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1.
Chemosphere ; : 142264, 2024 May 05.
Article in English | MEDLINE | ID: mdl-38714248

ABSTRACT

Extracellular DNA referred to DNA fragments existing outside the cell, originating from various cell release mechanisms, including active secretion, cell lysis, and phage-mediated processes. Extracellular DNA serves as a vital environmental biomarker, playing crucial ecological and environmental roles in water bodies. This review is summarized the mechanisms of extracellular DNA release, including pathways involving cell lysis, extracellular vesicles, and type IV secretion systems. Then, the extraction and detection methods of extracellular DNA from water, soil, and biofilm are described and analyzed. Finally, we emphasize the role of extracellular DNA in microbial community systems, including its significant contributions to biofilm formation, biodiversity through horizontal gene transfer (HGT), and electron transfer processes. This review offers a comprehensive insight into the sources, distribution, functions, and impacts of extracellular DNA within aquatic environments, aiming to foster further exploration and understanding of extracellular DNA dynamics in aquatic environments as well as other environments.

2.
Front Oncol ; 14: 1364702, 2024.
Article in English | MEDLINE | ID: mdl-38746673

ABSTRACT

Objective: To explore the clinical effect of bladder cancer patients with Fear of Cancer Recurrence (FCR) after applying the gratitude extension construction theory nursing program. Methods: 168 patients with bladder cancer hospitalized in the Department of Urology from December 2021 to June 2023 in a hospital are study subjects. The experimental subjects are uniformly designed as an experimental group and a control group, with 52 participants in each group. The former receives routine nursing care, while the later receives nursing interventions based on gratitude extension construction theory. The baseline data, Quality of life Questionnaire-core 30, Quality of Life Questionnaire-non Invasive Bladder Cancer 24, Fear of Progression Questionnaire-Short Form, gratitude level questionnaire, Self-Rating Depression Scale, Self-rating Anxiety Scale, patient compliance behavior score, Overall Survival, and Progression-free Survival are evaluated. Results: The basic data revealed no statistical significance. The quality of life questionnaire-core 30 and quality of life questionnaire-noninvasive bladder cancer 24 was no significant difference before treatment and after treatment for 1 month. After 9 months, There was a significant difference in pre-treatment scores. The experimental group had no significant difference before and after treatment. For the overall survival rates, the two groups were 67.25% and 79.56%. The progression-free survival rates were 56.35% and 72.35%, respectively, with statistical difference. The compliance rates were 86.54% and 98.08%. The compliance rate of the experimental group exceeded the control group. After 3, 6, and 12 months, the gratitude level questionnaire score and the fear of progression questionnaire-short form in the experimental group were improved. After 3, 6, and 12 months, the control group had no statistically significant difference in the gratitude level questionnaire and the fear of progression questionnaire-short form scores. Compared with the control group, the scores on the gratitude level questionnaire and the fear of progression questionnaire-short form were significantly higher after 3, 6, and 12 months of intervention. Conclusion: After applying the gratitude extension construction theory nursing program, the FCR of bladder cancer patients is significantly reduced. The quality of life and compliance rate are significantly improved, and anxiety and depression are relieved.

3.
Article in English | MEDLINE | ID: mdl-38747495

ABSTRACT

The excessive depositions of ß-amyloid (Aß) and abnormal level of reactive oxygen species (ROS) are considered as the important pathogenic factors of Alzheimer's disease (AD). Strategies targeting only one of them have no obvious effects in clinic. In this study, a multifunctional nanocarrier CICe@M-K that crosses the blood-brain barrier (BBB) efficiently was developed for inhibiting Aß aggregation and scavenging ROS synchronously. Antioxidant curcumin (Cur) and photosensitizer IR780 were loaded in mesoporous silica nanomaterials (MSNs). Their surfaces were grafted with cerium oxide nanoparticles (CeO2 NPs) and a short peptide K (CKLVFFAED). Living imaging showed that CICe@M-K was mainly distributed in the brain, liver, and kidneys, indicating CICe@M-K crossed BBB efficiently and accumulated in brain. After the irradiation of 808 nm laser, Cur was continuously released. Both of Cur and the peptide K can recognize and bind to Aß through multiple interaction including π-π stacking interaction, hydrophobic interaction, and hydrogen bond, inhibiting Aß aggregation. On the other hand, Cur and CeO2 NPs cooperate to relieve the oxidative stress in the brains by scavenging ROS. In vivo assays showed that the CICe@M-K could diminish Aß depositions, alleviate oxidative stress, and improve cognitive ability of the APP/PS1 AD mouse model, which demonstrated that CICe@M-K is a potential agent for AD treatment.

