ABSTRACT
The Crumbs homolog 1 (CRB1) gene is associated with retinal degeneration, most commonly Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Here, we demonstrate that murine retinas bearing the Rd8 mutation of Crb1 are characterized by the presence of intralesional bacteria. While normal CRB1 expression was enriched in the apical junctional complexes of retinal pigment epithelium and colonic enterocytes, Crb1 mutations dampened its expression at both sites. Consequent impairment of the outer blood retinal barrier and colonic intestinal epithelial barrier in Rd8 mice led to the translocation of intestinal bacteria from the lower gastrointestinal (GI) tract to the retina, resulting in secondary retinal degeneration. Either the depletion of bacteria systemically or the reintroduction of normal Crb1 expression colonically rescued Rd8-mutation-associated retinal degeneration without reversing the retinal barrier breach. Our data elucidate the pathogenesis of Crb1-mutation-associated retinal degenerations and suggest that antimicrobial agents have the potential to treat this devastating blinding disease.
Subject(s)
Nerve Tissue Proteins , Retinal Degeneration , Animals , Mice , Bacterial Translocation , Eye Proteins/genetics , Leber Congenital Amaurosis/genetics , Mutation , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Retina/metabolism , Retinal Degeneration/genetics , Retinitis Pigmentosa/genetics , Retinitis Pigmentosa/metabolism , Retinitis Pigmentosa/pathologyABSTRACT
Vemurafenib has been used as first-line therapy for unresectable or metastatic melanoma with BRAFV600E mutation. However, overall survival is still limited due to treatment resistance after about one year. Therefore, identifying new therapeutic targets for melanoma is crucial for improving clinical outcomes. In the present study, we found that lowering intracellular cholesterol by knocking down DHCR24, the limiting synthetase, impaired tumor cell proliferation and migration and abrogated the ability to xenotransplant tumors. More importantly, administration of DHCR24 or cholesterol mediated resistance to vemurafenib and promoted the growth of melanoma spheroids. Mechanistically, we identified that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol synthesized by the enzyme cytochrome P450 27A1 (CYP27A1), reproduces the phenotypes induced by DHCR24 or cholesterol administration and activates Rap1-PI3K/AKT signaling. Accordingly, CYP27A1 is highly expressed in melanoma patients and upregulated by DHCR24 induction. Dafadine-A, a CYP27A1 inhibitor, attenuates cholesterol-induced growth of melanoma spheroids and abrogates the resistance property of vemurafenib-resistant melanoma cells. Finally, we confirmed that the effects of cholesterol on melanoma resistance require its metabolite 27HC through CYP27A1 catalysis, and that 27HC further upregulates Rap1A/Rap1B expression and increases AKT phosphorylation. Thus, our results suggest that targeting 27HC may be a useful strategy to overcome treatment resistance in metastatic melanoma.
Subject(s)
Cell Proliferation , Cholestanetriol 26-Monooxygenase , Cholesterol , Hydroxycholesterols , Melanoma , Neoplastic Stem Cells , Vemurafenib , Vemurafenib/pharmacology , Vemurafenib/therapeutic use , Humans , Melanoma/drug therapy , Melanoma/pathology , Melanoma/metabolism , Melanoma/genetics , Hydroxycholesterols/metabolism , Hydroxycholesterols/pharmacology , Animals , Cell Proliferation/drug effects , Cholestanetriol 26-Monooxygenase/metabolism , Cholestanetriol 26-Monooxygenase/genetics , Cholesterol/metabolism , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , Cell Line, Tumor , Mice , Drug Resistance, Neoplasm/drug effects , Signal Transduction/drug effects , Cell Movement/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Rapid detection of pathogenic bacteria within a few minutes is the key to control infectious disease. However, rapid detection of pathogenic bacteria in clinical samples is quite a challenging task due to the complex matrix, as well as the low abundance of bacteria in real samples. Herein, we employ a label-free single-particle imaging approach to address this challenge. By tracking the scattering intensity variation of single particles in free solution, the morphological heterogeneity can be well identified with particle size smaller than the diffraction limit, facilitating the morphological identification of single bacteria from a complex matrix in a label-free manner. Furthermore, the manipulation of convection in free solution enables the rapid screening of low-abundance bacteria in a small field of view, which significantly improves the sensitivity of single-particle detection. As a proof of concept demonstration, we are able to differentiate the group B streptococci (GBS)-positive samples within 10 min from vaginal swabs without using any biological reagents. This is the most rapid and low-cost method to the best of our knowledge. We believe that such a single-particle imaging approach will find wider applications in clinical diagnosis and disease control due to its high sensitivity, rapidity, simplicity, and low cost.
