RESUMEN
Motile bacteria navigate toward favorable conditions and away from unfavorable environments using chemotaxis. Mechanisms of sensing attractants are well understood; however, molecular aspects of how bacteria sense repellents have not been established. Here, we identified malate as a repellent recognized by the MCP2201 chemoreceptor in a bacterium Comamonas testosteroni and showed that it binds to the same site as an attractant citrate. Binding determinants for a repellent and an attractant had only minor differences, and a single amino acid substitution in the binding site inverted the response to malate from a repellent to an attractant. We found that malate and citrate affect the oligomerization state of the ligand-binding domain in opposing way. We also observed opposing effects of repellent and attractant binding on the orientation of an alpha helix connecting the sensory domain to the transmembrane helix. We propose a model to illustrate how positive and negative signals might be generated.
Asunto(s)
Proteínas Bacterianas , Malatos , Proteínas Quimiotácticas Aceptoras de Metilo/química , Proteínas Bacterianas/metabolismo , Ligandos , Escherichia coli/metabolismo , Quimiotaxis/fisiología , Bacterias/metabolismo , CitratosRESUMEN
The commitment of stem cells to differentiate into osteoblasts is a highly regulated and complex process that involves the coordination of extrinsic signals and intrinsic transcriptional machinery. While rodent osteoblastic differentiation has been extensively studied, research on human osteogenesis has been limited by cell sources and existing models. Here, we systematically dissect human pluripotent stem cell-derived osteoblasts to identify functional membrane proteins and their downstream transcriptional networks involved in human osteogenesis. Our results reveal an enrichment of type II transmembrane serine protease CORIN in humans but not rodent osteoblasts. Functional analyses demonstrated that CORIN depletion significantly impairs osteogenesis. Genome-wide chromatin immunoprecipitation enrichment and mechanistic studies show that p38 MAPK-mediated CCAAT enhancer binding protein delta (CEBPD) upregulation is required for CORIN-modulated osteogenesis. Contrastingly, the type I transmembrane heparan sulfate proteoglycan SDC1 enriched in mesenchymal stem cells exerts a negative regulatory effect on osteogenesis through a similar mechanism. Chromatin immunoprecipitation-seq, bulk and single-cell transcriptomes, and functional validations indicated that CEBPD plays a critical role in controlling osteogenesis. In summary, our findings uncover previously unrecognized CORIN-mediated CEBPD transcriptomic networks in driving human osteoblast lineage commitment.
RESUMEN
The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant cells. By investigating transcriptomes and genome occupancies in RB iPSCderived osteoblasts (OBs), we discover that both E2F3a, which mediates spliceosomal gene expression, and pRB, which antagonizes E2F3a, coregulate more than one-third of spliceosomal genes by cobinding to their promoters or enhancers. Pharmacological inhibition of the spliceosome in RB1-mutant cells leads to global intron retention, decreased cell proliferation, and impaired tumorigenesis. Tumor specimen studies and genome-wide TCGA (The Cancer Genome Atlas) expression profile analyses support the clinical relevance of pRB and E2F3a in modulating spliceosomal gene expression in multiple cancer types including osteosarcoma (OS). High levels of pRB/E2F3aregulated spliceosomal genes are associated with poor OS patient survival. Collectively, these findings reveal an undiscovered connection between pRB, E2F3a, the spliceosome, and tumorigenesis, pointing to the spliceosomal machinery as a potentially widespread therapeutic vulnerability of pRB-deficient cancers.
