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1.
Org Lett ; 26(29): 6203-6208, 2024 Jul 26.
Article in English | MEDLINE | ID: mdl-39004824

ABSTRACT

Isoxerophilusins A (1) and B (2), two unprecedented diterpene heterodimers biogenetically from ent-atisanes and abietanes, were isolated from the rhizomes of Isodon xerophilus. Their structures were determined by extensive spectroscopic analysis and single-crystal X-ray diffraction. Selective esterification of 1 generated 11 new derivatives. All derivatives showed excellent α-glucosidase inhibitory activity in comparison to acarbose. Compounds 12 and 13 demonstrated significant inhibition against α-glucosidase with IC50 values of 4.92 and 3.83 µM, respectively.


Subject(s)
Diterpenes , Glycoside Hydrolase Inhibitors , Isodon , alpha-Glucosidases , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/isolation & purification , Diterpenes/chemistry , Diterpenes/pharmacology , Diterpenes/isolation & purification , alpha-Glucosidases/metabolism , Molecular Structure , Isodon/chemistry , Dimerization , Crystallography, X-Ray , Structure-Activity Relationship , Rhizome/chemistry
2.
Int J Mol Sci ; 25(13)2024 Jun 25.
Article in English | MEDLINE | ID: mdl-39000059

ABSTRACT

There is growing concern about the potential ecological risks posed by pharmaceutical residues in the aquatic environment. However, our understanding of the toxic effects of antiepileptic pharmaceuticals, such as carbamazepine (CBZ), on aquatic animal larvae is still limited. In this study, the tadpoles of the black-spotted pond frog (Pelophylax nigromaculatus) were exposed to environmentally relevant concentrations of CBZ (0.3 and 3.0 µg/L) for 30 days, and their growth, intestinal microbial composition, and metabolites were investigated to assess the potential toxic effects of CBZ in non-targeted aquatic organisms. Some tadpoles died during exposure, but there was no significant among-group difference in the survival and growth rates. CBZ exposure significantly altered the composition of tadpole intestinal microbiota. Relative abundances of some bacterial genera (e.g., Blautia, Prevotella, Bacillus, Microbacterium, etc.) decreased, while others (e.g., Paucibacter, etc.) increased in CBZ-exposed tadpoles. Interestingly, CBZ-induced alterations in some bacteria might not necessarily lead to adverse outcomes for animals. Meanwhile, small molecular intestinal metabolites related to energy metabolism, and antioxidant and anti-inflammatory activities were also altered after exposure. Taken together, environmentally relevant levels of CBZ might alter the metabolic and immune performances of amphibian larvae by modifying the abundance of some specific bacteria and the level of metabolites in their intestines, thereby potentially causing a long-term effect on their fitness.


Subject(s)
Anticonvulsants , Carbamazepine , Gastrointestinal Microbiome , Larva , Water Pollutants, Chemical , Animals , Larva/drug effects , Carbamazepine/pharmacology , Gastrointestinal Microbiome/drug effects , Anticonvulsants/pharmacology , Water Pollutants, Chemical/toxicity , Bacteria/drug effects
3.
bioRxiv ; 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-39026810

ABSTRACT

The prenatal environment can alter neurodevelopmental and clinical trajectories, markedly increasing risk for psychiatric disorders in childhood and adolescence. To understand if and how fetal exposures to stress and inflammation exacerbate manifestation of genetic risk for complex brain disorders, we report a large-scale context-dependent massively parallel reporter assay (MPRA) in human neurons designed to catalogue genotype x environment (GxE) interactions. Across 240 genome-wide association study (GWAS) loci linked to ten brain traits/disorders, the impact of hydrocortisone, interleukin 6, and interferon alpha on transcriptional activity is empirically evaluated in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons. Of ~3,500 candidate regulatory risk elements (CREs), 11% of variants are active at baseline, whereas cue-specific CRE regulatory activity range from a high of 23% (hydrocortisone) to a low of 6% (IL-6). Cue-specific regulatory activity is driven, at least in part, by differences in transcription factor binding activity, the gene targets of which show unique enrichments for brain disorders as well as co-morbid metabolic and immune syndromes. The dynamic nature of genetic regulation informs the influence of environmental factors, reveals a mechanism underlying pleiotropy and variable penetrance, and identifies specific risk variants that confer greater disorder susceptibility after exposure to stress or inflammation. Understanding neurodevelopmental GxE interactions will inform mental health trajectories and uncover novel targets for therapeutic intervention.