Subject(s)
Bacteria , Communicable Diseases , Single-Cell Analysis , Bacteria/isolation & purification , Bacteria/pathogenicity , Communicable Diseases/diagnostic imaging , Female , Humans , Particle Size , Single-Cell Analysis/methods , Vaginal SmearsABSTRACT
Metal ions play an important role in living organisms and are involved in essential physiological activities. However, the overload state of ions can cause excess free radicals, cell damage, and even cell death. Ferroptosis and cuproptosis are specific forms of cell death that are distinct from apoptosis, necroptosis, and other regulated cell death. These unique modalities of cell death, dependent on iron and copper, are regulated by multiple cellular metabolic pathways, including steady-state metal redox treatment mitochondrial activity of lipid, amino acid and glucose metabolism, and various signaling pathways associated with disease. Although the mechanisms of ferroptosis and cuproptosis are not yet fully understood, there is no doubt that ion overload plays a crucial act in these metal-dependent cell deaths. In this review, we discussed the core roles of ion overload in ferroptosis and cuproptosis, the association between metabolism imbalance and ferroptosis and cuproptosis, the extract the diseases caused by ion overload and current treatment modalities.
Subject(s)
Ferroptosis , Kidney Diseases , Regulated Cell Death , Humans , Ferroptosis/genetics , Apoptosis , IonsABSTRACT
Chloroplasts play a crucial role in plant defense against pathogens, making them primary targets for pathogen effectors that suppress host immunity. This study characterizes the Plasmopara viticola CRN-like effector, PvCRN20, which interacts with DEG5 in the cytoplasm but not with its interacting protein, DEG8, which is located in the chloroplast. By transiently overexpressing in tobacco leaves, we show that PvCRN20 could inhibit INF1- and Bax-triggered cell death. Constitutive expression of PvCRN20 suppresses the accumulation of reactive oxygen species (ROS) and promotes pathogen colonization. PvCRN20 reduces DEG5 entry into chloroplasts, thereby disrupting DEG5 and DEG8 interactions in chloroplasts. Overexpression of VvDEG5 and VvDEG8 induces ROS accumulation and enhances grapevine resistance to P. viticola, whereas knockout of VvDEG8 represses ROS production and promotes P. viticola colonization. Consistently, ectopic expression of VvDEG5 and VvDEG8 in tobacco promotes chloroplast-derived ROS accumulation, whereas co-expression of PvCRN20 counteracted this promotion by VvDEG5. Therefore, DEG5 is essential for the virulence function of PvCRN20. Although PvCRN20 is located in both the nucleus and cytoplasm, only cytoplasmic PvCRN20 suppresses plant immunity and promotes pathogen infection. Our results reveal that PvCRN20 dampens plant defenses by repressing the chloroplast import of DEG5, thus reducing host ROS accumulation and facilitating pathogen colonization.
