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Rich fossil evidence suggests that many traits and functions related to terrestrial evolution were present long before the ancestor of lobe- and ray-finned fishes. Here, we present genome sequences of the bichir, paddlefish, bowfin, and alligator gar, covering all major early divergent lineages of ray-finned fishes. Our analyses show that these species exhibit many mosaic genomic features of lobe- and ray-finned fishes. In particular, many regulatory elements for limb development are present in these fishes, supporting the hypothesis that the relevant ancestral regulation networks emerged before the origin of tetrapods. Transcriptome analyses confirm the homology between the lung and swim bladder and reveal the presence of functional lung-related genes in early ray-finned fishes. Furthermore, we functionally validate the essential role of a jawed vertebrate highly conserved element for cardiovascular development. Our results imply the ancestors of jawed vertebrates already had the potential gene networks for cardio-respiratory systems supporting air breathing.
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Evolução Biológica , Peixes/genética , Nadadeiras de Animais/fisiologia , Animais , Fenômenos Fisiológicos Cardiovasculares , Sistema Cardiovascular/anatomia & histologia , Extremidades/fisiologia , Peixes/classificação , Genoma , Pulmão/anatomia & histologia , Pulmão/fisiologia , Filogenia , Receptores Odorantes/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma , Vertebrados/classificação , Vertebrados/genéticaRESUMO
Lungfishes are the closest extant relatives of tetrapods and preserve ancestral traits linked with the water-to-land transition. However, their huge genome sizes have hindered understanding of this key transition in evolution. Here, we report a 40-Gb chromosome-level assembly of the African lungfish (Protopterus annectens) genome, which is the largest genome assembly ever reported and has a contig and chromosome N50 of 1.60 Mb and 2.81 Gb, respectively. The large size of the lungfish genome is due mainly to retrotransposons. Genes with ultra-long length show similar expression levels to other genes, indicating that lungfishes have evolved high transcription efficacy to keep gene expression balanced. Together with transcriptome and experimental data, we identified potential genes and regulatory elements related to such terrestrial adaptation traits as pulmonary surfactant, anxiolytic ability, pentadactyl limbs, and pharyngeal remodeling. Our results provide insights and key resources for understanding the evolutionary pathway leading from fishes to humans.
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Adaptação Biológica , Evolução Biológica , Peixes/genética , Sequenciamento Completo do Genoma , Nadadeiras de Animais/anatomia & histologia , Nadadeiras de Animais/fisiologia , Animais , Extremidades/anatomia & histologia , Extremidades/fisiologia , Peixes/anatomia & histologia , Peixes/classificação , Peixes/fisiologia , Filogenia , Fenômenos Fisiológicos Respiratórios , Sistema Respiratório/anatomia & histologia , Vertebrados/genéticaRESUMO
Gasdermin D (GSDMD) is a classical molecule involved in pyroptosis. It has been reported to be cleaved into N-terminal fragments to form pores in the neutrophil membrane and promote the release of neutrophil extracellular traps (NETs). However, it remains unclear if GSDMD is involved in neutrophil regulation and NET release during ARDS. The role of neutrophil GSDMD in the development of ARDS was investigated in a murine model of ARDS induced by lipopolysaccharide (LPS) using the neutrophil specific GSDMD-deficient mice. The neutrophil GSDMD cleavage and its relationship with NETosis were also explored in ARDS patients. The cleavage of GSDMD in neutrophils from ARDS patients and mice was upregulated. Inhibition of GSDMD by genetic knockout or inhibitors resulted in reduced production of NET both in vivo and in vitro, and attenuation of LPS-induced lung injury. Moreover, in vitro experiments showed that the inhibition of GSDMD attenuated endothelial injury co-cultured with neutrophils from ARDS patients, while extrinsic NETs reversed the protective effect of GSDMD inhibition. Collectively, our data suggest that the neutrophil GSDMD cleavage is crucial in NET release during ARDS. The NET release maintained by cleaved GSDMD in neutrophils may be a key event in the development of ARDS.
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Armadilhas Extracelulares , Síndrome do Desconforto Respiratório , Camundongos , Animais , Lipopolissacarídeos , Neutrófilos , PiroptoseRESUMO
The protocol of aerobic oxidative dehydroxycyclization installed in the synthesis of rarely studied 1-hydroxyphenothiazines from catechols and o-mercaptoanilines is presented. Utilizing a natural renewable low-toxicity gallic acid as an organocatalyst, this established transformation proceeded smoothly in an aqueous ethanol solution under mild conditions with good functional group compatibility and up to a 94% isolated yield. This protocol is also characterized by its operational simple workup involving only recrystallization, revealing its sustainability and synthetic practicability.
