ABSTRACT
Ag-specific effector CD4+ T cells play a crucial role in defending against exogenous pathogens. However, the mechanisms governing the differentiation and function of IFN-γ-producing effector CD4+ Th1 cells in immune responses remain largely unknown. In this study, we elucidated the pivotal role of zinc finger protein 335 (Zfp335) in regulating effector Th1 cell differentiation and survival during acute bacterial infection. Mice with Zfp335 knockout in OT-II cells exhibited impaired Ag-specific CD4+ T cell expansion accompanied by a significant reduction in resistance to Listeria infection. Furthermore, Zfp335 deficiency restricted the effector CD4+ Th1 cell population and compromised their survival upon Listeria challenge. The expression of T-bet and IFN-γ was accordingly decreased in Zfp335-deficient Th1 cells. Mechanistically, Zfp335 directly bound to the promoter region of the Lmna gene and regulated its expression. Overexpression of Lmna was able to rescue the survival and function of Zfp335-deficient effector Th1 cells. Therefore, our study provides novel insights into the mechanisms governing effector Th1 cell differentiation and survival during acute infection.
Subject(s)
Cell Differentiation , DNA-Binding Proteins , Lamin Type A , Mice, Knockout , Th1 Cells , Transcription Factors , Animals , Mice , Cell Differentiation/immunology , Cell Differentiation/genetics , Cell Survival/genetics , Cell Survival/immunology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Expression Regulation/immunology , Interferon-gamma/immunology , Interferon-gamma/metabolism , Lamin Type A/genetics , Listeriosis/immunology , Mice, Inbred C57BL , Th1 Cells/immunology , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Diabetic cardiomyopathy (DCM) is a prevalent complication of type 2 diabetes (T2D). 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a glycolysis regulator. However, the potential effects of PFKFB3 in the DCM remain unclear. In comparison to db/m mice, PFKFB3 levels decreased in the hearts of db/db mice. Cardiac-specific PFKFB3 overexpression inhibited myocardial oxidative stress and cardiomyocyte apoptosis, suppressed mitochondrial fragmentation, and partly restored mitochondrial function in db/db mice. Moreover, PFKFB3 overexpression stimulated glycolysis. Interestingly, based on the inhibition of glycolysis, PFKFB3 overexpression still suppressed oxidative stress and apoptosis of cardiomyocytes in vitro, which indicated that PFKFB3 overexpression could alleviate DCM independent of glycolysis. Using mass spectrometry combined with co-immunoprecipitation, we identified optic atrophy 1 (OPA1) interacting with PFKFB3. In db/db mice, the knockdown of OPA1 receded the effects of PFKFB3 overexpression in alleviating cardiac remodeling and dysfunction. Mechanistically, PFKFB3 stabilized OPA1 expression by promoting E3 ligase NEDD4L-mediated atypical K6-linked polyubiquitination and thus prevented the degradation of OPA1 by the proteasomal pathway. Our study indicates that PFKFB3/OPA1 could be potential therapeutic targets for DCM.
Subject(s)
Diabetic Cardiomyopathies , GTP Phosphohydrolases , Myocytes, Cardiac , Phosphofructokinase-2 , Ubiquitination , Phosphofructokinase-2/metabolism , Phosphofructokinase-2/genetics , Animals , Diabetic Cardiomyopathies/metabolism , Diabetic Cardiomyopathies/pathology , Diabetic Cardiomyopathies/genetics , Mice , GTP Phosphohydrolases/metabolism , GTP Phosphohydrolases/genetics , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Male , Oxidative Stress , Apoptosis/genetics , Myocardium/metabolism , Myocardium/pathology , Mice, Inbred C57BL , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/genetics , Glycolysis , Humans , Protein StabilityABSTRACT
Xylomyrocins, a unique group of nonribosomal peptide secondary metabolites, were discovered in Paramyrothecium and Colletotrichum spp. fungi by employing a combination of high-resolution tandem mass spectrometry (HRMS/MS)-based chemometrics, comparative genome mining, gene disruption, stable isotope feeding, and chemical complementation techniques. These polyol cyclodepsipeptides all feature an unprecedented d-xylonic acid moiety as part of their macrocyclic scaffold. This biosynthon is derived from d-xylose supplied by xylooligosaccharide catabolic enzymes encoded in the xylomyrocin biosynthetic gene cluster, revealing a novel link between carbohydrate catabolism and nonribosomal peptide biosynthesis. Xylomyrocins from different fungal isolates differ in the number and nature of their amino acid building blocks that are nevertheless incorporated by orthologous nonribosomal peptide synthetase (NRPS) enzymes. Another source of structural diversity is the variable choice of the nucleophile for intramolecular macrocyclic ester formation during xylomyrocin chain termination. This nucleophile is selected from the multiple available alcohol functionalities of the polyol moiety, revealing a surprising polyspecificity for the NRPS terminal condensation domain. Some xylomyrocin congeners also feature N-methylated amino acid residues in positions where the corresponding NRPS modules lack N-methyltransferase (M) domains, providing a rare example of promiscuous methylation in the context of an NRPS with an otherwise canonical, collinear biosynthetic program.