Subject(s)
Chloroplasts , Nicotiana , Plant Diseases , Plant Immunity , Plant Proteins , Protein Transport , Reactive Oxygen Species , Vitis , Chloroplasts/metabolism , Vitis/microbiology , Vitis/genetics , Vitis/metabolism , Reactive Oxygen Species/metabolism , Plant Proteins/metabolism , Plant Proteins/genetics , Plant Diseases/microbiology , Plant Diseases/immunology , Nicotiana/microbiology , Nicotiana/genetics , Nicotiana/immunology , Gene Expression Regulation, Plant , Oomycetes/pathogenicity , Plant Leaves/microbiology , Plant Leaves/metabolism , Plants, Genetically Modified , Disease Resistance/geneticsABSTRACT
Soil contamination with arsenic (As) can cause phytotoxicity and reduce crop yield. The mechanisms of As toxicity and tolerance are not fully understood. In this study, we used a forward genetics approach to isolate a rice mutant, ahs1, that exhibits hypersensitivity to both arsenate and arsenite. Through genomic resequencing and complementation tests, we identified OsLPD1 as the causal gene, which encodes a putative lipoamide dehydrogenase. OsLPD1 was expressed in the outer cell layer of roots, root meristem cells, and in the mesophyll and vascular tissues of leaves. Subcellular localization and immunoblot analysis demonstrated that OsLPD1 is localized in the stroma of plastids. In vitro assays showed that OsLPD1 exhibited lipoamide dehydrogenase (LPD) activity, which was strongly inhibited by arsenite, but not by arsenate. The ahs1 and OsLPD1 knockout mutants exhibited significantly reduced NADH/NAD+ and GSH/GSSG ratios, along with increased levels of reactive oxygen species and greater oxidative stress in the roots compared with wild-type (WT) plants under As treatment. Additionally, loss-of-function of OsLPD1 also resulted in decreased fatty acid concentrations in rice grain. Taken together, our finding reveals that OsLPD1 plays an important role for maintaining redox homeostasis, conferring tolerance to arsenic stress, and regulating fatty acid biosynthesis in rice.
Subject(s)
Arsenic , Dihydrolipoamide Dehydrogenase , Fatty Acids , Homeostasis , Oryza , Plant Proteins , Stress, Physiological , Adaptation, Physiological/drug effects , Adaptation, Physiological/genetics , Arsenic/toxicity , Arsenites/toxicity , Dihydrolipoamide Dehydrogenase/metabolism , Dihydrolipoamide Dehydrogenase/genetics , Fatty Acids/biosynthesis , Gene Expression Regulation, Plant/drug effects , Mutation/genetics , Oryza/genetics , Oryza/drug effects , Oryza/metabolism , Oxidation-Reduction/drug effects , Oxidative Stress/drug effects , Plant Proteins/metabolism , Plant Proteins/genetics , Plant Roots/drug effects , Plant Roots/metabolism , Plastids/metabolism , Plastids/drug effects , Reactive Oxygen Species/metabolism , Stress, Physiological/drug effects , Stress, Physiological/geneticsABSTRACT
Waterlogging stress (WS) hinders kernel development and directly reduces peanut yield; however, the mechanism of kernel filling in response to WS remains unknown. The waterlogging-sensitive variety Huayu 39 was subjected to WS for 3 days at 7 days after the gynophores touched the ground (DAG). We found that WS affected kernel filling at 14, 21, and 28 DAG. WS decreased the average filling rate and kernel dry weight, while transcriptome sequencing and widely targeted metabolomic analysis revealed that WS inhibited the gene expression in starch and sucrose metabolism, which reduced sucrose input and transformation ability. Additionally, genes related to ethylene and melatonin synthesis and the accumulation of tryptophan and methionine were upregulated in response to WS. WS upregulated the expression of the gene encoding tryptophan decarboxylase (AhTDC), and overexpression of AhTDC in Arabidopsis significantly reduced the seed length, width, and weight. Therefore, WS reduced the kernel-filling rate, leading to a reduction in the 100-kernel weight. This survey informs the development of measures that alleviate the negative impact of WS on peanut yield and quality and provides a basis for exploring high-yield and high-quality cultivation, molecular-assisted breeding, and waterlogging prevention in peanut farming.