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INTRODUCTION: Nicotinamide mononucleotide (NMN) is a nucleotide that is commonly recognized for its role as an intermediate of nicotinamide adenine dinucleotide (NAD+) biosynthesis with multiple pharmacological effects. The purpose of this study was to evaluate the protective effect of nicotinamide mononucleotide (NMN) against lipopolysaccharide (LPS)-induced acute lung injury (ALI). METHODS: We investigated the effect of NMN on ALI-induced inflammatory response, oxidative stress, and cell apoptosis. The ALI mouse model was performed by injecting LPS intratracheally at a dose of 10 mg/kg in 50 µL saline. Flow cytometry was used to detect neutrophil infiltration in bronchoalveolar lavage fluid (BALF), and ELISA was used to detect the contents of inflammatory cytokines TNF-α, IL-1ß and IL-6 in BALF. Oxidative stress was evaluated by determining the superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in lung tissue. ROS formation was analyzed by immunofluorescence. Western blotting was performed to detect apoptotic levels and p38MAPK/NF-κB phosphorylation levels in lung tissue. RESULTS: In the ALI mouse model, NMN showed a significant therapeutic effect compared to the LPS group. NMN attenuated the pathological damage and cell apoptosis in lung tissue, decreased the levels of TNF-α, IL-1ß, and IL-6 in BALF, and reduced the number of total cells and neutrophils in BALF. In addition, NMN attenuated the LPS-induced elevation of dry-to-wet ratio, MDA content, p38 MAPK and p65 NF-κB phosphorylation levels, and the SOD activity was increased by NMN treatment. CONCLUSIONS: In conclusion, the present study showed that NMN exerted a protective effect on LPS-induced ALI with anti-inflammatory, antioxidative, and antiapoptotic effects.
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Lesão Pulmonar Aguda , Mononucleotídeo de Nicotinamida , Animais , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Interleucina-6 , Lipopolissacarídeos , Pulmão/patologia , NF-kappa B , Mononucleotídeo de Nicotinamida/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno , Superóxido Dismutase/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Endothermy is a typical convergent phenomenon which has evolved independently at least eight times in vertebrates, and is of significant advantage to organisms in extending their niches. However, how vertebrates other than mammals or birds, especially teleosts, achieve endothermy has not previously been fully understood. In this study, we sequenced the genomes of two billfishes (swordfish and sailfish), members of a representative lineage of endothermic teleosts. Convergent amino acid replacements were observed in proteins related to heat production and the visual system in two endothermic teleost lineages, billfishes and tunas. The billfish-specific genetic innovations were found to be associated with heat exchange, thermoregulation, and the specialized morphology, including elongated bill, enlarged dorsal fin in sailfish and loss of the pelvic fin in swordfish.
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Evolução Biológica , Perciformes/genética , Termogênese/genética , Nadadeiras de Animais/anatomia & histologia , Animais , Genoma , Masculino , Perciformes/anatomia & histologia , Fenótipo , Visão Ocular/genéticaRESUMO
Magnetic coupling resonance wireless power transfer can efficiently provide energy to intracranial implants under safety constraints, and is the main way to power fully implantable brain-computer interface systems. However, the existing maximum efficiency tracking wireless power transfer system is aimed at optimizing the overall system efficiency, but the efficiency of the secondary side is not optimized. Moreover, the parameters of the transmitter and the receiver change nonlinearly in the power control process, and the efficiency tracking mainly depends on wireless communication. The heat dissipation caused by the unoptimized receiver efficiency and the wireless communication delay in power control will inevitably affect neural activity and even cause damage, thus affecting the results of neuroscience research. Here, a linear-power-regulated wireless power transfer method is proposed to realize the linear change of the received power regulation and optimize the receiver efficiency, and a miniaturized linear-power-regulated wireless power transfer system is developed. With the received power control, the efficiency of the receiver is increased to more than 80%, which can significantly reduce the heating of fully implantable microsystems. The linear change of the received power regulation makes the reflected impedance in the transmitter change linearly, which will help to reduce the dependence on wireless communication and improve biological safety in received power control applications.