4.
BMC Infect Dis ; 24(1): 493, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38745170

ABSTRACT

BACKGROUND: Diet plays an important role in Helicobacter pylori (HP) infection, and our objective was to investigate potential connections between dietary patterns, specific food groups, and HP infection status in U.S. adults. METHODS: The data for this study was obtained from the NHANES (National Health and Nutrition Survey) database for the year 1999-2000. This cross-sectional study involved the selection of adults aged 20 years and older who had undergone dietary surveys and HP testing. Factor analysis was employed to identify dietary patterns, and logistic regression models were utilized to assess the association between these dietary patterns and specific food groups with HP infection status. RESULT: Based on the inclusion and exclusion criteria, our final analysis included 2,952 individuals. The median age of participants was 51.0 years, and 48.7% were male. In the study population, the overall prevalence of HP infection was 44.9%. Factor analysis revealed three distinct dietary patterns: High-fat and high-sugar pattern (including solid fats, refined grains, cheese, and added sugars); Vegetarian pattern (comprising fruits, juices, and whole grains); Healthy pattern (encompassing vegetables, nuts and seeds, and oils). Adjusted results showed that the high-fat and high-sugar pattern (OR = 0.689, 95% CI: 0.688-0.690), vegetarian pattern (OR = 0.802, 95% CI: 0.801-0.803), and healthy pattern (OR = 0.717, 95% CI: 0.716-0.718) were all linked to a lower likelihood of HP infection. Further analysis of the high-fat and high-sugar pattern revealed that solid fats (OR = 0.717, 95% CI: 0.716-0.718) and cheese (OR = 0.863, 95% CI: 0.862-0.864) were protective factors against HP infection, while refined grains (OR = 1.045, 95% CI: 1.044-1.046) and added sugars (OR = 1.014, 95% CI: 1.013-1.015) were identified as risk factors for HP infection. CONCLUSION: Both the Vegetarian pattern and the Healthy pattern are associated with a reduced risk of HP infection. Interestingly, the High-fat and High-sugar pattern, which is initially considered a risk factor for HP infection when the score is low, becomes a protective factor as the intake increases. Within this pattern, animal foods like solid fats and cheese play a protective role, while the consumption of refined grains and added sugars increases the likelihood of HP infection.


Subject(s)
Cheese , Helicobacter Infections , Helicobacter pylori , Nutrition Surveys , Humans , Male , Cross-Sectional Studies , Helicobacter Infections/epidemiology , Middle Aged , Female , Cheese/microbiology , Adult , Diet , Dietary Fats , Aged , Young Adult , Prevalence , Risk Factors , United States/epidemiology , Feeding Behavior
5.
Int J Environ Health Res ; : 1-15, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38722165

ABSTRACT

The effects of endocrine disruptors including phenols and phthalates on adult lung function remain unclear. In the present study, data from 2007-2012 National Health and Nutrition Examination Survey (NHANES) were extracted, and 4338 participants were included in the final analyses. The associations of three phenols and four phthalate metabolites with six lung function parameters were investigated. In generalized linear regression models (GLM) and restricted cubic spline (RCS) analyses, bisphenol A (BPA) was associated with decreased forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC), and 2,5-dichlorophenol (DCP) was associated with reduced FEV1, FVC and peak expiratory flow rate (PEF), and increased prevalence of restrictive lung function (RLF) in adults. Furthermore, weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) models demonstrated that mixed exposures to phenols and phthalates were linked to reduced FEV1, FVC and PEF and increased prevalence of RLF, and these associations were mainly driven by BPA and 2,5-DCP. In conclusion, mixed exposure to phenols and phthalates was linked to compromised and a restrictive pattern of lung function. The mechanisms of the effects of phenol and phthalate exposures on lung function and respiratory diseases need to be further investigated.