4.
Front Oncol ; 14: 1408492, 2024.
Article in English | MEDLINE | ID: mdl-39040439

ABSTRACT

Objective: Although urinary extracellular vesicles (uEVs) have been extensively studied in various cancers, their involvement in breast cancer (BC) remains largely unexplored. The non-invasive nature of urine as a biofluid and its abundant protein content offer considerable potential for the early detection of breast cancer. Methods: This study analyzed the proteomic profiles of uEVs from BC patients and healthy controls (HC). The dysregulation of ECM1 and ANXA1 in the uEVs was validated in a larger cohort of 128 BC patients, 25 HC and 25 benign breast nodules (BBN) by chemiluminescence assay (CLIA). The expression levels of ECM1 and ANXA1 were also confirmed in the uEVs of MMTV-PyMT transgenic breast cancer mouse models. Results: LC-MS/MS analysis identified 571 dysregulated proteins in the uEVs of BC patients. ECM1 and ANXA1 were selected for validation in 128 BC patients, 25 HC and 25 BBN using CLIA, as their fold change showed a significant difference of more than 10 with p-value<0.05. Protein levels of ECM1 and ANXA1 in uEVs were significantly increased in BC patients. In addition, the protein levels of ECM1 and ANXA1 in the uEVs of MMTV-PyMT transgenic mice were observed to increase progressively with the progression of breast cancer. Conclusion: We developed a simple and purification-free assay platform to isolate uEVs and quantitatively detect ECM1 and ANXA1 in uEVs by WGA-coupled magnetic beads and CLIA. Our results suggest that ECM1 and ANXA1 in uEVs could potentially serve as diagnostic biomarkers for breast cancer.

5.
Toxicol Lett ; 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-39032790

ABSTRACT

In the event of a nuclear or radiation accident, rapid identification is required for those who exposed to potentially lethal dose irradiation. However, existing techniques are not adequate for the classification of lethal injury. Several studies have explored the potential of miRNAs as biomarkers for ionizing radiation injury, however, there are few miRNAs with specific expression for lethal radiation injury. Therefore, the aim of this study was to screen and validate the possibility of serum miRNAs as biomarkers of lethal radiation injury. We found the specific expression of mmu-miR-374c-5p / mmu-miR-194-5p on first day and mmu-miR-192-5p / mmu-miR-223-3p on third day in the mouse serum only under 10Gy irradiation by miRNA sequencing and all significantly correlated with lymphocyte counts by Pearson's correlation analysis. In addition, it was found that among the 4 candidate serum miRNAs, only highly-expressed mmu-miR-192-5p in mouse serum irradiated at lethal doses was returned to sham-like expression levels at 3 days post-irradiation with amifostine pretreatment and closely correlated with survival rate. We demonstrated for the first time that mmu-miR-192-5p screened from lethally irradiated mice sera can be used as a potential biomarker for lethal irradiation injury, which will be helpful to improve efficiency of medical treatment to minimize casualties after a large-scale nuclear accident.

6.
Alzheimers Dement ; 20(7): 4891-4902, 2024 07.
Article in English | MEDLINE | ID: mdl-38895921

ABSTRACT

INTRODUCTION: Long-term blood pressure variability (BPV) and plasma neurofilament light (pNfL) have been identified as potential biomarkers for Alzheimer's disease (AD) and cerebral small vessel disease (CSVD). However, the relationship between BPV, pNfL, and their association with the comorbidity of AD and CSVD remains unknown. METHODS: Participants with normal cognition and mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative study were included in the data analysis. Linear mixed-effects regression models and causal mediation analyses were conducted to investigate the relationship among BPV, pNfL, comorbidity-related brain structural changes (hippocampal atrophy and white matter hyperintensities [WMH]), and cognitive function. RESULTS: BPV was associated with pNfL, volumes of hippocampus and WMH, and cognition. pNfL mediated the effects of BPV on brain structural changes and cognition. DISCUSSION: Our findings suggest a potential role of BPV and pNfL in the mechanism of comorbidity between AD and CSVD, underscoring the importance of BPV intervention in the general population. HIGHLIGHTS: Individuals with both Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) pathologies had elevated blood pressure variability (BPV) and plasma neurofilament light (pNfL). The association between different components of BPV and brain structural changes may vary. BPV was associated with pNfL levels independent of average blood pressure. pNfL mediated the effects of BPV on comorbidity-related brain structural changes and cognitive performance.


