ABSTRACT
The aetiology of bone metastasis in prostate cancer (PCa) remains unclear. This study aims to identify hub genes involved in this process. We utilized machine learning, GO, KEGG, GSEA, Single-cell analysis, ROC methods to identify hub genes for bone metastasis in PCa using the TCGA and GEO databases. Potential drugs targeting these genes were identified. We validated these results using 16 specimens from patients with PCa and analysed the relationship between the hub genes and clinical features. The impact of APOC1 on PCa was assessed through in vitro experiments. Seven hub genes with AUC values of 0.727-0.926 were identified. APOC1, CFH, NUSAP1 and LGALS1 were highly expressed in bone metastasis tissues, while NR4A2, ADRB2 and ZNF331 exhibited an opposite trend. Immunohistochemistry further confirmed these results. The oxidative phosphorylation pathway was significantly enriched by the identified genes. Aflatoxin B1, benzo(a)pyrene, cyclosporine were identified as potential drugs. APOC1 expression was correlated with clinical features of PCa metastasis. Silencing APOC1 significantly inhibited PCa cell proliferation, clonality, and migration in vitro. This study identified 7 hub genes that potentially facilitate bone metastasis in PCa through mitochondrial metabolic reprogramming. APOC1 emerged as a promising therapeutic target and prognostic marker for PCa with bone metastasis.
Subject(s)
Bone Neoplasms , Cell Proliferation , Computational Biology , Gene Expression Regulation, Neoplastic , Prostatic Neoplasms , Humans , Bone Neoplasms/secondary , Bone Neoplasms/genetics , Bone Neoplasms/metabolism , Male , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Prostatic Neoplasms/metabolism , Computational Biology/methods , Cell Proliferation/genetics , Cell Line, Tumor , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Movement/genetics , Gene Expression Profiling , Gene Regulatory Networks , PrognosisABSTRACT
Pulmonary hypertension (PH) arises from increased pulmonary vascular resistance due to contraction and remodeling of the pulmonary arteries. The structural changes include thickening of the smooth muscle layer from increased proliferation and resistance to apoptosis. The mechanisms underlying apoptosis resistance in PH are not fully understood. In cancer cells, high expression of aquaporin 1 (AQP1), a water channel, is associated with apoptosis resistance. We showed AQP1 protein was expressed in pulmonary arterial smooth muscle cells (PASMCs) and upregulated in preclinical PH models. In this study, we used PASMCs isolated from control male rats and the SU5416 plus hypoxia (SuHx) model to test the role of AQP1 in modulating susceptibility to apoptosis. We found the elevated level of AQP1 in PASMCs from SuHx rats was necessary for resistance to apoptosis and that apoptosis resistance could be conferred by increasing AQP1 in control PASMCs. In exploring the downstream pathways involved, we found AQP1 levels influence the expression of Bcl-2, with enhanced AQP1 levels corresponding to increased Bcl-2 expression, reducing the ratio of BAX to Bcl-2, consistent with apoptosis resistance. These results provide a mechanism by which AQP1 can regulate PASMC fate.
Subject(s)
Apoptosis , Aquaporin 1 , Hypoxia , Indoles , Muscle, Smooth, Vascular , Myocytes, Smooth Muscle , Pulmonary Artery , Pyrroles , Animals , Aquaporin 1/metabolism , Aquaporin 1/genetics , Male , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Pulmonary Artery/cytology , Rats , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Muscle, Smooth, Vascular/cytology , Pyrroles/pharmacology , Indoles/pharmacology , Hypoxia/metabolism , Rats, Sprague-Dawley , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Cells, Cultured , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Disease Models, AnimalABSTRACT
MicroRNAs (miRNAs) have been confirmed to play important roles in plant defense response. However, the key maize miRNAs involved in the defense response against Bipolaris maydis are very limited. In this study, a novel member of the miR169 family in response to B. maydis, named zma-miR169s, was discovered and investigated. The expression levels of pre-miR169s and zma-miR169s were significantly repressed during B. maydis infection. CRISPR/Cas9-induced zma-miR169s mutant exhibited more resistance against B. maydis, whereas overexpression zma-miR169s enhanced susceptibility, supporting that zma-miR169s might play a negative role in maize resistance. Moreover, RNA-seq and GO analysis showed that differentially expressed genes were highly enriched in the oxidation-reduction process and plant hormone pathway. Hence, reactive oxygen species (ROS) and plant hormone levels were further investigated. ROS detection confirmed that zma-miR169s mutant accumulated more ROS, while less ROS was detected in transgenic maize OE-miR169s. Furthermore, more remarkable changes in PR-1 expression levels and salicylic acid (SA) contents were detected in zma-miR169s mutant compared to wild-type and transgenic maize during B. maydis infection. Additionally, nuclear transcription factors (NF-YA1 and NF-YA13) were identified as targets regulated by zma-miR169s through the agrobacterium-mediated transient expression method. Overexpression of ZmNF-YA13 enhanced Arabidopsis resistance to Pseudomonas syringae pv. tomato DC3000. Taken together, our results suggest that zma-miR169s negatively regulate maize defense responses by influencing ROS accumulation and the SA-dependent signaling pathway.
