RESUMEN

Infectious, inflammatory and autoimmune conditions present differently in males and females. SARS-CoV-2 infection in naive males is associated with increased risk of death, whereas females are at increased risk of long COVID1, similar to observations in other infections2. Females respond more strongly to vaccines, and adverse reactions are more frequent3, like most autoimmune diseases4. Immunological sex differences stem from genetic, hormonal and behavioural factors5 but their relative importance is only partially understood6-8. In individuals assigned female sex at birth and undergoing gender-affirming testosterone therapy (trans men), hormone concentrations change markedly but the immunological consequences are poorly understood. Here we performed longitudinal systems-level analyses in 23 trans men and found that testosterone modulates a cross-regulated axis between type-I interferon and tumour necrosis factor. This is mediated by functional attenuation of type-I interferon responses in both plasmacytoid dendritic cells and monocytes. Conversely, testosterone potentiates monocyte responses leading to increased tumour necrosis factor, interleukin-6 and interleukin-15 production and downstream activation of nuclear factor kappa B-regulated genes and potentiation of interferon-γ responses, primarily in natural killer cells. These findings in trans men are corroborated by sex-divergent responses in public datasets and illustrate the dynamic regulation of human immunity by sex hormones, with implications for the health of individuals undergoing hormone therapy and our understanding of sex-divergent immune responses in cisgender individuals.

Asunto(s)

Testosterona , Personas Transgénero , Adulto , Femenino , Humanos , Masculino , Conjuntos de Datos como Asunto , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/efectos de los fármacos , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/metabolismo , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-15/inmunología , Interleucina-15/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Monocitos/inmunología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , FN-kappa B/metabolismo , Caracteres Sexuales , Testosterona/efectos adversos , Testosterona/inmunología , Testosterona/farmacología , Testosterona/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

A complex heteropolysaccharide SCP-2 named schisanan B (Mw = 1.005 × 105 g/mol) was obtained from water extracts of Schisandra chinensis fruits, and its planar structure was finally deduced as a galacturonoglucan by a combination of monosaccharide compositions, methylation analysis, partial acid hydrolysis, enzymatic hydrolysis and 1D/2D-nuclear magnetic resonance spectroscopy. The conformation of SCP-2 exhibited a globular shape with branching in ammonium formate aqueous solutions. The rheological properties of SCP-2 were investigated on concentrations, temperature, pH and salts. The in vitro immunomodulatory activity assay demonstrated that SCP-2 significantly enhanced the production of nitric oxide (NO) and stimulated the secretion of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in macrophages. Through a combination of high-resolution live-cell imaging, surface plasmon resonance, and molecular docking techniques, SCP-2 exhibited a strong binding affinity with the Toll-like receptor 4 (TLR4). Moreover, western blot analysis revealed that SCP-2 effectively induced downstream signaling proteins associated with TLR4 activation, thereby promoting macrophage activation. The evidence strongly indicates that TLR4 functions as a membrane protein target in the activation of macrophages and immune regulation induced by SCP-2.

Asunto(s)

Frutas , Reología , Schisandra , Receptor Toll-Like 4 , Schisandra/química , Ratones , Frutas/química , Células RAW 264.7 , Animales , Receptor Toll-Like 4/metabolismo , Simulación del Acoplamiento Molecular , Óxido Nítrico/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Pectinas/química , Factor de Necrosis Tumoral alfa/metabolismo , Glucanos/química , Interleucina-6/metabolismo

