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1.
Immunity ; 57(1): 106-123.e7, 2024 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-38159573

RESUMEN

When the filtrate of the glomerulus flows through the renal tubular system, various microscopic sediment particles, including mineral crystals, are generated. Dislodging these particles is critical to ensuring the free flow of filtrate, whereas failure to remove them will result in kidney stone formation and obstruction. However, the underlying mechanism for the clearance is unclear. Here, using high-resolution microscopy, we found that the juxtatubular macrophages in the renal medulla constitutively formed transepithelial protrusions and "sampled" urine contents. They efficiently sequestered and phagocytosed intraluminal sediment particles and occasionally transmigrated to the tubule lumen to escort the excretion of urine particles. Mice with decreased renal macrophage numbers were prone to developing various intratubular sediments, including kidney stones. Mechanistically, the transepithelial behaviors of medulla macrophages required integrin ß1-mediated ligation to the tubular epithelium. These findings indicate that medulla macrophages sample urine content and remove intratubular particles to keep the tubular system unobstructed.


Asunto(s)
Cálculos Renales , Riñón , Ratones , Animales , Macrófagos
2.
Immunity ; 57(9): 2030-2042.e8, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39116878

RESUMEN

Hypertension is usually accompanied by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not clear. Recent advances revealed that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels and found that microglia in the hypothalamic paraventricular nucleus (PVN), a sympathetic center, were early responders to hypertensive challenges. Vasculature analyses revealed that the PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology relative to other brain regions. As such, the PVN was susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. Mechanistically, ATP ligation to microglial P2Y12 receptor was responsible for microglial inflammatory activation and the eventual sympathetic overflow. Together, these findings identified a distinct vasculature pattern rendering vulnerability of PVN pre-sympathetic neurons to hypertension-associated microglia-mediated inflammatory insults.


Asunto(s)
Hemodinámica , Hipertensión , Microglía , Núcleo Hipotalámico Paraventricular , Sistema Nervioso Simpático , Núcleo Hipotalámico Paraventricular/metabolismo , Animales , Microglía/metabolismo , Hipertensión/fisiopatología , Ratones , Sistema Nervioso Simpático/fisiopatología , Masculino , Ratones Endogámicos C57BL , Adenosina Trifosfato/metabolismo , Receptores Purinérgicos P2Y12/metabolismo , Inflamación/inmunología , Presión Sanguínea , Neuronas/metabolismo
3.
Immunity ; 55(8): 1466-1482.e9, 2022 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-35863346

RESUMEN

Although many studies have addressed the regulatory circuits affecting neuronal activities, local non-synaptic mechanisms that determine neuronal excitability remain unclear. Here, we found that microglia prevented overactivation of pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) at steady state. Microglia constitutively released platelet-derived growth factor (PDGF) B, which signaled via PDGFRα on neuronal cells and promoted their expression of Kv4.3, a key subunit that conducts potassium currents. Ablation of microglia, conditional deletion of microglial PDGFB, or suppression of neuronal PDGFRα expression in the PVN elevated the excitability of pre-sympathetic neurons and sympathetic outflow, resulting in a profound autonomic dysfunction. Disruption of the PDGFBMG-Kv4.3Neuron pathway predisposed mice to develop hypertension, whereas central supplementation of exogenous PDGFB suppressed pressor response when mice were under hypertensive insult. Our results point to a non-immune action of resident microglia in maintaining the balance of sympathetic outflow, which is important in preventing cardiovascular diseases.


Asunto(s)
Hipertensión , Microglía , Animales , Hipertensión/metabolismo , Ratones , Neuronas/fisiología , Potasio/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo
4.
Nat Immunol ; 19(6): 547-560, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29777223

RESUMEN

The adaptor CARD9 functions downstream of C-type lectin receptors (CLRs) for the sensing of microbial infection, which leads to responses by the TH1 and TH17 subsets of helper T cells. The single-nucleotide polymorphism rs4077515 at CARD9 in the human genome, which results in the substitution S12N (CARD9S12N), is associated with several autoimmune diseases. However, the function of CARD9S12N has remained unknown. Here we generated CARD9S12N knock-in mice and found that CARD9S12N facilitated the induction of type 2 immune responses after engagement of CLRs. Mechanistically, CARD9S12N mediated CLR-induced activation of the non-canonical transcription factor NF-κB subunit RelB, which initiated production of the cytokine IL-5 in alveolar macrophages for the recruitment of eosinophils to drive TH2 cell-mediated allergic responses. We identified the homozygous CARD9 mutation encoding S12N in patients with allergic bronchopulmonary aspergillosis and revealed activation of RelB and production of IL-5 in peripheral blood mononuclear cells from these patients. Our study provides genetic and functional evidence demonstrating that CARD9S12N can turn alveolar macrophages into IL-5-producing cells and facilitates TH2 cell-mediated pathologic responses.