Subject(s)
Depsipeptides , Fungal Proteins , Fungi , Amino Acids/chemistry , Carbohydrate Metabolism , Chemometrics , Depsipeptides/chemistry , Depsipeptides/genetics , Fungal Proteins/chemistry , Fungal Proteins/genetics , Fungi/genetics , Fungi/metabolism , Multigene Family , Peptide Biosynthesis, Nucleic Acid-Independent , Peptide Synthases/chemistry , SugarsABSTRACT
The deubiquitinating enzyme OTUB1 possesses canonical deubiquitinase (DUB) activity and noncanonical, catalytic-independent activity, which has been identified as an essential regulator of diverse physiological processes. Posttranslational modifications of OTUB1 affect both its DUB activity and its noncanonical activity of binding to the E2 ubiquitin-conjugation enzyme UBC13, but further investigation is needed to characterize the full inventory of modifications to OTUB1. Here, we demonstrate that SET7, a lysine monomethylase, directly interacts with OTUB1 to catalyze OTUB1 methylation at lysine 122. This modification does not affect DUB activity of OTUB1 but impairs its noncanonical activity, binding to UBC13. Moreover, we found using cell viability analysis and intracellular reactive oxygen species assay that SET7-mediated methylation of OTUB1 relieves its suppressive role on ferroptosis. Notably, the methylation-mimic mutant of OTUB1 not only loses the ability to bind to UBC13 but also relieves its suppressive role on Tert-Butyl hydroperoxide-induced cell death and Cystine starvation/Erastin-induced cellular reactive oxygen species. Collectively, our data identify a novel modification of OTUB1 that is critical for inhibiting its noncanonical activity.
Subject(s)
Deubiquitinating Enzymes , Ferroptosis , Histone-Lysine N-Methyltransferase , Ubiquitin-Conjugating Enzymes , Deubiquitinating Enzymes/metabolism , Lysine/metabolism , Protein Binding , Reactive Oxygen Species/metabolism , Ubiquitination , Humans , Histone-Lysine N-Methyltransferase/metabolismABSTRACT
The avermectin derivative doramectin is widely used clinically as an antiparasitic drug and, in addition, doramectin may have a modulatory role in obesity. Adipose tissue macrophage recruitment and polarization play an important role in obesity-induced inflammation and insulin resistance. The aim of this study was to investigate the effects of doramectin on high-fat diet-induced inflammation and macrophage polarization in white adipose tissue of epididymis of obese mice. We found that compared with high-fat diet-fed obese mice, doramectin treatment resulted in a significant decrease in body weight and lipid levels, improved insulin resistance, an increase in the proportion of M2-type macrophages and a decrease in the proportion of M1-type macrophages in the epididymal white adipose tissues, as well as a decrease in the infiltration of inflammatory cells in the adipose tissues. Thus, doramectin can ameliorate high-fat diet-induced obesity and adipose inflammation by affecting macrophage polarization in white adipose tissue.
