by 7F3, facilitating neutralization of the immune-evasive Omicron variant XBB.1.16. G7-Fc holds promise as a potential prophylactic countermeasure against SARS-CoV-2, particularly against circulating and emerging variants.


Assuntos
Anticorpos Biespecíficos , Anticorpos Antivirais , COVID-19 , Camundongos Endogâmicos BALB C , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Animais , SARS-CoV-2/imunologia , SARS-CoV-2/genética , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacologia , COVID-19/imunologia , COVID-19/virologia , COVID-19/prevenção & controle , Humanos , Feminino , Camundongos , Anticorpos Antivirais/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Anticorpos Neutralizantes/imunologia , Testes de Neutralização , Microscopia Crioeletrônica , Células HEK293
13.
PLoS One ; 19(6): e0304333, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38875253

RESUMO

Magnetic MnFe2O4 nanoparticles were successfully prepared by the rapid combustion method at 500 °C for 2 h with 30 mL absolute ethanol, and were characterized by SEM, TEM, XRD, VSM, and XPS techniques, their average particle size and the saturation magnetization were about 25.3 nm and 79.53 A·m2/kg, respectively. The magnetic MnFe2O4 nanoparticles were employed in a fixed bed experimental system to investigate the adsorption capacity of Hg0 from air. The MnFe2O4 nanoparticles exhibited the large adsorption performance on Hg0 with the adsorption capacity of 16.27 µg/g at the adsorption temperature of 50 °C with the space velocity of 4.8×104 h-1. The VSM and EDS results illustrated that the prepared MnFe2O4 nanoparticles were stable before and after adsorption and successfully adsorbed Hg0. The TG curves demonstrated that the mercury compound formed after adsorption was HgO, and both physical and chemical adsorption processes were observed. Magnetic MnFe2O4 nanoparticles revealed excellent adsorbance of Hg0 in air, which suggested that MnFe2O4 nanoparticles be promising for the removal of Hg0.


Assuntos
Compostos Férricos , Gases , Compostos de Manganês , Mercúrio , Adsorção , Mercúrio/química , Compostos de Manganês/química , Compostos Férricos/química , Gases/química , Tamanho da Partícula , Temperatura
14.
Int Immunopharmacol ; 134: 112247, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38759374

RESUMO

BACKGROUND: Epilepsy is a chronic disabling disease poorly controlled by available antiseizure medications. Oridonin, a bioactive alkaloid with anti-inflammatory properties and neuroprotective effects, can inhibit the increased excitability of neurons caused by glutamate accumulation at the cellular level. However, whether oridonin affects neuronal excitability and whether it has antiepileptic potential has not been reported in animal models or clinical studies. METHOD: Pentylenetetrazol was injected into mice to create a model of chronic epilepsy. Seizure severity was assessed using the Racine scale, and the duration and latency of seizures were observed. Abnormal neuronal discharge was detected using electroencephalography, and neuronal excitability was assessed using calcium imaging. Damage to hippocampal neurons was evaluated using Hematoxylin-Eosin and Nissl staining. The expression of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and other pyroptosis-related proteins was determined using western blotting and immunofluorescence. A neuronal pyroptosis model was established using the supernatant of BV2 cells treated with lipopolysaccharide and adenosine triphosphate to stimulate hippocampal neurons. RESULTS: Oridonin (1 and 5 mg/kg) reduced neuronal damage, increased the latency of seizures, and shortened the duration of fully kindled seizures in chronic epilepsy model mice. Oridonin decreased abnormal discharge during epileptic episodes and suppressed increased neuronal excitability. In vitro experiments showed that oridonin alleviated pyroptosis in hippocampal HT22 neurons. CONCLUSION: Oridonin exerts neuroprotective effects by inhibiting pyroptosis through the NLRP3/caspase-1 pathway in chronic epilepsy model mice. It also reduces pyroptosis in hippocampal neurons in vitro, suggesting its potential as a therapy for epilepsy.


