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BACKGROUND: The pathogenesis of Chlamydia trachomatis is associated with the induction of the host inflammatory response; however, the precise underlying molecular mechanisms remain poorly understood. METHODS: CT622, a T3SS effector protein, has an important role in the pathogenesis of C trachomatis; however, whether CT622 can induce a host inflammatory response is not understood. Our findings demonstrate that CT622 induces the expression of interleukins 6 and 8 (IL-6 and IL-8). Mechanistically, these effects involve the activation of the MAPK/NF-κB signaling pathways (mitogen-activated protein kinase/nuclear factor κB). RESULTS: Interestingly, we demonstrated that the suppression of toll-like receptor 4 using small interfering RNA markedly reduced the phosphorylation of ERK, p38, JNK, and IκBα, concomitant with a significant decrease in IL-6 and IL-8 secretion. Conversely, disruption of toll-like receptor 2 abrogated the CT622-induced upregulation of IL-8 and activation of ERK, whereas IL-6 expression and p38, JNK, and IκBα phosphorylation were unaffected. CONCLUSIONS: Taken together, these results indicate that CT622 contributes to the inflammatory response through the toll-like receptor 2/4-mediated MAPK/NF-κB pathways, which provides insight into the molecular pathology of C trachomatis infection.
Assuntos
Chlamydia trachomatis , Citocinas , NF-kappa B , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Humanos , Chlamydia trachomatis/imunologia , NF-kappa B/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Células THP-1 , Citocinas/metabolismo , Transdução de Sinais , Interleucina-6/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/microbiologia , Infecções por Chlamydia/metabolismo , Interleucina-8/metabolismo , Sistemas de Secreção Tipo III/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , FosforilaçãoRESUMO
Endothelial cell injury is a key factor in the spread of infection and pathogenicity of Treponema pallidum. The migration and adhesion reaction mediated by T. pallidum lipoprotein plays an important role. This study aimed to systematically explore the migration and adhesion effect of T. pallidum lipoprotein Tp0768 and its molecular mechanism. Stimulating vascular endothelial cells with Tp0768 increased the expression of ICAM-1, MCP-1, and IL-8. Moreover, it promoted the migration and adhesion of THP-1 cells to vascular endothelial cells. Our results revealed that Tp0768 promoted the THP-1 cells migrating and adhering to vascular endothelial cells by the PERK and IRE-1α pathways of endoplasmic reticulum (ER) stress. We further demonstrated that the inhibition of the NF-κB pathway and the downregulation of hypoxia-inducible factor 1 alpha (HIF-1α) reduced the mRNA levels of ICAM-1, MCP-1, and IL-8 induced by Tp0768. Also, the adhesion rate of THP-1 cells to endothelial cells decreased. After inhibiting ER stress, NF-κB p65 nuclear translocation was weakened, and the mRNA level of HIF-1α was also significantly downregulated. Our results indicated that T. pallidum lipoprotein Tp0768 promoted the migration and adhesion of THP-1 cells to vascular endothelial cells through ER stress and NF-κB/HIF-1α pathway.
Assuntos
NF-kappa B , Treponema pallidum , Humanos , NF-kappa B/metabolismo , Treponema pallidum/genética , Treponema pallidum/metabolismo , Células THP-1 , Molécula 1 de Adesão Intercelular/genética , Células Endoteliais/metabolismo , Interleucina-8 , RNA Mensageiro/metabolismo , Retículo Endoplasmático/metabolismoRESUMO
The inadequate hydrophobicity and the degradation in usage seriously hampered the applications of the existing antipollution flashover coatings. In this paper, a superhydrophobic polyurea coating with antipollution flashover ability was fabricated through chemically grafting the silica onto the chains of polyurea by utilizing silane coupling agent and hydrophobic modification. It is demonstrated that the coating exhibits outstanding antipollution flashover performances. Noteworthy, the surface pollution flashover voltage has been increased by 33.8% compared with the room temperature vulcanizing silicone rubber (RTV silicone rubber). In addition, the volume resistivity is above 1.0 × 1012 Ω·m, and the dielectric strength achieves to 28.85 kV/mm, which represents excellent insulating property. Furthermore, the superhydrophobic polyurea coating exhibits outstanding abrasion resistance, adhesion, acid-base resistance, and durability. As a result, it holds great promise for use in preventing pollution flashover in electrical insulators.