ABSTRACT
BACKGROUND: The distal transradial access (dTRA) has become an attractive and alternative access to the conventional transradial access (TRA) for cardiovascular interventional diagnosis and/or treatment. There was a lack of randomized clinical trials to evaluate the effect of the dTRA on the long-term radial artery occlusion (RAO). METHODS: This was a prospective, randomized controlled study. The primary endpoint was the incidence of long-term RAO at 3 months after discharge. The secondary endpoints included the successful puncture rate, puncture time, and other access-related complications. RESULTS: The incidence of long-term RAO was 0.8% (3/361) for dTRA and 3.3% (12/365) for TRA (risk ratio = 0.25, 95% confidence interval = 0.07-0.88, P = 0.02). The incidence of RAO at 24 h was significantly lower in the dTRA group than in the TRA group (2.5% vs. 6.7%, P < 0.01). The puncture success rate (96.0% vs. 98.5%, P = 0.03) and single puncture attempt (70.9% vs. 83.9%, P < 0.01) were significantly lower in the dTRA group than in the TRA group. However, the number of puncture attempts and puncture time were higher in the dTRA group. The dTRA group had a lower incidence of bleeding than the TRA group (1.5% vs. 6.0%, P < 0.01). There was no difference in the success rate of the procedure, total fluoroscopy time, or incidence of other access-related complications between the two groups. In the per-protocol analysis, the incidence of mEASY type ≥ II haematoma was significantly lower in the dTRA group, which was consistent with that in the as-treated analysis. CONCLUSIONS: The dTRA significantly reduced the incidence of long-term RAO, bleeding or haematoma. TRIAL REGISTRATION: ClinicalTrials.gov identifer: NCT05253820.
Subject(s)
Arterial Occlusive Diseases , Percutaneous Coronary Intervention , Humans , Radial Artery/surgery , Prospective Studies , Arterial Occlusive Diseases/diagnostic imaging , Arterial Occlusive Diseases/epidemiology , Hemorrhage , Hematoma/etiology , Hematoma/complications , Coronary Angiography/adverse effects , Coronary Angiography/methods , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/methods , Treatment OutcomeABSTRACT
The semiconductor thin film engineering technique plays a key role in the development of advanced electronics. Printing uniform nanofilms on freeform surfaces with high efficiency and low cost is significant for actual industrialization in electronics. Herein, a high-throughput colloidal printing (HTCP) strategy is reported for fabricating large-area and uniform semiconductor nanofilms on freeform surfaces. High-throughput and uniform printing rely on the balance of atomization and evaporation, as well as the introduced thermal Marangoni flows of colloidal dispersion, that suppresses outward capillary flows. Colloidal printing with in situ heating enables the fast fabrication of large-area semiconductor nanofilms on freeform surfaces, such as SiO2/Si, Al2O3, quartz glass, poly(ethylene terephthalate) (PET), Al foil, plastic tube, and Ni foam, expanding their technological applications where substrates are essential. The printed SnS2 nanofilms are integrated into thin-film semiconductor gas sensors with one of the fastest responses (8 s) while maintaining the highest sensitivity (Rg/Ra = 21) (toward 10 ppm NO2), as well as an ultralow limit of detection (LOD) of 46 ppt. The ability to print uniform semiconductor nanofilms on freeform surfaces with high-throughput promises the development of next-generation electronics with low cost and high efficiency.
ABSTRACT
Hepatic venous pressure gradient (HVPG) is the gold standard for evaluating clinically significant portal hypertension (CSPH). However, reliable noninvasive methods are limited. Our study aims to investigate the diagnostic value of serum Golgi protein 73 (GP73) for CSPH in patients with compensated cirrhosis. The study enrolled 262 consecutive patients with compensated cirrhosis from three centers in China from February 2021 to September 2023, who underwent both serum GP73 tests and HVPG measurements. CSPH was defined as HVPG ≥ 10 mmHg. Diagnostic accuracy was evaluated using the areas under the receiver operating characteristic curve (AUC). The prevalence of CSPH was 56.9% (n = 149). There were significant differences between the CSPH and non-CSPH groups in the median serum GP73 level (126.8 vs. 73.1 ng/mL, p < 0.001). GP73 level showed a significant positive linear correlation with HVPG (r = 0.459, p < 0.001). The AUC for the diagnosis of CSPH using serum GP73 alone was 0.75 (95% confidence interval [CI] 0.68-0.81). Multivariate logistic regression analysis determined that the levels of GP73, platelets and international normalized ratio were independently associated with CSPH. The combination of these three markers was termed "IP73" score with an AUC value of 0.85 (95% CI 0.80-0.89) for CSPH. Using 0 as a cut-off value, the specificity and sensitivity of IP73 score were 77.9% and 81.9%, respectively. The IP73 score offers a novel, simple and noninvasive method of assessing CSPH in patients with compensated cirrhosis. A cut-off value of the IP73 score at 0 can distinguish patients with or without CSPH.
