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Purpose: Accurate differentiation between early and late latent syphilis stages is pivotal for patient management and treatment strategies. Nontreponemal IgM antibodies have shown potential in discriminating latent syphilis staging by differentiating syphilis activity. This study aimed to develop a predictive nomogram model for latent syphilis staging based on nontreponemal IgM antibodies. Patients and Methods: We explored the correlation between nontreponemal IgM antibodies and latent syphilis staging and developed a nomogram model to predict latent syphilis staging based on 352 latent syphilis patients. Model performance was assessed using AUC, calibration curve, Hosmer-Lemeshow χ2 statistics, C-index, Brier score, decision curve analysis, and clinical impact curve. Additionally, an external validation set was used to further assess the model's stability. Results: Nontreponemal IgM antibodies correlated with latent syphilis staging. The constructed model demonstrated a strong discriminative capability with an AUC of 0.743. The calibration curve displayed a strong fit, key statistics including Hosmer-Lemeshow χ² at 2.440 (P=0.486), a C-index score of 0.743, and a Brier score of 0.054, all suggesting favorable model calibration performance. Decision curve analysis and clinical impact curve highlighted the model's robust clinical applicability. The external validation set yielded an AUC of 0.776, Hosmer-Lemeshow χ² statistics of 2.440 (P=0.486), a C-index score of 0.767, and a Brier score of 0.054, further underscored the reliability of the model. Conclusion: The nontreponemal IgM antibody-based predicted model could equip clinicians with a valuable tool for the precise staging of latent syphilis and enhancing clinical decision-making.
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Metabolic syndrome (MetS) is a group of conditions characterized by hypertension (HTN), hyperglycaemia or insulin resistance (IR), hyperlipidaemia, and abdominal obesity. MetS is associated with a high incidence of cardiovascular events and mortality and is an independent risk factor for chronic kidney disease (CKD). MetS can cause CKD or accelerate the progression of kidney disease. Recent studies have found that MetS and kidney disease have a cause-and-effect relationship. Patients with CKD, those undergoing kidney transplantation, or kidney donors have a significantly higher risk of developing MetS than normal people. The present study reviewed the possible mechanisms of MetS in patients with CKD, including the disorders of glucose and fat metabolism after kidney injury, IR, HTN and the administration of glucocorticoid and calcineurin inhibitors. In addition, this study reviewed the effect of MetS in patients with CKD on important target organs such as the kidney, heart, brain and blood vessels, and the treatment and prevention of CKD combined with MetS. The study aims to provide strategies for the diagnosis, treatment and prevention of CKD in patients with MetS.
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OBJECTIVE: The pathogenic mechanisms of syphilis and the host defense mechanisms against syphilis remain poorly understood. Exploration of the susceptibility factors of syphilis may provide crucial clues for unraveling its underlying mechanisms. METHODS: A two-sample Mendelian Randomization framework was utilized, and the inverse-variance weighted method was used as the main analysis. All data was sourced from Genome-wide association studies datasets from 2015 to 2022 in Europe, and all participants were of European descent. Only summary-level statistics were used. Sensitivity analyses were conducted to evaluate the heterogeneity and pleiotropy of the datasets. RESULTS: Our study established 18 exposure factors (12 risk factors and 6 protective factors) for syphilis susceptibility. Twelve factors encompassing body mass index, waist circumference, darker natural skin, cooked vegetable intake, processed meat intake, diabetes mellitus, glucose regulation disorders, gout, autoimmune diseases, rheumatoid arthritis, diverticulitis, and longer menstrual cycles were found to increase susceptibility to syphilis. In contrast, 6 factors including easier skin tanning, blonde natural hair color, irritability, higher neuroticism scores, extended sleep duration, and delayed age at first sexual intercourse were connected to a reduced risk of syphilis infection (all P < 0.05). CONCLUSIONS: This study identified 18 influencing factors of syphilis susceptibility. These findings offered novel insights for further probing into the underlying pathogenic mechanisms of syphilis and underscored the importance of multifaceted prevention strategies against syphilis.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Sífilis , Humanos , Sífilis/epidemiología , Factores de Riesgo , Europa (Continente)/epidemiología , Femenino , MasculinoRESUMEN