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Treponema pallidum is the causative factor of syphilis, a sexually transmitted disease (STD) characterized by perivascular infiltration of inflammatory cells, vascular leakage, swelling and proliferation of endothelial cells (ECs). The endothelium lining blood and lymphatic vessels is a key barrier separating body fluids from host tissues and is a major target of T. pallidum. In this review, we focus on how T. pallidum establish intimate interactions with ECs, triggering endothelial dysfunction such as endothelial inflammation, abnormal repairment and damage of ECs. In addition, we summarize that migration and invasion of T. pallidum across vascular ECs may occur through two pathways. These two mechanisms of transendothelial migration are paracellular and cholesterol-dependent, respectively. Herein, clarifying the relationship between T. pallidum and endothelial dysfunction is of great significance to provide novel strategies for diagnosis and prevention of syphilis, and has a great potential prospect of clinical application.
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Endotélio Vascular , Sífilis , Treponema pallidum , Humanos , Sífilis/microbiologia , Endotélio Vascular/fisiopatologia , Endotélio Vascular/patologia , Células Endoteliais/patologia , Células Endoteliais/microbiologiaRESUMO
Syphilis, a sexually transmitted disease (STD) caused by Treponema pallidum (T. pallidum), has had a worldwide resurgence in recent years and remains a public health threat. As such, there has been a great deal of research into clinical strategies for the disease, including diagnostic biomarkers and possible strategies for treatment and prevention. Although serological testing remains the predominant laboratory diagnostic method for syphilis, it is worth noting that investigations pertaining to the DNA of T. pallidum, non-coding RNAs (ncRNAs), chemokines, and metabolites in peripheral blood, cerebrospinal fluid, and other bodily fluids have the potential to offer novel perspectives on the diagnosis of syphilis. In addition, the global spread of antibiotic resistance, such as macrolides and tetracyclines, has posed significant challenges for the treatment of syphilis. Fortunately, there is still no evidence of penicillin resistance. Hence, penicillin is the recommended course of treatment for syphilis, whereas doxycycline, tetracycline, ceftriaxone, and amoxicillin are viable alternative options. In recent years, efforts to discover a vaccine for syphilis have been reignited with better knowledge of the repertoire of T. pallidum outer membrane proteins (OMPs), which are the most probable syphilis vaccine candidates. However, research on therapeutic interventions and vaccine development for human subjects is limited due to practical and ethical considerations. Thus, the preclinical model is ideal for conducting research, and it plays an important role in clinical transformation. Different preclinical models have recently emerged, such as in vitro culture and mouse models, which will lay a solid foundation for clinical treatment and prevention of syphilis. This review aims to provide a comprehensive summary of the most recent syphilis tactics, including detection, drug resistance treatments, vaccine development, and preclinical models in clinical practice.
Assuntos
Sífilis , Vacinas , Animais , Camundongos , Humanos , Sífilis/tratamento farmacológico , Treponema pallidum , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Doxiciclina/uso terapêutico , Vacinas/uso terapêuticoRESUMO
BACKGROUND: Syphilis is a chronic sexually transmitted disease caused by Treponema pallidum subspecies pallidum (T. pallidum), which is a public health problem that seriously affects human health worldwide. T. pallidum is characterized by early transmission and immune escape and is therefore termed an "invisible pathogen". METHODS: This review systematically summarizes the host's innate and adaptive immune responses to T. pallidum infection as well as the escape mechanisms of T. pallidum. PURPOSE: To lay the foundation for assessing the pathogenic mechanism and the systematic prevention and treatment of syphilis. CONCLUSION: The immune escape mechanism of T. pallidum plays an important role in its survival. Exploring the occurrence and development of these mechanisms has laid the foundation for the development of syphilis vaccine.