Assuntos
Anticonvulsivantes , Modelos Animais de Doenças , Diterpenos do Tipo Caurano , Epilepsia , Hipocampo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Neurônios , Fármacos Neuroprotetores , Piroptose , Animais , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Epilepsia/tratamento farmacológico , Piroptose/efeitos dos fármacos , Camundongos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Masculino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Pentilenotetrazol , Camundongos Endogâmicos C57BL , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Linhagem Celular , Convulsões/tratamento farmacológico
15.
Chemosphere ; 359: 142287, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38723685

RESUMO

Sulfamethoxazole (SMX), a widely utilized antibiotic, was continually detected in the environment, causing serious risks to aquatic ecology and water security. In this study, carbon nanotubes (CNTs) with abundant defects were developed by argon plasma-etching technology to enhance the activation of persulfate (PS, including peroxymonosulfate (PMS) and peroxydisulfate (PDS)) for SMX degradation while reducing environmental toxicity. Obviously, the increase of ID/IG value from 0.980 to 1.333 indicated that Ar plasma-etching successfully introduced rich defects into CNTs. Of note, Ar-90-CNT, whose Ar plasma-etching time was 90 min with optimum catalytic performance, exhibited a significant discrepancy between PMS activation and PDS activation. Interestingly, though the Ar-90-CNT/PDS system (kobs = 0.0332 min-1) was more efficient in SMX elimination than the Ar-90-CNT/PMS system (kobs = 0.0190 min-1), Ar plasma-etching treatment had no discernible enhancement in the catalytic efficiency of MWCNT for PDS activation. Then the discrepancy on activation mechanism between PMS and PDS was methodically investigated through quenching experiments, electron spin resonance (ESR), chemical probes, electrochemical measurements and theoretical calculations, and the findings unraveled that the created vacancy defects were the ruling active sites for the production of dominated singlet oxygen (1O2) in the Ar-90-CNT/PMS system to degrade SMX, while the electron transfer pathway (ETP), originated from PDS activation by the inherent edge defects, was the central pathway for SMX removal in the Ar-90-CNT/PDS system. Based on the toxicity test of Microcystis aeruginosa, the Ar-90-CNT/PDS system was more effective in alleviating environmental toxicity during SMX degradation. These findings not only provide insights into the discrepancy between PMS activation and PDS activation via carbon-based materials with controlled defects regulated by the plasma-etching strategy, but also efficiently degrade sulfonamide antibiotics and reduce the toxicity of their products.


Assuntos
Nanotubos de Carbono , Peróxidos , Sulfametoxazol , Sulfametoxazol/química , Nanotubos de Carbono/química , Peróxidos/química , Poluentes Químicos da Água/química , Poluentes Químicos da Água/metabolismo , Sulfatos/química , Catálise , Antibacterianos/química
16.
Int J Biol Macromol ; 270(Pt 1): 132314, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38740160

RESUMO

Tartary buckwheat (Fagopyrum tataricum) is an annual coarse cereal from the Polygonaceae family, known for its high content of flavonoid compounds, particularly rutin. But so far, the mechanisms of the flavonoid transport and storage in Tartary buckwheat (TB) remain largely unexplored. This study focuses on ATP-binding cassette transporters subfamily C (ABCC) members, which are crucial for the biosynthesis and transport of flavonoids in plants. The evolutionary and expression pattern analyses of the ABCC genes in TB identified an ABCC protein gene, FtABCC2, that is highly correlated with rutin synthesis. Subcellular localization analysis revealed that FtABCC2 protein is specifically localized to the vacuole membrane. Heterologous expression of FtABCC2 in Saccharomyces cerevisiae confirmed that its transport ability of flavonoid glycosides such as rutin and isoquercetin, but not the aglycones such as quercetin and dihydroquercetin. Overexpression of FtABCC2 in TB hairy root lines resulted in a significant increase in total flavonoid and rutin content (P < 0.01). Analysis of the FtABCC2 promoter revealed potential cis-acting elements responsive to hormones, cold stress, mechanical injury and light stress. Overall, this study demonstrates that FtABCC2 can efficiently facilitate the transport of rutin into vacuoles, thereby enhancing flavonoids accumulation. These findings suggest that FtABCC2 is a promising candidate for molecular-assisted breeding aimed at developing high-flavonoid TB varieties.