Subject(s)
Alzheimer Disease , Biomarkers , Blood Pressure , Cerebral Small Vessel Diseases , Neurofilament Proteins , Humans , Alzheimer Disease/blood , Alzheimer Disease/epidemiology , Cerebral Small Vessel Diseases/blood , Aged , Male , Female , Blood Pressure/physiology , Neurofilament Proteins/blood , Biomarkers/blood , Cognitive Dysfunction/blood , Cognitive Dysfunction/epidemiology , Cognitive Dysfunction/physiopathology , Comorbidity , Magnetic Resonance Imaging , White Matter/pathology , White Matter/diagnostic imaging , Brain/pathology , Brain/diagnostic imaging , Aged, 80 and over , Atrophy/pathology
7.
J Oral Rehabil ; 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38873703

ABSTRACT

OBJECTIVE: This study aimed to investigate whether flow fluid shear stress (FFSS)-mediated signal transduction affects the function of Piezo1 ion channel in chondrocyte and to further explore the role of mechanical overloading in development of temporomandibular joint osteoarthritis (TMJ OA). METHODS: Immunohistochemical staining was used to determine the expression of Piezo1 in TMJ OA tissue collected from rat unilateral anterior crossbite (UAC) models. Chondrocytes harvested from normal adult SD rats were treated with FFSS (0, 4, 8, 12 dyn/cm2) in vitro. Immunofluorescent staining, real-time polymerase chain reaction, western blotting, flow cytometry and phalloidin assay were performed to detect the changes of cellular morphology as well as the expression of Piezo1 and certain pro-inflammatory and degradative factors in chondrocyte. RESULTS: Immunohistochemical analysis revealed that significantly increased Piezo1 expression was associated with UAC stimulation (p < .05). As applied FFSS escalated (4, 8 and 12 dyn/cm2), the expression levels of Piezo1, ADAMTS-5, MMP-13 and Col-X gradually increased, compared with the non-FFSS group (p < .05). Administering Piezo1 ion channel inhibitor to chondrocytes beforehand, it was observed that expression of ADAMTS-5, MMP-13 and Col-X was substantially decreased following FFSS treatment (p < .05) and the effect of cytoskeletal thinning was counteracted. The activated Piezo1 ion channel enhanced intracellular Ca2+ excess in chondrocytes during abnormal mechanical stimulation and the increased intracellular Ca2+ thinned the cytoskeleton of F-actin. CONCLUSIONS: Mechanical overloading activates Piezo1 ion channel to promote pro-inflammation and degradation and to increase Ca2+ concentration in chondrocyte, which may eventually result in TMJ OA.

8.
Proc Natl Acad Sci U S A ; 121(25): e2305260121, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38857398

ABSTRACT

Human Cep57 is a coiled-coil scaffold at the pericentriolar matrix (PCM), controlling centriole duplication and centrosome maturation for faithful cell division. Genetic truncation mutations of Cep57 are associated with the mosaic-variegated aneuploidy (MVA) syndrome. During interphase, Cep57 forms a complex with Cep63 and Cep152, serving as regulators for centrosome maturation. However, the molecular interplay of Cep57 with these essential scaffolding proteins remains unclear. Here, we demonstrate that Cep57 undergoes liquid-liquid phase separation (LLPS) driven by three critical domains (NTD, CTD, and polybasic LMN). In vitro Cep57 condensates catalyze microtubule nucleation via the LMN motif-mediated tubulin concentration. In cells, the LMN motif is required for centrosomal microtubule aster formation. Moreover, Cep63 restricts Cep57 assembly, expansion, and microtubule polymerization activity. Overexpression of competitive constructs for multivalent interactions, including an MVA mutation, leads to excessive centrosome duplication. In Cep57-depleted cells, self-assembly mutants failed to rescue centriole disengagement and PCM disorganization. Thus, Cep57's multivalent interactions are pivotal for maintaining the accurate structural and functional integrity of human centrosomes.