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Sífilis , Treponema pallidum , Humanos , Vacinas BacterianasRESUMO
This study presents the first-ever synthesis of samarium-doped indium vanadate nanosheets (IVONSs:Sm) via microemulsion-mediated solvothermal method. The nanosheets were subsequently utilized as a nano-matrix in laser desorption/ionization mass spectrometry (LDI-MS). It was discovered that the as-synthesized IVONSs:Sm possessed the following advantages: improved mass spectrometry signal, minimal matrix-related background, and exceptional stability in negative-ion mode. These qualities overcame the limitations of conventional matrices and enabled the sensitive detection of small biomolecules such as fatty acids. The negative-ion LDI mechanism of IVONSs:Sm was examined through the implementation of density functional theory simulation. Using IVONSs:Sm-assisted LDI-MS, fingerprint recognitions based on morphology and chemical profiles of endogenous/exogenous compounds were also achieved. Notably, crucial characteristics such as the age of an individual's fingerprints and their physical state could be assessed through the longitudinal monitoring of particular biomolecules (e.g., ascorbic acid, fatty acid) or the specific biomarker bilirubin glucuronide. Critical information pertinent to the identification of an individual would thus be facilitated by the analysis of the compounds underlying the fingerprint patterns.
Assuntos
Índio , Vanadatos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Ácidos Graxos , LasersRESUMO
"Clinical basic inspection technology" is one of the essential courses in the medical laboratory profession. Combining the characteristics of the discipline itself, the research and practice of the BOPPPS model based on the OBE concept in clinical basic laboratory experiment teaching are discussed, and the reform of in teaching objectives, teaching contents, and teaching design path is implemented. The "student-centered" teaching process is divided into six stages: before, during, and after class, and the teaching process is continuously improved to achieve the desired teaching effect. Results of the experiment teaching show that the model has improved students' active participation and developed their clinical thinking skills, and more than 95% of students are satisfied with this teaching model.
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Medicina , Estudantes , Humanos , Pensamento , Competência Clínica , LaboratóriosRESUMO
BACKGROUND: Syphilis, caused by Treponema pallidum (T. pallidum), is a multi-organ, multiple systems, multi-stage sexually transmitted diseases with various clinical manifestations, among of which pathological lesions of skin and mucosa are the typical clinical manifestations of syphilis. However, the immunopathogenesis of this process is poorly understood. T. pallidum flagellin FlaA2, as a part of the important organelle responsible for the causative agent's motility, may contributes to the host skin inflammatory response. OBJECTIVES: To determine the mechanisms of T. pallidum FlaA2 stimulating the expression of pro-inflammatory cytokines in human keratinocytes. METHODS: Recombinant FlaA2 protein was performed to stimulate human keratinocytes. The mRNA transcription levels and protein expression levels of IL-6 and IL-8 were detected by qRT-PCR and ELISA, respectively. Western blot was used to detect the total protein and phosphorylation levels of ERK, p38, JNK and NF-κB, respectively. The intracellular location of NF-κB p65 was detected by immunofluorescence staining. RESULTS: Recombinant FlaA2 could considerably induced the expression of pro-inflammation cytokines IL-6 and IL-8 in HaCaT cells, and FlaA2-induced IL-6 and IL-8 secretion could be decreased by inhibiting TLR2 using pZERO-hTLR2. Further investigation showed that FlaA2 could activate the phosphorylation of ERK, p38 and IκBα and FlaA2-stimulated secretion of IL-6, IL-8 were attenuated by ERK, p38 and NF-κB inhibitors in HaCaT cells. Moreover, FlaA2 activates the ERK, p38 and NF-κB pathways through TLR2 signaling pathway in HaCaT cells. CONCLUSIONS: From the findings above, these results confirm that T. pallidum FlaA2 activates ERK, p38 and NF-κB signaling pathway through TLR2 pathway to induce the production of IL-6 and IL-8, which could contribute to enhance the understanding of the skin inflammatory response induced by the pathogen in syphilis patients.