RESUMEN

OBJECTIVE: To study the biological role and related mechanism of autophagy in acute lung injury (ALI) of hemorrhagic shock mice. METHODS: According to random number table method, wild-type male C57BL/6 mice were divided into control group, ALI group, rapamycin group and 3-methyladenine (3-MA) group, with 8 mice in each group. Light chain 3 (LC3) gene knockout mice with C57BL/6 background were divided into LC3 knockout group and LC3 knockout+ALI group, with 8 mice in each group. Control group, ALI group, LC3 knockout group, LC3 knockout+ALI group were intraperitoneally injected with 2 mL/kg normal saline, rapamycin group was intraperitoneally injected with 3 mg/kg autophagy activator rapamycin, 3-MA group was intraperitoneally injected with 15 mg/kg autophagy inhibitor 3-MA, all of which were given for 3 consecutive days. 2 hours after the last administration, the hemorrhagic shock induced ALI model was established. 24 hours after modeling, the lung index was calculated. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of lung tissue and lung injury score was performed. The expressions of autophagy genes LC3- II/LC3- I and Beclin-1 in lung tissue were detected by Western blotting. The contents of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and malondialdehyde (MDA) in lung tissue were detected according to the steps of the kit. RESULTS: Compared with the control group, the lung tissue structure was destroyed and exudation increased, lung index, lung injury score, the expressions of LC3- II/LC3- I, Beclin-1, and the contents of TNF-α, IL-6 and MDA in lung tissue significantly increased in the ALI group. Compared with the ALI group, the structural damage and exudation of lung tissue were reduced in the rapamycin group, lung index, lung injury score and the contents of TNF-α, IL-6 and MDA in lung tissue decreased, while the expressions of LC3- II/LC3- I and Beclin-1 in lung tissue increased [lung index: (7.56±0.39)% vs. (9.12±0.59)%, lung injury score: 3.04±0.58 vs. 9.32±2.14, TNF-α (ng/mg): 1.85±0.32 vs. 3.51±0.62, IL-6 (ng/mg): 1.61±0.32 vs. 2.52±0.44, MDA (nmol/mg): 1.03±0.16 vs. 1.88±0.24, LC3- II/LC3- I: 1.21±0.12 vs. 0.39±0.05, Beclin-1/ß-actin: 1.10±0.12 vs. 0.58±0.06, all P < 0.05], while lung tissue structure damage was aggravated and exudation was further increased in the 3-MA group, lung index, lung injury score and the contents of TNF-α, IL-6 and MDA in lung tissue increased, the expressions of LC3- II/LC3- I and Beclin-1 in lung tissue decreased [lung index: (10.44±0.62)% vs. (9.12±0.59)%, lung injury score: 11.59±2.28 vs. 9.32±2.14, TNF-α (ng/mg): 4.77±0.71 vs. 3.51±0.62, IL-6 (ng/mg): 3.44±0.52 vs. 2.52±0.44, MDA (nmol/mg): 2.71±0.42 vs. 1.88±0.24, LC3- II/LC3- I: 0.25±0.04 vs. 0.39±0.05, Beclin-1/ß-actin: 0.21±0.03 vs. 0.58±0.06, all P < 0.05]. Lung index, lung injury score and the contents of TNF-α, IL-6 and MDA in lung tissue of LC3 knockout ALI mice were higher than those of wild-type ALI mice [lung index: (10.44±0.75)% vs. (9.12±0.59)%, lung injury score: 12.41±2.86 vs. 9.32±2.14, TNF-α (ng/mg): 4.85±0.72 vs. 3.51±0.62, IL-6 (ng/mg): 3.28±0.51 vs. 2.52±0.44, MDA (nmol/mg): 2.75±0.41 vs. 1.88±0.24, all P < 0.05]. CONCLUSIONS: Autophagy plays a protective role in ALI of hemorrhagic shock mice, and the related molecular mechanism is the inhibition of inflammatory response and oxidative stress response.

Asunto(s)

Lesión Pulmonar Aguda , Autofagia , Interleucina-6 , Ratones Endogámicos C57BL , Ratones Noqueados , Choque Hemorrágico , Factor de Necrosis Tumoral alfa , Animales , Lesión Pulmonar Aguda/metabolismo , Masculino , Choque Hemorrágico/metabolismo , Choque Hemorrágico/complicaciones , Ratones , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Modelos Animales de Enfermedad , Pulmón/metabolismo , Pulmón/patología , Proteínas Asociadas a Microtúbulos/metabolismo

RESUMEN

The pathogenesis of acute lung injury is complex. Studies have demonstrated the role of neutrophil extracellular traps (NETs) in the process of lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, the underlying mechanism remains unclear. In this study, the regulation of Nrf2 in the formation of NETs, which was pathogenic in LPS-induced ALI, was identified by analyzing the levels of Cit-H3, lung function, lung tissue pathology, lung wet/dry ratio, the inflammatory cells, cytokines and proteins in the bronchoalveolar lavage fluid (BALF) and in addition, the activity of lung myeloperoxidase (MPO) was also measured. Results showed that the levels of Cit-H3 measured by western blot in Nrf2-knockout (KO) mice were higher compared with the WT mice after LPS stimulation. To further investigate the NETs formation was pathogenic during LPS-induced ALI, the Nrf2-KO mice were treated with DNase I. Results showed that DNase I improved lung function and lung tissue pathology and significantly reduced lung wet/dry ratio and proteins in the BALF. Besides, DNase I also attenuated the infiltration of inflammatory cells and the cytokines (TNF-α, IL-1ß) production in the BALF and the activity of lung MPO. Therefore, these results together indicate that Nrf2 may intervene in the release of NETs during LPS-induced ALI in mice.

Asunto(s)

Lesión Pulmonar Aguda , Líquido del Lavado Bronquioalveolar , Trampas Extracelulares , Lipopolisacáridos , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 2 Relacionado con NF-E2 , Animales , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Trampas Extracelulares/metabolismo , Líquido del Lavado Bronquioalveolar/química , Masculino , Peroxidasa/metabolismo , Neutrófilos/metabolismo , Pulmón/metabolismo , Pulmón/patología , Interleucina-1beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Desoxirribonucleasa I/metabolismo , Citocinas/metabolismo , Western Blotting

RESUMEN

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has led to significant global morbidity and mortality. Understanding the genetic factors that influence disease outcomes can provide critical insights into pathogenesis and potential therapeutic targets. OBJECTIVE: This study aimed to investigate the potential correlation between single nucleotide polymorphisms (SNPs) in Interleukin 12 Subunit Alpha (IL-12A), Interleukin 12 Subunit Beta (IL-12B), Interleukin 6 (IL-6), and Tumor Necrosis Factor (TNF) genes and the severity as well as susceptibility to COVID-19 among Moroccan patients. PATIENTS AND METHODS: Next-Generation sequencing (NGS) was conducted on 325 Moroccan participants, 207 patients with PCR-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and 118 controls. Among these patients, 51% presented moderate to severe symptoms requiring hospitalization, while 49% were asymptomatic or experienced mild symptoms and did not require hospitalization. Statistical analysis was performed using codominant, dominant, and recessive logistic regression models to assess correlations with the severity and susceptibility to COVID-19 infection. RESULTS: No association was found between SNPs of IL-12A, IL-12B, IL-6 or TNF and COVID-19 severity and susceptibility. However, our results unveiled a noteworthy association with IL-6 rs2069840, which exhibited a negative correlation (OR = 0.21, 95% CI = 0.07-0.69, p = .006), suggesting a protective effect against SARS-CoV-2 infection. CONCLUSION: Polymorphisms in IL-12A, IL-12B, IL-6, and TNF genes are not correlated to the severity and susceptibility of COVID-19.