Asunto(s)
Aspergilosis Broncopulmonar Alérgica/inmunología , Proteínas Adaptadoras de Señalización CARD/inmunología , Interleucina-5/biosíntesis , Macrófagos Alveolares/inmunología , Células Th2/inmunología , Animales , Aspergilosis Broncopulmonar Alérgica/genética , Proteínas Adaptadoras de Señalización CARD/genética , Humanos , Interleucina-5/inmunología , Macrófagos Alveolares/metabolismo , Ratones , Polimorfismo de Nucleótido Simple , Transducción de Señal/inmunología
5.
Proc Natl Acad Sci U S A ; 121(25): e2322264121, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38865265

RESUMEN

Despite the tremendous clinical potential of nucleic acid-based vaccines, their efficacy to induce therapeutic immune response has been limited by the lack of efficient local gene delivery techniques in the human body. In this study, we develop a hydrogel-based organic electronic device (µEPO) for both transdermal delivery of nucleic acids and in vivo microarrayed cell electroporation, which is specifically oriented toward one-step transfection of DNAs in subcutaneous antigen-presenting cells (APCs) for cancer immunotherapy. The µEPO device contains an array of microneedle-shaped electrodes with pre-encapsulated dry DNAs. Upon a pressurized contact with skin tissue, the electrodes are rehydrated, electrically triggered to release DNAs, and then electroporate nearby cells, which can achieve in vivo transfection of more than 50% of the cells in the epidermal and upper dermal layer. As a proof-of-concept, the µEPO technique is employed to facilitate transdermal delivery of neoantigen genes to activate antigen-specific immune response for enhanced cancer immunotherapy based on a DNA vaccination strategy. In an ovalbumin (OVA) cancer vaccine model, we show that high-efficiency transdermal transfection of APCs with OVA-DNAs induces robust cellular and humoral immune responses, including antigen presentation and generation of IFN-γ+ cytotoxic T lymphocytes with a more than 10-fold dose sparing over existing intramuscular injection (IM) approach, and effectively inhibits tumor growth in rodent animals.


Asunto(s)
Electroporación , Inmunoterapia , Vacunas de ADN , Animales , Vacunas de ADN/administración & dosificación , Vacunas de ADN/inmunología , Electroporación/métodos , Ratones , Inmunoterapia/métodos , Administración Cutánea , Neoplasias/terapia , Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Ovalbúmina/inmunología , Ovalbúmina/administración & dosificación , Células Presentadoras de Antígenos/inmunología , Femenino , Ratones Endogámicos C57BL , Humanos , Vacunación/métodos
6.
EMBO Rep ; 25(3): 971-990, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38279020

RESUMEN

Tumor metastasis involves cells migrating directionally in response to external chemical signals. Reactive oxygen species (ROS) in the form of H2O2 has been demonstrated as a chemoattractant for neutrophils but its spatial characteristics in tumor microenvironment and potential role in tumor cell dissemination remain unknown. Here we investigate the spatial ROS distribution in 3D tumor spheroids and identify a ROS concentration gradient in spheroid periphery, which projects into a H2O2 gradient in tumor microenvironment. We further reveal the role of H2O2 gradient to induce chemotaxis of tumor cells by activating Src and subsequently inhibiting RhoA. Finally, we observe that the absence of mitochondria cristae remodeling proteins including the mitochondria-localized actin motor Myosin 19 (Myo19) enhances ROS gradient and promotes tumor dissemination. Myo19 downregulation is seen in many tumors, and Myo19 expression is negatively associated with tumor metastasis in vivo. Together, our study reveals the chemoattractant role of tumor microenvironmental ROS and implies the potential impact of mitochondria cristae disorganization on tumor invasion and metastasis.