ABSTRACT
The pathogenesis of intestinal fibrosis in Crohn's disease (CD) remains unclear. Mer receptor tyrosine kinase (MerTK) is an immunosuppressive protein specifically expressed in macrophages. Osteopontin (OPN), also known as secreted phosphoprotein 1, contributes to inflammation and wound repair. This study investigates the potential profibrotic pathway in MerTK+ macrophages in order to provide a possible therapeutic target for intestinal fibrosis. MerTK expression in the inflamed and stenotic bowels was evaluated. The MerTK/ERK/TGF-ß1 pathway was overactivated in the fibrotic intestinal tissues of patients with CD. This pathway was induced by epithelial cell apoptosis, resulting in activated fibroblasts with increased TGF-ß1 secretion. OPN upregulated TGF production by altering ERK1/2 phosphorylation, as evidenced by OPN or MerTK knockdown and OPN overexpression in vitro. MerTK inhibitor UNC2025 alleviated intestinal fibrosis in mouse colitis models, suggesting a potential therapeutic target for intestinal fibrosis in patients with CD.
ABSTRACT
Developing a simple, economical, sensitive, and selective method for label-free direct detection analytes is attractive, especially the strategies that could achieve signal amplification without complicated operations. Herein, a dual-fluorescence colorimetric nanoswitch sensing platform for label-free direct melamine (MEL) detection was established. We first explored the relationship between MEL-induced aggregation of gold nanoparticles (AuNPs) and size and determined the optimal size to be 37 nm. Using surfactant Triton X-100 to modify AuNPs and clarify possible interaction mechanisms to improve detection performance. The dynamic changes of surface plasmon resonance absorption peaks in the dispersed and aggregated states of AuNPs were skillfully utilized to match the emission of multicolor gold nanoclusters to trigger the multi-inner filter effect. Accompanied by the addition of MEL-induced AuNPs to change from dispersed to aggregated state, the fluorescence of green-emitting and red-emitting gradually turned on and turned off, respectively. The fluorescence turn-on mode detection limit was 10 times higher than the colorimetric method and as low as 5.5 ng/mL; the detection took only 10 min. The sensor detected MEL in spiked milk samples with a good recovery in the range of 81.2-111.0 % with a coefficient of variation less than 11.4 % and achieved a good correlation with commercial kits. The proposed sensor integrates numerous merits of label-free, multi-signal readout, self-calibration, simple operations, and economical, which provides a promising tool for convenient on-site detection of MEL.
Subject(s)
Colorimetry , Gold , Metal Nanoparticles , Milk , Triazines , Triazines/analysis , Triazines/chemistry , Gold/chemistry , Metal Nanoparticles/chemistry , Colorimetry/methods , Milk/chemistry , Animals , Limit of Detection , Fluorescence , Food Contamination/analysis , Spectrometry, Fluorescence/methodsABSTRACT
An imbalance of energy intake and expenditure is commonly considered as the fundamental cause of obesity. However, individual variations in susceptibility to obesity do indeed exist in both humans and animals, even among those with the same living environments and dietary intakes. To further explore the potential influencing factors of these individual variations, male C57BL/6J mice were used for the development of obesity-prone and obesity-resistant mice models and were fed high-fat diets for 16 weeks. Compared to the obesity-prone mice, the obesity-resistant group showed a lower body weight, liver weight, adipose accumulation and pro-inflammatory cytokine levels. 16S rRNA sequencing, which was conducted for fecal microbiota analysis, found that the fecal microbiome's structural composition and biodiversity had changed in the two groups. The genera Allobaculumbiota, SMB53, Desulfovibrio and Clostridium increased in the obesity-prone mice, and the genera Streptococcus, Odoribacter and Leuconostoc were enriched in the obesity-resistant mice. Using widely targeted metabolomics analysis, 166 differential metabolites were found, especially those products involved in arachidonic acid (AA) metabolism, which were significantly reduced in the obesity-resistant mice. Moreover, KEGG pathway analysis exhibited that AA metabolism was the most enriched pathway. Significantly altered bacteria and obesity-related parameters, as well as AA metabolites, exhibited strong correlations. Overall, the phenotypes of the obesity-prone and obesity-resistant mice were linked to gut microbiota and AA metabolism, providing new insight for developing an in-depth understanding of the driving force of obesity resistance and a scientific reference for the targeted prevention and treatment of obesity.