Assuntos
Sífilis , Treponema pallidum , Humanos , Treponema pallidum/genética , Treponema pallidum/metabolismo , Citocinas/metabolismo , NF-kappa B/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Queratinócitos/metabolismo , Fatores Imunológicos/metabolismoRESUMO
In response to danger signals, macrophages rapidly produce many inflammatory cytokines that trigger the cascade release of inflammatory mediators, leading to tissue damage, which is an important cause of clinical manifestations of syphilis at all stages. However, we still know very little about the specific mechanism of this process. Tp0768 is an infection-stage-dependent antigen that plays an important role in the infection of Treponema pallidum. In this study, we demonstrated that Tp0768 stimulation of macrophages can cause IL-1ß, IL-6, and IL-8 mRNA expression levels to increase in a dose- and time-dependent manner. Further research showed that Tp0768 activated ER stress and the ROS/NF-κB pathway in macrophages. Inhibition of ER stress and the ROS/NF-κB pathway inhibited the expression of IL-1ß, IL-6, and IL-8 induced by Tp0768. In addition, pretreatment with a PERK pathway inhibitor significantly reduced the expression of the NF-κB and JNK pathways, while also downregulating the expression of IL-1ß, IL-6, and IL-8. Tp0768 stimulation can activate IRE1α/XBP-1 signaling and participate in the induction of inflammatory cytokines through the JNK pathway. These findings indicate that Tp0768 promotes the secretion of proinflammatory cytokines IL-1ß, IL-6, and IL-8 by macrophages through ER stress and the ROS/NF-κB pathway, which are also involved in the activation of the NF-κB and JNK pathways that are induced by the PERK pathway and activation of IRE1α/XBP-1 signaling. KEY POINTS: ⢠This study found for the first time that the recombinant Treponema pallidum protein Tp0768 promotes the production of IL-1ß, IL-6, and IL-8 by macrophages through ER stress. ⢠Recombinant Treponema pallidum protein Tp0768 regulates the ROS/NF-κB pathway through ER stress. ⢠ER stress-related pathway PERK induces the expression of IL-1ß, IL-6, and IL-8 by activating the NF-κB pathway and the JNK pathway. ⢠IRE1α can induce the splicing of XBP-1mRNA and activate the JNK pathway.
Assuntos
Proteínas de Bactérias/imunologia , Citocinas/imunologia , Estresse do Retículo Endoplasmático , Macrófagos/imunologia , NF-kappa B , Animais , Endorribonucleases/genética , Humanos , Camundongos , NF-kappa B/genética , Proteínas Serina-Treonina Quinases , Células RAW 264.7 , Espécies Reativas de Oxigênio , Células THP-1 , Treponema pallidum/genéticaRESUMO
The endoplasmic reticulum (ER) is a multifunctional organelle, which is crucial for correct folding and assembly of secretory and transmembrane proteins. Perturbations of ER function can cause ER stress. ER stress can activate the unfolded protein response (UPR) to cope with the accumulation of misfolded proteins and protein toxicity. UPR is a coordination system that regulates transcription and translation, leading to the recovery of ER homeostasis or cell death. However, cells have an integrated signaling system to cope with ER stress, which helps cells to restore and balance their ER function. The main components of this system are ER-associated degradation (ERAD), autophagy, hypoxia signaling, and mitochondrial biogenesis. If the balance cannot be restored, the imbalance will lead to cell death or apoptosis, or even to a series of diseases. In this review, a series of activities to restore the homeostasis of cells during ER stress are discussed. KEY POINTS: ⢠Endoplasmic reticulum (ER) plays a key role in the biological process of cells. ⢠Perturbations of ER function can cause ER stress, including the ER overload response (EOR), sterol-regulated cascade reaction, and the UPR. ⢠Cells have an integrated signaling system (ERAD, autophagy, hypoxia signaling, and mitochondrial biogenesis) to cope with the adverse impact caused by ER stress.