Asunto(s)
Quimiotaxis , Peróxido de Hidrógeno , Especies Reactivas de Oxígeno , Miosinas/metabolismo , Factores Quimiotácticos
7.
Plant Physiol ; 194(4): 2679-2696, 2024 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-38146904

RESUMEN

Drought is a major adverse environmental factor that plants face in nature but the molecular mechanism by which plants transduce stress signals and further endow themselves with tolerance remains unclear. Malectin/malectin-like domains containing receptor-like kinases (MRLKs) have been proposed to act as receptors in multiple biological signaling pathways, but limited studies show their roles in drought-stress signaling and tolerance. In this study, we demonstrate OsMRLK63 in rice (Oryza sativa L.) functions in drought tolerance by acting as the receptor of 2 rapid alkalization factors, OsRALF45 and OsRALF46. We show OsMRLK63 is a typical receptor-like kinase that positively regulates drought tolerance and reactive oxygen species (ROS) production. OsMRLK63 interacts with and phosphorylates several nicotinamide adenine dinucleotide phosphate (NADPH) oxidases with the primarily phosphorylated site at Ser26 in the N-terminal of RESPIRATORY BURST OXIDASE HOMOLOGUE A (OsRbohA). The application of the 2 small signal peptides (OsRALF45/46) on rice can greatly alleviate the dehydration of plants induced by mimic drought. This function depends on the existence of OsMRLK63 and the NADPH oxidase-dependent ROS production. The 2 RALFs interact with OsMRLK63 by binding to its extracellular domain, suggesting they may act as drought/dehydration signal sensors for the OsMRLK63-mediated process. Our study reveals a OsRALF45/46-OsMRLK63-OsRbohs module which contributes to drought-stress signaling and tolerance in rice.


Asunto(s)
Oryza , Especies Reactivas de Oxígeno/metabolismo , Oryza/metabolismo , Resistencia a la Sequía , Deshidratación , Estrés Fisiológico , Plantas Modificadas Genéticamente/metabolismo , Sequías , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regulación de la Expresión Génica de las Plantas
8.
Cell Mol Life Sci ; 81(1): 366, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39172275

RESUMEN

BACKGROUND: Chromosome stability is crucial for homeostasis of pluripotent stem cells (PSCs) and early-stage embryonic development. Chromosomal defects may raise carcinogenic risks in regenerative medicine when using PSCs as original materials. However, the detailed mechanism regarding PSCs chromosome stability maintenance is not fully understood. METHODS: Mouse embryonic stem cells (line D3) and human embryonic stem cells (line H9) were cultured under standard conditions. To confirm the loading of RetSat protein on mitotic chromosomes of PSCs, immunostaining was performed in PSCs spontaneous differentiation assay and iPSC reprogramming assay from mouse embryonic fibroblasts (MEFs), respectively. In addition, qPCR, immunoprecipitation, LC-MS/MS and immunoblotting were used to study the expression of RetSat, and interactions of RetSat with cohesin/condensin components. RNA sequencing and teratoma formation assay was conducted to evaluate the carcinogenic risk of mouse embryonic stem cells with RetSat deletion. RESULTS: We reported a PSC high-expressing gene, RetSat, plays key roles in chromosome stabilization. We identified RetSat protein localizing onto mitotic chromosomes specifically in stemness positive cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). We found dramatic chromosome instability, e.g. chromosome bridging, lagging and interphase micronuclei in mouse and human ESCs when down regulating RetSat. RetSat knock-out mouse ESCs upregulated cancer associated gene pathways, and displayed higher tumorigenic capacities in teratoma formation assay. Mechanistically, we confirmed that RetSat interacts with cohesin/condensin components Smc1a and Nudcd2. RetSat deletion impaired the chromosome loading dosage of Smc1a, Smc3 and Nudcd2. CONCLUSIONS: In summary, we reported RetSat to be a key stabilizer of chromosome condensation in pluripotent stem cells. This highlights the crucial roles of RetSat in early-stage embryonic development, and potential value of RetSat as an effective biomarker for assessing the quality of pluripotent stem cells.