Subject(s)
Arachidonic Acid , Diet, High-Fat , Gastrointestinal Microbiome , Mice, Inbred C57BL , Obesity , Animals , Gastrointestinal Microbiome/physiology , Diet, High-Fat/adverse effects , Obesity/microbiology , Obesity/metabolism , Male , Arachidonic Acid/metabolism , Mice , Feces/microbiology , RNA, Ribosomal, 16S/genetics , Disease Models, Animal , Bacteria/classification , Body WeightABSTRACT
Metal-semiconductor junctions play an important role in the development of electronic and optoelectronic devices. A Schottky junction photodetector based on two-dimensional (2D) materials is promising for self-powered photodetection with fast response speed and large signal-to-noise ratio. However, it usually suffers from an uncontrolled Schottky barrier due to the Fermi level pinning effect arising from the interface states. In this work, all-2D Schottky junctions with near-ideal Fermi level depinning are realized, attributed to the high-quality interface between 2D semimetals and semiconductors. We further demonstrate asymmetric diodes based on multilayer graphene/MoS2/PtSe2 with a current rectification ratio exceeding 105 and an ideality factor of 1.2. Scanning photocurrent mapping shows that the photocurrent generation mechanism in the heterostructure switches from photovoltaic effect to photogating effect at varying drain biases, indicating both energy conversion and optical sensing are realized in a single device. In the photovoltaic mode, the photodetector is self-powered with a response time smaller than 100 µs under the illumination of a 405 nm laser. In the photogating mode, the photodetector exhibits a high responsivity up to 460 A/W originating from a high photogain. Finally, the photodetector is employed for single-pixel imaging, demonstrating its high-contrast photodetection ability. This work provides insight into the development of high-performance self-powered photodetectors based on 2D Schottky junctions.
ABSTRACT
Early breast cancer (EBC) is cancer that has not spread beyond the breast or the axillary lymph nodes. The present retrospective cohort study investigated the efficacy and safety of the Pingxiao capsule (PXC), which contains a formula of traditional Chinese herbs, as adjuvant therapy in patients with EBC in a single Chinese academic medical center. Patients with EBC who had received surgery and chemotherapy were analyzed and divided into the PXC and non-PXC groups. Disease-free survival (DFS) time, overall survival (OS) time, demographic characteristics and adverse events were examined. Kaplan-Meier survival curves were used to compare the differences in DFS and OS. A total of 371 participants with a median age of 54 years were included in this study. The median DFS time of all patients was 101 months. The overall DFS rate was 72.1% in the PXC group compared with 63.6% in the non-PXC group. For women with hormone receptor-negative tumors, the DFS rate in the PXC group was significantly higher than that in the non-PXC group, irrespective of node status. Adjuvant treatment with PXC for ≥3 months was associated with significantly longer median DFS time compared with that in the non-PXC group. In addition, the incidence of neutropenia rated to be grade 2 or higher was significantly lower in the PXC group compared with that in the control group, and a markedly, but non-significantly, lower prevalence of nausea was observed in PXC group (0 vs. 4.1%). In conclusion, PXC as an adjuvant therapy along with chemotherapy is associated with prolonged DFS times in patients with EBC when compared with chemotherapy alone. The therapeutic value of combined PXC and systemic chemotherapy should be further elucidated by rigorous prospective clinical trials.