BACKGROUND: Eukaryotic genes contain introns that are removed by the spliceosomal machinery during mRNA maturation. Introns impose a huge energetic burden on a cell; therefore, they must play an essential role in maintaining genome stability and/or regulating gene expression. Many genes (> 50%) in Plasmodium parasites contain predicted introns, including introns in 5' and 3' untranslated regions (UTR). However, the roles of UTR introns in the gene expression of malaria parasites remain unknown. METHODS: In this study, an episomal dual-luciferase assay was developed to evaluate gene expression driven by promoters with or without a 5'UTR intron from four Plasmodium yoelii genes. To investigate the effect of the 5'UTR intron on endogenous gene expression, the pytctp gene was tagged with 3xHA at the N-terminal of the coding region, and parasites with or without the 5'UTR intron were generated using the CRISPR/Cas9 system. RESULTS: We showed that promoters with 5'UTR introns had higher activities in driving gene expression than those without 5'UTR introns. The results were confirmed in recombinant parasites expressing an HA-tagged gene (pytctp) driven by promoter with or without 5'UTR intron. The enhancement of gene expression was intron size dependent, but not the DNA sequence, e.g. the longer the intron, the higher levels of expression. Similar results were observed when a promoter from one strain of P. yoelii was introduced into different parasite strains. Finally, the 5'UTR introns were alternatively spliced in different parasite development stages, suggesting an active mechanism employed by the parasites to regulate gene expression in various developmental stages. CONCLUSIONS: Plasmodium 5'UTR introns enhance gene expression in a size-dependent manner; the presence of alternatively spliced mRNAs in different parasite developmental stages suggests that alternative slicing of 5'UTR introns is one of the key mechanisms in regulating parasite gene expression and differentiation.
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Regiones no Traducidas 5' , Intrones , Plasmodium yoelii , Regiones Promotoras Genéticas , Regiones no Traducidas 5'/genética , Intrones/genética , Plasmodium yoelii/genética , Plasmodium yoelii/crecimiento & desarrollo , Animales , Expresión Génica , Ratones , Regulación de la Expresión Génica , Sistemas CRISPR-CasRESUMEN
We present ab initio simulations based on subsystem DFT of group 10 aqua ions accurately compared against experimental data on hydration structure. Our simulations provide insights into the molecular structures and dynamics of hydration shells, offering recalibrated interpretations of experimental results. We observe a soft, but distinct second hydration shell in Palladium (Pd) due to a balance between thermal fluctuations, metal-water interactions, and hydrogen bonding. Nickel (Ni) and platinum (Pt) exhibit more rigid hydration shells. Notably, our simulations align with experimental findings for Pd, showing axial hydration marked by a broad peak at about 3 Å in the Pd-O radial distribution function, revising the previously sharp "mesoshell" prediction. We introduce the "hydrogen bond dome" concept to describe a resilient network of hydrogen-bonded water molecules around the metal, which plays a critical role in the axial hydration dynamics.
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Mutations in a Plasmodium de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown. Through drug selection, genetic mapping, allelic exchange, and functional characterization, here we show that simultaneous mutations of two amino acids (I1560N and P2874T) in the Plasmodium yoelii UBP1 can mediate high-level resistance to mefloquine, lumefantrine, and piperaquine. Mechanistically, the double mutations are shown to impair UBP1 cytoplasmic aggregation and de-ubiquitinating activity, leading to increased ubiquitination levels and altered protein localization, from the parasite digestive vacuole to the plasma membrane, of the P. yoelii multidrug resistance transporter 1 (MDR1). The MDR1 on the plasma membrane enhances the efflux of substrates/drugs out of the parasite cytoplasm to confer multidrug resistance, which can be reversed by inhibition of MDR1 transport. This study reveals a previously unknown drug-resistant mechanism mediated by UBP1 through altered MDR1 localization and substrate transport direction in a mouse model, providing a new malaria treatment strategy.