Assuntos
Fagopyrum , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas , Rutina , Rutina/metabolismo , Fagopyrum/genética , Fagopyrum/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regiões Promotoras Genéticas , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Transporte Biológico , Flavonoides/metabolismo , Filogenia , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética
17.
Eur J Med Chem ; 273: 116493, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38761790

RESUMO

The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents to treat drug-resistant bacteria. We previously discovered compound OB-158 with potent antibacterial activity but exhibited poor oral bioavailability. Herein, a systematic structural optimization of OB-158 to improve pharmacokinetic profiles yielded 26 novel biaryloxazolidinone analogues, and their activities against Gram-positive S. aureus, multidrug resistant S. aureus and Enterococcus faecalis were evaluated. Remarkably, compound 8b was identified with potent antibacterial activity against S. aureus (MIC = 0.06 µg/mL), MSSA (MIC = 0.125 µg/mL), MRSA (MIC = 0.06 µg/mL), LRSA (MIC = 0.125 µg/mL) and LREFa (MIC = 0.5 µg/mL). Compound 8b was demonstrated as a promising candidate through druglikeness evaluation including metabolism in microsomes and plasma, Caco-2 cell permeability, plasma protein binding, cytotoxicity, and inhibition of CYP450 and human monoamine oxidase. Notably, compound 8b displayed excellent PK profile with appropriate T1/2 of 1.49 h, high peak plasma concentration (Cmax = 2320 ng/mL), high plasma exposure (AUC0-t = 8310 h ng/mL), and superior oral bioavailability (F = 68.1 %) in Sprague-Dawley rats. Ultimately, in vivo efficacy of compound 8b in a mouse model of LRSA systemic infection was also demonstrated. Taken together, compound 8b represents a promising drug candidate for the treatment of linezolid-resistant Gram-positive bacterial strains infection.


Assuntos
Antibacterianos , Linezolida , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Humanos , Animais , Linezolida/farmacologia , Relação Estrutura-Atividade , Células CACO-2 , Camundongos , Estrutura Molecular , Relação Dose-Resposta a Droga , Staphylococcus aureus/efeitos dos fármacos , Ratos , Farmacorresistência Bacteriana/efeitos dos fármacos , Masculino , Enterococcus faecalis/efeitos dos fármacos , Oxazolidinonas/farmacologia , Oxazolidinonas/química , Oxazolidinonas/síntese química , Ratos Sprague-Dawley
18.
Sci Total Environ ; 931: 172936, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38701923

RESUMO

Nitrous oxide (N2O) emission from composting is a significant contributor to greenhouse effect and ozone depletion, which poses a threat to environment. To address the challenge of mitigating N2O emission during composting, this study investigated the response of N2O emission and denitrifier communities (detected by metagenome sequencing) to aeration intensities of 6 L/min (C6), 12 L/min (C12), and 18 L/min (C18) in cattle manure composting using multi-factor interaction analysis. Results showed that N2O emission occurred mainly at mesophilic phase. Cumulative N2O emission (QN2O, 9.79 mg·kg-1 DW) and total nitrogen loss (TN loss, 16.40 %) in C12 composting treatment were significantly lower than those in the other two treatments. The lower activity of denitrifying enzymes and the more complex and balanced network of denitrifiers and environmental factors might be responsible for the lower N2O emission. Denitrification was confirmed to be the major pathway for N2O production. Moisture content (MC) and Luteimonas were the key factors affecting N2O emission, and nosZ-carrying denitrifier played a significant role in reducing N2O emission. Although relative abundance of nirS was lower than that of nirK significantly (P < 0.05), nirS was the key gene influencing N2O emission. Community composition of denitrifier varied significantly with different aeration treatments (R2 = 0.931, P = 0.001), and Achromobacter was unique to C12 at mesophilic phase. Physicochemical factors had higher effect on QN2O, whereas denitrifying genes, enzymes and NOX- had lower effect on QN2O in C12. The complex relationship between N2O emission and the related factors could be explained by multi-factor interaction analysis more comprehensively. This study provided a novel understanding of mechanism of N2O emission regulated by aeration intensity in composting.