Asunto(s)

COVID-19 , Predisposición Genética a la Enfermedad , Subunidad p35 de la Interleucina-12 , Subunidad p40 de la Interleucina-12 , Interleucina-6 , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa , Humanos , COVID-19/genética , COVID-19/inmunología , COVID-19/virología , Interleucina-6/genética , Masculino , Femenino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/genética , Subunidad p40 de la Interleucina-12/genética , Adulto , Subunidad p35 de la Interleucina-12/genética , SARS-CoV-2 , Marruecos , Anciano , Estudios de Casos y Controles

RESUMEN

OBJECTIVE: This meta-analysis aims to clarify the association between the TNF-α -308G > A and - 238G > A polymorphisms and lung cancer risk. METHOD: A comprehensive search was conducted for relevant articles across databases such as PubMed, Google Scholar, Web of Science, EMBASE, and CNKI, up to September 25, 2023. Lung cancer risk was assessed by calculating odds ratios (ORs) and their 95% confidence intervals (CIs). The Z-test was used to determine the significance of combined ORs, with P < 0.05 considered statistically significant. All analyses were performed using Comprehensive Meta-Analysis (CMA) 2.0 software. RESULTS: The analysis included 19 case-control studies with 3,838 cases and 5,306 controls for the TNF-α -308G > A polymorphism, along with 10 studies comprising 2,427 cases and 2,357 controls for the - 238G > A polymorphism. The - 308G > A polymorphism showed no significant overall relationships, though in the Asian subgroup, the A allele was significantly reduced compared to G (OR: 0.831, p = 0.028) and the AA genotype showed significant reductions versus GG (OR: 0.571, p = 0.021), with no significant correlation in Caucasians. In non-small cell lung cancer (NSCLC), the A allele was associated with increased risk compared to G (OR: 1.131, p = 0.049). For the - 238G > A polymorphism, the AA genotype significantly increased risk compared to GG (OR: 3.171, p = 0.014), while showing a protective effect in Caucasians (OR: 0.120, p = 0.024) and a heightened risk in Asians (OR: 7.990, p = 0.007). In small cell lung cancer (SCLC), the A allele conferred protective effects, whereas NSCLC showed increased risk for the AA genotype (OR: 11.375, p = 0.002). CONCLUSION: The - 308G > A polymorphism has no significant overall relationships but suggests a protective role of the A allele in the Asian subgroup. Conversely, the - 238G > A polymorphism presents a complex risk profile, increasing lung cancer likelihood in Asians while protecting Caucasians. Notably, the AA genotype significantly raises risk for NSCLC, indicating its potential as a risk factor.

Asunto(s)

Predisposición Genética a la Enfermedad , Neoplasias Pulmonares , Polimorfismo de Nucleótido Simple , Factor de Necrosis Tumoral alfa , Humanos , Neoplasias Pulmonares/genética , Factor de Necrosis Tumoral alfa/genética , Estudios de Casos y Controles , Alelos , Pueblo Asiatico/genética , Oportunidad Relativa , Genotipo , Factores de Riesgo , Población Blanca/genética

RESUMEN

Molecular ultrasound imaging with actively targeted microbubbles (MB) proved promising in preclinical studies but its clinical translation is limited. To achieve this, it is essential that the actively targeted MB can be produced with high batch-to-batch reproducibility with a controllable and defined number of binding ligands on the surface. In this regard, poly (n-butyl cyanoacrylate) (PBCA)-based polymeric MB have been used for US molecular imaging, however, ligand coupling was mostly done via hydrolysis and carbodiimide chemistry, which is a multi-step procedure with poor reproducibility and low MB yield. Herein, we developed a single-step coupling procedure resulting in high MB yields with minimal batch-to-batch variation. Actively targeted PBCA-MB were generated using an aminolysis protocol, wherein amine-containing cRGD was added to the MB using lithium methoxide as a catalyst. We confirmed the successful conjugation of cRGD on the MB surface, while preserving their structure and acoustic signal. Compared to the conventional hydrolysis protocol, aminolysis resulted in higher MB yields and better reproducibility of coupling efficiency. Optical imaging revealed that under flow conditions, cRGD- and rhodamine-labelled MB, generated by aminolysis, specifically bind to tumor necrosis factor-alpha (TNF-α) activated endothelial cells in vitro. Furthermore, US molecular imaging demonstrated a markedly higher binding of the cRGD-MB than of control MB in TNF-α activated mouse aortas and 4T1 tumors in mice. Thus, using the aminolysis based conjugation approach, important refinements on the production of cRGD-MB could be achieved that will facilitate the production of clinical-scale formulations with excellent binding and ultrasound imaging performance.