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Antimaláricos , Endopeptidasas , Malaria Falciparum , Plasmodium yoelii , Animales , Ratones , Plasmodium yoelii/genética , Malaria Falciparum/parasitología , Plasmodium falciparum/genética , Antimaláricos/uso terapéutico , Resistencia a Múltiples Medicamentos/genética , Resistencia a Medicamentos/genéticaRESUMEN
Two-electron oxidation of a NiIIPh(PCP) pincer complex initiates phosphine ligand insertion, generating an η6-arylphosphonium moiety coordinated to NiII. The reaction is fully reversible under reducing conditions. X-ray crystallography, NMR/EPR spectroscopy, electrochemistry, and DFT calculations support the proposed Ni-C-P bond reorganization mechanisms, which access oxidation states from Ni0 to NiIV.
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AIMS/INTRODUCTION: The coronary physiology and prognosis of patients with different hemoglobin A1c (HbA1c) levels after percutaneous coronary intervention (PCI) are currently unknown. The aim of this study was to assess the effect of different levels of HbA1c control on coronary physiology in patients who underwent PCI for coronary heart disease combined with type 2 diabetes mellitus by quantitative flow ratio (QFR). MATERIALS AND METHODS: Patients who successfully underwent PCI and completed 1-year coronary angiographic follow up were enrolled, clinical data were collected, and QFR at immediate and 1-year follow up after PCI was retrospectively analyzed. A total of 257 patients (361 vessels) were finally enrolled and divided into the hemoglobin A1c (HbA1c)-compliance group (103 patients, 138 vessels) and non-HbA1c-compliance group (154 patients, 223 vessels) according to the HbA1c cut-off value of 7%. We compared the results of QFR analysis and clinical outcomes between the two groups. RESULTS: At 1-year follow up after PCI, the QFR was significantly higher (0.94 ± 0.07 vs 0.92 ± 0.10, P = 0.019) and declined less (0.014 ± 0.066 vs 0.033 ± 0.095, P = 0.029) in the HbA1c-compliance group. Meanwhile, the incidence of physiological restenosis was lower in the HbA1c-compliance group (2.9% vs 8.5%, P = 0.034). Additionally, the target vessel revascularization rate was lower in the HbA1c-compliance group (6.8% vs 16.9%, P = 0.018). Furthermore, HbA1c ≥7% (OR 2.113, 95% confidence interval 1.081-4.128, P = 0.029) and QFR decline (OR 2.215, 95% confidence interval 1.147-4.277, P = 0.018) were independent risk factors for target vessel revascularization. CONCLUSION: Patients with well-controlled HbA1c levels have better coronary physiological benefits and the incidence of adverse clinical outcome events might be reduced.
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Diabetes Mellitus Tipo 2 , Intervención Coronaria Percutánea , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Hemoglobina Glucada , Estudios Retrospectivos , Angiografía CoronariaRESUMEN
BACKGROUND: Suboptimal stent deployment is frequently observed in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI). This study sought to investigate whether these patients could benefit from post-dilatation with respect to post-procedural physiology, microcirculatory resistance, and long-term clinical outcomes. METHODS: This was a retrospective study of consecutive STEMI patients who underwent successful stent implantation during PPCI from February 2016 to November 2021. Post-procedural physiology and microcirculatory resistance were assessed by Murray law-based quantitative flow ratio (µQFR) and angiographic microcirculatory resistance (AMR), respectively. The primary outcome was target vessel failure (TVF), a composite of cardiac death, target vessel-oriented myocardial infarction, and clinically driven target vessel revascularization. RESULTS: A total of 671 patients (671 culprit vessels) were included. Post-dilatation was selectively performed in 430 (64.1%) culprit vessels, resulting in a 0.02 (interquartile range: 0.00-0.05, p < 0.001) increase in post-procedural µQFR but no significant impact on AMR. During a median follow-up of 2.8 years (interquartile range: 1.4-3.0 years), TVF occurred in 47 (7.0%) patients. Post-dilatation demonstrated a trend toward a reduction in TVF (5.3% vs. 10.0%; adjusted hazard ratio: 0.60, 95% confidence interval: 0.33-1.09, p = 0.094), mainly driven by a lower incidence of clinically driven target vessel revascularization (1.6% vs. 4.1%; adjusted hazard ratio: 0.32, 95% confidence interval: 0.11-0.90, p = 0.030). CONCLUSIONS: In STEMI patients undergoing PPCI, selective post-dilatation was associated with improved post-procedural physiological results and a trend toward less TVF events without aggravating microcirculatory resistance.