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Temperatura Alta , Tecnologia sem Fio , Próteses e Implantes , Impedância Elétrica , Regulação da Temperatura CorporalRESUMO
MOTIVATION: Metalloenzymes are attractive targets for therapeutic intervention owing to their central roles in various biological processes and pathological situations. The fast-growing body of structural data on metalloenzyme-ligand interactions is facilitating efficient drug discovery targeting metalloenzymes. However, there remains a shortage of specific databases that can provide centralized, interconnected information exclusive to metalloenzyme-ligand associations. RESULTS: We created a Metalloenzyme-Ligand Association Database (MeLAD), which is designed to provide curated structural data and information exclusive to metalloenzyme-ligand interactions, and more uniquely, present expanded associations that are represented by metal-binding pharmacophores (MBPs), metalloenzyme structural similarity (MeSIM) and ligand chemical similarity (LigSIM). MeLAD currently contains 6086 structurally resolved interactions of 1416 metalloenzymes with 3564 ligands, of which classical metal-binding, non-classical metal-binding, non-metal-binding and metal water-bridging interactions account for 63.0%, 2.3%, 34.4% and 0.3%, respectively. A total of 263 monodentate, 191 bidentate and 15 tridentate MBP chemotypes were included in MeLAD, which are linked to different active site metal ions and coordination modes. 3726 and 52 740 deductive metalloenzyme-ligand associations by MeSIM and LigSIM analyses, respectively, were included in MeLAD. An online server is provided for users to conduct metalloenzyme profiling prediction for small molecules of interest. MeLAD is searchable by multiple criteria, e.g. metalloenzyme name, ligand identifier, functional class, bioinorganic class, metal ion and metal-containing cofactor, which will serve as a valuable, integrative data source to foster metalloenzyme related research, particularly involved in drug discovery targeting metalloenzymes. AVAILABILITY AND IMPLEMENTATION: MeLAD is accessible at https://melad.ddtmlab.org. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Metaloproteínas , Domínio Catalítico , Descoberta de Drogas , Ligantes , MetaisRESUMO
BACKGROUND: The role of dexmedetomidine in preventing postoperative delirium (POD) after cardiac surgery remains controversial because of several recent trials with negative results. We aimed to perform an updated meta-analysis of randomized controlled trials (RCTs) to clarify this controversy. METHODS: RCTs investigating the perioperative administration of dexmedetomidine in cardiac surgery were retrieved from PubMed, Web of Science, and the Cochrane library until August,27,2020. Two researchers independently screened the literature, collected the data and evaluated the bias risk of the included studies. The meta-analysis was performed with the RevMan 5.3. RESULTS: A total of 15 studies including 2813 patients were included in the study. A pooled result showed that dexmedetomidine could reduce the risk of POD in adult population underwent cardiac surgery (OR 0.56, 95%CI 0.36-0.89, P = 0.0004, I2 = 64%). The subgroup analysis demonstrated that the protective effect of dexmedetomidine was only present in the patients injected with dexmedetomidine after surgery but not from the start of surgery, in the adult patients without specific age limitation but not in the elderly, and in the studies in comparison with other sedatives but not with placebo. There were no statistical differences when analyzing the secondary outcomes including hypotension (OR 1.13; 95% CI 0.54-2.37, P < 0.00001, I2 = 85%), bradycardia (OR 1.72; 95% CI 0.84-3.53, P = 0.04, I2 = 58%) and atrial fibrillation (OR 0.87; 95% CI 0.70-1.08, P = 0.43, I2 = 0). CONCLUSIONS: Dexmedetomidine can reduce the incidence of POD compared to other sedatives and opioids after cardiac surgery in adult patients. The proper population and timing for perioperative use of dexmedetomidine after cardiac surgery remain to be further investigated.
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Procedimentos Cirúrgicos Cardíacos , Delírio/tratamento farmacológico , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Complicações Pós-Operatórias/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Delírio/epidemiologia , Humanos , Incidência , Complicações Pós-Operatórias/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricosRESUMO
This paper considers an adaptive fault-tolerant control problem for a class of uncertain strict feedback nonlinear systems, in which the actuator has an unknown drift fault and the loss of effectiveness fault. Based on the event-triggered theory, the adaptive backstepping technique, and Lyapunov theory, a novel fault-tolerant control strategy is presented. It is shown that an appropriate comprise between the control performance and the sensor data real-time transmission consumption is made, and the fault-tolerant tracking control problem of the strict feedback nonlinear system with uncertain and unknown control direction is solved. The adaptive backstepping method is introduced to compensate the actuator faults. Moreover, a new adjustable event-triggered rule is designed to determine the sampling state instants. The overall control strategy guarantees that the output signal tracks the reference signal, and all the signals of the closed-loop systems are convergent. Finally, the fan speed control system is constructed to demonstrate the validity of the proposed strategy and the application of the general systems.