ABSTRACT
STING (stimulator of interferon genes) is a critical immunoregulatory protein in sepsis and is regulated by various mechanisms, especially palmitoylation. FASN (fatty acid synthase) is the rate-limiting enzyme to generate cellular palmitic acid (PA) via acetyl-CoA and malonyl-CoA and participates in protein palmitoylation. However, the mechanisms underlying the interaction between STING and FASN have not been completely understood. In this study, STING-knockout mice were used to confirm the pivotal role of STING in sepsis-induced liver injury. Metabolomics confirmed the dyslipidemia in septic mice and patients. The compounds library was screened, revealing that FASN inhibitors exerted a significant inhibitory effect on the STING pathway. Mechanically, the regulatory effect of FASN on the STING pathway was dependent on palmitoylation. Further experiments indicated that the upstream of FASN, malonyl-CoA inhibited STING pathway possibly due to C91 (palmitoylated residue) of STING. Overall, this study reveals a novel paradigm of STING regulation and provides a new perspective on immunity and metabolism.
Subject(s)
Fatty Acid Synthase, Type I , Lipoylation , Macrophages , Malonyl Coenzyme A , Membrane Proteins , Sepsis , Animals , Humans , Male , Mice , Fatty Acid Synthase, Type I/metabolism , Fatty Acid Synthase, Type I/genetics , Liver/metabolism , Liver/pathology , Macrophages/metabolism , Malonyl Coenzyme A/metabolism , Membrane Proteins/metabolism , Membrane Proteins/genetics , Mice, Inbred C57BL , Mice, Knockout , Palmitic Acid/pharmacology , Sepsis/metabolism , Sepsis/complications , Sepsis/drug therapy , Signal Transduction/drug effectsABSTRACT
Air pollution by sulfur dioxide (SO2) remains a pressing concern for both the environment and human health. Desulfurization enhanced by persulfate based advanced oxidation processes (PS-AOPs) has been proven to be a feasible method. However, the inherent contradiction between the rapid diffusion mass transfer of SO2 in the "gas-liquid-gas" phase and the limited lifespan of reactive oxygen species (ROS) can not be ignored. Excessive investment in PS is required to sustainably generate ROS to achieve continuous desulfurization performance, which may lead to excessive PS consumption. To address this issue, whether PS can achieve the oxidation absorption of SO2 via a non-reactive oxygen species pathway was investigated. Experimental and computational results demonstrated that peroxymonosulfate (PMS) instead of peroxydisulfate (PDS) had a great SO2 removal performance, the utilization of PS could be effectively achieved by maintaining a 1:1 molar ratio of PMS and removed SO2. The presence of HOO bonds in the PMS introduced a partial positive charge to the oxygen atom, making the PMS polar and more susceptible to be attacked by the nucleophile HSO3-. So SO2 underwent a series of processes including dissolution, dissociation, one-oxygen atom transfer, and ionization before ultimately being converted into SO42- ions, effectively achieving its removal from flue gas. This study may presents a novel approach for achieving high-efficiency flue gas desulfurization.
ABSTRACT
Florfenicol resistance genes (FRGs) are widely present in livestock farms. The aim of this study was to evaluate the removal efficiencies of FRGs as well as the relationships between FRGs, mobile genetic elements (MGEs) and bacterial communities during the natural drying (ND) and anaerobic digestion (AD) processes of manure treatment in swine farms by combining bacterial isolation, quantitative PCR and metagenomic approaches. Solid manure showed a higher abundance of FRGs than fresh manure and was the main contamination source of fexA and fexB in ND farms, whilst biogas slurry displayed a lower abundance of FRGs than the wastewater in AD farms. Moreover, fresh manure and wastewater showed a high abundance of optrA, and wastewater was the main contamination source of cfr in both ND and AD farms. Both optrA/fexA-positive enterococci and cfr/fexA-positive staphylococci were mainly isolated along the farms' treatment processes. The cfr-positive staphylococci were highly prevalent in wastewater (57.14 % - 100 %) and may be associated with nasal-derived cfr-positive porcine staphylococci. An increased abundance of Enterococcus, Jeotgalibaca and Vagococcus in the bacterial community structures may account for the high optrA abundance in wastewater and Jeotgalibaca may be another potential host of optrA. Furthermore, the abundance of FRG-related MGEs increased by 22.63 % after the ND process and decreased by 66.96 % in AD farms. A significant correlation was observed between cfr and ISEnfa4, whereas no significance was found between optrA and IS1216E, although IS1216E is the predominant insertion sequence involved in the transfer of optrA. In conclusion, manure and wastewater represented independent pollution sources of FRGs in swine farms. Associated MGEs might play a key role in the transfer and persistence of FRGs. The AD process was more efficient in the removal of FRGs than the ND method, nevertheless a longer storage of slurry may be required for a complete removal.