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Infarto del Miocardio , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Humanos , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/cirugía , Resultado del Tratamiento , Microcirculación , Estudios Retrospectivos , DilataciónRESUMEN
BACKGROUND: The sensitivity of HIV screening assays often leads to a high rate of false-positive results, requiring retests and confirmatory tests. This study aimed to analyze the capability of signal-to-cutoff (S/CO) ratios of HIV screening assay to predict HIV infection. METHODS: A retrospective study on the HIV screening-positive population was performed at Zhongshan Hospital, Xiamen University, the correlation between HIV screening assay S/CO ratios and HIV infection was assessed, and plotted Receiver Operating Characteristic (ROC) curves were generated to establish the optimal cutoff value for predicting HIV infection. RESULTS: Out of 396,679 patients, 836 were confirmed to be HIV-infected, with an HIV prevalence of 0.21%. The median S/CO ratios in HIV infection were significantly higher than that in non-HIV infection (296.9 vs. 2.41, P < 0.001). The rate of confirmed HIV infection was increased with higher S/CO ratios in the screening assay. The ROC curve based on the HIV screening assay S/CO ratio achieved a sensitivity of 93.78% and a specificity of 93.12% with an optimal cutoff value of 14.09. The area under the ROC curve was 0.9612. Further analysis of the ROC curve indicated that the S/CO ratio thresholds yielding positive predictive values of 99%, 99.5%, and 100% for HIV infection were 26.25, 285.7, and 354.5, respectively. CONCLUSION: Using HIV screening assay S/CO ratio to predict HIV infection can largely reduce necessitating retests and confirmatory tests. Incorporating the S/CO ratio into HIV testing algorithms can have significant implications for medical and public health practices.
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Infecciones por VIH , Humanos , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Sensibilidad y Especificidad , Estudios Retrospectivos , Curva ROC , Prueba de VIH , Tamizaje Masivo/métodosRESUMEN
OBJECTIVE: The purpose of this paper is to promote the medical treatment of colorectal cancer in our country and to save the lives of patients with colorectal cancer by studying mammalian target of rapamycin (mTOR) and the biologic information analysis of colorectal cancer. METHODS: We analyzed mTOR expression and survival differences using data from Coad & read from the TCGA public database and explored the coexpression regulatory network of mTOR. mTOR-regulated mirnas were screened using the Linked Omics database. In addition, we explored the association of mTOR with drug sensitivity, immune cell correlations, microsatellite deletions, tumor mutational burden, and mutational analysis. RESULTS: The expression and survival of mTOR were significant different in colorectal cancer, and were related to the sensitivity of Bleomycin, Cisplatin and Gemcitabine. mTOR is associated with dendritic cell activation, NK cell dormancy, dendritic cell dormancy, and eosinophil granulocyte. mTOR is associated with microsatellite deletions, and tumor mutational load. CONCLUSIONS: Based on these findings, we consumer mTOR as a biomarker for the diagnosis and prognosis of colorectal cancer.