Subject(s)
Elasticity Imaging Techniques , Hypertension, Portal , Humans , Biomarkers , Hypertension, Portal/complications , Hypertension, Portal/diagnosis , Liver , Liver Cirrhosis/complications , Liver Cirrhosis/diagnosis , ROC Curve , Time FactorsABSTRACT
The aim of this study is to report the risk factors of severe statin induced liver injury (SILI). From the database of Shandong ADR Monitoring Center and Outpatients and inpatients in our hospital, SILI cases reported from 2013 to 2021 were extracted and screened. The diagnostic criteria of SILI, the inclusion and exclusion criteria of severe and general SILI were established separately. After the SILI cases were selected and confirmed, the socio-demographic and clinical characteristics were collected. Single factor chi-square test and multi-factor unconditional logistic regression analysis were used to analyze the influencing factors of severe SILI. From 1391 reported cases, 1211 met SILI diagnostic criteria, of which 157 were severe SILI and 964 were general SILI. Univariate analysis showed that age, drug combination, statin category were the influencing factors of severe SILI (p<0.1). Multivariate logistic analysis showed that drug combination and statin category were the influencing factors of severe SILI (p<0.05). Atorvastatin caused the most serious SILI, and its risk is 1.77 times higher than rosuvastatin. The serious SILI risk of drug combination was 2.08 times higher than statin alone. The patient with these factors should be monitored intensively during clinical treatment, to ensure their medication safety.
ABSTRACT
We aimed to investigate the cardiomyocyte-protective effects of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes on ischemia/reperfusion (I/R)-injured rats and to explore the mechanisms. Cardiomyocytes were divided into control group, ischemia/reperfusion group (I/R group), ischemia/reperfusion+exosome group (I/R+Exo group) or ischemia/reperfusion+exosomes transfected with miR-101a-3p inhibitor group (I/R+Exo inhibitor group). MiR-101a-3p levels were lower in I/R and I/R+Exo inhibitor groups than in control and I/R+Exo groups. Apoptosis rate and cleaved caspase 3 expression were higher in I/R and I/R+Exo inhibitor groups. The levels of superoxide dismutase (SOD) in cardiomyocytes of I/R group and I/R+Exo inhibitor group were lower than those of control group and I/R+Exo group, and the levels of malondialdehyde (MDA) and the relative production of oxygen species clusters (ROS) in cardiomyocytes of I/R group and I/R+Exo inhibitor group were higher than those of control group and I/R+Exo group. The levels of interleukin-10 (IL-10), interleukin-6 (IL-6), tumour necrosis factor α (TNF-α), and nuclear factor κB (NF-κB) were higher in the I/R group and the I/R +Exo inhibitor group than in the control group and the I/R+Exo group. Bioinformatics analysis suggested that Pik3c3 is the most promising gene involved in miR-101a-3p-mediated apoptosis in cardiomyocytes, and in vitro experiments confirmed that low expression of miR-101a-3p significantly up-regulated the mRNA and protein expression levels of Pik3c3. BMSCs-derived exosomes have a protective effect on cardiomyocytes from I/R-injured rats, and the mechanism may be related to the inhibition of oxidative stress and inflammatory responses in cardiomyocytes by exosome-delivered miR-101a-3p.