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Fenômenos Biológicos , Estresse do Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Eucariotos , Resposta a Proteínas não DobradasRESUMO
Endoplasmic reticulum stress (ERS) is a protective response to restore protein homeostasis by activating the unfolded protein response (UPR). However, UPR can trigger cell death under severe and/or persistently high ERS. The NLRP3 inflammasome is a complex of multiple proteins that activates the secretion of the proinflammatory cytokine IL-1ß in a caspase-1-dependent manner to participate in the regulation of inflammation. The NLRP3 inflammasome involvement in ERS-induced inflammation has not been completely described. The intersection of ERS with multiple inflammatory pathways can initiate and aggravate chronic diseases. Accumulating evidence suggests that ERS-induced activation of NLRP3 inflammasome is the pathological basis of various inflammatory diseases. In this review, we have discussed the networks between ERS and NLRP3 inflammasome, with the view to identifying novel therapeutic targets in inflammatory diseases. KEY POINTS: ⢠Endoplasmic reticulum stress (ERS) is an important factor for the activation of the NLRP3 inflammasomes that results in pathological processes. ⢠ERS can activate the NLRP3 inflammasome to induce inflammatory responses via oxidative stress, calcium homeostasis, and NF-κB activation. ⢠The interactions between ERS and NLRP3 inflammasome are associated with inflammation, which represent a potential therapeutic opportunity of inflammatory diseases.
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Estresse do Retículo Endoplasmático , Inflamassomos/metabolismo , Inflamação/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Cálcio/metabolismo , Humanos , Inflamação/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Proteostase , Transdução de Sinais , Resposta a Proteínas não DobradasRESUMO
Atherosclerosis is a progressive vascular disease with increasing morbidity and mortality year by year in modern society. Human cytomegalovirus (HCMV) infection is closely associated with the development of atherosclerosis. HCMV infection may accelerate graft atherosclerosis and the development of transplant vasculopathy in organ transplantation. However, our current understanding of HCMV-associated atherosclerosis remains limited and is mainly based on clinical observations. The underlying mechanism of the involvement of HCMV infection in atherogenesis remains unclear. Here, we summarized current knowledge regarding the multiple influences of HCMV on a diverse range of infected cells, including vascular endothelial cells, vascular smooth muscle cells, monocytes, macrophages, and T cells. In addition, we described potential HCMV-induced molecular mechanisms, such as oxidative stress, endoplasmic reticulum stress, autophagy, lipid metabolism, and miRNA regulation, which are involved in the development of HCMV-associated atherogenesis. Gaining an improved understanding of these mechanisms will facilitate the development of novel and effective therapeutic strategies for the treatment of HCMV-related cardiovascular disease.
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Aterosclerose , Infecções por Citomegalovirus , Citomegalovirus/metabolismo , Estresse do Retículo Endoplasmático , Metabolismo dos Lipídeos , Estresse Oxidativo , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/virologia , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Endoteliais/virologia , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Macrófagos/virologia , MicroRNAs/metabolismo , Monócitos/metabolismo , Monócitos/patologia , Monócitos/virologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Linfócitos T/virologiaRESUMO
Treponema pallidum is the pathogen that causes syphilis, a sexually transmitted disease; however, the pathogenic mechanism of this organism remains unclear. Tp92 is the only T. pallidum outer membrane protein that has structural features similar to the outer membrane proteins of other Gram-negative bacteria, but the exact functions of this protein remain unknown. In the present study, we demonstrated that the recombinant Tp92 protein can induce human mononuclear cell death. Tp92 mediated the human monocytic cell line derived from an acute monicytic leukemia patient (THP-1) cell death by recognizing CD14 and/or TLR2 on cell surfaces. After the stimulation of THP-1 cells by the Tp92 protein, Tp92 may induce atypical pyroptosis of THP-1 cells via the pro-caspase-1 pathway. Meanwhile, this protein caused the apoptosis of THP-1 cells via the receptor-interacting protein kinase 1/caspase-8/aspase-3 pathway. Tp92 reduced the number of monocytes among peripheral blood mononuclear cells. Interestingly, further research showed that Tp92 failed to increase the tumour necrosis factor-α, interleukin (IL)-1ß, IL-6, IL-10, IL-18 and monocyte chemotactic protein 1 (MCP)-1 levels but slightly elevated the IL-8 levels via the Nuclear Factor (NF)-κB pathway in THP-1 cells. The data suggest that Tp92 recognizes CD14 and TLR2, transfers the signal to a downstream pathway, and activates NF-κB to mediate the production of IL-8. This mechanism may help T. pallidum escape recognition and elimination by the host innate immune system.