6.
Drug Des Devel Ther ; 18: 1385-1398, 2024.
Article in English | MEDLINE | ID: mdl-38689609

ABSTRACT

In the past few decades, chemotherapy has been one of the most effective cancer treatment options. Drug resistance is currently one of the greatest obstacles to effective cancer treatment. Even though drug resistance mechanisms have been extensively investigated, they have not been fully elucidated. Recent genome-wide investigations have revealed the existence of a substantial quantity of long non-coding RNAs (lncRNAs) transcribed from the human genome, which actively participate in numerous biological processes, such as transcription, splicing, epigenetics, the cell cycle, cell differentiation, development, pluripotency, immune microenvironment. The abnormal expression of lncRNA is considered a contributing factor to the drug resistance. Furthermore, drug resistance may be influenced by genetic and epigenetic variations, as well as individual differences in patient treatment response, attributable to polymorphisms in metabolic enzyme genes. This review focuses on the mechanism of lncRNAs resistance to target drugs in the study of tumors with high mortality, aiming to establish a theoretical foundation for targeted therapy.


Subject(s)
Antineoplastic Agents , Drug Resistance, Neoplasm , Neoplasms , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Antineoplastic Agents/pharmacology , Animals
7.
ACS Infect Dis ; 10(5): 1576-1589, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38581387

ABSTRACT

Exploring novel antimicrobial drugs and strategies has become essential to the fight MRSA-associated infections. Herein, we found that membrane-disrupted repurposed antibiotic salifungin had excellent bactericidal activity against MRSA, with limited development of drug resistance. Furthermore, adding salifungin effectively decreased the minimum inhibitory concentrations of clinical antibiotics against Staphylococcus aureus. Evaluations of the mechanism demonstrated that salifungin disrupted the level of H+ and K+ ions using hydrophilic and lipophilic groups to interact with bacterial membranes, causing the disruption of bacterial proton motive force followed by impacting on bacterial the function of the respiratory chain and adenosine 5'-triphosphate, thereby inhibiting phosphatidic acid biosynthesis. Moreover, salifungin also significantly inhibited the formation of bacterial biofilms and eliminated established bacterial biofilms by interfering with bacterial membrane potential and inhibiting biofilm-associated gene expression, which was even better than clinical antibiotics. Finally, salifungin exhibited efficacy comparable to or even better than that of vancomycin in the MRSA-infected animal models. In conclusion, these results indicate that salifungin can be a potential drug for treating MRSA-associated infections.


Subject(s)
Anti-Bacterial Agents , Biofilms , Drug Repositioning , Methicillin-Resistant Staphylococcus aureus , Microbial Sensitivity Tests , Staphylococcal Infections , Methicillin-Resistant Staphylococcus aureus/drug effects , Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Animals , Mice , Drug Resistance, Bacterial/drug effects
8.
J Orthop Surg Res ; 19(1): 264, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38664852

ABSTRACT

OBJECTIVE: This study aimed to evaluate the influence of herniation of cartilaginous endplates on postoperative pain and functional recovery in patients undergoing percutaneous endoscopic lumbar discectomy (PELD) for lumbar disc herniation (LDH). METHODS: A retrospective analysis was conducted on 126 patients with LDH treated with PELD at the Third Hospital of Hebei Medical University from January 2021 to January 2022. Whether cartilaginous endplates had herniated was identified by analyzing these specific findings from MRI scans: posterior marginal nodes, posterior osteophytes, mid endplate irregularities, heterogeneous low signal intensity of extruded material, and Modic changes in posterior corners and mid endplates. Patients were assessed for postoperative pain using the Visual Analogue Scale (VAS) and functional recovery using the Oswestry Disability Index (ODI) and Modified MacNab criteria. Statistical analyses compared outcomes based on the presence of herniation of cartilaginous endplates. RESULTS: Patients with herniation of cartilaginous endplates experienced higher pain scores early postoperatively but showed significant improvement in pain and functional status over the long term. The back pain VAS scores showed significant differences between the groups with and without herniation of cartilaginous endplates on postoperative day 1 and 1 month (P < 0.05). Leg pain VAS scores showed significant differences on postoperative day 1 (P < 0.05). Modic changes were significantly associated with variations in postoperative recovery, highlighting their importance in predicting patient outcomes. In patients with herniation of cartilaginous endplates, there were statistically significant differences in the back pain VAS scores at 1 month postoperatively and the ODI functional scores on postoperative day 1 between the groups with and without Modic changes (P < 0.05). There were no significant differences in the surgical outcomes between patients with and without these conditions regarding the Modified MacNab criteria (P > 0.05). CONCLUSION: Herniation of cartilaginous endplates significantly affect early postoperative pain and functional recovery in LDH patients undergoing PELD. These findings emphasize the need for clinical consideration of these imaging features in the preoperative planning and postoperative management to enhance patient outcomes and satisfaction.