Subject(s)
Exosomes , Mesenchymal Stem Cells , MicroRNAs , Reperfusion Injury , Rats , Animals , Myocytes, Cardiac/metabolism , Exosomes/metabolism , Reperfusion Injury/metabolism , Apoptosis , Hypoxia , Interleukin-6/metabolism , MicroRNAs/metabolism , Ischemia , Mesenchymal Stem Cells/metabolismABSTRACT
BACKGROUND: Red cell distribution width to albumin ratio (RAR) has been demonstrated to be associated with the risk of cardiovascular diseases. However, it is still unknown whether the RAR affects atrial fibrillation (AF). Therefore, this study aimed to investigate the association between RAR and AF in subjects hospitalized with coronary angiography. METHODS: A total of 2436 participants were retrospectively included. Red cell distribution width, albumin and other data were collected. AF was confirmed using 12-lead electrocardiogram (ECG) or 24-h Holter. All participants were divided into four groups according to the RAR values by quartile (Q1, Q2, Q3, Q4). Univariate and multivariate logistic regression were performed to examine the correlation between RAR and AF. RESULTS: Among the 2436 participants, 227 (9.3%) AF cases were observed. The RDW and RAR were significantly higher in AF group than in non-AF group (all P < 0.001). Univariate logistic regression showed an positive association between RAR and AF (P < 0.001). In multivariate logistic regression, RAR was found to be an independent risk factor of AF after adjusting for confounding factors (OR:2.015, 95%CI:1.315-3.089, P = 0.001). CONCLUSIONS: The present study indicated that elevated RAR level was independently correlated with increased risk of AF in subjects hospitalized with coronary angiography.
Subject(s)
Atrial Fibrillation , Erythrocyte Indices , Humans , Atrial Fibrillation/diagnosis , Atrial Fibrillation/etiology , Retrospective Studies , Coronary Angiography/adverse effects , Risk FactorsABSTRACT
Dimefluthrin (DIM) is a synthetic pyrethroid insecticide commonly used for the control of pests, particularly for mosquitoes and other flying insects. However, the effects of DIM on non-target aquatic organisms are not known. In this study, we evaluated the long-term effects of DIM on juvenile Acrossocheilus fasciatus (a species of teleost fish) by exposing them to two different concentrations (0.8 µg/L and 4 µg/L) for 60 days. After 60 d of exposure, DIM induced a significant decrease in body weight and irregular, diffused villi in the intestines of A. fasciatus, accompanied by alterations in the expression of immune-related genes. Furthermore, Gene Ontology (GO) enrichment analysis revealed that among the differentially expressed genes (DEGs), all downregulated genes were enriched in processes such as small molecule/cellular amino acid metabolism, generation of precursor metabolites and energy, and phosphatase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the downregulated genes were associated with processes such as cytokine-cytokine receptor interaction, chemokine signaling pathway, JAK-STAT signaling pathway, intestinal immune network for IgA production, natural killer cell-mediated cytotoxicity, and antigen processing and presentation. In contrast, upregulated DEGs were linked to processes such as necroptosis, phototransduction, and Hippo signaling pathway. These results demonstrate the potential toxicity of DIM to non-target aquatic organisms, indicating the broader ecological implications of its use.
ABSTRACT
BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) is widespread in the treatment of ischemic heart disease, and its treatment options are currently limited. Adiponectin (APN) is an adipocytokine with cardioprotective properties; however, the mechanisms of APN in MIRI are unclear. Therefore, based on preclinical (animal model) evidence, the cardioprotective effects of APN and the underlying mechanisms were explored. METHODS: The literature was searched for the protective effect of APN on MIRI in six databases until 16 November 2023, and data were extracted according to selection criteria. The outcomes were the size of the myocardial necrosis area and hemodynamics. Markers of oxidation, apoptosis, and inflammation were secondary outcome indicators. The quality evaluation was performed using the animal study evaluation scale recommended by the Systematic Review Center for Laboratory animal Experimentation statement. Stata/MP 14.0 software was used for the summary analysis. RESULTS: In total, 20 papers with 426 animals were included in this study. The pooled analysis revealed that APN significantly reduced myocardial infarct size [weighted mean difference (WMD) = 16.67 (95% confidence interval (CI) = 13.18 to 20.16, P < 0.001)] and improved hemodynamics compared to the MIRI group [Left ventricular end-diastolic pressure: WMD = 5.96 (95% CI = 4.23 to 7.70, P < 0.001); + dP/dtmax: WMD = 1393.59 (95% CI = 972.57 to 1814.60, P < 0.001); -dP/dtmax: WMD = 850.06 (95% CI = 541.22 to 1158.90, P < 0.001); Left ventricular ejection fraction: WMD = 9.96 (95% CI = 7.29 to 12.63, P < 0.001)]. Apoptosis indicators [caspase-3: standardized mean difference (SMD) = 3.86 (95% CI = 2.97 to 4.76, P < 0.001); TUNEL-positive cells: WMD = 13.10 (95% CI = 8.15 to 18.05, P < 0.001)], inflammatory factor levels [TNF-α: SMD = 4.23 (95% CI = 2.48 to 5.98, P < 0.001)], oxidative stress indicators [Superoxide production: SMD = 4.53 (95% CI = 2.39 to 6.67, P < 0.001)], and lactate dehydrogenase levels [SMD = 2.82 (95% CI = 1.60 to 4.04, P < 0.001)] were significantly reduced. However, the superoxide dismutase content was significantly increased [SMD = 1.91 (95% CI = 1.17 to 2.65, P < 0.001)]. CONCLUSION: APN protects against MIRI via anti-inflammatory, antiapoptotic, and antioxidant effects, and this effect is achieved by activating different signaling pathways.