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The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player in pyroptosis. This recently characterized class of pore-forming effector proteins is pivotal in orchestrating processes such as membrane permeabilization, pyroptosis, and the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants and infections. GSDMs have been implicated in a range of diseases including, but not limited to, sepsis, viral infections, and cancer, either through involvement in pyroptosis or independently of this process. The regulation of GSDM-mediated pyroptosis is gaining recognition as a promising therapeutic strategy for the treatment of various diseases. Current strategies for inhibiting GSDMD primarily involve binding to GSDMD, blocking GSDMD cleavage or inhibiting GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In this review, we delve into the cutting-edge understanding of the interplay between GSDMs and pyroptosis, elucidate the activation mechanisms of GSDMs, explore their associations with a range of diseases, and discuss recent advancements and potential strategies for developing GSDMD inhibitors.
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Peptídeos e Proteínas de Sinalização Intracelular , Sepse , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Gasderminas , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , PiroptoseRESUMO
The escalating airway management demands of cancer patients have prompted us to continually curate airway devices, with supraglottic airway devices (SADs) playing a significant role in this regard. SADs serve as instrumental tools for maintaining an open upper airway. Since the inception of the earliest SADs in the early 1980s, an array of advanced and enhanced second-generation devices have been employed in clinical settings. These upgraded SADs integrate specific features designed to enhance positive-pressure ventilation and mitigate the risk of aspiration. Nowadays, they are extensively used in general anesthesia procedures and play a critical role in difficult airway management, pre-hospital care, and emergency medicine. In certain situations, SADs may be deemed a superior alternative to endotracheal tube (ETT) and can be employed in a broader spectrum of surgical and non-surgical cases. This review provides an overview of the current evidence, a summary of classifications, relevant application scenarios, and areas for improvement in the development or clinical application of future SADs.
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GPX4 (Glutathione peroxidase 4) serves as a crucial intracellular regulatory factor, participating in various physiological processes and playing a significant role in maintaining the redox homeostasis within the body. Ferroptosis, a form of iron-dependent non-apoptotic cell death, has gained considerable attention in recent years due to its involvement in multiple pathological processes. GPX4 is closely associated with ferroptosis and functions as the primary inhibitor of this process. Together, GPX4 and ferroptosis contribute to the pathophysiology of several diseases, including sepsis, nervous system diseases, ischemia reperfusion injury, cardiovascular diseases, and cancer. This review comprehensively explores the regulatory roles and impacts of GPX4 and ferroptosis in the development and progression of these diseases, with the aim of providing insights for identifying potential therapeutic strategies in the future.
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Ferroptose , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Animais , Humanos , Neoplasias/patologia , Neoplasias/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , PatologiaRESUMO
The striated frogfish (Antennarius striatus), a member of the sub-order Antennarioidei within the order Lophiiformes, possesses remarkable adaptations. These include the ability to modulate body coloration for camouflage, utilize bioluminescent esca for predation, and employ elbow-like pectoral fins for terrestrial locomotion, making it a valuable model for studying bioluminescence, adaptive camouflage, fin-to-limb transition, and walking-like behaviors. To better study and contribute to the conservation of the striated frogfish, we obtained the micro-CT image of the pectoral fin bones and generated a high-quality, chromosome-level genome assembly using multiple sequencing technologies. The assembly spans 548.56 Mb with a contig N50 of 21.05 Mb, and 99.35% of the genome is anchored on 24 chromosomes, making it the most complete genome available within Lophiiformes. The genome annotation revealed 28.43% repetitive sequences and 23,945 protein-coding genes. This chromosome-level genome provides valuable genetic resources for frogfish conservation and offers insights into the genetic mechanisms underlying its unique phenotypic evolution. Furthermore, it establishes a foundation for future research on limb development and adaptive camouflage in this species.