Asunto(s)
Neoplasias Óseas , Carcinogénesis , Factor de Transcripción E2F3 , Regulación Neoplásica de la Expresión Génica , Células Madre Pluripotentes Inducidas , Osteosarcoma , Proteínas de Unión a Retinoblastoma , Empalmosomas , Ubiquitina-Proteína Ligasas , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Carcinogénesis/genética , Factor de Transcripción E2F3/genética , Factor de Transcripción E2F3/metabolismo , Genes de Retinoblastoma , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Mutación , Osteosarcoma/genética , Osteosarcoma/patología , Neoplasias de la Retina/genética , Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/metabolismo , Empalmosomas/genética , Empalmosomas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Recently, subclassification of pancreatoduodenectomy in 4 differing types has been reported, because additional major vascular and multivisceral resections have been shown to be associated with an increased risk of postoperative morbidity and mortality. OBJECTIVE: To classify distal pancreatectomy (DP) based on the extent of resection and technical difficulty and to evaluate postoperative outcomes with regards to this classification system. METHODS: All consecutive patients who had undergone DP between 2001 and 2020 in a high-volume pancreatic surgery center were included in this study. DPs were subclassified into 4 distinct categories reflecting the extent of resection and technical difficulty, including standard DP (type 1), DP with venous (type 2), multivisceral (type 3), or arterial resection (type 4). Patient characteristics, perioperative data, and postoperative outcomes were analyzed and compared among the 4 groups. RESULTS: A total of 2135 patients underwent DP. Standard DP was the most frequently performed procedure (64.8%). The overall 90-day mortality rate was 1.6%. Morbidity rates were higher in patients with additional vascular or multivisceral resections, and 90-day mortality gradually increased with the extent of resection from standard DP to DP with arterial resection (type 1: 0.7%; type 2: 1.3%; type 3: 3%; type 4: 8.7%; P <0.0001). Multivariable analysis confirmed the type of DP as an independent risk factor for 90-day mortality. CONCLUSIONS: Postoperative outcomes after DP depend on the extent of resection and correlate with the type of DP. The implementation of the 4-type classification system allows standardized reporting of surgical outcomes after DP improving comparability of future studies.
Asunto(s)
Pancreatectomía , Neoplasias Pancreáticas , Humanos , Pancreatectomía/métodos , Resultado del Tratamiento , Factores de Riesgo , Pancreaticoduodenectomía/efectos adversos , Estudios Retrospectivos , Complicaciones Posoperatorias/etiologíaRESUMEN
In recent years, graphitic carbon nitride (g-C3N4) has attracted considerable attention because it includes earth-abundant carbon and nitrogen elements and exhibits good chemical and thermal stability owing to the strong covalent interaction in its conjugated layer structure. However, bulk g-C3N4 has some disadvantages of low specific surface area, poor light absorption, rapid recombination of photogenerated charge carriers, and insufficient active sites, which hinder its practical applications. In this study, we design and synthesize potassium single-atom (K SAs)-doped g-C3N4 porous nanosheets (CM-KX, where X represents the mass of KHP added) via supramolecular self-assembling and chemical cross-linking copolymerization strategies. The results show that the utilization of supramolecules as precursors can produce g-C3N4 nanosheets with reduced thickness, increased surface area, and abundant mesopores. In addition, the intercalation of K atoms within the g-C3N4 nitrogen pots through the formation of K-N bonds results in the reduction of the band gap and expansion of the visible-light absorption range. The optimized K-doped CM-K12 nanosheets achieve a specific surface area of 127 m2 g-1, which is 11.4 times larger than that of the pristine g-C3N4 nanosheets. Furthermore, the optimal CM-K12 sample exhibits the maximum H2 production rate of 127.78 µmol h-1 under visible light (λ ≥ 420 nm), which is nearly 23 times higher than that of bare g-C3N4. This significant improvement of photocatalytic activity is attributed to the synergistic effects of the mesoporous structure and K SAs doping, which effectively increase the specific surface area, improve the visible-light absorption capacity, and facilitate the separation and transfer of photogenerated electron-hole pairs. Besides, the optimal sample shows good chemical stability for 20 h in the recycling experiments. Density functional theory calculations confirm that the introduction of K SAs significantly boosts the adsorption energy for water and decreases the activation energy barrier for the reduction of water to hydrogen.
RESUMEN
This study presents a green and practical visible-light-induced photosensitizer-free decarbonylative Minisci-type reaction using aldehydes as alkyl radical precursors. The photocatalytic system exhibits a broad substrate scope and synthetically useful yields. Mechanistic experiments revealed that alkyl radicals could be generated through auto-oxidation of aldehydes under irradiation, which is a mild and effective method for achieving late-stage functionalization of N-heteroarenes. Some biologically active N-heteroarenes could be alkylated using this photocatalytic system smoothly.