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Antígenos de Superfície/genética , Proteínas de Bactérias/genética , Interleucina-8/genética , Receptores de Lipopolissacarídeos/genética , Sífilis/microbiologia , Receptor 2 Toll-Like/genética , Caspase 1/genética , Morte Celular/genética , Linhagem Celular Tumoral , Citocinas/genética , Interações Hospedeiro-Patógeno/genética , Humanos , Leucemia Monocítica Aguda/genética , Leucemia Monocítica Aguda/microbiologia , Leucemia Monocítica Aguda/patologia , Leucócitos Mononucleares/microbiologia , Leucócitos Mononucleares/patologia , NF-kappa B/genética , Proteínas Recombinantes/genética , Transdução de Sinais/genética , Sífilis/genética , Sífilis/patologia , Treponema pallidum/genética , Treponema pallidum/patogenicidadeRESUMO
BACKGROUND: Over the past decade, the incidence of syphilis and widespread macrolide resistance in its etiological agent, Treponema pallidum subsp. pallidum, have become a major health concern across countries, including China. Regional trends in subtypes and antibiotic resistance can be monitored effectively by molecular surveillance programs. In this study, whole blood samples were used to assess circulating T. pallidum strains collected from various regions of Hunan, China, between 2013 and 2015. METHODS: Traditional polymerase chain reaction, targeting polA, tpp47, bmp, and tp0319 genes, was used as preliminary screening assay. About 455 polymerase chain reaction-positive specimens were obtained from 2253 whole blood samples of patients with secondary or latent syphilis. Molecular subtyping was performed using a Centers for Disease Control and Prevention-based typing method combined with an analysis of the variable region of tp0548 gene. Resistance to macrolides was analyzed by examining point mutations in 23S rRNA, and the presence of the G1058C point mutation within 16S rRNA associated with decreased susceptibility to doxycycline was assessed. RESULTS: Circulating T. pallidum strains were resolved into 32 subtypes, among which subtype 14d/f was predominant. A2059G mutation in 23S rRNA, and the G1058C mutation in 16S rRNA was absent, but the prevalence of A2058G mutation in 23S rRNA was 97.5%. CONCLUSIONS: We found that it is possible to use whole blood to evaluate molecular subtypes and monitor antibiotic resistance in circulating T. pallidum strains, especially when chancres are absent. High frequency of macrolide-resistant T. pallidum indicates that macrolide antibiotics, such as azithromycin, should be avoided as a treatment option for syphilis in Hunan, China.