Assuntos
Compostagem , Desnitrificação , Esterco , Óxido Nitroso , Esterco/análise , Óxido Nitroso/análise , Animais , Compostagem/métodos , Bovinos , Poluentes Atmosféricos/análise , Microbiologia do Solo
19.
Appl Environ Microbiol ; 90(6): e0014924, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38808978

RESUMO

Glucaric acid (GA) is a value-added chemical and can be used to manufacture food additives, anticancer drugs, and polymers. The non-genetic cell-to-cell variations in GA biosynthesis are naturally inherent, indicating the presence of both high- and low-performance cells in culture. Low-performance cells can lead to nutrient waste and inefficient production. Furthermore, myo-inositol oxygenase (MIOX) is a key rate-limiting enzyme with the problem of low stability and activity in GA production. Therefore, eliminating cell-to-cell variations and increasing MIOX stability can select high-performance cells and improve GA production. In this study, an in vivo GA bioselector was constructed based on GA biosensor and tetracycline efflux pump protein TetA to continuously select GA-efficient production strains. Additionally, the upper limit of the GA biosensor was improved to 40 g/L based on ribosome-binding site optimization, achieving efficient enrichment of GA high-performance cells. A small ubiquitin-like modifier (SUMO) enhanced MIOX stability and activity. Overall, we used the GA bioselector and SUMO-MIOX fusion in fed-batch GA production and achieved a 5.52-g/L titer in Escherichia coli, which was 17-fold higher than that of the original strain.IMPORTANCEGlucaric acid is a non-toxic valuable product that was mainly synthesized by chemical methods. Due to the problems of non-selectivity, inefficiency, and environmental pollution, GA biosynthesis has attracted significant attention. The non-genetic cell-to-cell variations and MIOX stability were both critical factors for GA production. In addition, the high detection limit of the GA biosensor was a key condition for performing high-throughput screening of GA-efficient production strains. To increase GA titer, this work eliminated the cell-to-cell variations by GA bioselector constructed based on GA biosensor and TetA, and improved the stability and activity of MIOX in the GA biosynthetic pathway through fusing the SUMO to MIOX. Finally, these approaches improved the GA production by 17-fold to 5.52 g/L at 65 h. This study represents a significant step toward the industrial application of GA biosynthetic pathways in E. coli.


Assuntos
Escherichia coli , Ácido Glucárico , Inositol Oxigenase , Inositol , Escherichia coli/genética , Escherichia coli/metabolismo , Inositol/metabolismo , Inositol Oxigenase/metabolismo , Inositol Oxigenase/genética , Ácido Glucárico/metabolismo , Engenharia Metabólica , Técnicas Biossensoriais
20.
Clin Chim Acta ; 560: 119749, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38796052

RESUMO

Thalassemia is one of the most common and damaging monogenic diseases in the world. It is caused by pathogenic variants of α- and/or ß-globin genes, which disrupt the balance of these two protein chains and leads to α-thalassemia or ß-thalassemia, respectively. Patients with α-thalassemia or ß-thalassemia could exhibit a severe phenotype, with no simple and effective treatment. A three-tiered strategy of carrier screening, prenatal diagnosis and newborn screening has been established in China for the prevention and control of thalassemia, of which the first two parts have been studied thoroughly. The implementation of neonatal thalassemia screening is lagging, and the effectiveness of various screening programs has not yet been demonstrated. In this study, hemoglobin capillary electrophoresis (CE), hotspot testing method, and third-generation sequencing (TGS) were used in the variant detection of 2000 newborn samples, to assess the efficacy of these methods in neonatal thalassemia screening. Compared with CE (249, 12.45 %) and hotspot analysis (424, 21.2 %), CATSA detected the largest number of thalassemia variants (535, 26.75 %), which included 24 hotspot variants, increased copy number of α-globin gene, rare pathogenic variants, and three unreported potentially disease-causing variants. More importantly, CATSA directly determined the cis-trans relationship of variants in three newborns, which greatly shortens the clinical diagnosis time of thalassemia. CATSA showed a great advantage over other genetic tests and could become the most powerful technical support for the three-tiered prevention and control strategy of thalassemia.


Assuntos
Alelos , Triagem Neonatal , Talassemia , Humanos , Recém-Nascido , Talassemia/genética , Talassemia/diagnóstico , Eletroforese Capilar , alfa-Globinas/genética , Sequenciamento de Nucleotídeos em Larga Escala
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