Subject(s)
Cell Cycle Proteins , Centrioles , Centrosome , Microtubules , Humans , Centrosome/metabolism , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Microtubules/metabolism , Centrioles/metabolism , Centrioles/genetics , Tubulin/metabolism , Tubulin/genetics , Mutation , Microtubule-Associated Proteins/metabolism , Microtubule-Associated Proteins/genetics , Protein Binding , Nuclear Proteins
9.
Clin Interv Aging ; 19: 817-825, 2024.
Article in English | MEDLINE | ID: mdl-38765794

ABSTRACT

Background: The role of total bilirubin (TBIL) in cardiovascular disease has been increasingly recognized in recent decades. Studies have shown a correlation between total bilirubin levels and the prognosis of patients after heart surgery. This study aimed to investigate the clinical significance of bilirubin elevation in persistent atrial fibrillation (PAF) patients who received radiofrequency catheter ablation (RFCA). Methods and Results: A total of 184 patients with PAF who received RFCA were retrospectively studied. Laboratory examinations and demographic data were analyzed to identify independent predictors of TBIL elevation. The relationship between TBIL and prognosis was further investigated. Our results indicated that TBIL increased significantly after RFCA. Multiple linear regression analysis showed that TBIL elevation owned a negative correlation with the percentile of low voltage areas (LVAs) in left atria (ß=-0.490, P<0.001). In contrast, a positive correlation was observed with the white blood cell (WBC) ratio (ß=0.153, P=0.042) and left atrial diameter (LAD) (ß=0.232, P=0.025). It was found that postoperative TBIL levels increased and then gradually decreased to baseline within 5 days without intervention. The bilirubin ratio <1.211 indicated the possibility of 1-year AF recurrence after ablation with a predictive value of 0.743 (specificity = 75.00%, sensitivity = 66.67%). Conclusion: Bilirubin elevation post PAF RFCA was a common phenomenon and was associated with 1-year recurrence of AF in PAF patients after RFCA.


Subject(s)
Atrial Fibrillation , Bilirubin , Catheter Ablation , Recurrence , Humans , Atrial Fibrillation/surgery , Bilirubin/blood , Male , Female , Middle Aged , Retrospective Studies , Aged , Prognosis , Hospitalization , Linear Models , Risk Factors
10.
Heliyon ; 10(10): e30527, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38778981

ABSTRACT

Objective: It's crucial to identify an easily detectable biomarker that is specific to radiation injury in order to effectively classify injured individuals in the early stage in large-scale nuclear accidents. Methods: C57BL/6J mice were subjected to whole-body and partial-body γ irradiation, as well as whole-body X-ray irradiation to explore the response of serum sSelectin-L to radiation injury. Then, it was compared with its response to lipopolysaccharide-induced acute infection and doxorubicin-induced DNA damage to study the specificity of sSelectin-L response to radiation. Furthermore, it was further evaluated in serum samples from nasopharyngeal carcinoma patients before and after radiotherapy. Simulated rescue experiments using Amifostine or bone marrow transplantation were conducted in mice with acute radiation syndrome to determine the potential for establishing sSelectin-L as a prognostic marker. The levels of sSelectin-L were dynamically measured using the ELISA method. Results: Selectin-L is mainly expressed in hematopoietic tissues and lymphatic tissues. Mouse sSelectin-L showed a dose-dependent decrease from 1 day after irradiation and exhibited a positive correlation with lymphocyte counts. Furthermore, the level of sSelectin-L reflected the degree of radiation injury in partial-body irradiation mice and in nasopharyngeal carcinoma patients. sSelectin-L was closely related to the total dose of γ or X ray. There was no significant change in the sSelectin-L levels in mice intraperitoneal injected with lipopolysaccharide or doxorubicin. The sSelectin-L was decreased slower and recovered faster than lymphocyte count in acute radiation syndrome mice treated with Amifostine or bone marrow transplantation. Conclusions: Our study shows that sSelectin-L has the potential to be an early biomarker to classify injured individuals after radiation accidents, and to be a prognostic indicator of successful rescue of radiation victims.