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Sífilis/epidemiologia , Treponema pallidum/classificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacteriemia/microbiologia , China/epidemiologia , Farmacorresistência Bacteriana/genética , Feminino , Genótipo , Humanos , Incidência , Macrolídeos/farmacologia , Macrolídeos/uso terapêutico , Pessoa de Meia-Idade , Tipagem Molecular , Mutação Puntual , Prevalência , RNA Ribossômico 16S/genética , RNA Ribossômico 23S/genética , Sífilis/tratamento farmacológico , Sífilis/microbiologia , Sífilis Latente/tratamento farmacológico , Sífilis Latente/epidemiologia , Sífilis Latente/microbiologia , Treponema pallidum/efeitos dos fármacos , Treponema pallidum/genética , Treponema pallidum/isolamento & purificação , Adulto JovemRESUMO
Human cytomeglovirus (HCMV) infection predisposes blood vessels to atherosclerosis (AS) and post-transplantation restenosis, but the underlying molecular basis remains elusive. Here, we found that HCMV infection activates AIM2 inflammasome and pyroptosis in vascular endothelial cells by inducing mitochondrial iron overload. Mechanistically, under normal conditions, ubiquitin carboxyl terminal hydrolase-L1 (UCHL1) was identified as a DUB enzyme that interacts with, deubiquitylates, and stabilizes ferredoxin reductase (FDXR), an important mitochondrial protein that regulates mitochondral iron homeostasis. However, HCMV infection induces the aberrantly elevated m6A modification and R-loops, the three-stranded DNA-DNA:RNA hybrid structures. The expression of UCHL1 was remarkably reduced by m6A modification-mediated mRNA decay and R-loop-dependent transcriptional termination after HCMV infection. Deficiency of UCHL1 causes ubiquitination and degradation of FDXR. Loss of FDXR induces the mitochondrial iron overload, which consequently leads to AIM2 inflammasome activation and endothelial injury. Moreover, both downregulation expression of UCHL1 and related inflammatory injury in vascular endothelium was observed in MCMV-infected mice. Notably, STM2457, a METTL3 specific inhibitor, restores the expression of UCHL1 upon HCMV infection, thereby inhibiting the inflammatory injury of vascular endothelial cells. Our findings delineate a novel mechnism involved in HCMV-induced inflammatory injury to vascular endothelium and implicate the role of METTL3 inhibitor as a potential therapeutic approach.
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Células Endoteliais , Sobrecarga de Ferro , Animais , Humanos , Camundongos , DNA/metabolismo , Células Endoteliais/metabolismo , Inflamassomos/metabolismo , Sobrecarga de Ferro/genética , Metiltransferases/genética , Metiltransferases/metabolismo , Ubiquitina Tiolesterase/genética , UbiquitinaçãoRESUMO
Angiogenesis is the growth of new blood vessels on preexisting ones. It is the outcome of a multifactorial effect involving several cells, which can be brought on by different stress reactions.The accumulation of unfolded proteins in the endoplasmic reticulum occurs when cells are stressed due to environmental changes, where physical or chemical stimuli induce endoplasmic reticulum stress, thereby activating the unfolded protein response (UPR), a homeostasis response designed to re-establish protein balance. Ferroptosis is a planned death of lipid peroxidation and anomalies in metabolism that is dependent on iron. Large concentrations of iron ions accumulate there, along with high concentrations of lipid peroxides and reactive oxygen species, all of which can contribute to the development of several diseases. Through the production of growth factors, adhesion factors, and inflammatory factors that trigger the start of angiogenesis, both UPR and Ferroptosis can be implicated in angiogenesis.To set the stage for further research on angiogenesis, this work concentrated on the effects of Ferroptosis and UPR on angiogenesis, respectively.
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Ferroptose , Angiogênese , Resposta a Proteínas não Dobradas , Estresse do Retículo Endoplasmático/fisiologia , FerroRESUMO
Syphilis, a sexually transmitted infection caused by Treponema pallidum, has been experiencing a rise in prevalence in recent years. "Syphilis serofast" describes a unique serological reaction in patients with syphilis whose clinical symptoms have resolved following consistent anti-syphilitic therapy, but the non-Treponema pallidum antigen serologic test is still positive. Syphilis serofast is a risk factor for syphilis recurrence, neurosyphilis, and multisystem involvement. Considering the current lack of comprehensive knowledge about the epidemiological characteristics, pathogenesis, and therapies of syphilis serofast, we conducted an online search of research relating to syphilis serofast over the last twenty years. Previous research has shown that the pathogenesis of syphilis serofast is mainly related to clinical factors, immune factors, syphilis subtypes, and T.pallidum membrane protein repeat gene antigen. There are two distinct viewpoints on the treatment of serofast: no excessive treatment and active treatment. In addition, serofast patients also showed two clinical outcomes: syphilis recurrence and persistent serofast status. This article systematically reviews the related factors, treatment, and clinical outcomes of syphilis serofast, provides a theoretical basis for its research, diagnosis, and treatment, and helps clinicians develop a follow-up treatment management plan for syphilis serofast.