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Cromossomos , Genoma , Animais , Peixes/genéticaRESUMO
The pig-nosed turtle (Carettochelys insculpta) represents the only extant species within the Carettochelyidae family, is a unique Trionychia member fully adapted to aquatic life and currently facing endangerment. To enhance our understanding of this species and contribute to its conservation efforts, we employed high-fidelity (HiFi) and Hi-C sequencing technology to generate its genome assembly at the chromosome level. The assembly result spans 2.18 Gb, with a contig N50 of 126 Mb, encompassing 34 chromosomes that account for 99.6% of the genome. The assembly has a BUSCO score above 95% with different databases and strong collinearity with Yangtze giant softshell turtles (Rafetus swinhoei), indicating its completeness and continuity. A total of 19,175 genes and 46.86% repetitive sequences were annotated. The availability of this chromosome-scale genome represents a valuable resource for the pig-nosed turtle, providing insights into its aquatic adaptation and serving as a foundation for future turtle research.
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Genoma , Tartarugas , Animais , Cromossomos/genética , Anotação de Sequência Molecular , Filogenia , Sequências Repetitivas de Ácido Nucleico , Tartarugas/genéticaRESUMO
BACKGROUND: Sepsis, a complex and life-threatening disease, poses a significant global burden affecting over 48 million individuals. Recently, it has been reported that programmed death-ligand 1 (PD-L1) expressed on neutrophils is involved in both inflammatory organ dysfunction and immunoparalysis in sepsis. However, there is a dearth of strategies to specifically target PD-L1 in neutrophils in vivo. METHODS: We successfully developed two lipid nanoparticles (LNPs) specifically targeting neutrophils by delivering PD-L1 siRNA via neutrophil-specific antibodies and polypeptides. In vivo and in vitro experiments were performed to detect lipid nanoparticles into neutrophils. A mouse cecal ligation and puncture (CLP) model was used to detect neutrophil migration, neutrophil extracellular traps (NETs) level, and organ damage. RESULT: The PD-L1 siRNA-loaded LNPs that target neutrophils suppressed inflammation, reduced the release of NETs, and inhibited T-lymphocyte apoptosis. This approach could help maintain homeostasis of both the immune and inflammatory responses during sepsis. Furthermore, the PD-L1 siRNA-loaded LNPs targeting neutrophils have the potential to ameliorate the multi-organ damage and lethality resulting from CLP. CONCLUSIONS: Taken together, our data identify a previously unknown drug delivery strategy targeting neutrophils, which represents a novel, safe, and effective approach to sepsis therapy.
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The evolution of the vertebrate liver is a prime example of the evolution of complex organs, yet the driving genetic factors behind it remain unknown. Here we study the evolutionary genetics of liver by comparing the amphioxus hepatic caecum and the vertebrate liver, as well as examining the functional transition within vertebrates. Using in vivo and in vitro experiments, single-cell/nucleus RNA-seq data and gene knockout experiments, we confirm that the amphioxus hepatic caecum and vertebrate liver are homologous organs and show that the emergence of ohnologues from two rounds of whole-genome duplications greatly contributed to the functional complexity of the vertebrate liver. Two ohnologues, kdr and flt4, play an important role in the development of liver sinusoidal endothelial cells. In addition, we found that liver-related functions such as coagulation and bile production evolved in a step-by-step manner, with gene duplicates playing a crucial role. We reconstructed the genetic footprint of the transfer of haem detoxification from the liver to the spleen during vertebrate evolution. Together, these findings challenge the previous hypothesis that organ evolution is primarily driven by regulatory elements, underscoring the importance of gene duplicates in the emergence and diversification of a complex organ.
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Sepsis is defined as a life-threatening dysfunction due to a dysregulated host response to infection. It is a common and complex syndrome and is the leading cause of death in intensive care units. The lungs are most vulnerable to the challenge of sepsis, and the incidence of respiratory dysfunction has been reported to be up to 70%, in which neutrophils play a major role. Neutrophils are the first line of defense against infection, and they are regarded as the most responsive cells in sepsis. Normally, neutrophils recognize chemokines including the bacterial product N-formyl-methionyl-leucyl-phenylalanine (fMLP), complement 5a (C5a), and lipid molecules Leukotriene B4 (LTB4) and C-X-C motif chemokine ligand 8 (CXCL8), and enter the site of infection through mobilization, rolling, adhesion, migration, and chemotaxis. However, numerous studies have confirmed that despite the high levels of chemokines in septic patients and mice at the site of infection, the neutrophils cannot migrate to the proper target location, but instead they accumulate in the lungs, releasing histones, DNA, and proteases that mediate tissue damage and induce acute respiratory distress syndrome (ARDS). This is closely related to impaired neutrophil migration in sepsis, but the mechanism involved is still unclear. Many studies have shown that chemokine receptor dysregulation is an important cause of impaired neutrophil migration, and the vast majority of these chemokine receptors belong to the G protein-coupled receptors (GPCRs). In this review, we summarize the signaling pathways by which neutrophil GPCR regulates chemotaxis and the mechanisms by which abnormal GPCR function in sepsis leads to impaired neutrophil chemotaxis, which can further cause ARDS. Several potential targets for intervention are proposed to improve neutrophil chemotaxis, and we hope that this review may provide insights for clinical practitioners.