Subject(s)
Myocardial Infarction , Myocardial Reperfusion Injury , Rats , Animals , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/prevention & control , Myocardial Reperfusion Injury/metabolism , Rats, Sprague-Dawley , Adiponectin/genetics , Signal Transduction , ApoptosisABSTRACT
Surface modification is a promising method to change the surface properties of nanomaterials, but it is limited in enhancing their intrinsic redox nature. In this work, a "filter amplifier" strategy is proposed for the first time to reverse the intrinsic redox nature of materials. This is demonstrated by coating a COF-316 layer with controlled thickness on TiO2 to form core-sheath nanowire arrays. This unique structure forms a Z-scheme heterojunction to function as "a filter amplifier" which can conceal the intrinsic oxidative sites and increase the extrinsic reductive sites. Consequently, the selective response of TiO2 is dramatically reversed from reductive ethanol and methanol to oxidative NO2. Moreover, TiO2@COF-316 provides remarkably improved sensitivity, response, and recovery speed, as well as unusual anti-humidity properties as compared with TiO2. This work not only provides a new strategy to rationally modulate the surface chemistry properties of nanomaterials but also opens an avenue to design high-performance electronic devices with a Z-scheme heterojunction.
ABSTRACT
Layer-by-layer (LbL) deposition of active layers in organic solar cells (OSCs) offers immense potential for optimizing performance through precise tailoring of each layer. However, achieving high-performance LbL OSCs with distinct solid additives in each layer remains challenging. In this study, we explore a novel approach that strategically incorporates different solid additives into specific layers of LbL devices. To this end, we introduce FeCl3 into the lower donor (D18) layer as a p-type dopant to enhance hole concentration and mobility. Concurrently, we incorporate the wide-band gap conjugated polymer poly(9,9-di-n-octylfluorenyl-2,7-diyl) (PFO) into the upper acceptor (L8-BO) layer to improve the morphology and prolong exciton lifetime. Unlike previous studies, our approach combines these two strategies to achieve higher and more balanced electron and hole mobility without affecting device open-circuit voltage, while also suppressing charge recombination. Consequently, the power conversion efficiency (PCE) of the D18+FeCl3/L8-BO device increases to 18.12 %, while the D18/L8-BO+PFO device attains a PCE of 18.79 %. These values represent substantial improvements over the control device's PCE of 17.59 %. Notably, when both FeCl3 and PFO are incorporated, the D18+FeCl3/L8-BO+PFO device achieves a remarkable PCE of 19.17 %. In summary, our research results demonstrate the effectiveness of the layered solid additive strategy in improving OSC performance.