RESUMEN
Aluminum-based coagulation has long been regarded as a reliable and cost-effective process for the defluoridation of industrial effluents. However, such a well-recognized viewpoint is challenged by the underestimation of fluoride levels in treated effluents. Herein, we developed a systematic protocol to distinguish different fluoride species, including free F-, exchangeable fluoride (EF), and nonexchangeable fluoride (NEF). We demonstrated that EF forms complexes with octahedral aluminum (AlO6) on the surface of polyaluminum and can be exchanged with (1,2-cyclohexylenedinitrilo)-tetraacetic acid (CDTA). However, NEF is incorporated with tetrahedral aluminum (AlO4) at the core of polyaluminum, as confirmed by 19F/23Al NMR and ESI-MS analysis, and cannot be exchanged with CDTA due to steric hindrance. Increasing the aluminum coagulant dosage effectively reduced free F- levels in photovoltaic and electroplating effluents to below 1 mg/L. However, the total fluoride content, with over half in the form of EF and NEF, was above 2 mg/L, exceeding the discharge limit regulated by many local governments of China. Furthermore, both EF and NEF can gradually transform to free F- in natural waters. Our findings indicate that aluminum-based coagulation inevitably accompanies the formation of substantial amounts of EF and NEF, compromising its defluoridation efficiency toward industrial effluents.
Asunto(s)
Aluminio , Fluoruros , Aluminio/química , Fluoruros/química , Purificación del Agua/métodosRESUMEN
As a typical energetic compound widely used in military activities, 2,4,6-trinitrotoluene (TNT) has attracted great attention in recent years due to its heavy pollution and wide distribution in and around the training facilities, firing ranges, and demolition sites. However, the subcellular targets and the underlying toxic mechanism of TNT remain largely unknown. In this study, we explored the toxic effects of TNT biological reduction on the mitochondrial function and homeostasis in Caenorhabditis elegans (C. elegans). With short-term exposure of L4 larvae, 10-1000 ng/mL TNT reduced mitochondrial membrane potential and adenosine triphosphate (ATP) content, which was associated with decreased expression of specific mitochondrial complex involving gas-1 and mev-1 genes. Using fluorescence-labeled transgenic nematodes, we found that fluorescence expression of sod-3 (muls84) and gst-4 (dvls19) was increased, suggesting that TNT disrupted the mitochondrial antioxidant defense system. Furthermore, 10 ng/mL TNT exposure increased the expression of the autophagy-related gene pink-1 and activated mitochondrial unfolded protein response (mt UPR), which was indicated by the increased expression of mitochondrial stress activated transcription factor atfs-1, ubiquitin-like protein ubl-5, and homeobox protein dve-1. Our findings demonstrated that TNT biological reduction caused mitochondrial dysfunction and the development of mt UPR protective stress responses, and provided a basis for determining the potential risks of energetic compounds to living organisms.
Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Mitocondrias , Trinitrotolueno , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Trinitrotolueno/toxicidad , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Transporte de Electrón/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Adenosina Trifosfato/metabolismoRESUMEN
Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.
Asunto(s)
Complejo I de Transporte de Electrón/genética , Osteosarcoma/genética , ARN Largo no Codificante/genética , RecQ Helicasas/genética , Síndrome Rothmund-Thomson/genética , Adenosina Trifosfato/biosíntesis , Proliferación Celular/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Senescencia Celular/genética , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Mutación/genética , Osteoblastos/efectos de los fármacos , Osteogénesis/genética , Osteosarcoma/complicaciones , Osteosarcoma/patología , Oxadiazoles/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Piperidinas/farmacología , Síndrome Rothmund-Thomson/complicaciones , Síndrome Rothmund-Thomson/patologíaRESUMEN
Flame retardants (FRs) have raised public concerns because of their environmental persistence and negative impacts on human health. Recent evidence has revealed that many FRs exhibit reproductive toxicities and transgenerational impacts, whereas the toxic effects of FRs on germ cells remain barely explored. Here we investigated the multigenerational effects of three flame retardants (TBBPA, TCEP and TCPP) on germ cell development in Caenorhabditis elegans, and examined the germ cell mutagenicity of these FRs by using whole genome sequencing. Parental exposure to three FRs markedly increased germ cell apoptosis, and impeded oogenesis in F1-F6 offspring. In addition, the double-increased mutation frequencies observed in progeny genomes uncover the mutagenic actions of FRs on germ cells. Analysis of mutation spectra revealed that these FRs predominantly induced point mutations at A:T base pairs, whereas both small and large indels were almost unaffected. These results revealed the long-term effects of FRs on development and genomic stability of germ cells, which may pose risks to environmental organisms and human reproductive health. Taken together, our findings suggest that germ cell mutagenicity should be carefully examined for the environmental risk assessment of FRs and other emerging pollutants.