Subject(s)
Diskectomy, Percutaneous , Endoscopy , Intervertebral Disc Displacement , Lumbar Vertebrae , Recovery of Function , Humans , Intervertebral Disc Displacement/surgery , Intervertebral Disc Displacement/diagnostic imaging , Male , Female , Diskectomy, Percutaneous/methods , Retrospective Studies , Lumbar Vertebrae/surgery , Lumbar Vertebrae/diagnostic imaging , Middle Aged , Adult , Endoscopy/methods , Pain, Postoperative/etiology , Treatment Outcome , Pain Measurement , Cartilage/diagnostic imaging , Aged , Magnetic Resonance Imaging
9.
Nutrients ; 16(7)2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38612987

ABSTRACT

This study assesses the enduring impact of combined school- and family-based interventions on reducing the consumption of sugar-sweetened beverages (SSBs) among schoolchildren in China. Two primary schools were assigned at random to either the Intervention Group or the Control Group, in Nanjing, eastern China. All students were in grade three and received an invitation to participate. In the first year, students in the Intervention Group received one-year intervention measures, including monthly monitoring, aiming to decrease the consumption of SSBs. Students in the Control Group only received regular monitoring without interventions. In the second year, both groups received only regular monitoring, without active interventions. A generalized estimating equations model (GEE) was used to assess the intervention effects. After two years, relative to the Control Group, the Intervention Group had a significantly improved knowledge of SSBs and an improved family environment with parents. In the Intervention Group, 477 students (97.3%) had adequate knowledge about SSBs, compared to 302 students (83.2%) in the Control Group (X2 = 52.708, p < 0.001). Two years later, the number of students who stated 'my home always has SSBs' in the Intervention Group (7.8%) was fewer than that in the Control Group (12.4%), which was a statistically significant finding (p < 0.05). One year later, both the frequency and the quantity of SSB consumption in the Intervention Group were less than those in the Control Group; such differences between the groups remained statistically significant for the quantity but not for the frequency of SSB consumption two years later. In the Intervention Group, the frequency of SSB consumption was significantly reduced by 1.0 times per week, compared to a reduction of 0.1 times per week in the Control Group in the first year (p < 0.05). In the second year, the frequency of SSB consumption was reduced by 0.8 times per week in the Intervention Group, compared to 0.5 times per week in the Control Group (p > 0.05). In the first year, the volume of SSB consumption was significantly reduced by 233 mL per week in the Intervention Group, compared to an increase of 107 mL per week in the Control Group (p < 0.05). In the second year, the volume of SSB consumption was reduced by 122 mL per week in the Intervention Group compared to an increase of 31 mL per week in the Control Group (p > 0.05). The combined school-based and family-based interventions had a positive effect on the students' knowledge of SSBs and their family dynamics during the first and second year. Relative to the Control Group, the Intervention Group had a statistically significant reduction in SSB consumption after 1 year, but not after 2 years.


Subject(s)
Sugar-Sweetened Beverages , Humans , Child , Asian People , China , Schools , Habits
10.
Nat Aging ; 2024 Apr 22.
Article in English | MEDLINE | ID: mdl-38649614

ABSTRACT

Age-related changes in testicular function can impact health and well-being. The mechanisms underlying age-related testicular dysfunction, such as late-onset hypogonadism (LOH), remain incompletely understood. Using single-cell RNA sequencing on human testes with LOH, we delineated Sertoli cells (SCs) as pivotal metabolic coordinators within the testicular microenvironment. In particular, lysosomal acidity probing revealed compromised degradative capacity in aged SCs, hindering autophagy and phagocytic flux. Consequently, SCs accumulated metabolites, including cholesterol, and have increased inflammatory gene expression; thus, we termed these cells as phago-/auto-lysosomal deregulated SCs. Exposure to a high-fat diet-induced phago-/auto-lysosomal dysregulated-like SCs, recapitulating LOH features in mice. Notably, efferent ductular injection and systemic TRPML1 agonist administration restored lysosomal function, normalizing testosterone deficiency and associated abnormalities in high-fat diet-induced LOH mice. Our findings underscore the central role of SCs in testis aging, presenting a promising therapeutic avenue for LOH.