ABSTRACT
BACKGROUND: Colorectal cancer (CRC) is one of the most threatening tumors in the world, and chemotherapy remains dominant in the treatment of metastatic CRC (mCRC) patients. The purpose of this study was to develop a biomarker panel to predict the response of the first line chemotherapy in mCRC patients. METHODS: Totally 190 mCRC patients treated with FOLFOX or XEOLX chemotherapy in 3 different institutions were included. We extracted the plasma extracellular vesicle (EV) RNA, performed RNA sequencing, constructed a model and generated a signature through shrinking the number of variables by the random forest algorithm and the least absolute shrinkage and selection operator (LASSO) algorithm in the training cohort (n = 80). We validated it in an internal validation cohort (n = 62) and a prospective external validation cohort (n = 48). RESULTS: We established a signature consisted of 22 EV RNAs which could identify responders, and the area under the receiver operating characteristic curve (AUC) values was 0.986, 0.821, and 0.816 in the training, internal validation, and external validation cohort respectively. The signature could also identify the progression-free survival (PFS) and overall survival (OS). Besides, we constructed a 7-gene signature which could predict tumor response to first-line oxaliplatin-containing chemotherapy and simultaneously resistance to second-line irinotecan-containing chemotherapy. CONCLUSIONS: The study was first to develop a signature of EV-derived RNAs to predict the response of the first line chemotherapy in mCRC with high accuracy using a non-invasive approach, indicating that the signature could help to select the optimal regimen for mCRC patients.
Subject(s)
Cell-Free Nucleic Acids , Colonic Neoplasms , Colorectal Neoplasms , Extracellular Vesicles , Rectal Neoplasms , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Bevacizumab/therapeutic use , Prospective Studies , Cell-Free Nucleic Acids/genetics , Fluorouracil/therapeutic use , Leucovorin/therapeutic use , RNA , Liquid Biopsy , Extracellular Vesicles/geneticsABSTRACT
BACKGROUND & AIMS: Alterations of multiple metabolites characterize distinct features of metabolic reprograming in hepatocellular carcinoma (HCC). However, the role of most metabolites, including propionyl-CoA (Pro-CoA), in metabolic reprogramming and hepatocarcinogenesis remains elusive. In this study, we aimed to dissect how Pro-CoA metabolism affects these processes. METHODS: TCGA data and HCC samples were used to analyze ALDH6A1-mediated Pro-CoA metabolism and its correlation with HCC. Multiple metabolites were assayed by targeted mass spectrometry. The role of ALDH6A1-generated Pro-CoA in HCC was evaluated in HCC cell lines as well as xenograft nude mouse models and primary liver cancer mouse models. Non-targeted metabolomic and targeted energy metabolomic analyses, as well as multiple biochemical assays, were performed. RESULTS: Decreases in Pro-CoA and its derivative propionyl-L-carnitine due to ALDH6A1 downregulation were tightly associated with HCC. Functionally, ALDH6A1-mediated Pro-CoA metabolism suppressed HCC proliferation in vitro and impaired hepatocarcinogenesis in mice. The aldehyde dehydrogenase activity was indispensable for this function of ALDH6A1, while Pro-CoA carboxylases antagonized ALDH6A1 function by eliminating Pro-CoA. Mechanistically, ALDH6A1 caused a signature enrichment of central carbon metabolism in cancer and impaired energy metabolism: ALDH6A1-generated Pro-CoA suppressed citrate synthase activity, which subsequently reduced tricarboxylic acid cycle flux, impaired mitochondrial respiration and membrane potential, and decreased ATP production. Moreover, Pro-CoA metabolism generated 2-methylcitric acid, which mimicked the inhibitory effect of Pro-CoA on citrate synthase and dampened mitochondrial respiration and HCC proliferation. CONCLUSIONS: The decline of ALDH6A1-mediated Pro-CoA metabolism contributes to metabolic remodeling and facilitates hepatocarcinogenesis. Pro-CoA, propionyl-L-carnitine and 2-methylcitric acid may serve as novel metabolic biomarkers for the diagnosis and treatment of HCC. Pro-CoA metabolism may provide potential targets for development of novel strategies against HCC. IMPACT AND IMPLICATIONS: Our study presents new insights on the role of propionyl-CoA metabolism in metabolic reprogramming and hepatocarcinogenesis. This work has uncovered potential diagnostic and predictive biomarkers, which could be used by physicians to improve clinical practice and may also serve as targets for the development of therapeutic strategies against HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Mice , Animals , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Citrate (si)-Synthase , Carnitine/metabolism , Carnitine/pharmacologyABSTRACT
Tumour-derived exosomes (TDEs) play an important role in tumourigenesis and progression by regulating components in the tumour microenvironment (TME), however, the role of TDE-related immune genes in hepatocellular carcinoma is not fully known. We systematically analysed TDE genes from ExoCarta and immune genes from Immport,Machine learning ultimately identified eight TDE-related prognostic immune genes and used them as the basis for constructing a risk model, which was constructed to better predict patients with hepatocellular carcinoma (HCC) compared with published prognostic models. There were significant differences between the high and low risk groups in terms of biological functioning. Low-risk group were more sensitive to immunotherapy, the sensitivity to oxaliplatin and cisplatin differed between the high- and low-risk groups, and knockout of the core gene RAC1 limited the malignant biological behaviour of hepatocellular carcinoma cells. In conclusion, TIRGs are effective in predicting the prognosis of patients with hepatocellular carcinoma and provide a new perspective on immunotherapy and chemotherapy for patients.