Subject(s)
Arachis , Seeds , Stress, Physiological , Transcriptome , Arachis/genetics , Arachis/physiology , Arachis/metabolism , Arachis/growth & development , Seeds/physiology , Seeds/genetics , Seeds/growth & development , Seeds/metabolism , Gene Expression Regulation, Plant , Water/metabolism , Metabolomics , Gene Expression Profiling , Metabolome , Sucrose/metabolism , Arabidopsis/genetics , Arabidopsis/physiology , Arabidopsis/metabolism , Starch/metabolismABSTRACT
OBJECTIVES: Inflammatory proteins are implicated in the progression of abdominal aortic aneurysms (AAA); however, it remains debated whether they are causal or consequential. This study aimed to assess the influence of circulating inflammatory proteins on AAA via two-sample Mendelian randomization (MR) and colocalization analysis. METHODS: Summary data on 91 circulating inflammatory protein levels were extracted from a comprehensive protein quantitative trait loci (pQTL) study involving 14,824 individuals. Genetic associations with AAA were derived from the FinnGen study (3,869 cases and 381,977 controls). MR analysis was conducted to assess the relationships between proteins and AAA risk. Colocalization analysis was employed to explore potential shared causal variants between identified proteins and AAA. RESULTS: Using a two-sample bidirectional MR study, our findings suggested that genetically predicted elevated levels of TGFB1 (OR = 1.21, P = 0.003), SIRT2 (OR = 1.196, P = 0.031) and TNFSF14 (OR = 1.129, P = 0.034) were linked to an increased risk of AAA. Conversely, genetically predicted higher levels of CD40 (OR = 0.912, P = 0.049), IL2RB (OR = 0.839, P = 0.028) and KITLG (OR = 0.827, P = 0.008) were associated with a decreased risk of AAA. Colocalization analyses supported the association of TGFB1 and SIRT2 levels with AAA risk. CONCLUSIONS: The proteome-wide MR and colocalization study identified TGFB1 and SIRT2 as being associated with the risk of AAA, warranting further investigation as potential therapeutic targets.
Subject(s)
Aortic Aneurysm, Abdominal , Mendelian Randomization Analysis , Quantitative Trait Loci , Aortic Aneurysm, Abdominal/genetics , Aortic Aneurysm, Abdominal/blood , Aortic Aneurysm, Abdominal/metabolism , Humans , Mendelian Randomization Analysis/methods , Inflammation/blood , Inflammation/genetics , Inflammation/metabolism , Male , Risk Factors , Female , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide/geneticsABSTRACT
We report, to the best of our knowledge, the first demonstration of an O + E-band tunable watt-level bismuth-doped phosphosilicate fiber laser and its frequency doubling to tunable red laser. Benefiting from the two types of bismuth active centers associated with silicon and phosphorus introduced in one fiber, an ultrabroad gain is available in the designed low-water-peak bismuth-doped phosphosilicate fiber (Bi-PSF) pumped by a self-made 1239 nm Raman fiber laser. The high-efficiency tunable lasing is achieved with a maximum output power of 1.705 W around 1320 nm and a slope efficiency of 33.0%. The wavelength can be continuously tuned from 1283 to 1460 nm over a 177 nm spectral range, almost covering the whole O+E-bands. We further employ a polarization beam splitter in the cavity to output an O + E-band linear-polarization laser for second-harmonic generation by a designed multi-period MgO2:PPLN crystal, and a 650-690-nm tunable visible laser is correspondingly obtained. Such an O+E-wideband tunable high-power laser and the SHG red laser may have great potential in the all-band optical communications, biophotonics, and spectroscopy.