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Neoplasias Colorrectales , MicroARNs , Serina-Treonina Quinasas TOR , Humanos , Línea Celular Tumoral , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , MicroARNs/genética , Pronóstico , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
A 68-year-old male, who was undergoing XELOX plus trastuzumab therapy for gastric cancer, developed proteinuria, hematuria, and progressive increase in creatinine after 3 months. Subsequently, the patient also experienced hemoptysis, nasal bleeding. Chest CT examination shown pulmonary hemorrhage. The MRI of the nasopharynx ruled out nasopharyngeal cancer recurrence. The MPO and PR3 were elevated, and renal biopsy confirmed ANCA-related vasculitis, which affected the lungs, kidneys, and nasopharynx. Based on the review of the patient''s medical history and medication, it is believed that ANCA-related vasculitis was caused by XELOX plus trastuzumab chemotherapy, but it is difficult to confirm which specific drug caused it. After stopping XELOX plus trastuzumab chemotherapy, glucocorticoids and cyclophosphamide was given, the patient''s pulmonary hemorrhage and nasal bleeding stopped, and the lung lesions were absorbed. The renal function also improved. The patient later experienced pulmonary infection again, and tNGS indicated Legionella pneumophila and pulmonary tuberculosis infection. Despite anti-infection treatment, steroid dose was rapidly reduced. Ultimately, the patient gave up on treatment and eventually died.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Enfermedades Renales , Enfermedades Pulmonares , Neoplasias Nasofaríngeas , Masculino , Humanos , Anciano , Oxaliplatino , Anticuerpos Anticitoplasma de Neutrófilos , Trastuzumab/efectos adversos , Capecitabina , Epistaxis/complicaciones , Neoplasias Nasofaríngeas/complicaciones , Recurrencia Local de Neoplasia/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inducido químicamente , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Enfermedades Pulmonares/inducido químicamente , Enfermedades Renales/complicaciones , PeroxidasaRESUMEN
M2 macrophages were related to local immune homeostasis and maternal-fetal tolerance in normal pregnancy; whether M2 macrophages can respond to the stimulation of Treponema pallidum to mediate placental vascular inflammation injury is unclear. In this study, M2 macrophages were constructed to investigate the impact of T. pallidum on macrophage polarization and the underlying signaling pathway involved in this process, and the influence of macrophage polarization triggered by T. pallidum on the apoptosis and angiogenesis of human umbilical vein endothelial cells (HUVEC) was also explored. The results showed that M2 macrophage markers (CD206 and PPARγ) and anti-inflammatory factors (TGFß and CCL18) were decreased, while M1 macrophage marker CD80 and inflammatory cytokines (IL1ß and TNFα) were increased when M2 macrophages were treated with T. pallidum, indicating that T. pallidum promoted the polarization of M2 subtype macrophages to the M1 subtype. Moreover, T. pallidum-induced M1 macrophage polarization was found to be significantly correlated with the activation of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 1 (STAT1). In addition, T. pallidum-induced M1 macrophages were found to promote apoptosis and inhibit the angiogenesis of HUVECs, and JAK1 or STAT1 inhibitors could weaken the apoptosis rate and promote the angiogenesis of HUVECs. These findings revealed that T. pallidum promoted the polarization of M2 macrophages to the M1 subtype through the JAK1-STAT1 signal pathway mediating the apoptosis and inhibiting angiogenesis of HUVECs, which may provide a possible mechanism for T. pallidum-induced adverse pregnancy outcomes.
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Angiogénesis , Treponema pallidum , Humanos , Femenino , Embarazo , Células Endoteliales de la Vena Umbilical Humana , Placenta , Macrófagos/metabolismo , ApoptosisRESUMEN
Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection with acute brain lesions. Genetic variations in both host and parasite have been associated with susceptibility to CM, but the underlying molecular mechanism remains unclear. Here, we demonstrate that variants of human apolipoprotein E (hApoE) impact the outcome of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). Mice carrying the hApoE2 isoform have fewer intracerebral hemorrhages and are more resistant to ECM than mice bearing the hApoE3, hApoE4, or endogenous murine ApoE (mApoE). hApoE2 mice infected with PbA showed increased splenomegaly and IFN-γ levels in serum but reduced cerebral cell apoptosis that correlated with the survival advantage against ECM. In addition, upregulated expression of genes associated with lipid metabolism and downregulated expression of genes linked to immune responses were observed in the brain tissue of hApoE2 mice relative to ECM-susceptible mice after PbA infection. Notably, serum cholesterol and the cholesterol content of brain-infiltrating CD8+ T cells are significantly higher in infected hApoE2 mice, which might contribute to a significant reduction in the sequestration of brain CD8+ T cells. Consistent with the finding that fewer brain lesions occurred in infected hApoE2 mice, fewer behavioral deficits were observed in the hApoE2 mice. Finally, a meta-analysis of publicly available data also showed an increased hApoE2 allele in the malaria-endemic African population, suggesting malaria selection. This study shows that hApoE2 protects mice from ECM through suppression of CD8+ T cell activation and migration to the brain and enhanced cholesterol metabolism.IMPORTANCECerebral malaria (CM) is the deadliest complication of malaria infection with an estimated 15%-25% mortality. Even with timely and effective treatment with antimalarial drugs such as quinine and artemisinin derivatives, survivors of CM may suffer long-term cognitive and neurological impairment. Here, we show that human apolipoprotein E variant 2 (hApoE2) protects mice from experimental CM (ECM) via suppression of CD8+ T cell activation and infiltration to the brain, enhanced cholesterol metabolism, and increased IFN-γ production, leading to reduced endothelial cell apoptosis, BBB disruption, and ECM symptoms. Our results suggest that hApoE can be an important factor for risk assessment and treatment of CM in humans.