Asunto(s)
Inestabilidad Cromosómica , Segregación Cromosómica , Mitosis , Células Madre Pluripotentes , Animales , Ratones , Humanos , Células Madre Pluripotentes/metabolismo , Células Madre Pluripotentes/citología , Diferenciación Celular/genética , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/citología , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Células Madre Embrionarias de Ratones/metabolismo , Células Madre Embrionarias de Ratones/citología
9.
Cell Mol Life Sci ; 81(1): 116, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38438808

RESUMEN

Microglia regulate synaptic function in various ways, including the microglial displacement of the surrounding GABAergic synapses, which provides important neuroprotection from certain diseases. However, the physiological role and underlying mechanisms of microglial synaptic displacement remain unclear. In this study, we observed that microglia exhibited heterogeneity during the displacement of GABAergic synapses surrounding neuronal soma in different cortical regions under physiological conditions. Through three-dimensional reconstruction, in vitro co-culture, two-photon calcium imaging, and local field potentials recording, we found that IL-1ß negatively modulated microglial synaptic displacement to coordinate regional heterogeneity in the motor cortex, which impacted the homeostasis of the neural network and improved motor learning ability. We used the Cre-Loxp system and found that IL-1R1 on glutamatergic neurons, rather than that on microglia or GABAergic neurons, mediated the negative effect of IL-1ß on synaptic displacement. This study demonstrates that IL-1ß is critical for the regional heterogeneity of synaptic displacement by coordinating different actions of neurons and microglia via IL-1R1, which impacts both neural network homeostasis and motor learning ability. It provides a theoretical basis for elucidating the physiological role and mechanism of microglial displacement of GABAergic synapses.


Asunto(s)
Aprendizaje , Microglía , Calcio , Neuronas GABAérgicas , Interleucina-1beta , Sinapsis
10.
J Am Chem Soc ; 146(30): 20878-20890, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39016781

RESUMEN

The investigation of long noncoding RNAs (lncRNAs) and RNA binding proteins (RBPs) interactions in living cell holds great significance for elucidating their critical roles in a variety of biological activities, but limited techniques are available to profile the temporal-spatial dynamic heterogeneity. Here, we introduced a molecular beacon-functionalized nanoneedle array designed for spatially resolved profiling of lncRNA-RBP interactions (Nano-SpatiaLR). A nanoneedle array modified with a molecular beacon is employed to selectively isolate specific intracellular lncRNAs and their associated RBPs without affecting cell viability. The RBPs are then in situ analyzed with a fluorescent labeled antibody and colocalized with lncRNA signals to get a quantitative measurement of their dynamic interactions. Additionally, leveraging the spatial distribution and nanoscale modality of the nanoneedle array, this technique provides the spatial heterogeneity information on cellular lncRNA-RBPs interaction at single cell resolution. In this study, we tracked the temporal-spatial interactive heterogeneity dynamics of lncRNA-RBPs interaction within living cells across different biological progresses. Our findings demonstrated that the interactions between lncRNA HOTAIR and RBPs EZH2 and LSD1 undergo significant changes in response to drug treatments, particularly in tumor cells. Moreover, these interactions become more intensified as tumor cells aggregate during the proliferation process.


Asunto(s)
ARN Largo no Codificante , Proteínas de Unión al ARN , Análisis de la Célula Individual , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/genética , Humanos , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/química , Proteína Potenciadora del Homólogo Zeste 2/metabolismo
11.
Small ; 20(11): e2306638, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37922530

RESUMEN

The achievement of rapid multiplexed protein imaging is limited by the use of stimulating reagents, extensive incubating and washing steps, and the low fluorescence intensity of targets. In this study, sequentially-activated DNA tags are developed and combined them with primary antibodies using signal enhancement strategies to create sequentially-activated antibodies (SAAs). These SAAs enable rapid, wash-free sequential imaging of different protein targets. The samples are pre-processed to label all targets of interest with SAAs simultaneously, and the signal is turned ON for only one target in each stage. The sequential imaging of multiple targets is achieved through wash-free strand displacement reactions that exhibit rapid kinetics with t1/2  < 10 s in a cellular context. Remarkably, this method successfully demonstrates sequential imaging of nine different protein targets within just a few minutes. This all-in-one platform for multiplexed protein imaging holds great promise for diverse applications in immunofluorescence imaging.