Asunto(s)

Enbucrilato , Microburbujas , Imagen Molecular , Ultrasonografía , Animales , Enbucrilato/química , Ratones , Imagen Molecular/métodos , Ultrasonografía/métodos , Humanos , Medios de Contraste/química , Femenino , Células Endoteliales de la Vena Umbilical Humana , Ratones Endogámicos BALB C , Línea Celular Tumoral , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

Mycobacterium abscessus (Mab) is an opportunistic nontuberculous mycobacterium responsible of difficult-to-treat pulmonary infections in vulnerable patients, such as those suffering from Cystic Fibrosis (CF), where it represents a major cause of morbidity and mortality. Additionally, due to the intrinsic extensive antimicrobial resistance spectrum displayed by this species and the side effects reported for some available antibiotics, the therapeutic management of such infections remains extremely difficult. In the present study, we show that phosphatidylserine liposomes (PS-L) enhance intracellular mycobacterial killing of Mab infected human macrophages with functional or pharmacologically inhibited cystic fibrosis conductance regulator (CFTR), by a mechanism involving phagosome acidification and reactive oxygen species (ROS) production. Additionally, PS-L significantly reduce proinflammatory response of Mab infected macrophages in terms of NF-kB activation and TNF-α production, irrespective of CFTR inhibition. Altogether, these results represent the proof of concept for a possible future development of PS-L as a therapeutic strategy against difficult-to-treat Mab infection.

Asunto(s)

Liposomas , Macrófagos , Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Fagosomas , Fosfatidilserinas , Especies Reactivas de Oxígeno , Humanos , Mycobacterium abscessus/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Liposomas/metabolismo , Macrófagos/microbiología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Fagosomas/microbiología , Fagosomas/metabolismo , Fosfatidilserinas/metabolismo , Infecciones por Mycobacterium no Tuberculosas/microbiología , Factor de Necrosis Tumoral alfa/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , FN-kappa B/metabolismo , Fibrosis Quística/microbiología

RESUMEN

PURPOSE: Oral mucositis is a severe adverse event in patients undergoing chemotherapy and radiotherapy that may lead to the termination of cancer treatment. This study aimed to elucidate the relationship between salivary inflammatory mediators and oral mucositis in patients undergoing chemotherapy. METHODS: This prospective cohort study included 167 patients who underwent chemotherapy at our institution between June 2020 and November 2023. We evaluated the association between chemotherapy-induced oral mucositis and salivary inflammatory mediators using multiple comparison tests and logistic regression analyses. RESULTS: Of the 167 patients, 67 (40.1%) had oral mucositis. Dunn's multiple comparison test revealed that interleukin-6 was significantly higher in oral mucositis of grades 2 and ≥ 3 (P < 0.01) and tumor necrosis factor (TNF)-α was significantly higher in oral mucositis of grades 3-4 (P < 0.01). Logistic regression analysis showed that the risk of oral mucositis was significantly higher for tumor necrosis factor (TNF)-α > 4.4 pg/mL than for TNF-α ≤ 4.4 pg/mL (adjusted odds ratio, 2.4; 95% confidence interval, 1.1-5.3; P = 0.03). CONCLUSION: Saliva is useful in evaluating inflammation in patients with chemotherapy-induced oral mucositis. Furthermore, TNF-α may be a predictive marker for the severity of oral mucositis in patients undergoing chemotherapy.

Asunto(s)

Antineoplásicos , Mediadores de Inflamación , Neoplasias , Saliva , Estomatitis , Factor de Necrosis Tumoral alfa , Humanos , Estomatitis/inducido químicamente , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Neoplasias/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/metabolismo , Antineoplásicos/efectos adversos , Anciano , Adulto , Mediadores de Inflamación/metabolismo , Interleucina-6/metabolismo , Interleucina-6/análisis , Estudios de Cohortes , Índice de Severidad de la Enfermedad

RESUMEN

BACKGROUND: The pathogenesis of osteoarthritis (OA) involves the progressive degradation of articular cartilage. Exosomes derived from mesenchymal stem cells (MSC-EXOs) have been shown to mitigate joint pathological injury by attenuating cartilage destruction. Optimization the yield and therapeutic efficacy of exosomes derived from MSCs is crucial for promoting their clinical translation. The preconditioning of MSCs enhances the therapeutic potential of engineered exosomes, offering promising prospects for application by enabling controlled and quantifiable external stimulation. This study aims to address these issues by employing pro-inflammatory preconditioning of MSCs to enhance exosome production and augment their therapeutic efficacy for OA. METHODS: The exosomes were isolated from the supernatant of infrapatellar fat pad (IPFP)-MSCs preconditioned with a pro-inflammatory factor, TNF-α, and their production was subsequently quantified. The exosome secretion-related pathways in IPFP-MSCs were evaluated through high-throughput transcriptome sequencing analysis, q-PCR and western blot analysis before and after TNF-α preconditioning. Furthermore, exosomes derived from TNF-α preconditioned IPFP-MSCs (IPFP-MSC-EXOsTNF-α) were administered intra-articularly in an OA mouse model, and subsequent evaluations were conducted to assess joint pathology and gait alterations. The expression of proteins involved in the maintenance of cartilage homeostasis within the exosomes was determined through proteomic analysis. RESULTS: The preconditioning with TNF-α significantly enhanced the exosome secretion of IPFP-MSCs compared to unpreconditioned MSCs. The potential mechanism involved the activation of the PI3K/AKT signaling pathway in IPFP-MSCs by TNF-α precondition, leading to an up-regulation of autophagy-related protein 16 like 1(ATG16L1) levels, which subsequently facilitated exosome secretion. The intra-articular administration of IPFP-MSC-EXOsTNF-α demonstrated superior efficacy in ameliorating pathological changes in the joints of OA mice. The preconditioning of TNF-α enhanced the up-regulation of low-density lipoprotein receptor-related protein 1 (LRP1) levels in IPFP-MSC-EXOsTNF-α, thereby exerting chondroprotective effects. CONCLUSION: TNF-α preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of IPFP-MSCs derived exosomes in the treatment of OA.