Asunto(s)
Contaminantes Ambientales , Retardadores de Llama , Animales , Humanos , Retardadores de Llama/toxicidad , Retardadores de Llama/análisis , Caenorhabditis elegans/genética , Mutágenos , Contaminantes Ambientales/toxicidad , Medición de Riesgo , Éteres Difenilos Halogenados/análisisRESUMEN
The biology and diversity of glomerular parietal epithelial cells (PECs) are important for understanding podocyte regeneration and crescent formation. Although protein markers have revealed the morphological heterogeneity of PECs, the molecular characteristics of PEC subpopulations remain largely unknown. Here, we performed a comprehensive analysis of PECs using single-cell RNA sequencing (scRNA-seq) data. Our analysis identified five distinct PEC subpopulations: PEC-A1, PEC-A2, PEC-A3, PEC-A4 and PEC-B. Among these subpopulations, PEC- A1 and PEC-A2 were characterized as podocyte progenitors while PEC-A4 represented tubular progenitors. Further dynamic signaling network analysis indicated that activation of PEC-A4 and the proliferation of PEC-A3 played pivotal roles in crescent formation. Analyses suggested that upstream signals released by podocytes, immune cells, endothelial cells and mesangial cells serve as pathogenic signals and may be promising intervention targets in crescentic glomerulonephritis. Pharmacological blockade of two such pathogenic signaling targets, proteins Mif and Csf1r, reduced hyperplasia of the PECs and crescent formation in anti-glomerular basement membrane glomerulonephritis murine models. Thus, our study demonstrates that scRNA-seq-based analysis provided valuable insights into the pathology and therapeutic strategies for crescentic glomerulonephritis.
Asunto(s)
Glomerulonefritis , Enfermedades Renales , Podocitos , Ratones , Animales , Células Endoteliales/patología , Células Epiteliales/metabolismo , Glomérulos Renales/patología , Podocitos/patología , Glomerulonefritis/patología , Proteínas/metabolismo , Enfermedades Renales/patologíaRESUMEN
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive and inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) characterized by hepatocellular injury, inflammation, and fibrosis in various stages. More than 20% of patients with NASH will progress to cirrhosis. Currently, there is a lack of clinically effective drugs for treating NASH, as improving liver histology in NASH is difficult to achieve and maintain through weight loss alone. Hence, the present study aimed to investigate potential therapeutic drugs for NASH. METHODS: BMDMs and THP1 cells were used to construct an inflammasome activation model, and then we evaluated the effect of epalrestat on the NLRP3 inflammasome activation. Western blot, real-time qPCR, flow cytometry, and ELISA were used to evaluate the mechanism of epalrestat on NLRP3 inflammasome activation. Next, MCD-induced NASH models were used to evaluate the therapeutic effects of epalrestat in vivo. In addition, to evaluate the safety of epalrestat in vivo, mice were gavaged with epalrestat daily for 14 days. RESULTS: Epalrestat, a clinically effective and safe drug, inhibits NLRP3 inflammasome activation by acting upstream of caspase-1 and inducing ASC oligomerization. Importantly, epalrestat exerts its inhibitory effect on NLRP3 inflammasome activation by inhibiting the activation of aldose reductase. Further investigation revealed that the administration of epalrestat inhibited NLRP3 inflammasome activation in vivo, alleviating liver inflammation and improving NASH pathology. CONCLUSIONS: Our study indicated that epalrestat, an aldose reductase inhibitor, effectively suppressed NLRP3 inflammasome activation in vivo and in vitro and might be a new therapeutic approach for NASH.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Humanos , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/patología , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Aldehído Reductasa/uso terapéutico , Inflamación , Fibrosis , Ratones Endogámicos C57BLRESUMEN