Asunto(s)
Anticuerpos , Proteínas , Anticuerpos/metabolismo , ADN , Diagnóstico por Imagen
12.
Small ; 20(29): e2310461, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38396201

RESUMEN

Bacteria-induced keratitis is a major cause of corneal blindness in both developed and developing countries. Instillation of antibiotic eyedrops is the most common management of bacterial keratitis but usually suffers from low bioavailability (i.e., <5%) and frequent administration, due to the existence of corneal epithelial barrier that prevents large and hydrophilic drug molecules from entering the cornea, and the tear film on corneal surface that rapidly washes drug away from the cornea. Here, a self-implantable core-shell microneedle (MN) patch with programmed drug release property to facilitate bacterial keratitis treatment is reported. The pH-responsive antimicrobial nanoparticles (NPs), Ag@ZIF-8, which are capable of producing antibacterial metal ions in the infected cornea and generating oxidative stress in bacteria, are loaded in the dissolvable core, while the anti-angiogenic drug, rapamycin (Rapa), is encapsulated in the biodegradable shell, thereby enabling rapid release of Ag@ZIF-8 NPs and sustained release of Rapa after corneal insertion. Owing to the programmed release feature, one single administration of the core-shell MN patch in a rat model of bacterial keratitis, can achieve satisfactory antimicrobial activity and superior anti-angiogenic and anti-inflammation effects as compared to daily topical eyedrops, indicating a great potential for the infectious keratitis therapy in clinics.


Asunto(s)
Liberación de Fármacos , Queratitis , Agujas , Animales , Queratitis/tratamiento farmacológico , Queratitis/microbiología , Ratas , Sirolimus/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/administración & dosificación , Antibacterianos/química , Antibacterianos/uso terapéutico , Ratas Sprague-Dawley , Córnea/metabolismo , Córnea/efectos de los fármacos , Plata/química , Sistemas de Liberación de Medicamentos
13.
Small ; 20(34): e2401578, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38616738

RESUMEN

Photo enhanced oxygen evolution reaction has recently emerged as an advanced strategy with great application prospects for highly efficient energy conversion and storage. In the course of photo enhanced oxygen evolution reactions, the other works focus has predominantly centered on catalysts while inadvertently overlooking the pivotal role of photo. Consequently, this manuscript embarks upon a comprehensive review of recent advancements in photo-driven, aiming to illuminate this critical dimension. A detailed introduction to the photothermal effect, photoelectronic effect, photon-induced surface plasmon resonance, photo and heterojunction, photo-induced reversible geometric conversion, photo-induced energy barrier reduction, photo-induced chemical effect, photo-charging, and the synthesis of laser/photo-assisted catalysts, offering prospects for the development of each case is provided. A detailed introduction to the photothermal effect, photoelectronic effect, photon-induced surface plasmon resonance, photo and heterojunction, photo-induced reversible geometric conversion, photo-induced energy barrier reduction, photo-induced chemical effect, photo-charging, and the synthesis of laser/photo-assisted catalysts is provided. At the same time, the overpotential and Tafel slope of some catalysts mentioned above at 10 mA cm-2 is collected, and calculated the lifting efficiency of light on them, offering prospects for the development of each case.

14.
Opt Express ; 32(3): 4167-4179, 2024 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-38297623

RESUMEN

The recent emerging appearance of optical analogs of magnetic quasiparticles, i.e., optical skyrmions constructed via spin, field, and Stokes vectors, has garnered substantial interest from deep-subwavelength imaging and quantum entanglement. Here, we investigate systematically the topological state transitions of skyrmionic beams constructed by the Stokes vectors in the focusing configuration. We theoretically demonstrated that in the weak focusing, the skyrmion topological number is protected. Whereas, in the tight focusing, a unique topological transformation with skyrmion number variation is exhibited for the optical skyrmion, anti-skyrmion, and 2nd-order skyrmion structures. The significant difference between the topological state transitions of these two cases originates from the transformation from the paraxial optical system to the nonparaxial optical system, and the approximate two-dimensional polarization structure to the three-dimensional polarization structure. The results provide new insights into the topological state transitions in topological structures, which promote applications in information processing, data storage, and free-space optical communications.

15.
Chemistry ; 30(25): e202303989, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38345999

RESUMEN

Benzobicyclo[3.2.1]octane is a cage-like unique motif containing a bicyclo[3.2.1]octane structure fused with at least one benzene ring. It is found in various natural products that exhibit structural complexities and important biological activities. The total synthesis of natural products possessing this challenging structure has received considerable attention, and great advances have been made in this field during the past 15 years. This review summarizes thus far achieved chemical syntheses and synthetic studies of natural compounds featuring the benzobicyclo[3.2.1]octane core. It focuses on strategic approaches constructing the bridged structure, aiming to provide a useful reference for inspiring further advancements in strategies and total syntheses of natural products with such a framework.