11.
Article in English | MEDLINE | ID: mdl-38655618

ABSTRACT

The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ligase complex in which the ubiquitin-like (UBL) domains of SHARPIN and HOIL-1L interact with HOIP to determine the structural stability of LUBAC. The interactions between subunits within LUBAC have been a topic of extensive research. However, the impact of the LTM motif on the interaction between the UBL domains of SHARPIN and HOIL-1L with HOIP remains unclear. Here, we discover that the absence of the LTM motif in the AlphaFold2-predicted LUBAC structure alters the HOIP-UBA structure. We employ GeoPPI to calculate the changes in binding free energy (ΔG) caused by single-point mutations between subunits, simulating their protein-protein interactions. The results reveal that the presence of the LTM motif decreases the interaction between the UBL domains of SHARPIN and HOIL-1L with HOIP, leading to a decrease in the structural stability of LUBAC. Furthermore, using the AlphaFold2-predicted results, we find that HOIP (629‒695) and HOIP-UBA bind to both sides of HOIL-1L-UBL, respectively. The experiments of Gromacs molecular dynamics simulations, SPR and ITC demonstrate that the elongated domain formed by HOIP (629‒695) and HOIP-UBA, hereafter referred to as the HOIP (466‒695) structure, interacts with HOIL-1L-UBL to form a structurally stable complex. These findings illustrate the collaborative interaction between HOIP-UBA and HOIP (629‒695) with HOIL-1L-UBL, which influences the structural stability of LUBAC.

12.
Brain Behav Immun ; 119: 539-553, 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38663774

ABSTRACT

Interleukin-33 (IL-33), secreted by astrocytes, regulates the synapse development in the spinal cord and hippocampus and suppresses autoimmune disease in the central nervous system (CNS). However, the mechanism of unconventional protein secretion of this cytokine remains unclear. In this study, we found that IFN-γ promotes the active secretion of IL-33 from astrocytes, and the active secretion of IL-33 from cytoplasm to extracellular space was dependent on interaction with transmembrane emp24 domain 10 (TMED10) via the IL-1 like cytokine domain in astrocytes. Knockout of Il-33 or its receptor St2 induced hippocampal astrocyte activation and depressive-like disorder in naive mice, as well as increased spinal cord astrocyte activation and polarization to a neurotoxic reactive subtype and aggravated passive experimental autoimmune encephalomyelitis (EAE). Our results have identified that IL-33 is actively secreted by astrocytes through the unconventional protein secretion pathway facilitated by TMED10 channels. This process helps maintain CNS homeostasis by inhibiting astrocyte activation.

13.
J Exerc Sci Fit ; 22(3): 194-201, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38559906

ABSTRACT

Background: Insomnia and depression are prevalent mental disorders that are often comorbid among older adults. Lifestyle intervention strategies incorporating Tai Chi or conventional exercise have been shown to alleviate symptoms of insomnia and depression. However, the comparative efficacy of these exercise modalities in individuals with both disorders has yet to be determined. Therefore, the aim of this study is to examine the efficacy of Tai Chi and conventional exercise for reducing depressive symptoms in older adults with chronic insomnia and depressive symptoms, when compared to a health education control. Methods: This study is a prospective, assessor-blinded, three-arm, parallel group, randomized controlled trial. Older adults aged ≥60 years with a diagnosis of chronic insomnia and depressive symptoms will be randomly assigned to a Tai Chi, conventional exercise or health education control condition on a 1:1:1 basis. Interventions will last for 3 months, with a 6-month follow-up period. The primary outcome is depressive symptoms, assessed using the Hospital Anxiety and Depression Scale. Secondary outcomes include subjective sleep quality, 7-day actigraphy, 7-day sleep diary, anxiety symptoms, quality of life, medication usage and physical function. All measurements will be conducted at baseline, 3 months and 9 months by outcome assessors who are blinded to group allocation. Discussion: This study will compare the efficacy of Tai Chi and conventional exercise in improving depression outcomes in older adults with chronic insomnia and depressive symptoms. Our results will shed light on the clinical potential of these interventions for combating insomnia and depression in older adults.