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Syphilis has resurged in many countries, which has called attention to vaccine development. Based on the immunization-based rabbit model of infection with the Nichols strain, this study explored the protective immune response of a controversial syphilis vaccine candidate, TprK, and found that immunization with full-length rTprK was effective in attenuating lesion development and accelerating lesion resolution, which could reduce the probability of the pathogen spreading to distant tissue sites to prevent the progression of the disease to some extent. Furthermore, the results revealed that immunization with rTprK not only rapidly induced a strong Th1-like cellular response but also elicited a humoral immune response to produce opsonic antibodies to enhance macrophage-mediated opsonophagocytosis. Although complete protection against infection was not achieved, the study provided a comprehensive and in-depth exploration of the immunogenicity of TprK and highlighted the importance of TprK as a promising syphilis vaccine component.
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OBJECTIVES: Renal diseases caused by primary hypertension (HTN) are often asymptomatic without sensitive markers for early diagnosis and prediction, easily progressing to severe and irreversible renal damage in patients with clinical manifestations. This study explored whether a set of urinary peptides could serve as a potential biomarker for early prediction of renal damage in HTN. METHODS: Urinary peptides level of healthy individuals, HTNâ+ânormoalbuminuric and HTNâ+âalbuminuria patients were compared, and 22 baseline data including sex, age, renal function, hypertensive fundus lesions were collected. Patients diagnosed with HTN, albuminuria, and normal renal function were followed up. According to the follow-up results, the cut-off value of a set of urinary peptides in predicting hypertensive renal injury was calculated and analyzed in the high-risk and low-risk groups of HTN patients for its performance in detecting early hypertensive renal injury. RESULTS: Among a sum of 319 participants, average urinary peptides level was significantly higher in patients with HTN than in normal individuals. A total of 147 HTN patients with normal albuminuria were followed up for a mean of 3.8âyears. Thirty-five patients showed urinary albumin-to-creatinine ratio (uACR) at least 30âmg/g for three consecutive times. The receiver-operating characteristic (ROC) curve showed that the urinary peptides cut-off value for evaluating new-onset proteinuria in patients with HTN was 0.097. Based on this cut-off value, 39 and 108 patients were included in the high-risk and low-risk groups, respectively. Specifically, compared with patients in the low-risk group, those in the high-risk group showed significantly longer duration of HTN, higher proportions of hypertensive fundus lesions and at least 30âmg/g uACR, and higher levels of homocysteine (Hcy), cystatin C (CysC), beta-2 microglobulin (ß2-MG), and uACR. 76.9% of high-risk patients had significantly higher new-onset proteinuria than the low-risk group. Correlation analysis demonstrated a positive correlation between urinary peptides and UACR ( r â=â0.494, P â<â0.001). The incidence of new-onset albuminuria was significantly higher in the high-risk group than in the low-risk group, as shown by Cox regression analysis. The areas under the curve of urinary peptides, Hcy, ß2-MG and CysC were 0.925, 0.753, 0.796 and 0.769, respectively. CONCLUSION: A set of urinary peptides is a predictor of new-onset proteinuria in patients with HTN, therefore, it can be used for diagnosing patients with early renal injury in patients with HTN, contributing to early prevention and treatment of hypertensive nephropathy.