16.
FASEB J ; 37(1): e22699, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36520055

RESUMEN

Cardiac fibrosis is an essential pathological process in pressure overload (PO)-induced heart failure. Recently, myocyte-fibroblast communication is proven to be critical in heart failure, in which, pathological growth of cardiomyocytes (CMs) may promote fibrosis via miRNAs-containing exosomes (Exos). Peli1 regulates the activation of NF-κB and AP-1, which has been demonstrated to engage in miRNA transcription in cardiomyocytes. Therefore, we hypothesized that Peli1 in CMs regulates the activation of cardiac fibroblasts (CFs) through an exosomal miRNA-mediated paracrine mechanism, thereby promoting cardiac fibrosis. We found that CM-conditional deletion of Peli1 improved PO-induced cardiac fibrosis. Moreover, Exos from mechanical stretch (MS)-induced WT CMs (WT MS-Exos) promote activation of CFs, Peli1-/- MS-Exos reversed it. Furthermore, miRNA microarray and qPCR analysis showed that miR-494-3p was increased in WT MS-Exos while being down regulated in Peli1-/- MS-Exos. Mechanistically, Peli1 promoted miR-494-3p expression via NF-κB/AP-1 in CMs, and then miR-494-3p induced CFs activation by inhibiting PTEN and amplifying the phosphorylation of AKT, SMAD2/3, and ERK. Collectively, our study suggests that CMs Peli1 contributes to myocardial fibrosis via CMs-derived miR-494-3p-enriched exosomes under PO, and provides a potential exosomal miRNA-based therapy for cardiac fibrosis.


Asunto(s)
Comunicación Celular , Exosomas , Insuficiencia Cardíaca , Miocitos Cardíacos , Humanos , Exosomas/genética , Exosomas/metabolismo , Fibrosis/etiología , Fibrosis/genética , Fibrosis/metabolismo , Fibrosis/patología , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , MicroARNs/genética , MicroARNs/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factor de Transcripción AP-1/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Cardiopatías/etiología , Cardiopatías/genética , Cardiopatías/metabolismo , Cardiopatías/patología , Fibroblastos/metabolismo , Fibroblastos/patología , Comunicación Celular/genética , Comunicación Celular/fisiología
17.
Brain Behav Immun ; 115: 705-717, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37992789

RESUMEN

Pericyte is an indispensable cellular constituent of blood-brain barrier (BBB) and its homeostasis heavily rely on PDGFB-PDGFRß signaling. However, the primary cellular sources of PDGFB in the central nervous system (CNS) are unclear. Microglia is not considered a component of BBB and its role in maintaining BBB integrity in steady state is controversial. In this study, by analyzing transcriptomic data and performing in situ hybridization, we revealed a transition of the primary central PDGFB producers from endothelial cells in newborns to microglia in adults. Acute loss of microglial PDGFB profoundly impaired BBB integrity in adult but not newborn mice, and thus, adult mice deficient of microglial PDGFB could not survive from a sublethal endotoxin challenge due to rampant microhemorrhages in the CNS. In contrast, acute abrogation of endothelial PDGFB had minimal effects on the BBB of adult mice but led to a severe impairment of CNS vasculature in the neonates. Moreover, we found that microglia would respond to a variety of BBB insults by upregulating PDGFB expression. These findings underscore the physiological importance of the microglia-derived PDGFB to the BBB integrity of adult mice both in steady state and under injury.