Asunto(s)

Exosomas , Células Madre Mesenquimatosas , Osteoartritis , Factor de Necrosis Tumoral alfa , Exosomas/metabolismo , Animales , Células Madre Mesenquimatosas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ratones , Osteoartritis/terapia , Osteoartritis/metabolismo , Tejido Adiposo/citología , Ratones Endogámicos C57BL , Masculino , Modelos Animales de Enfermedad , Cartílago Articular/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Células Cultivadas , Humanos

RESUMEN

OBJECTIVES: To study the effects and mechanisms of tetramethylpyrazine (TMP) on tumor necrosis factor-α (TNF-α)-induced inflammatory injury in human coronary artery endothelial cells (HCAEC). METHODS: HCAEC were randomly divided into four groups: the control group (no treatment), the model group (treated with TNF-α, 50 ng/mL for 24 hours), the TMP group (pre-treated with TMP, 80 µg/mL for 12 hours followed by TNF-α treatment for 24 hours), and the SIRT1 inhibitor group (pre-treated with TMP and the specific SIRT1 inhibitor EX527 for 12 hours followed by TNF-α treatment for 24 hours). Cell viability was assessed using the CCK-8 method, lactate dehydrogenase (LDH) activity was measured using an LDH assay kit, reactive oxygen species (ROS) levels were observed using DCFH-DA staining, expression of pyroptosis-related proteins was detected by Western blot, and SIRT1 expression was analyzed using immunofluorescence staining. RESULTS: Compared to the control group, the model group showed decreased cell viability, increased LDH activity, ROS level and expression of pyroptosis-related proteins, and decreased SIRT1 expression (P<0.05). Compared to the model group, the TMP group exhibited increased cell viability, decreased LDH activity, ROS level and expression of pyroptosis-related proteins, and increased SIRT1 expression (P<0.05). In comparison to the TMP group, the SIRT1 inhibitor group showed decreased cell viability, increased LDH activity, ROS level and expression of pyroptosis-related proteins, and decreased SIRT1 expression (P<0.05). CONCLUSIONS: TMP may attenuate TNF-α-induced inflammatory injury in HCAEC, which is associated with the inhibition of pyroptosis and activation of the SIRT1 signaling pathway.

Asunto(s)

Células Endoteliales , Pirazinas , Especies Reactivas de Oxígeno , Transducción de Señal , Sirtuina 1 , Factor de Necrosis Tumoral alfa , Sirtuina 1/metabolismo , Sirtuina 1/fisiología , Humanos , Pirazinas/farmacología , Transducción de Señal/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Supervivencia Celular/efectos de los fármacos , Piroptosis/efectos de los fármacos , Células Cultivadas , Inflamación/tratamiento farmacológico

RESUMEN

OBJECTIVES: To evaluate the tuberculin skin test (TST) conversion in chronic inflammatory arthropathies (CIA) patients on TNFα inhibitors (TNFi) and without previous latent tuberculosis infection (LTBI) treatment. METHODS: Patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) with negative LTBI were retrospectively evaluated for TST conversion and active tuberculosis (TB) after six months of exposition to TNFi. Two groups were compared: patients who repeated TST (TST-repetition) during the follow-up and patients who did not (non-TST-repetition). RESULTS: A total of 355 CIA patients on TNFi were screened and 138 (38.9%) did not fulfill the inclusion criteria. Of the remaining 217 CIA patients, 81 (37.3%) repeated TST during TNFi treatment. TST conversion rate was observed in 18 (22.2%) patients without significant differences among CIA (p = 0.578). The number of TB cases was low (n = 10; 4.6%) and was similar in TST-repetition and non-TST-repetition groups [2 (2.5%) vs. 8 (5.9%), p = 0.328]. Of note, 30% of active TB occurred early (6-12 months of TNFi exposure) and the median (full range) time to incident TB was 1.3 (0.6-10.6) years, whereas the median (full range) time to TST repetition was later [3.3 (0.5-13.4) years]. The incidence of active TB was lower among RA patients than AS patients [342 (95% CI 41 - 1446) vs. 1.454 (95% CI 594-2993)/100,000 patient-years, p = 0.049]. CONCLUSION: These results indicate that TST repetition is associated with a high conversion rate, suggesting the need for recommended treatment. The delayed repetition of TST and low number of active TB cases hampered the evaluation of this strategy effectiveness to prevent active infection. Larger studies with systematic repetition patterns are necessary. In addition, the study highlights the need for a greater surveillance for TB in AS patients.