ABSTRACT
BACKGROUND: The identification of survival predictors is crucial for early intervention to improve outcome in acute myeloid leukemia (AML). This study aim to identify chest computed tomography (CT)-derived features to predict prognosis for acute myeloid leukemia (AML). METHODS: 952 patients with pathologically-confirmed AML were retrospectively enrolled between 2010 and 2020. CT-derived features (including body composition and subcutaneous fat features), were obtained from the initial chest CT images and were used to build models to predict the prognosis. A CT-derived MSF nomogram was constructed using multivariate Cox regression incorporating CT-based features. The performance of the prediction models was assessed with discrimination, calibration, decision curves and improvements. RESULTS: Three CT-derived features, including myosarcopenia, spleen_CTV, and SF_CTV (MSF) were identified as the independent predictors for prognosis in AML (P < 0.01). A CT-MSF nomogram showed a performance with AUCs of 0.717, 0.794, 0.796 and 0.792 for predicting the 1-, 2-, 3-, and 5-year overall survival (OS) probabilities in the validation cohort, which were significantly higher than the ELN risk model. Moreover, a new MSN stratification system (MSF nomogram plus ELN risk model) could stratify patients into new high, intermediate and low risk group. Patients with high MSN risk may benefit from intensive treatment (P = 0.0011). CONCLUSIONS: In summary, the chest CT-MSF nomogram, integrating myosarcopenia, spleen_CTV, and SF_CTV features, could be used to predict prognosis of AML.
Subject(s)
Leukemia, Myeloid, Acute , Nomograms , Humans , Retrospective Studies , Tomography, X-Ray Computed , Area Under Curve , Leukemia, Myeloid, Acute/diagnostic imagingABSTRACT
Epigenetic regulation of lineage-specific genes is important for the differentiation and function of T cells. Ten-eleven translocation (Tet) proteins catalyze 5-methylcytosine (5 mC) conversion to 5-hydroxymethylcytosine (5 hmC) to mediate DNA demethylation. However, the roles of Tet proteins in the immune response are unknown. Here, we characterized the genome-wide distribution of 5 hmC in CD4(+) T cells and found that 5 hmC marks putative regulatory elements in signature genes associated with effector cell differentiation. Moreover, Tet2 protein was recruited to 5 hmC-containing regions, dependent on lineage-specific transcription factors. Deletion of Tet2 in T cells decreased their cytokine expression, associated with reduced p300 recruitment. In vivo, Tet2 plays a critical role in the control of cytokine gene expression in autoimmune disease. Collectively, our findings suggest that Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells.
Subject(s)
Cytokines/biosynthesis , DNA-Binding Proteins/immunology , Epigenesis, Genetic/immunology , Proto-Oncogene Proteins/immunology , Th1 Cells/immunology , Th17 Cells/immunology , 5-Methylcytosine/analogs & derivatives , Animals , Cell Differentiation , Cytokines/immunology , Cytosine/analogs & derivatives , Cytosine/immunology , Cytosine/metabolism , DNA/immunology , DNA/metabolism , DNA Methylation , DNA-Binding Proteins/genetics , Dioxygenases , E1A-Associated p300 Protein/genetics , E1A-Associated p300 Protein/immunology , Gene Expression Regulation , Genome , Humans , Mice , Mice, Transgenic , Proto-Oncogene Proteins/genetics , STAT4 Transcription Factor/genetics , STAT4 Transcription Factor/immunology , T-Box Domain Proteins/genetics , T-Box Domain Proteins/immunology , Th1 Cells/cytology , Th1 Cells/enzymology , Th17 Cells/cytology , Th17 Cells/enzymologyABSTRACT
BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is caused by perinatal hypoxia and subsequent reductions in cerebral blood flow and is one of the leading causes of severe disability or death in newborns. Despite its prevalence, we currently lack an effective drug therapy to combat HIE. Celastrol (Cel) is a pentacyclic triterpene extracted from Tripterygium Wilfordi that can protect against oxidative stress, inflammation, and cancer. However, whether Cel can alleviate neonatal hypoxic-ischemic (HI) brain damage remains unclear. METHODS: Here, we established both in vitro and in vivo models of HI brain damage using CoCl2-treated PC12 cells and neonatal rats, respectively, and explored the neuroprotective effects of Cel in these models. RESULTS: Analyses revealed that Cel administration reduced brain infarction size, microglia activation, levels of inflammation factors, and levels of oxidative stress markers by upregulating levels of p-AMPKα, Nrf2, HO-1, and by downregulating levels of TXNIP and NLRP3. Conversely, these beneficial effects of Cel on HI brain damage were largely inhibited by AMPKα inhibitor Compound C and its siRNA. CONCLUSIONS: We present compelling evidence that Cel decreases inflammation and oxidative stress through the AMPKα/Nrf2/TXNIP signaling pathway, thereby alleviating neonatal HI brain injury. Cel therefore represents a promising therapeutic agent for treating HIE. IMPACT: We firstly report that celastrol can ameliorate neonatal hypoxic-ischemic brain injury both in in vivo and in vitro, which represents a promising therapeutic agent for treating related brain injuries. Celastrol activates the AMPKα/Nrf2/TXNIP signaling pathway to relieve oxidative stress and inflammation and thereby alleviates neonatal hypoxic-ischemic brain injury.