Asunto(s)
Barrera Hematoencefálica , Microglía , Animales , Ratones , Barrera Hematoencefálica/metabolismo , Sistema Nervioso Central/metabolismo , Células Endoteliales/metabolismo , Microglía/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismo
18.
Protein Expr Purif ; 216: 106416, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38104790

RESUMEN

A major cellobiohydrolase of Neurospora crassa CBH2 was successfully expressed in Pichia pastoris. The maximum Avicelase activity in shake flask among seven transformants which selected on 4.0 g/L G418 plates was 0.61 U/mL. The optimal pH and temperature for Avicelase activity of the recombinant CBH2 were determined to be 4.8 and 60 °C, respectively. The new CBH2 maintained 63.5 % Avicelase activity in the range of pH 4.0-10.4, and 60.2 % Avicelase activity in the range of 30-90 °C. After incubation at 70-90 °C for 1 h, the Avicelase activity retained 60.5 % of its initial activity. The presence of Zn2+, Ca2+ or Cd2+ enhanced the Avicelase activity of the CBH2, of which Cd2+ at 10 mM causing the highest increase. The recombinant CBH2 was used to enhance the Avicel hydrolysis by improving the exo-exo-synergism between CBH2 and CBH1 in N.crassa cellulase. The enzymatic hydrolysis yield was increased by 38.1 % by adding recombinant CBH2 and CBH1, and the yield was increased by 215.4 % when the temperature is raised to 70 °C. This work provided a CBH2 with broader pH range and better heat resistance, which is a potential enzyme candidate in food, textile, pulp and paper industries, and other industrial fields.


Asunto(s)
Celulosa 1,4-beta-Celobiosidasa , Neurospora crassa , Saccharomycetales , Celulosa 1,4-beta-Celobiosidasa/genética , Neurospora crassa/genética , Neurospora crassa/metabolismo , Cadmio , Pichia/genética , Pichia/metabolismo , Clonación Molecular , Proteínas Recombinantes
19.
Environ Sci Technol ; 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39223996

RESUMEN

Bacterial contamination in drinking water is a global health concern, necessitating the development of highly efficient treatment techniques. Anion-exchange resins (AERs) have long been employed for removing anionic contaminants from drinking water, but their performance for bacterial contamination is poor. Here, we develop a novel AER (AER6-1) with exceptional bactericidal effects and ultrafast adsorption rates of extracellular DNA (eDNA) (2.2- and 11.5-fold compared to other AERs) achieved through preloading quaternary ammonium groups (QAGs) with hexyl chain (-C6-N+-) on the resin exterior and successively grafting QAGs with a methyl chain (-C1-N+-) inside a resin pore. The AER6-1 outperforms other commercial AERs and ultraviolet disinfection, exhibiting superior elimination of total bacteria, potential pathogens (Escherichia coli and Pseudomonas aeruginosa), eDNA, and antibiotic resistance genes (mexF, mexB, and bacA) in actual drinking water, while maintaining a comparable anion exchange capacity with other commercial AERs. Theoretical calculations of density functional theory and xDLVO combined with XPS elucidate the crucial roles of hydrogen bonding and hydrophobic force provided by the resin skeleton and -C6-N+- in cleaving the bacterial cell membrane and increasing the adsorption kinetics on eDNA. This study broadens the scope of AERs and highlights an effective way of simultaneously removing bacterial and anionic contaminants from drinking water.

20.
Environ Sci Technol ; 58(37): 16632-16641, 2024 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-39216011

RESUMEN

Conductive nanofiltration (CNF) membranes hold great promise for removing small organic pollutants from water through enhanced Donnan exclusion and electrocatalytic degradation. However, current CNF membranes face limitations in conductivity, structural stability, and nanochannel control strategies. This work addresses these challenges by introducing aniline-functionalized carbon nanotubes (NH2-CNTs) as an interlayer. NH2-CNTs enhance the dispersibility and adhesion of pristine carbon nanotubes, leading to a more conductive and stable composite nanofiltration membrane. The redesigned NH2-CNTs interlayered conductive nanofiltration (NICNF) membrane exhibits a 10-fold increase in conductivity and a high response degree (80%) with excellent cyclic stability, surpassing existing CNF membranes. The synergistic effects of enhanced Donnan exclusion, voltage switching, and electrocatalysis enable the NICNF membrane to achieve selective recovery of mixed dyes, 98.97% removal of residual wastewater toxicity, and a 5.2-fold increase in permeance compared to the commercial NF270 membrane. This research paves the way for next-generation multifunctional membranes capable of the efficient recovery and degradation of toxic organic pollutants in wastewater.


Asunto(s)
Filtración , Membranas Artificiales , Nanotubos de Carbono , Contaminantes Químicos del Agua , Nanotubos de Carbono/química , Contaminantes Químicos del Agua/química , Compuestos de Anilina/química , Aguas Residuales/química , Purificación del Agua/métodos , Conductividad Eléctrica
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