11.
Quintessence Int ; 0(0): 0, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38757949

ABSTRACT

OBJECTIVE: To determine the oral health status of patients on maintenance hemodialysis (MHD) and to identify the factors influencing their oral health. METHODS: This observational study included 1,186 patients with chronic kidney disease who received MHD across 33 hospitals in China. The patients were recruited for a questionnaire survey between April and August 2023 at Beijing Chaoyang Hospital using stratified sampling. Data collection tools included the General Information Questionnaire for Maintenance Hemodialysis Patients, the Oral Health Assessment Tool, the Pittsburgh Sleep Quality Index, and the Hospital Anxiety and Depression Scale. Spearman's rank correlation coefficients were used to assess the relationships between the oral health of patients on MHD and continuous variables such as sleep quality and emotional status. Multiple linear regression analysis was employed to explore the relationship between oral health and various variables. RESULTS: The oral health scores of the patients ranged from 8 to 22, with a mean score of 12.54 ± 2.63. The final model of the multiple linear regression analysis indicated a goodness of fit of 22.19%. Independent factors affecting the oral health of patients included smoking, the proportion of medical expenses, water consumption, sleep quality, and anxiety scores (all P < 0.05). High levels of smoking, substantial medical expenses, poor sleep quality, and elevated anxiety scores were risk factors for poor oral health (all P < 0.05). Adequate daily water intake served as a protective factor for oral health (P < 0.05). CONCLUSION: This study proposes targeted interventions to enhance the management and improvement of oral health in patients on hemodialysis, aiming to provide highly personalised and effective oral health care. These interventions are expected to improve oral health outcomes in future clinical practice.

12.
Ecotoxicol Environ Saf ; 279: 116488, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38776782

ABSTRACT

Organophosphorus flame retardants, such as triphenyl phosphate (TPhP), exist ubiquitously in various environments owing to their widespread usage. Potential toxic effects of residual flame retardants on cultured non-fish species are not concerned commonly. TPhP-induced physiological and biochemical effects in an aquatic turtle were evaluated here by systematically investigating the changes in growth and locomotor performance, hepatic antioxidant ability and metabolite, and intestinal microbiota composition of turtle hatchlings after exposure to different TPhP concentrations. Reduced locomotor ability and antioxidant activity were only observed in the highest concentration group. Several metabolic perturbations that involved in amino acid, energy and nucleotide metabolism, in exposed turtles were revealed by metabolite profiles. No significant among-group difference in intestinal bacterial diversity was observed, but the composition was changed markedly in exposed turtles. Increased relative abundances of some bacterial genera (e.g., Staphylococcus, Vogesella and Lawsonella) probably indicated adverse outcomes of TPhP exposure. Despite having only limited impacts of exposure at environmentally relevant levels, our results revealed potential ecotoxicological risks of residual TPhP for aquatic turtles considering TPhP-induced metabolic perturbations and intestinal bacterial changes.


Subject(s)
Flame Retardants , Gastrointestinal Microbiome , Liver , Organophosphates , Turtles , Water Pollutants, Chemical , Animals , Gastrointestinal Microbiome/drug effects , Liver/drug effects , Liver/metabolism , Water Pollutants, Chemical/toxicity , Flame Retardants/toxicity , Organophosphates/toxicity , Bacteria/drug effects , Intestines/drug effects , Antioxidants/metabolism
13.
Fitoterapia ; 176: 105998, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38734212

ABSTRACT

Three Stemona alkaloids named stemotuberines A-C (1-3) with unique C17N frameworks, presumably formed by elimination of the C-11-C-15 lactone ring of the stichoneurine skeleton, were isolated from the roots of Stemona tuberosa. Their structures were elucidated by spectroscopic analysis, X-ray diffraction, and computational methods. Compounds 2 and 3 showed inhibition (IC50 values of 37.1 and 23.2 µM, respectively) against LPS-induced nitric oxide production in RAW 264.7 cells. In addition, concern was expressed about the reported plant origin (S. sessilifolia) of the recently described alkaloids tuberostemonols O-R (4-7), which should be S. tuberosa. NMR calculations indicated structural misassignment of these compounds except for 6. Isolation of tuberostemonol P (5) from our material of S. tuberosa allowed for a close examination of the spectroscopic data leading to the revised structure 5a. Tuberostemonol R (7) was found to have identical 1H and 13C NMR data to the well-known alkaloid croomine, and therefore its structure including relative stereochemistry must be revised as 7a.