Exceptional points (EPs) in non-Hermitian systems have recently attracted wide interest and spawned intriguing prospects for enhanced sensing. However, EPs have not yet been realized in thermal atomic ensembles, which is one of the most important platforms for quantum sensing. Here we experimentally observe EPs in multilevel thermal atomic ensembles and realize enhanced sensing of the magnetic field for 1 order of magnitude. We take advantage of the rich energy levels of atoms and construct effective decays for selected energy levels by employing laser coupling with the excited state, yielding unbalanced decay rates for different energy levels, which finally results in the existence of EPs. Furthermore, we propose the optical polarization rotation measurement scheme to detect the splitting of the resonance peaks, which makes use of both the absorption and dispersion properties and shows an advantage with enhanced splitting compared with the conventional transmission measurement scheme. Additionally, in our system both the effective coupling strength and decay rates are flexibly adjustable, and thus the position of the EPs are tunable, which expands the measurement range. Our Letter not only provides a new controllable platform for studying EPs and non-Hermitian physics, but also provide new ideas for the design of EP-enhanced sensors and opens up realistic opportunities for practical applications in the high-precision sensing of magnetic field and other physical quantities.
Asunto(s)
Campos Magnéticos , Física , VibraciónRESUMEN
Narrow linewidth is a long-pursued goal in precision measurement and sensing. We propose a parity-time symmetric (PT-symmetric) feedback method to narrow the linewidths of resonance systems. By using a quadrature measurement-feedback loop, we transform a dissipative resonance system into a PT-symmetric system. Unlike the conventional PT-symmetric systems that typically require two or more modes, here the PT-symmetric feedback system contains only a single resonance mode, which greatly extends the scope of applications. The method enables remarkable linewidth narrowing and enhancement of measurement sensitivity. We illustrate the concept in a thermal ensemble of atoms, achieving a 48-fold narrowing of the magnetic resonance linewidth. By applying the method in magnetometry, we realize a 22-times improvement of the measurement sensitivity. This work opens the avenue for studying non-Hermitian physics and high-precision measurements in resonance systems with feedback.
RESUMEN
The current effective method for the treatment of myocardial infarction is timely restoration of the blood supply to the ischemic area of the heart. Although reperfusion is essential for reestablishing oxygen and nutrient supplies, it often leads to additional myocardial damage, creating an important clinical dilemma. Reports from long-term studies have confirmed that mitochondrial damage is the critical mechanism in cardiac ischemia/reperfusion (I/R) injury. Mitochondria are dynamic and possess a quality control system that targets mitochondrial quantity and quality by modifying mitochondrial fusion, fission, mitophagy, and biogenesis and protein homeostasis to maintain a healthy mitochondrial network. The system of mitochondrial quality control involves complex molecular machinery that is highly interconnected and associated with pathological changes such as oxidative stress, calcium overload, and endoplasmic reticulum (ER) stress. Because of the critical role of the mitochondrial quality control systems, many reports have suggested that defects in this system are among the molecular mechanisms underlying myocardial reperfusion injury. In this review, we briefly summarize the important role of the mitochondrial quality control in cardiomyocyte function and focus on the current understanding of the regulatory mechanisms and molecular pathways involved in mitochondrial quality control in cardiac I/R damage.