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Albuminuria , Nefritis , Humanos , Albuminuria/diagnóstico , Riñón/fisiología , Proteinuria , Homocisteína , Hipertensión EsencialRESUMEN
The migratory ability of microglia facilitates their rapid transport to a site of injury to kill and remove pathogens. However, the effect of Treponema pallidum membrane proteins on microglia migration remains unclear. The effect of Tp47 on the migration ability and autophagy and related mechanisms were investigated using the human microglial clone 3 cell line. Tp47 inhibited microglia migration, the expression of autophagy-associated protein P62 decreased, the expression of Beclin-1 and LC3-II/LC3-I increased, and the autophagic flux increased in this process. Furthermore, autophagy was significantly inhibited, and microglial cell migration was significantly increased after neutralisation with an anti-Tp47 antibody. In addition, Tp47 significantly inhibited the expression of p-PI3K, p-AKT, and p-mTOR proteins, and the sequential activation of steps in the PI3K/AKT/mTOR pathways effectively prevented Tp47-induced autophagy. Moreover, Tp47 significantly inhibited the expression of p-FOXO1 protein and promoted FOXO1 nuclear translocation. Inhibition of FOXO1 effectively suppressed Tp47-induced activation of autophagy and inhibition of migration. Treponema pallidum membrane protein Tp47-induced autophagy and inhibited cell migration in HMC3 Cells via the PI3K/AKT/FOXO1 pathway. These data will contribute to understanding the mechanism by which T. pallidum escapes immune killing and clearance after invasion into the central nervous system.
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Interleukin-6 (IL-6) is a multi-effective cytokine involved in multiple immune responses. Whether fibroblasts also turn out to be a cytokine IL-6 factory during interaction with Treponema pallidum is not yet understood. To explore whether fibroblasts participate in inflammation due to syphilis, a series of experiments were performed to explore the role of T. pallidum lipoprotein Tp47 in IL-6 production in human dermal fibroblasts. The Toll-like receptor 2 (TLR2) and participating signalling pathways in this process were also evaluated. The results showed that the expressions of IL-6 and the protein levels of TLR2 in fibroblasts were upregulated after stimulation with Tp47, and this effect was impeded by the TLR2 inhibitor C29. In addition, Tp47 promoted the phosphorylation of p38, PI3K/Akt, and nuclear factor-kappaB (NF-κB), and the translocation of NF-κB in fibroblasts. Moreover, p38, PI3K, and NF-κB inhibitors significantly reduced IL-6 production in fibroblasts stimulated with Tp47. Furthermore, the TLR2 inhibitor C29 inhibited the phosphorylation of p38, Akt, and NF-κB, and the translocation of NF-κB in fibroblasts. In conclusion, our results showed that Tp47 enhanced IL-6 secretion in human dermal fibroblasts through TLR2 via p38, PI3K/Akt, and NF-κB signalling pathways. These findings contribute to our understanding of syphilis inflammation.