Asunto(s)

Artritis Psoriásica , Artritis Reumatoide , Tuberculosis Latente , Espondilitis Anquilosante , Prueba de Tuberculina , Factor de Necrosis Tumoral alfa , Humanos , Estudios Retrospectivos , Artritis Reumatoide/tratamiento farmacológico , Masculino , Femenino , Artritis Psoriásica/tratamiento farmacológico , Persona de Mediana Edad , Espondilitis Anquilosante/tratamiento farmacológico , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/epidemiología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Anciano , Estudios de Cohortes , Enfermedades Endémicas , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico

RESUMEN

BACKGROUND: Peripheral neuropathy (PN) constitutes a dose-limiting side effect of oxaliplatin chemotherapy that often compromises the efficacy of antineoplastic treatments. Sensory neurons damage in dorsal root ganglia (DRG) are the cellular substrate of PN complex molecular origin. Dehydropeptidase-1 (DPEP1) inhibitors have shown to avoid platin-induced nephrotoxicity without compromising its anticancer efficiency. The objective of this study was to describe DPEP1 expression in rat DRG in health and in early stages of oxaliplatin toxicity. To this end, we produced and characterized anti-DPEP1 polyclonal antibodies and used them to define the expression, and cellular and subcellular localization of DPEP1 by immunohistochemical confocal microscopy studies in healthy controls and short term (six days) oxaliplatin treated rats. RESULTS: DPEP1 is expressed mostly in neurons and in glia, and to a lesser extent in endothelial cells. Rats undergoing oxaliplatin treatment developed allodynia. TNF-𝛼 expression in DRG revealed a pattern of focal and at different intensity levels of neural cell inflammatory damage, accompanied by slight variations in DPEP1 expression in endothelial cells and in nuclei of neurons. CONCLUSIONS: DPEP1 is expressed in neurons, glia and endothelial cells of DRG. Oxaliplatin caused allodynia in rats and increased TNF-α expression in DRG neurons. The expression of DPEP1 in neurons and other cells of DRG suggest this protein as a novel strategic molecular target in the prevention of oxaliplatin-induced acute neurotoxicity.

Asunto(s)

Antineoplásicos , Ganglios Espinales , Oxaliplatino , Enfermedades del Sistema Nervioso Periférico , Animales , Oxaliplatino/toxicidad , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/prevención & control , Enfermedades del Sistema Nervioso Periférico/patología , Masculino , Antineoplásicos/toxicidad , Ratas , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Hiperalgesia/prevención & control , Factor de Necrosis Tumoral alfa/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Ratas Sprague-Dawley , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Inflamación/metabolismo , Inflamación/inducido químicamente

RESUMEN

In vivo studies on the hazards of deep-fried foods were commonly done by feeding used-or heated-cooking oil to rats. The aim of this study was to determine the effect of feeding tempe deep-fried in palm, olive, and coconut oils and the used frying oil on the blood biochemical profile of laboratory rats. An in vivo randomized control group study with pre-test and post-test was conducted. This study included healthy male Sprague-Dawley rats aged 2-3 months and weighing 100-200 grams. After acclimatization, the rats were randomly assigned to seven groups, which were: (1) regular diet (control diet); (2) diet of tempe deep-fried in 5× used palm oil (Tempe-in-used-Po); (3) diet of tempe deep-fried in 5× used coconut oil (Tempe-in-used-Co); (4) diet of tempe deep-fried in 5× used olive oil (Tempe-in-used-Oo); (5) diet of 5× used palm oil (Used-Po); (6) diet of 5× used coconut oil (Used-Co); and (7) diet of 5× used olive oil (Used-Oo). Each rat received 15 grams of a treatment diet daily and blood samples were collected after four weeks for a complete blood count and serum biochemistry analysis. The results showed that the final body weight and the weight gain of Tempe-in-used-Po, Tempe-in-used-Co, Tempe-in-used-Oo group, and Used-Po groups increased significantly compared to the control, Used-Co, and Used-Oo groups. However, there was a significant increase in serum tumor necrosis factor-alpha (TNF-α) in the Used-Co and Used-Oo groups (p<0.05), suggesting the used oil's detrimental effect. The Used-Co and Used-Oo were the only two groups whose creatinine increased significantly (p<0.05). Subsequently, only the Used-Oo group had a significantly increased malondialdehyde (MDA) level compared to all groups (p<0.05). These results prove that the effect of feeding fried food differs from used oils. Feeding used oil did not reflect the consumption of fried foods as part of the whole diet and generally resulted in more harmful effects. This is the first study to report an in vivo rat feeding study of deep-fried tempe and the used oil as part of the diet.