Asunto(s)
Infarto del Miocardio , Daño por Reperfusión Miocárdica , Humanos , Mitocondrias/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Infarto del Miocardio/patologíaRESUMEN
Inhibition of NLRP3 inflammasome activation produces potent therapeutic effects in a wide array of inflammatory diseases. Bergapten (BeG), a furocoumarin phytohormone present in many herbal medicines and fruits, exibits anti-inflammatory activity. In this study we characterized the therapeutic potential of BeG against bacterial infection and inflammation-related disorders, and elucidated the underlying mechanisms. We showed that pre-treatment with BeG (20 µM) effectively inhibited NLRP3 inflammasome activation in both lipopolysaccharides (LPS)-primed J774A.1 cells and bone marrow-derived macrophages (BMDMs), evidenced by attenuated cleaved caspase-1 and mature IL-1ß release, as well as reduced ASC speck formation and subsequent gasdermin D (GSDMD)-mediated pyroptosis. Transcriptome analysis revealed that BeG regulated the expression of genes involved in mitochondrial and reactive oxygen species (ROS) metabolism in BMDMs. Moreover, BeG treatment reversed the diminished mitochondrial activity and ROS production after NLRP3 activation, and elevated the expression of LC3-II and enhanced the co-localization of LC3 with mitochondria. Treatment with 3-methyladenine (3-MA, 5 mM) reversed the inhibitory effects of BeG on IL-1ß, cleaved caspase-1 and LDH release, GSDMD-N formation as well as ROS production. In mouse model of Escherichia coli-induced sepsis and mouse model of Citrobacter rodentium-induced intestinal inflammation, pre-treatment with BeG (50 mg/kg) significantly ameliorated tissue inflammation and injury. In conclusion, BeG inhibits NLRP3 inflammasome activation and pyroptosis by promoting mitophagy and maintaining mitochondrial homeostasis. These results suggest BeG as a promising drug candidate for the treatment of bacterial infection and inflammation-related disorders.
Asunto(s)
Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Ratones , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis , Especies Reactivas de Oxígeno/metabolismo , 5-Metoxipsoraleno/farmacología , Mitofagia , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Caspasa 1/metabolismo , Interleucina-1beta/metabolismoRESUMEN
Recent evidence shows that targeting NLRP3 inflammasome activation is an important means to treat inflammasome-driven diseases. Scoparone, a natural compound isolated from the Chinese herb Artemisia capillaris Thunb, has anti-inflammatory activity. In this study we investigated the effect of scoparone on NLRP3 inflammasome activation in inflammatory diseases. In LPS-primed, ATP or nigericin-stimulated mouse macrophage J774A.1 cells and bone marrow-derived macrophages (BMDMs), pretreatment with scoparone (50 µM) markedly restrained canonical and noncanonical NLRP3 inflammasome activation, evidenced by suppressed caspase-1 cleavage, GSDMD-mediated pyroptosis, mature IL-1ß secretion and the formation of ASC specks. We then conducted a transcriptome analysis in scoparone-pretreated BMDMs, and found that the differentially expressed genes were significantly enriched in mitochondrial reactive oxygen species (ROS) metabolic process, mitochondrial translation and assembly process, as well as in inflammatory response. We demonstrated in J774A.1 cells and BMDMs that scoparone promoted mitophagy, a well-characterized mechanism to control mitochondrial quality and reduce ROS production and subsequent NLRP3 inflammasome activation. Mitophagy blockade by 3-methyladenine (3-MA, 5 mM) reversed the protective effects of scoparone on mitochondrial damage and inflammation in the murine macrophages. Moreover, administration of scoparone (50 mg/kg) exerted significant preventive effects via inhibition of NLRP3 activation in mouse models of bacterial enteritis and septic shock. Collectively, scoparone displays potent anti-inflammatory effects via blocking NLRP3 inflammasome activation through enhancing mitophagy, highlighting a potential action mechanism in treating inflammasome-related diseases for further clinical investigation.