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FN-kappa B , Sífilis , Humanos , FN-kappa B/metabolismo , Interleucina-6/metabolismo , Treponema pallidum/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Sífilis/metabolismo , Citocinas/metabolismo , Inflamación , Proteínas Recombinantes/metabolismo , Fibroblastos/metabolismoRESUMEN
Heterogeneous tprK sequences have been hypothesized to be an important factor for persistent infection of Treponema pallidum subsp. pallidum (T. pallidum) in humans. Previous research has only explored tprK diversity using a rabbit model infected with almost clonal isolates, which is inconsistent with the fact that infected human isolates contain multiple heterogeneous tprK sequences. Here, we used the T. pallidum Amoy strain with heterogeneous tprK sequences to establish a rabbit infection model and explore longitudinal variations in the tprK gene under normal infection, immunosuppression treatment, and benzathine penicillin G (BPG) treatment using next-generation sequencing. The diversity of the tprK gene was high in all three groups but was highest in the control group and lowest in the BPG group. Interestingly, the overall diversity of tprK in all three groups decreased during infection, exhibiting a "more to less" trend, indicating that survival selection may be an important factor affecting tprK variation in the later infection stage. BPG treatment appeared to reduce the diversity of tprK but increased the frequency of predominant sequence changes, which might facilitate the escape of T. pallidum from the host immune clearance. Furthermore, the original predominant V region sequence did not disappear with disease progression but retained a relatively high proportion within the population, suggesting a new direction for tprK-related vaccine research. This study provides insights into longitudinal variations within the highly heterogeneous tprK gene sequences of T. pallidum and will contribute to further exploration of the pathogenesis of syphilis. IMPORTANCE The tprK variations are an important factor in persistent T. pallidum infection. A nearly clonal isolate has been used previously to investigate the mechanism of tprK gene variations; however, clinical T. pallidum isolates in infected humans exhibit multiple heterogeneous tprK sequences. Here, we use next-generation sequencing to explore longitudinal variations in the tprK gene under normal infection and immunosuppression and benzathine penicillin G treatment in a rabbit model infected with the Amoy strain with heterogeneous tprK sequences. The overall diversity of tprK in all three groups was high and decreased during infection, exhibiting a "more to less" trend. Benzathine penicillin G treatment reduced the diversity of tprK but increased the frequency of predominant sequence changes. Moreover, the original predominant V region sequence did not disappear as the disease progressed but remained at a relatively high proportion within the population. The research results give us a new understanding about tprK variation.
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Sífilis , Treponema pallidum , Animales , Conejos , Humanos , Treponema pallidum/genética , Penicilina G Benzatina , Treponema/genética , Infección PersistenteRESUMEN
OBJECTIVES: Renal diseases caused by primary hypertension (HTN) are often asymptomatic without sensitive markers for early diagnosis and prediction, easily progressing to severe and irreversible renal damage in patients with clinical manifestations. This study explored whether a classifier developed based on 273 urinary peptides (CKD273) could serve as a potential biomarker for early prediction of renal damage in HTN. METHODS: Urinary CKD273 level of healthy individuals, HTNâ+ânormoalbuminuric and HTNâ+âalbuminuria patients were compared, and 22 baseline data including sex, age, renal function, and hypertensive fundus lesions were collected. Patients diagnosed with HTN, albuminuria, and normal renal function were followed up. According to the follow-up results, the cut-off value of CKD273 in predicting hypertensive renal injury was calculated and analyzed in the high-risk and low-risk groups of HTN patients for its performance in detecting early hypertensive renal injury. RESULTS: Among a sum of 319 participants, average urinary CKD273 level was significantly higher in patients with HTN than in normal individuals. A total of 147 HTN patients with normal albuminuria were followed up for a mean of 3.8âyears. Thirty-five patients showed urinary albumin-to-creatinine ratio (uACR) at least 30âmg/g for three consecutive times. The receiver-operating characteristic (ROC) curve showed that the urinary CKD273 cut-off value for evaluating new-onset proteinuria in patients with HTN was 0.097. Based on this cut-off value, 39 and 108 patients were included in the high-risk and low-risk groups, respectively. Specifically, compared with patients in the low-risk group, those in the high-risk group showed significantly longer duration of HTN, higher proportions of hypertensive fundus lesions and at least 30âmg/g uACR, and higher levels of homocysteine (Hcy), cystatin C (CysC), beta-2 microglobulin (ß2-MG), and uACR. 76.9% of high-risk patients had significantly higher new-onset proteinuria than the low-risk group. Correlation analysis demonstrated a positive correlation between urinary CKD273 and UACR ( r â=â0.494, P â=â0.000). The incidence of new-onset albuminuria was significantly higher in the high-risk group than in the low-risk group, as shown by Cox regression analysis. The areas under the curve of CKD273, Hcy, ß2-MG, and CysC were 0.925, 0.753, 0.796, and 0.769, respectively. CONCLUSION: Urinary CKD273 is a predictor of new-onset proteinuria in patients with HTN, therefore, it can be used for diagnosing patients with early renal injury in patients with HTN, contributing to early prevention and treatment of hypertensive nephropathy.