Subject(s)
Alkaloids , Nitric Oxide , Phytochemicals , Plant Roots , Stemonaceae , Molecular Structure , Stemonaceae/chemistry , Alkaloids/isolation & purification , Alkaloids/pharmacology , Alkaloids/chemistry , Mice , Plant Roots/chemistry , RAW 264.7 Cells , Animals , Phytochemicals/isolation & purification , Phytochemicals/pharmacology
14.
Se Pu ; 42(5): 481-486, 2024 Apr 08.
Article in Chinese | MEDLINE | ID: mdl-38736392

ABSTRACT

Ibandronate sodium, a third-generation diphosphate drug used worldwide to treat osteoporosis, has the advantages of convenient use, low toxicity, and significant therapeutic effects. However, the residual organic solvents in the synthesis process of sodium ibandronate not only have a negative impact on the efficacy of the drug, but also lead to a decrease in drug stability. Moreover, if the residual amounts of these solvents exceed safety standards, they may pose serious threats to human health. This study successfully established a convenient and efficient method based on headspace-gas chromatography (HS-GC) for the simultaneous determination of five residual solvents (methanol, acetone, benzene, toluene, 1-pentanol) in the raw materials of ibandronate sodium. The results indicated that satisfactory analytical performance can be achieved by using DB-624 capillary column (30 m×0.32 mm×1.8 µm) and a flame ionization detector in conjunction with headspace autosampling and a temperature program. The specific operating conditions included an initial temperature of 40 ℃, with a hold of 2 min, followed by a temperature ramp first to 200 ℃ at a rate of 5 ℃/min and then to 240 ℃ at a rate of 20 ℃/min, with a hold of 5 min. Nitrogen with a flow rate of 1 mL/min and split ratio of 14∶1 was used as the carrier gas. The headspace vial temperature was maintained at 80 ℃, and the sample equilibration time was 20 min. Under the established analytical conditions, good linear relationships were obtained between the mass concentrations of methanol (72-216 µg/mL), acetone (120-360 µg/mL), benzene (0.048-0.144 µg/mL), toluene (21.36-64.08 µg/mL), and 1-pentanol (120-360 µg/mL) and their corresponding peak areas, with correlation coefficients (r) greater than 0.990. The limits of detection for these solvents were 2.88, 0.011, 0.90, 0.24, and 0.024 ng/mL, respectively, with limits of quantification of 11.5, 0.043, 3.6, 0.96, and 0.096 ng/mL, respectively. Furthermore, the recoveries of these solvents ranged from 86.3% to 101.9%, with relative standard deviations (RSDs, n=3) of less than 2.49%. The proposed method is simple, accurate, reliable, and suitable for the rapid and simultaneous determination of five residual solvents in the raw materials of ibandronate sodium. This study has important practical significance in improving drug safety and ensuring public health.


Subject(s)
Ibandronic Acid , Solvents , Chromatography, Gas/methods , Solvents/chemistry , Ibandronic Acid/analysis , Diphosphonates/analysis , Drug Contamination
15.
ACS Nano ; 18(17): 11165-11182, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38626338

ABSTRACT

Glioblastoma (GBM) is an aggressive brain cancer that is highly resistant to treatment including chimeric antigen receptor (CAR)-T cells. Tumor-associated microglia and macrophages (TAMs) are major contributors to the immunosuppressive GBM microenvironment, which promotes tumor progression and treatment resistance. Hence, the modulation of TAMs is a promising strategy for improving the immunotherapeutic efficacy of CAR-T cells against GBM. Molecularly targeting drug pexidartinib (PLX) has been reported to re-educate TAMs toward the antitumorigenic M1-like phenotype. Here, we developed a cell-drug integrated technology to reversibly conjugate PLX-containing liposomes (PLX-Lip) to CAR-T cells and establish tumor-responsive integrated CAR-T cells (PLX-Lip/AZO-T cells) as a combination therapy for GBM. We used a mouse model of GBM to show that PLX-Lip was stably maintained on the surface of PLX-Lip/AZO-T cells in circulation and these cells could transmigrate across the blood-brain barrier and deposit PLX-Lip at the tumor site. The uptake of PLX-Lip by TAMs effectively re-educated them into the M1-like phenotype, which in turn boosted the antitumor function of CAR-T cells. GBM tumor growth was completely eradicated in 60% of the mice after receiving PLX-Lip/AZO-T cells and extended their overall survival time beyond 50 days; in comparison, the median survival time of mice in other treatment groups did not exceed 35 days. Overall, we demonstrated the successful fusion of CAR-T cells and small-molecule drugs with the cell-drug integrated technology. These integrated CAR-T cells provided a superior combination strategy for GBM treatment and presented a reference for the construction of integrated cell-based drugs.