ABSTRACT
We have developed a metal-free photocatalytic selective hydroxylation of benzylic methylenes to secondary alcohols. This approach utilizes low-cost eosin Y as photocatalyst, O2 as green oxidant, and inexpensive triethylamine as inhibitor for overoxidation. The mild reaction conditions enable the production of secondary alcohols with 56-95% yields, making it a promising and environmental-friendly method for the synthesis of secondary alcohols from benzylic methylenes.
ABSTRACT
BACKGROUND: Benign prostatic hyperplasia (BPH) affects 30% of men worldwide, folate is essential for life. However, few studies have investigated the relationship between folate levels and BPH. The present study aims to explore the relationship between red blood cell (RBC) folate, a better indicator of long-term folate intake, and BPH in United States (US) men. METHODS: We used statistics from four cycles of the "National Health and Nutrition Examination Survey" (NHANES2001-2008), RBC folate data come from laboratory data and BPH date come from questionnaire data. A multivariate conditional logistic regression model and subgroup analysis were using to assess the association between RBC folate and BPH. RESULTS: 647 males from four survey cycles in the NHANES2001-2008, of which, 574 men (88.7%) had BPH. After adjusting for potential confounders, a considerable correlation was observed between RBC folate and BPH; With the first quintiles of RBC folate as the reference, multivariable-adjusted odds ratios (ORs) and confidence intervals (95% CIs) of the second, third, fourth, and the highest quintiles were 1.19 (0.58 â¼ 2.44), 1.39 (0.65 â¼ 2.97), 2.27 (0.96 â¼ 5.39), 2.26 (1.35 â¼ 3.76) and 5.37 (1.85 â¼ 15.59), respectively. CONCLUSIONS: Individuals with high levels of RBC folate were associated with an increased risk of self-reported benign prostatic hyperplasia of US men.
Subject(s)
Erythrocytes , Folic Acid , Nutrition Surveys , Prostatic Hyperplasia , Humans , Male , Prostatic Hyperplasia/blood , Prostatic Hyperplasia/epidemiology , Folic Acid/blood , Middle Aged , United States/epidemiology , Erythrocytes/chemistry , Erythrocytes/metabolism , Aged , Adult , Logistic Models , Risk FactorsABSTRACT
Gout is a self-limited inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints and surrounding tissues due to abnormal purine metabolism. Neutrophil extracellular traps (NETs) are formed by neutrophils in response to pathogen attack. During gout, NETs induced by MSU crystals exacerbate inflammation, and aggregated NETs (aggNETs) promote the resolution of gout-associated inflammation by encapsulating MSU crystals, degrading cytokines and chemokines, and blocking the recruitment and activation of neutrophils. With disease progression, NETs participate in the formation of tophi. Therefore, aggNETs are a possible mechanism of spontaneous gout regression. Studying the specific mechanism by which NETs affect inflammatory bursts and spontaneous regression in gout patients is important. This review summarises the role of NETs in different stages of gout and the specific pathogenesis of NETs in gout to provide new ideas for the diagnosis and treatment of gout.