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Síndrome do Desconforto Respiratório , Sepse , Animais , Camundongos , Neutrófilos/metabolismo , N-Formilmetionina Leucil-Fenilalanina/metabolismo , Sepse/complicações , Sepse/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/metabolismoRESUMO
Sepsis currently remains a major contributor to mortality in the intensive care unit (ICU), with 48.9 million cases reported globally and a mortality rate of 22.5% in 2017, accounting for almost 20% of all-cause mortality worldwide. This highlights the urgent need to improve the understanding and treatment of this condition. Sepsis is now recognized as a dysregulation of the host immune response to infection, characterized by an excessive inflammatory response and immune paralysis. This dysregulation leads to secondary infections, multiple organ dysfunction syndrome (MODS), and ultimately death. PD-L1, a co-inhibitory molecule expressed in immune cells, has emerged as a critical factor in sepsis. Numerous studies have found a significant association between the expression of PD-1/PD-L1 and sepsis, with a particular focus on PD-L1 expressed on neutrophils recently. This review explores the role of PD-1/PD-L1 in immunostimulatory and anti-inflammatory pathways, illustrates the intricate link between PD-1/PD-L1 and sepsis, and summarizes current therapeutic approaches against PD-1/PD-L1 in the treatment and prognosis of sepsis in preclinical and clinical studies.
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Receptor de Morte Celular Programada 1 , Sepse , Humanos , Antígeno B7-H1 , Imunização , Sepse/tratamento farmacológico , Anti-Inflamatórios/uso terapêuticoRESUMO
BACKGROUND: Sepsis is a critical systemic inflammatory syndrome which usually leads to multiple organ dysfunction. Caffeic acid (CA), a phenolic compound derived from various plants, has been proved to be essential in neuroprotection, but its role in septic organ damage is unclear. This research aimed to investigate whether CA protects against organ injury in a mouse model of cecal ligation and puncture (CLP). METHODS: CA (30 mg/kg) or vehicle was administered by intraperitoneal injection immediately after CLP. The samples of blood, lungs, and livers were collected 24 h later. Organ injury was assessed by histopathological examination (HE staining), neutrophil infiltration (myeloperoxidase fluorescence), oxidative stress levels (MDA, SOD, HO-1), and inflammatory cytokines (TNF-α, IL-1ß, and IL-6) release in lung and liver tissues. Neutrophil extracellular trap (NET) formation was analyzed by immunofluorescence. In vitro experiments were performed to investigate the potential mechanisms of CA using small interfering RNA (siRNA) techniques in neutrophils, and the effect of CA on neutrophil apoptosis was analyzed by flow cytometry. RESULTS: Results showed that CA treatment improved the 7-day survival rate and attenuated the histopathological injury in the lung and liver of CLP mice. CA significantly reduced neutrophil infiltration in the lungs and livers of CLP mice. TNF-α, IL-1ß, IL-6 and LTB4 were reduced in serum, lung, and liver of CA-treated CLP mice, and phosphorylation of MAPK (p38, ERK, JNK) and p65 NF-κB was inhibited in lungs and livers. CA treatment further increased HO-1 levels and enhanced superoxide dismutase (SOD) activity, but reduced malondialdehyde (MDA) levels and NET formation. Similarly, in vitro experiments showed that CA treatment and 5-LOX siRNA interference inhibited inflammatory activation and NET release in neutrophils, suppressed MAPK and NF-κB phosphorylation in LPS-treated neutrophils, and decreased LTB4 and cfDNA levels. Flow cytometric analysis revealed that CA treatment reversed LPS-mediated delayed apoptosis in human neutrophils, and Western blot also indicated that CA treatment inhibited Bcl-2 expression but increased Bax expression. CA treatment did not induce further changes in neutrophil apoptosis, inflammatory activation, and NET release when 5-LOX was knocked down by siRNA interference. CONCLUSIONS: CA has a protective effect on lung and liver injury in a murine model of sepsis, which may be related to inhibition of the 5-LOX/LTB4 pathway.