Subject(s)
Anti-Bacterial Agents , Drug Resistance, Bacterial , Manure , Thiamphenicol , Animals , Thiamphenicol/analogs & derivatives , Swine , Drug Resistance, Bacterial/genetics , Wastewater/microbiology , Waste Disposal, Fluid/methods , Animal Husbandry , Genes, Bacterial , Bacteria/geneticsABSTRACT
As one of the most important food and feed crops worldwide, maize suffers much more tremendous damages under heat stress compared to other plants, which seriously inhibits plant growth and reduces productivity. To mitigate the heat-induced damages and adapt to high temperature environment, plants have evolved a series of molecular mechanisms to sense, respond and adapt high temperatures and heat stress. In this review, we summarized recent advances in molecular regulations underlying high temperature sensing, heat stress response and memory in maize, especially focusing on several important pathways and signals in high temperature sensing, and the complex transcriptional regulation of ZmHSFs (Heat Shock Factors) in heat stress response. In addition, we highlighted interactions between ZmHSFs and several epigenetic regulation factors in coordinately regulating heat stress response and memory. Finally, we laid out strategies to systematically elucidate the regulatory network of maize heat stress response, and discussed approaches for breeding future heat-tolerance maize.
ABSTRACT
To investigate the impact of Poa alpigena Lindm on rhizosphere and bulk soil microorganisms in Haixin Mountain, Qinghai Lake, this study employed metagenomics technology to analyze the microbial communities of the samples. Results showed that 65 phyla, 139 classes, 278 orders, 596 families, 2376 genera, and 5545 species of soil microorganisms were identified from rhizosphere and bulk soil samples. Additionally, a microbial gene library specific to Poa alpigena Lindm was established for Qinghai Lake. Through α-diversity analysis, the richness and diversity of bulk microorganisms both significantly had a higher value than that in rhizosphere soil. The indicator microorganisms of rhizosphere and bulk soil at class level were Actinobacteria and Alphaproteobacteria, respectively. KEGG pathway analysis indicated that Carotenoid biosynthesis, Starch and sucrose metabolism, Bacterial chemotaxis, MAPK signaling pathway, Terpenoid backbone biosynthesis, and vancomycin resistance were the key differential metabolic pathways of rhizosphere soil microorganisms; in contrast, in bulk soil, the key differential metabolic were Benzoate degradation, Glycolysis gluconeogenesis, Aminobenzoate degradation, ABC transporters, Glyoxylate and dicarboxylate metabolism, oxidative phosphorylation, Degradation of aromatic compounds, Methane metabolism, Pyruvate metabolism and Microbial metabolism diverse environments. Our results indicated that Poa alpigena Lindm rhizosphere soil possessed selectivity for microorganisms in Qinghai Lake Haixin Mountain, and the rhizosphere soil also provided a suitable survival environment for microorganisms.
ABSTRACT
The abuse of olaquindox (OLA) as both an antimicrobial agent and a growth promoter poses significant threats to the environment and human health. While nanoreactors have proven effective in hazard detection, their widespread adoption has been hindered by tedious chemical processes and limited functionality. In this study, we introduce a novel green self-assembly strategy utilizing invertase, horseradish peroxidase, antibodies, and gold nanoclusters to form an aggregation-induced emission-type zeolitic imidazolate framework-8 nanoreactor. The results demonstrate that the lateral flow immunoassay not only allows for qualitative naked eye detection but also enables optical analysis through the fluorescence generated by aggregated gold nanoclusters and enzyme-catalyzed enhancement of visible colorimetric signals. To accommodate more detection scenarios, the photothermal effects and redox reactions of the nanoreactor can fulfill the requirements of thermal sensing and electrochemical analysis for smartphone applications. Remarkably, the proposed approach achieves a detection limit 17 times lower than conventional methods. Besides, the maximum linear range spans from 0.25 to 5 µg/L with high specificity, and the recovery is 85.2-112.9% in environmental water and swine urine. The application of this high-performance nanoreactor opens up avenues for the construction of multifunctional biosensors with great potential in monitoring hazardous materials.