14.
Commun Biol ; 7(1): 342, 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38503825

ABSTRACT

DNA damage repair (DDR) genes are known to be closely associated with the progression of Hepatocellular carcinoma (HCC). Here we report a unique cluster of "deletion-up" genes in HCC, which are accordantly overexpressed in HCC patients and predict the unfavorable prognosis. Binding motif analysis and further validation with ChIP-qPCR unveil that the AP-2α directly modulate the transcription of critical DNA repair genes including TOP2A, NUDT1, POLD1, and PARP1, which facilitates the sanitation of oxidized DNA lesions. Structural analysis and the following validation identify LEI110 as a potent AP-2α inhibitor. Together, we demonstrate that LEI110 stabilizes AP-2α and sensitizes HCC cells toward DNA-damaging reagents. Altogether, we identify AP-2α as a crucial transcription modulator in HCC and propose small-molecule inhibitors targeting AP-2α are a promising novel class of anticancer agents. Our study provides insights into the concept of macroscopic inhibition of DNA damage repair-related genes in cancer treatment.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Transcription Factor AP-2/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Cell Line, Tumor , DNA Damage
15.
Front Oncol ; 14: 1336191, 2024.
Article in English | MEDLINE | ID: mdl-38529373

ABSTRACT

High mobility group protein 1 (HMGB1) plays a complex role in tumor biology. When released into the extracellular space, it binds to the receptor for advanced glycation end products (RAGE) located on the cell membrane, playing an important role in tumor development by regulating a number of biological processes and signal pathways. In this review, we outline the multifaceted functions of the HMGB1/RAGE axis, which encompasses tumor cell proliferation, apoptosis, autophagy, metastasis, and angiogenesis. This axis is instrumental in tumor progression, promoting tumor cell proliferation, autophagy, metastasis, and angiogenesis while inhibiting apoptosis, through pivotal signaling pathways, including MAPK, NF-κB, PI3K/AKT, ERK, and STAT3. Notably, small molecules, such as miRNA-218, ethyl pyruvate (EP), and glycyrrhizin exhibit the ability to inhibit the HMGB1/RAGE axis, restraining tumor development. Therefore, a deeper understanding of the mechanisms of the HMGB1/RAGE axis in tumors is of great importance, and the development of inhibitors targeting this axis warrants further exploration.

16.
J Med Chem ; 67(6): 4950-4976, 2024 Mar 28.
Article in English | MEDLINE | ID: mdl-38456618

ABSTRACT

Histone deacetylases (HDACs) inhibitors such as vorinostat (SAHA) has been used to treat hematologic malignancies (rather than solid tumors) and have been found to suppress the JAK/STAT, a critical signal pathway for antitumor immunity, while PARP7 inhibitor RBN-2397 could activate the type I interferons (IFN-I) pathway, facilitating downstream effects such as STAT1 phosphorylation and immune activation. To elucidate whether simultaneous inhibition of these two targets could interfere with these two signal pathways, a series of pyridazinone-based PARP7/HDACs dual inhibitors have been designed, synthesized, and evaluated in vitro and in vivo experiments. Compound 9l was identified as a potent and balanced dual inhibitor for the first time, exhibiting excellent antitumor capabilities both in vitro and in vivo. This suggests that 9l can be used as a valuable tool molecule for investigating the relationship between anticancer immunity and HDAC inhibition.


Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Vorinostat/pharmacology , Structure-Activity Relationship , Neoplasms/drug therapy , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Cell Proliferation
17.
ACS Synth Biol ; 13(4): 1177-1190, 2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38552148

ABSTRACT

The small ultrared fluorescent protein (smURFP) is a bright near-infrared (NIR) fluorescent protein (FP) that forms a dimer and binds its fluorescence chromophore, biliverdin, at its dimer interface. To engineer a monomeric NIR FP based on smURFP potentially more suitable for bioimaging, we employed protein design to extend the protein backbone with a new segment of two helices that shield the original dimer interface while covering the biliverdin binding pocket in place of the second chain in the original dimer. We experimentally characterized 13 designs and obtained a monomeric protein with a weak fluorescence. We enhanced the fluorescence of this designed protein through two rounds of directed evolution and obtained designed monomeric smURFP (DMsmURFP), a bright, stable, and monomeric NIR FP with a molecular weight of 19.6 kDa. We determined the crystal structures of DMsmURFP both in the apo state and in complex with biliverdin, which confirmed the designed structure. The use of DMsmURFP in in vivo imaging of mammalian systems was demonstrated. The backbone design-based strategy used here can also be applied to monomerize other naturally multimeric proteins with intersubunit functional sites.