Subject(s)
Aminopyridines , Brain Neoplasms , Glioblastoma , Microglia , Receptors, Chimeric Antigen , Glioblastoma/therapy , Glioblastoma/pathology , Glioblastoma/immunology , Glioblastoma/drug therapy , Animals , Mice , Receptors, Chimeric Antigen/immunology , Receptors, Chimeric Antigen/metabolism , Humans , Microglia/drug effects , Microglia/metabolism , Microglia/immunology , Brain Neoplasms/therapy , Brain Neoplasms/immunology , Brain Neoplasms/pathology , Brain Neoplasms/drug therapy , Liposomes/chemistry , Pyrroles/chemistry , Pyrroles/pharmacology , Immunotherapy , Macrophages/immunology , Macrophages/metabolism , Macrophages/drug effects , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Cell Line, Tumor , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/drug effects , Tumor-Associated Macrophages/metabolism , Immunotherapy, Adoptive , T-Lymphocytes/immunology , T-Lymphocytes/drug effects
16.
Inorg Chem ; 63(15): 6787-6797, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38556762

ABSTRACT

The electrocatalytic reduction of NO2- (NO2RR) holds promise as a sustainable pathway to both promoting the development of emerging NH3 economies and allowing the closing of the NOx loop. Highly efficient electrocatalysts that could facilitate this complex six-electron transfer process are urgently desired. Herein, tremella-like CoNi-LDH intercalated by cyclic polyoxometalate (POM) anion P8W48 (P8W48/CoNi-LDH) prepared by a simple two-step hydrothermal-exfoliation assembly method is proposed as an effective electrocatalyst for NO2- to NH3 conversion. The introduction of POM with excellent redox ability tremendously increased the electrocatalytic performance of CoNi-LDH in the NO2RR process, causing P8W48/CoNi-LDH to exhibit large NH3 yield of 0.369 mmol h-1 mgcat-1 and exceptionally high Faradic efficiency of 97.0% at -1.3 V vs the Ag/AgCl reference electrode in 0.1 M phosphate buffer saline (PBS, pH = 7) containing 0.1 M NO2-. Furthermore, P8W48/CoNi-LDH demonstrated excellent durability during cyclic electrolysis. This work provides a new reference for the application of POM-based nanocomposites in the electrochemical reduction of NO2- to obtain value-added NH3.

17.
J Phys Chem A ; 128(17): 3311-3320, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38654690

ABSTRACT

Herein, we employed linear-response time-dependent functional theory nonadiabatic dynamic simulations to explore the photoinduced exciton dynamics of a chiral single-walled carbon nanotube CNT(6,5) covalently doped with a 4-nitrobenzyl group (CNT65-NO2). The results indicate that the introduction of a sp3 defect leads to the splitting of the degenerate VBM/VBM-1 and CBM/CBM+1 states. Both the VBM upshift and the CBM downshift are responsible for the experimentally observed redshifted E11* trapping state. The simulations reveal that the photoinduced exciton relaxation dynamics completes within 500 fs, which is consistent with the experimental work. On the other hand, we also conducted the nonadiabatic carrier (electron and hole) dynamic simulations, which completely ignore the excitonic effects. The comparison demonstrates that excitonic effects are indispensable. Deep analyses show that such effects induce several dark states, which play an important role in regulating the photoinduced dynamics of CNT65-NO2. The present work demonstrates the importance of including excitonic effects in simulating photoinduced processes of carbon nanotubes. In addition, it not only rationalizes previous experiments but also provides valuable insights that will help in the future rational design of novel covalently doped carbon nanotubes with superior photoluminescent properties.