Asunto(s)

Aceite de Coco , Culinaria , Creatinina , Malondialdehído , Aceite de Oliva , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa , Animales , Masculino , Ratas , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/metabolismo , Creatinina/sangre , Malondialdehído/sangre , Malondialdehído/metabolismo , Aceite de Oliva/administración & dosificación , Aceite de Oliva/farmacología , Aceite de Palma/administración & dosificación , Aceite de Palma/farmacología , Aceite de Palma/química , Aceites de Plantas/farmacología , Aceites de Plantas/química

RESUMEN

OBJECTIVE: To investigate the correlation between serum Rac1 enzyme (Rac1) level with asthma control, airway inflammatory response and lung function in asthmatic children. METHODS: A retrospective analysis was performed on 79 children with asthma who were diagnosed and treated in our hospital from June 2020 to January 2023. According to the severity of the disease, the children were divided into mild group (25 cases), moderate group (30 cases) and severe group (24 cases). 36 healthy children who underwent physical examination at the same period in our hospital were selected as the control group. The state of an illness, control level, serum mRNA Rac1, inflammatory factors, and lung function of the children in two groups were compared between the control group and the observation group. RESULTS: The Rac1 mRNA levels, forced vital capacity (FVC), forced expiratory volume in one second/FVC (FEV1/FVC), peak expiratory flow (PEF), and maximum mid-expiratory flow (MMEF) in the observation group were significantly lower than these in the control group (P < 0.05). The tumor necrosis factor-alpha (TNF-α), interleukin-5 (IL-5), IL-6, and IL-33 in the observation group were markedly higher than these in the control group (P < 0.05). As the state of an illness worsened, the Rac1 mRNA levels, FVC, FEV1/FVC, PEF, and MMEF gradually reduced (P < 0.05), while the levels of TNF-α, IL-5, IL-6, and IL-33 increased (P < 0.05). As the degree of disease control improved, the Rac1 mRNA levels, FVC, FEV1/FVC, PEF, and MMEF gradually elevated (P < 0.05), and the levels of TNF- α, IL-5, IL-6, and IL-33 showed the opposite trend (P < 0.05). Rac1 was negatively related to the levels of TNF-α, IL-5, IL-6 and IL-33 (P < 0.05), and positively to the levels of FVC, FEV1/FVC, PEF and MMEF (P < 0.001). Rac1 mRNA levels, FVC, FEV1/FVC, PEF and MMEF were protective factors, while TNF-α, IL-5, IL-6 and IL-33 were risk factors for the prognosis of children with asthma (P < 0.05). CONCLUSION: Children with asthma have obviously lower serum Rac1 mRNA levels, higher inflammatory factor levels and lower lung function. Serum Rac1 mRNA level may be associated with better asthma control, lower airway inflammatory response, better lung function and lower disease severity. It has important reference value for the evaluation of the state of an illness, efficacy and prognosis of children with bronchial asthma.

Asunto(s)

Asma , Proteína de Unión al GTP rac1 , Humanos , Asma/fisiopatología , Asma/genética , Asma/sangre , Proteína de Unión al GTP rac1/metabolismo , Proteína de Unión al GTP rac1/genética , Femenino , Masculino , Niño , Estudios Retrospectivos , Capacidad Vital , Volumen Espiratorio Forzado , Pulmón/fisiopatología , Pruebas de Función Respiratoria , Factor de Necrosis Tumoral alfa/sangre , Estudios de Casos y Controles , Interleucina-33/sangre , Interleucina-33/genética , Preescolar , Interleucina-6/sangre , Adolescente , Índice de Severidad de la Enfermedad , Interleucina-5/sangre , ARN Mensajero/metabolismo

RESUMEN

Anti-tumor necrosis factor alpha (anti-TNF-α) comprises a group of drugs that inhibit the action of cytokine TNF-α, and are used to treat diseases mainly caused by this cytokine. An increase in cutaneous adverse events has been observed with similar anti-TNF biologic treatments frequently used in clinical practice.

Asunto(s)

Adalimumab , Esclerodermia Localizada , Factor de Necrosis Tumoral alfa , Humanos , Adalimumab/efectos adversos , Adalimumab/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Esclerodermia Localizada/inducido químicamente , Fibrosis/inducido químicamente , Antiinflamatorios/efectos adversos , Antiinflamatorios/uso terapéutico

RESUMEN

BACKGROUND: Major depressive disorder (MDD) is characterized by hippocampal volume reduction, impacting cognitive function. Inflammation, particularly elevated tumor necrosis factor-alpha (TNF-α) levels, is consistently implicated in MDD pathophysiology. This study investigates the relationships between TNF-α levels, hippocampal volume, beta-amyloid (Aß) burden, and cognitive abilities in MDD patients, aiming to illuminate the complex interplay among inflammatory markers, pathology indicators, structural brain alterations, and cognitive performance in non-demented MDD individuals. METHOD: Fifty-two non-demented MDD patients, comprising 25 with mild cognitive impairment (MCI), were recruited along with 10 control subjects. Each participant underwent a thorough assessment encompassing TNF-α blood testing, 18F-florbetapir positron emission tomography, magnetic resonance imaging scans, and neuropsychological testing. Statistical analyses, adjusted for age and education, were performed to investigate the associations between TNF-α levels, adjusted hippocampal volume (HVa), global Aß burden, and cognitive performance. RESULTS: MCI MDD patients displayed elevated TNF-α levels and reduced HVa relative to controls. Correlation analyses demonstrated inverse relationships between TNF-α level and HVa in MCI MDD, all MDD, and all subjects groups. Both TNF-α level and HVa exhibited significant correlations with processing speed across all MDD and all subjects. Notably, global 18F-florbetapir standardized uptake value ratio did not exhibit significant correlations with TNF-α level, HVa, and cognitive measures. CONCLUSION: This study highlights elevated TNF-α levels and reduced hippocampal volume in MCI MDD patients, indicating a potential association between peripheral inflammation and structural brain alterations in depression. Furthermore, our results suggest that certain cases of MDD may be affected by non-amyloid-mediated process, which impacts their TNF-α and hippocampal volume. These findings emphasize the importance of further investigating the complex interplay among inflammation, neurodegeneration, and cognitive function in MDD.