ABSTRACT
Artificial photosynthesis provides a sustainable strategy for producing usable fuels and fine chemicals and attracts broad research interest. However, conventional approaches suffer from low reactivity or low selectivity. Herein, we demonstrate that photocatalytic reduction of CO2 coupled with selective oxidation of aromatic alcohol into corresponding syngas and aromatic aldehydes can be processed efficiently and fantastically over the designed S-scheme ZnIn2S4@CdS core-shell hollow nanocage under visible light. In the ZnIn2S4@CdS heterostructure, the photoexcited electrons and holes with weak redox capacities are eliminated, while the photoexcited electrons and holes with powder redox capacities are separated spatially and preserved on the desired active sites. Therefore, even if there are no cocatalysts and no vacancies, ZnIn2S4@CdS exhibits high reactivity. For instance, the CO production of ZnIn2S4@CdS is about 3.2 and 3.4 times higher than that of pure CdS and ZnIn2S4, respectively. More importantly, ZnIn2S4@CdS exhibits general applicability and high photocatalytic stability. Trapping agent experiments, 13CO2 isotopic tracing, in situ characterizations, and theoretical calculations reveal the photocatalytic mechanism. This study provides a new strategy to design efficient and selective photocatalysts for dual-function redox reactions by tailoring the active sites and regulating vector separation of photoexcited charge carriers.
ABSTRACT
Compared to the effect of the active hydrogen atom in the cation in protic ionic liquids (ILs) on their properties and applications, there are very few reports on the role of the active hydrogen atom in the anion. In order to better understand the role of the active hydrogen atom in the anion, the physical properties, CO2 capture and conversion of three hydantoin-based anion-functionalized ILs ([P4442][Hy], [P4442]2[Hy], and [HDBU][Hy]) have been investigated via experiments, spectroscopy, and DFT calculations in this work. The results show that the active hydrogen atom in the anion can form anionic hydrogen bonding networks, which significantly increase the melting point and viscosity and decrease the basicity of the IL, thereby weakening its ability to capture and convert CO2. Interestingly, [P4442][Hy] undergoes a solid/liquid two-phase transition during CO2 absorption/desorption due to the formation of quasi-intramolecular hydrogen bonding between the active hydrogen atom and the O- atom of the absorbed CO2, suggesting that the presence of the active hydrogen atom gives [P4442][Hy] the potential to be an excellent molecular switch. As there is no active hydrogen atom in the anion of [P4442]2[Hy], it shows excellent CO2 capture and conversion performance through the double-site interaction. [HDBU][Hy] shows the weakest catalytic CO2 conversion due to the presence of active hydrogen atoms on both its anion and cation. Therefore, the active hydrogen atom in the anion may play a more important role in the properties and potential applications of ILs than the active hydrogen atom in the cation.
ABSTRACT
Dysfunctional T cells in the tumour microenvironment have abnormally high expression of PD-1 and antibody inhibitors against PD-1 or its ligand (PD-L1) have become commonly used drugs to treat various types of cancer1-4. The clinical success of these inhibitors highlights the need to study the mechanisms by which PD-1 is regulated. Here we report a mechanism of PD-1 degradation and the importance of this mechanism in anti-tumour immunity in preclinical models. We show that surface PD-1 undergoes internalization, subsequent ubiquitination and proteasome degradation in activated T cells. FBXO38 is an E3 ligase of PD-1 that mediates Lys48-linked poly-ubiquitination and subsequent proteasome degradation. Conditional knockout of Fbxo38 in T cells did not affect T cell receptor and CD28 signalling, but led to faster tumour progression in mice owing to higher levels of PD-1 in tumour-infiltrating T cells. Anti-PD-1 therapy normalized the effect of FBXO38 deficiency on tumour growth in mice, which suggests that PD-1 is the primary target of FBXO38 in T cells. In human tumour tissues and a mouse cancer model, transcriptional levels of FBXO38 and Fbxo38, respectively, were downregulated in tumour-infiltrating T cells. However, IL-2 therapy rescued Fbxo38 transcription and therefore downregulated PD-1 levels in PD-1+ T cells in mice. These data indicate that FBXO38 regulates PD-1 expression and highlight an alternative method to block the PD-1 pathway.