Subject(s)
Quinoxalines , Smartphone , Zeolites , Animals , Bionics , Gold , Nanotechnology , SwineABSTRACT
BACKGROUND: The utilization of inner filter effect (IFE) brings more opportunities for construction of fluorescence immunoassays but remains a great challenge, especially how to select best donor in the face of extensive fluorescent nanomaterials. Aflatoxin B1 possesses high toxicity among mycotoxins and is frequently found in agricultural products that may significantly threaten to human health. Therefore, with the help of signal transduction mechanism of IFE to develop a convenient and sensitive approach for AFB1 detection is of great significance in ensuring food safety. RESULTS: Herein, the classical alkaline phosphatase (ALP) catalyzes hydrolysis of p-nitrophenylphosphate to produce p-nitrophenol (PNP) was employed as a model reaction, which intends to explore tunable multicolor fluorescence of gold nanoclusters (AuNCs) for matching PNP to maximize IFE efficiency. The luminescent green-emitting AuNCs were selected as an optimal donor in terms of excellent spectral overlap, high photoluminescence, and adequate system adaptability, thus achieving a 22-fold increase in sensitivity improvement compared to colorimetric method for ALP detection. The fluorescence quenching mechanism between PNP and AuNCs was validated as IFE by studying ultraviolet absorption, zeta potentials and fluorescence lifetime. In light of this, we integrated a highly specific antibody-antigen recognition system, efficient enzymatic reaction and excellent optical characteristics of AuNCs to develop dual-mode immunoassay for AFB1 monitoring. The sensitivity of fluorometric immunoassay was lower to 0.06 ng/mL, which obtained a 3.5-fold improvement compared to "gold standard" ELISA. Their practicability and applicability were confirmed in the tap water, corn, wheat and peanuts samples. SIGNIFICANCE: This work provides an easy-to-understand screening procedure to select optimal donor-acceptor pairs in IFE analysis. Furthermore, we expect that integration of IFE-based signal conversion strategy into mature immunoassay not only extends the signal types, simplifies signal amplification steps, and reduces the false-positive/false-negative rates, but also provides a simple, convenient, and versatile strategy for monitoring of trace other contaminants.
Subject(s)
Alkaline Phosphatase , Metal Nanoparticles , Humans , Limit of Detection , Alkaline Phosphatase/analysis , Hydrolysis , Spectrometry, Fluorescence/methods , Fluorometry , Coloring AgentsABSTRACT
Pulmonary hypertension (PH) is a condition in which remodeling of the pulmonary vasculature leads to hypertrophy of the muscular vascular wall and extension of muscle into nonmuscular arteries. These pathological changes are predominantly due to the abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), enhanced cellular functions that have been linked to increases in the cell membrane protein aquaporin 1 (AQP1). However, the mechanisms underlying the increased AQP1 abundance have not been fully elucidated. Here we present data that establishes a novel interaction between AQP1 and the proteolytic enzyme caspase-3. In silico analysis of the AQP1 protein reveals two caspase-3 cleavage sites on its C-terminal tail, proximal to known ubiquitin sites. Using biotin proximity ligase techniques, we establish that AQP1 and caspase-3 interact in both human embryonic kidney (HEK) 293A cells and rat PASMCs. Furthermore, we demonstrate that AQP1 levels increase and decrease with enhanced caspase-3 activity and inhibition, respectively. Ultimately, further work characterizing this interaction could provide the foundation for novel PH therapeutics.NEW & NOTEWORTHY Pulmonary arterial smooth muscle cells (PASMCs) are integral to pulmonary vascular remodeling, a characteristic of pulmonary arterial hypertension (PAH). PASMCs isolated from robust animal models of disease demonstrate enhanced proliferation and migration, pathological functions associated with increased abundance of the membrane protein aquaporin 1 (AQP1). We present evidence of a novel interaction between the proteolytic enzyme caspase-3 and AQP1, which may control AQP1 abundance. These data suggest a potential new target for novel PAH therapies.