18.
Eur J Clin Microbiol Infect Dis ; 43(5): 1031-1036, 2024 May.
Article in English | MEDLINE | ID: mdl-38472521

ABSTRACT

PURPOSE: We aimed to show the increasing incidence of invasive fungal infections due to Volvariella Volvacea in patients with immunosuppression. METHODS: We present a case of an invasive fungal infection caused by Volvariella volvacea, and summarize the clinical and pathological features based on this case and a review of the literature. RESULTS: A total of seven patients with IFIs due to Volvariella Volvacea have been reported in the literature. The majority of cases have been obtained between 2019 and 2022. Including our case, they all had acquired immunosuppression. The lung and brain were the most commonly affected organs. All eight of these patients received antifungal therapy, but five still died one to seven months after occurrences of IFIs. CONCLUSION: The incidence of invasive fungal infections due to Volvariella Volvacea is increasing in recent years. It mainly occurred in patients with immunosuppression, especially in patients with malignant hematological cancers, and increased mortality.


Subject(s)
Antifungal Agents , Invasive Fungal Infections , Volvariella , Humans , Volvariella/genetics , Invasive Fungal Infections/epidemiology , Invasive Fungal Infections/drug therapy , Invasive Fungal Infections/microbiology , Invasive Fungal Infections/mortality , Incidence , Male , Antifungal Agents/therapeutic use , Immunocompromised Host , Middle Aged , Female , Aged
19.
Heliyon ; 10(6): e28222, 2024 Mar 30.
Article in English | MEDLINE | ID: mdl-38545230

ABSTRACT

Recent studies have revealed that endophytes in plants can produce metabolites with activity that is comparable to or identical to the host. Dendrobine has attracted much attention in the field of neurodegenerative diseases by exhibiting anti-oxidative stress and neuroprotective effects. This study aimed to investigate the protective effects and mechanisms of metabolites of dendrobium endophytes Pseudomonas protegens CM-YJ44 and Priestia megaterium D-HT207 against H2O2-induced oxidative stress injury in SH-SY5Y cells. Results showed that there were 50 neuroprotective compounds in CM-YJ44 and 72 neuroprotective compounds in D-HT207. Those both increased significantly cell viability, decreased contents of ROS in H2O2-induced SH-SY5Y cells. It was confirmed that metabolites of CM-YJ44 and D-HT207 inhibited the H2O2-induced oxidative stress injury in SH-SY5Y cells, which mechanism is related to inhibition of ROS production, alteration of MMP, and inhibition of apoptosis and inflammatory factors expression via the Nrf2/Keap1 pathway.

20.
Huan Jing Ke Xue ; 45(3): 1349-1360, 2024 Mar 08.
Article in Chinese | MEDLINE | ID: mdl-38471851

ABSTRACT

Pollution variation, source characteristics, and meteorological effects of water-soluble inorganic ions (WSIIs) in PM2.5 were analyzed in Xinxiang city, Henan Province. PM2.5 samples and their chemical components were monitored online by using URG-9000 in four seasons:winter (January, 2022), spring (April, 2022), summer (July, 2022), and fall (October, 2022). The results showed that the TWSIIs had the same seasonal fluctuations as PM2.5. The average seasonal concentrations of WSIIs ranged from 19.62-72.15 µg·m-3, accounting for more than 60% of PM2.5, demonstrating that WSIIs were the major components of PM2.5. The annual concentration value of NO3-/SO42- was 2.11, which showed an increasing trend, suggesting predominantly mobile sources for secondary inorganic aerosols (SNA). Further, the molar concentration value [NH4+]/[NO3-] was 1.95, demonstrating that agriculture emissions were the dominant contributors to atmospheric nitrogen. Furthermore, the backward trajectory analysis showed that the concentrations of Ca2+ and Mg2+ were higher when the northeasterly wind prevailed and the wind speed was high. High values of SOR and NOR were correlated with low temperatures and high relative humidity (T < 8℃, RH > 60%), demonstrating that more gaseous precursors were converted into sulfate and nitrate. At high temperatures (T > 24℃), there was no apparent high NOR value like that for SOR, mainly due to the decomposition of NH4NO3 at high temperatures. Finally, backward trajectories associated with the PMF-resolved results were used to explore the regional transport characteristics. The results illustrated that dust sources in the study areas were mainly influenced by air trajectories originating from the northwest regions, whereas secondary sulfate, secondary nitrate, and biomass sources contributed more to WSIIs when wind speed and altitude air masses were low in the area surrounding the observation site.

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