Subject(s)
Bacterial Proteins , Biliverdine , Animals , Luminescent Proteins/metabolism , Biliverdine/chemistry , Microscopy, Fluorescence/methods , Bacterial Proteins/metabolism , Fluorescent Dyes , Mammals/metabolism
18.
Microbiol Res ; 283: 127647, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38452551

ABSTRACT

The Type VI secretion system (T6SS) functions as a protein transport nanoweapon in several stages of bacterial life. Even though bacterial competition is the primary function of T6SS, different bacteria exhibit significant variations. Particularly in Extraintestinal pathogenic Escherichia coli (ExPEC), research into T6SS remains relatively limited. This study identified the uncharacterized gene evfG within the T6SS cluster of ExPEC RS218. Through our experiments, we showed that evfG is involved in T6SS expression in ExPEC RS218. We also found evfG can modulate T6SS activity by competitively binding to c-di-GMP, leading to a reduction in the inhibitory effect. Furthermore, we found that evfG can recruit sodA to alleviate oxidative stress. The research shown evfG controls an array of traits, both directly and indirectly, through transcriptome and additional tests. These traits include cell adhesion, invasion, motility, drug resistance, and pathogenicity of microorganisms. Overall, we contend that evfG serves as a multi-functional regulator for the T6SS and several crucial activities. This forms the basis for the advancement of T6SS function research, as well as new opportunities for vaccine and medication development.


Subject(s)
Escherichia coli Proteins , Extraintestinal Pathogenic Escherichia coli , Type VI Secretion Systems , Type VI Secretion Systems/genetics , Type VI Secretion Systems/metabolism , Extraintestinal Pathogenic Escherichia coli/metabolism , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Virulence , Virulence Factors/genetics , Bacterial Proteins/genetics , Bacterial Proteins/metabolism
19.
ACS Nano ; 18(13): 9354-9364, 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38517038

ABSTRACT

Na3V2(PO4)3 (NVP) based on the multielectron reactions between V2+ and V5+ has been considered a promising cathode for sodium-ion batteries (SIBs). However, it still suffers from unsatisfactory stability, caused by the poor reversibility of the V5+/V4+ redox couple and structure evolution. Herein, we propos a strategy that combines high-entropy substitution and electrolyte optimization to boost the reversible multielectron reactions of NVP. The high reversibility of the V5+/V4+ redox couple and crystalline structure evolution are disclosed by in situ X-ray absorption near-edge structure spectra and in situ X-ray diffraction. Meanwhile, the electrochemical reaction kinetics of high-entropy substitution NVP (HE-NVP) can be further improved in the diglyme-based electrolyte. These enable HE-NVP to deliver a superior electrochemical performance (capacity retention of 93.1% after 2000 cycles; a large reversible capacity of 120 mAh g-1 even at 5.0 A g-1). Besides, the long cycle life and high power density of the HE-NVP∥natural graphite full-cell configuration demonstrated the superiority of HE-NVP cathode in SIBs. This work highlights that the synergism of high-entropy substitution and electrolyte optimization is a powerful strategy to enhance the sodium-storage performance of polyanionic cathodes for SIBs.

20.
Article in English | MEDLINE | ID: mdl-38518144

ABSTRACT

Objective: To analyze the application of the Enhanced Recovery After Surgery (ERAS) nursing mode in patients undergoing radical cystectomy with urinary diversion. Methods: A retrospective analysis was conducted on clinical data of 72 patients with bladder cancer who underwent "robot-assisted laparoscopic radical cystectomy + urinary diversion" in Nanjing University Medical College Affiliated Gulou Hospital between January 2021 and January 2023. All patients met the complete inclusion criteria. They were divided into a control group (n=35) and a observation group (n=37). Patients in the control group received routine rehabilitation nursing intervention, while patients in the study group received ERAS nursing mode intervention. The outcomes include time to first intake, time to first defecation, duration of enteral nutrition, duration of antibiotic use, duration of drainage tube placement, length of hospital stay, psychological status Self-rating Depression Scale (SDS), Self-rating Anxiety Scale (SAS), quality of life (SF-36) scores, sexual function assessment Arizona Sexual Experience Scale (ASEX), International Index of Erectile Function-5 (IIEF-5), and occurrence of complications were compared between the two groups. Results: In the observation group, perioperative indicators, psychological status, quality of life, sexual function, and complication rates were notably improved compared to the control group (all P < .05). Conclusion: ERAS nursing mode intervention in bladder cancer patients exhibited significant effectiveness, enhancing postoperative recovery, reducing anxiety and depression, improving quality of life and sexual function, and lowering complication risks. These findings support the clinical merit and applicability of ERAS nursing in urinary diversion for bladder cancer patients.

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