Subject(s)
Aquaporin 1 , Caspase 3 , Muscle, Smooth, Vascular , Myocytes, Smooth Muscle , Pulmonary Artery , Animals , Humans , Male , Rats , Aquaporin 1/metabolism , Aquaporin 1/genetics , Caspase 3/metabolism , Cell Proliferation , HEK293 Cells , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Intracranial aneurysm (IA) is a common cerebrovascular disease and the leading cause of spontaneous subarachnoid hemorrhage. Recent evidence suggests that gut microbiota is involved in the pathophysiological process of IA through the gut-brain axis. However, the role of gut inflammation in the development of IA has yet to be clarified. Our study aimed to investigate whether fecal calprotectin (FC) level, a sensitive marker of gut inflammation, is correlated with the development of IA and the prognosis of patients with ruptured IA (RIA). METHODS: 182 patients were collected from January 2022 to January 2023, including 151 patients with IA and 31 healthy individuals. 151 IA patients included 109 patients with unruptured IA (UIA) and 42 patients with RIA. The FC level was measured by enzyme-linked immunosorbent assay. Other detailed information was obtained from an electronic medical record system. RESULTS: Compared with healthy controls, the FC levels in patients with IA were increased (P < 0.0001). Patients with RIA had significantly higher FC levels than UIA patients (P < 0.0001). Moreover, the FC level in RIA patients with unfavorable outcomes was higher than in RIA patients with favorable outcomes. Logistic regression analysis showed that the elevated FC level was an independent risk factor for a 3-month poor prognosis in patients with RIA (OR=1.005, 95% CI = 1.000 -1.009, P = 0.044). CONCLUSION: Fecal calprotectin level is significantly elevated in IA patients, especially those with RIA. FC is a novel biomarker of 3-month poor outcomes in RIA patients.
Subject(s)
Aneurysm, Ruptured , Intracranial Aneurysm , Subarachnoid Hemorrhage , Humans , Intracranial Aneurysm/complications , Intracranial Aneurysm/diagnosis , Subarachnoid Hemorrhage/etiology , Aneurysm, Ruptured/etiology , Biomarkers , Inflammation/complicationsABSTRACT
Metal-organic framework (MOF)-based drug delivery nanomaterials for cancer therapy have attracted increasing attention in recent years. Here, an enhanced chemodynamic anti-tumor therapy strategy by promoting the Fenton reaction by using core-shell zeolitic imidazolate framework-8 (ZIF-8)@Fe3O4 as a therapeutic platform is proposed. Carboxymethyl cellulose (CMC) is used as a stabilizer of Fe3O4, which is then decorated on the surface of ZIF-8 via the electrostatic interaction and serves as an efficient Fenton reaction trigger. Meanwhile, the pH-responsive ZIF-8 scaffold acts as a container to encapsulate the chemotherapeutic drug doxorubicin (DOX). The obtained DOX-ZIF-8@Fe3O4/CMC (DZFC) nanoparticles concomitantly accelerate DOX release and generate more hydroxyl radicals by targeting the lysosomes in cancer cells. In vitro and in vivo studies verify that the DZFC nanoparticles trigger glutathione peroxidase 4 (GPX4)-dependent ferroptosis via the activation of the c-Jun N-terminal kinases (JNK) signaling pathway, following to achieve the chemo/ferroptosis synergistic anti-tumor efficacy. No marked toxic effects are detected during DZFC treatment in a tumor-bearing mouse model. This composite nanoparticle remarkably suppresses the tumor growth with minimized systemic toxicity, opening new horizons for the next generation of theragnostic nanomedicines.
Subject(s)
Doxorubicin , Ferroptosis , Metal-Organic Frameworks , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Doxorubicin/chemistry , Doxorubicin/pharmacology , Animals , Humans , Mice , Ferroptosis/drug effects , Cell Line, Tumor , Mice, Inbred BALB C , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Carboxymethylcellulose Sodium/chemistry , Mice, Nude , Zeolites/chemistry , ImidazolesABSTRACT
Fipronil, classified as a phenylpyrazole insecticide, is utilized to control agricultural, public health, and veterinary pests. Notably, its unique ecological fate involves degradation to toxic metabolites, which poses the risk of contamination in water and foodstuffs and potential human exposure through the food chain. In response to these concerns, there is a pressing need to develop analytical methodologies for detecting fipronil and its metabolites. This review provides a concise overview of the mode of action, metabolism, and toxicology of fipronil. Additionally, various detection strategies, encompassing antibody-based immunoassays and emerging analytical techniques, such as fluorescence assays based on aptamer/molecularly imprinted polymer/fluorescent probes, electrochemical sensors, and Raman spectroscopy, are thoroughly reviewed and discussed. The focus extends to detecting fipronil and its metabolites in crops, fruits, vegetables, animal-derived foods, water, and bodily fluids. This comprehensive exploration contributes valuable insights into the field, aiming to foster the development and innovation of more sensitive, rapid, and applicable analytical methods.