Asunto(s)
Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Ratones , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Mitofagia , Especies Reactivas de Oxígeno/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BLRESUMEN
Although STAT3 has been reported as a negative regulator of type I interferon (IFN) signaling, the effects of pharmacologically inhibiting STAT3 on innate antiviral immunity are not well known. Capsaicin, approved for the treatment of postherpetic neuralgia and diabetic peripheral nerve pain, is an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), with additional recognized potencies in anticancer, anti-inflammatory, and metabolic diseases. We investigated the effects of capsaicin on viral replication and innate antiviral immune response and discovered that capsaicin dose-dependently inhibited the replication of VSV, EMCV, and H1N1. In VSV-infected mice, pretreatment with capsaicin improved the survival rate and suppressed inflammatory responses accompanied by attenuated VSV replication in the liver, lung, and spleen. The inhibition of viral replication by capsaicin was independent of TRPV1 and occurred mainly at postviral entry steps. We further revealed that capsaicin directly bound to STAT3 protein and selectively promoted its lysosomal degradation. As a result, the negative regulation of STAT3 on the type I IFN response was attenuated, and host resistance to viral infection was enhanced. Our results suggest that capsaicin is a promising small-molecule drug candidate, and offer a feasible pharmacological strategy for strengthening host resistance to viral infection.
Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Interferón Tipo I , Infecciones por Orthomyxoviridae , Ratones , Animales , Capsaicina/farmacología , Factor de Transcripción STAT3 , Transducción de Señal , Proteínas Portadoras , Replicación ViralRESUMEN
Owing to accelerated urbanization and industrialization, many plastic products have been manufactured and discharged into the environment, causing environmental and public health problems. Plastics in environmental media are further degraded by prolonged exposure to light, heat, mechanical friction, and other factors to form new pollutants called microplastics (MPs). Medical plastics have become a crucial source of plastics in environmental media. However, the release profiles of MPs from medical plastics and their potential ecological and health risks remain unclear. We used optical photothermal infrared spectroscopy to explore the release profiles of eight typical disposable medical devices under high-temperature steam disinfection (HSD). We also evaluated the toxicity of disposable medical devices-derived MPs in Caenorhabditis elegans (C. elegans). Our results showed that the changes in the surface morphology and modification of the disposable medical devices were mainly associated with the material. Polypropylene (PP) and polystyrene (PS) materials exhibited high aging phenomena (e.g., bumps, depressions, bulges and cracks), and HSD broke their oxygen-containing functional groups and carbon chains. By contrast, minor changes in the chemical and physical properties were observed in the polyvinyl chloride (PVC)-prepared disposable medical devices under the same conditions. Further physicochemical characterization indicated that the amount of MPs released from PP-prepared disposable medical devices (P4: 1.27 ± 0.34 × 106) was greater than that from PVC-prepared disposable medical devices (P7: 1.08 ± 0.14 × 105). The particle size of the released MPs was the opposite, PVC-prepared disposable medical devices (P7: 11.45 ± 1.79 µm) > PP-prepared disposable medical devices (P4: 7.18 ± 0.52 µm). Toxicity assessment revealed that disposable medical devices-released MPs significantly increased germ cell apoptosisin C. elegans. Moreover, MPs from PP-prepared disposable medical devices disrupted the intestinal barrier of worms, decreasing their lifespan. Our findings provided novel information regarding the profiles and mechanisms of MP release from disposable medical devices and revealed their potential risks to ecological environment.
Asunto(s)
Microplásticos , Plásticos , Animales , Microplásticos/toxicidad , Caenorhabditis elegans , Polipropilenos , CarbonoRESUMEN
As one of the most frequently used explosives, hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) can cause persistent pollution in the environment, leading to the potential ecological threat crossing the generations. In this study, we employed Caenorhabditis elegans to explore the toxic effects of RDX on the parental and offspring worms and the involved signaling pathways. Exposure up to 1000 ng/mL of RDX produced a significant increase in reactive oxygen species (ROS) production, germ cell apoptosis, and decrease in eggs laid. Various mutants were used to demonstrate the RDX-induced apoptosis signaling pathway, and the metabolism of RDX in the nematodes was found related to cytochrome P450 and GST through RNA sequencing. Exposure of parental worms to RDX produced significant reproductive toxicity in F1 and F2, but was recovered in F3 and F4. The transgenerational effects were associated with the decreased expression of met-2, spr-5, and set-2. Our findings revealed the signaling pathways related to the reproductive toxicity caused by RDX in C. elegans and their future generations, which provided the basis for further exploration of the ecological risks of energetic compounds in the environment.