Subject(s)
Carcinoma, Hepatocellular , Exosomes , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/genetics , Exosomes/genetics , Liver Neoplasms/genetics , Cell Line , Cell Transformation, Neoplastic , Tumor Microenvironment/genetics , PrognosisABSTRACT
For the precise visualization of GPCR, subtype selectivity of turn-on fluorescent ligands is of major relevance. Although there are many thriving ß-adrenergic receptors (ß-ARs) probes, none of them are selective to the ß3-subtype, which severely limits the development of ß3-AR investigations. Using a polyethylene glycol (PEG) chain to conjugate the Py-5 fluorophore with mirabegron, we present here a highly selective fluorescent ligand, H2, for ß3-AR. It was established by the radioligand and NanoLuc-based bioluminescence resonance energy transfer (NanoBRET) binding experiments that molecule H2 has a substantially higher affinity for ß3-AR than the other two subtypes (1/3, 45-fold; 2/3, 16-fold). More crucially, when molecule H2 was incubated with ß3-AR, the turn-on fluorescent signals could be quickly released. The subsequent investigations, which included cell imaging, tissue imaging, and flow-cytometry analysis, proved that molecule H2 may make it possible to quickly and accurately fluorescently identify ß3-AR at different levels. We offer a prospective fluorescent turn-on ligand with exceptional selectivity for ß3-AR as a result of our combined efforts.
Subject(s)
Adrenergic beta-Agonists , Receptors, Adrenergic, beta , Ligands , Prospective Studies , Receptors, Adrenergic, beta/chemistry , Receptors, Adrenergic, beta/metabolismABSTRACT
Background: To investigate the incidence of contrast-induced acute kidney injury (CI-AKI) in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) in relation to the neutrophil to high-density lipoprotein cholesterol ratio (NHR), and to further compare the predictive value of NHR and the neutrophil to lymphocyte ratio (NLR) for CI-AKI. Methods: We retrospectively analyzed 1243 AMI patients undergoing PCI from January 2019 to December 2021, and collected creatinine within 72 h after PCI. All patients were divided into a CI-AKI group and non-CI-AKI group according to the definition of CI-AKI, and the clinical information of the two groups was compared. Potential risk factors for CI-AKI in AMI patients undergoing primary PCI were screened by using logistic regression analysis, and receiver operating characteristic (ROC) curves were used to compare the predictive value of NHR and NLR. Results: A high NHR and high NLR were correlated with a high incidence of CI-AKI in AMI patients undergoing primary PCI, and NHR (odds ratio (OR): 1.313, 95% confidence interval (CI): 1.199-1.438) and NLR (OR: 1.105, 95% CI: 1.041-1.174) were independent risk factors for CI-AKI (p < 0.05). Compared with NLR, the area under the curve (AUC) of NHR was larger (AUC = 0.668, 95% CI: 0.641-0.694 vs. AUC = 0.723, 95% CI: 0.697-0.748), and the difference was significant (p < 0.05), with higher sensitivity (61.67% vs. 70.83%) and specificity (64.91% vs. 66.10%). Conclusions: Compared with the NLR, the NHR is more valuable in predicting the incidence of CI-AKI in AMI patients undergoing primary PCI.