Subject(s)
F-Box Proteins/genetics , Neoplasms/immunology , Programmed Cell Death 1 Receptor/metabolism , T-Lymphocytes/immunology , Ubiquitination , Animals , F-Box Proteins/metabolism , Female , HEK293 Cells , Humans , Interleukin-2/immunology , Lysine/metabolism , Male , Melanoma, Experimental/immunology , Mice , Programmed Cell Death 1 Receptor/chemistry , Proteasome Endopeptidase Complex/metabolism , Tumor MicroenvironmentABSTRACT
BACKGROUND: Poly ADP-ribose polymerase inhibitors (PARPi) treatment has radically changed the treatment strategy for epithelial ovarian cancer. Cancer progression with PARPi maintenance is a new problem that has arisen in clinical practice, and the value of secondary cytoreduction surgery remains unknown. PRIMARY OBJECTIVE: To evaluate the benefits of secondary cytoreductive surgery and to clarify the sensitivity to platinum in patients with firstline or secondline recurrent epithelial ovarian cancer who have completed ≥6 months of PARPi maintenance. STUDY HYPOTHESIS: Carefully selected patients who progress on PARPi maintenance will benefit from secondary cytoreductive surgery. TRIAL DESIGN: This is a multicenter phase III trial. Eligible patients will be randomly assigned at a ratio of 1:1 to either the experimental or standard arm. Patients in the experimental arm will receive secondary cytoreductive surgery followed by platinum based chemotherapy, while patients in the standard arm will be provided with chemotherapy alone. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients diagnosed with firstline or secondline recurrent epithelial ovarian cancer who had previously received ≥4 cycles of platinum based chemotherapy in initial treatment followed by PARPi maintenance therapy for ≥6 months prior to recurrence. PRIMARY ENDPOINT: Progression free survival. SAMPLE SIZE: 400 patients. ESTIMATED DATES FOR COMPETING ACCRUAL AND PRESENTING RESULTS: Accrual completion is expected in December 2024 with results mature after 2 years of follow-up in 2026. TRIAL REGISTRATION: ClinicalTrials.gov NCT05607329.
Subject(s)
Carcinoma, Ovarian Epithelial , Cytoreduction Surgical Procedures , Neoplasm Recurrence, Local , Ovarian Neoplasms , Poly(ADP-ribose) Polymerase Inhibitors , Humans , Female , Carcinoma, Ovarian Epithelial/surgery , Carcinoma, Ovarian Epithelial/drug therapy , Cytoreduction Surgical Procedures/methods , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/surgery , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/surgery , Ovarian Neoplasms/pathology , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Middle Aged , AdultABSTRACT
Hair analysis is a crucial method in forensic toxicology with potential applications in revealing doping histories in sports. Despite its widespread use, knowledge about detectable substances in hair is limited. This study systematically assessed the detectability of prohibited substances in sports using a multifaceted approach. Initially, an animal model received a subset of 17 model drugs to compare dose dependencies and detection windows across different matrices. Subsequently, hair incorporation data from the animal experiment were extrapolated to all substances on the World Anti-Doping Agency's List through in-silico prediction. The detectability of substances in hair was further validated in a proof-of-concept human study involving the consumption of diuretics and masking agents. Semi-quantitative analysis of substances in specimens was performed using ultra-performance liquid chromatography-tandem mass spectrometry. Results showed plasma had optimal dose dependencies with limited detection windows, while urine, faeces, and hair exhibited a reasonable relationship with the administered dose. Notably, hair displayed the highest detection probability (14 out of 17) for compounds, including anabolic agents, hormones, and diuretics, with beta-2 agonists undetected. Diuretics such as furosemide, canrenone, and hydrochlorothiazide showed the highest hair incorporation. Authentic human hair confirmed diuretic detectability, and their use duration was determined via segmental analysis. Noteworthy is the first-time reporting of canrenone in human hair. Anabolic agents were expected in hair, whereas undetectable compounds, such as peptide hormones and beta-2 agonists, were likely due to large molecular mass or high polarity. This study enhances understanding of hair analysis in doping investigations, providing insights into substance detectability.