Asunto(s)

Péptidos beta-Amiloides , Atrofia , Disfunción Cognitiva , Trastorno Depresivo Mayor , Hipocampo , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Factor de Necrosis Tumoral alfa , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/patología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Hipocampo/metabolismo , Masculino , Femenino , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/sangre , Anciano , Péptidos beta-Amiloides/metabolismo , Atrofia/patología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/diagnóstico por imagen , Persona de Mediana Edad , Pruebas Neuropsicológicas , Compuestos de Anilina , Glicoles de Etileno

RESUMEN

OBJECTIVE: Environmental factors such as noise and music can significantly impact physiological responses, including inflammation. This study explored how environmental factors like noise and music affect lipopolysaccharide (LPS)-induced inflammation, with a focus on systemic and organ-specific responses. MATERIALS AND METHODS: 24 Wistar rats were divided into four groups (n = 6 per group): Control group, LPS group, noise-exposed group, and music-exposed group. All rats, except for the Control group, received 10 mg/kg LPS intraperitoneally. The rats in the noise-exposed group were exposed to 95 dB noise, and the music-exposed group listened to Mozart's K. 448 music (65-75 dB) for 1 h daily over 7 days. An enzyme-linked immunosorbent assay was utilized to detect the levels of inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), in serum and tissues (lung, liver, and kidney). Western blot examined the phosphorylation levels of nuclear factor-κB (NF-κB) p65 in organ tissues. RESULTS: Compared with the Control group, LPS-induced sepsis rats displayed a significant increase in the levels of TNF-α and IL-1ß in serum, lung, liver, and kidney tissues, as well as a remarkable elevation in the p-NF-κB p65 protein expression in lung, liver, and kidney tissues. Noise exposure further amplified these inflammatory markers, while music exposure reduced them in LPS-induced sepsis rats. CONCLUSION: Noise exposure exacerbates inflammation by activating the NF-κB pathway, leading to the up-regulation of inflammatory markers during sepsis. On the contrary, music exposure inhibits NF-κB signaling, indicating a potential therapeutic effect in reducing inflammation.

Asunto(s)

Lipopolisacáridos , Música , Ruido , Ratas Wistar , Sepsis , Animales , Lipopolisacáridos/toxicidad , Sepsis/inmunología , Sepsis/complicaciones , Ruido/efectos adversos , Masculino , Interleucina-1beta/sangre , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Inflamación , Hígado/metabolismo , Ratas , Riñón/metabolismo , FN-kappa B/metabolismo , Citocinas/sangre , Citocinas/metabolismo

RESUMEN

OBJECTIVE: The chronic pain syndromes (CPS) include syndromes such as chronic widespread pain (CWP), dry eye disease (DED) and irritable bowel syndrome (IBS). Highly prevalent and lacking pathognomonic biomarkers, the CPS are known to cluster in individuals in part due to their genetic overlap, but patient diagnosis can be difficult. The success of quantitative sensory testing (QST) and inflammatory biomarkers as phenotyping tools in conditions such as painful neuropathies warrant their investigation in CPS. We aimed to examine whether individual QST modalities and candidate inflammatory markers were associated with CWP, DED or IBS in a large, highly phenotyped population sample. DESIGN: Cross-sectional study. SETTING: Community-dwelling cohort. PARTICIPANTS: Twins from the TwinsUK cohort PRIMARY AND SECONDARY OUTCOME MEASURES: We compared 10 QST modalities, measured in participants with and without a CWP diagnosis between 2007 and 2012. We investigated whether inflammatory markers measured by Olink were associated with CWP, including interleukin-6 (IL-6), IL-8, IL-10, monocyte chemoattractant protein-1 and tumour necrosis factor. All analyses were repeated in DED and IBS with correction for multiple testing. RESULTS: In N=3022 twins (95.8% women), no association was identified between individual QST modalities and CPS diagnoses (CWP, DED and IBS). Analyses of candidate inflammatory marker levels and CPS diagnoses in n=1368 twins also failed to meet statistical significance. CONCLUSION: Our findings in a large population cohort suggest a lack of true association between singular QST modalities or candidate inflammatory markers and CPS.

Asunto(s)

Dolor Crónico , Síndromes de Ojo Seco , Síndrome del Colon Irritable , Humanos , Estudios Transversales , Masculino , Femenino , Dolor Crónico/diagnóstico , Persona de Mediana Edad , Síndrome del Colon Irritable/diagnóstico , Adulto , Síndromes de Ojo Seco/diagnóstico , Anciano , Biomarcadores/sangre , Interleucina-6/sangre , Interleucina-8/sangre , Factor de Necrosis Tumoral alfa/sangre , Quimiocina CCL2/sangre , Reino Unido/epidemiología , Interleucina-10/sangre , Dimensión del Dolor/métodos

RESUMEN

BACKGROUND AND OBJECTIVES: Emerging research suggests that hyperammonemia may enhance the probability of hepatic encephalopathy (HE), a condition associated with elevated levels of circulating ammonia in patients with cirrhosis. However, some studies indicate that blood ammonia levels may not consistently correlate with the severity of HE, highlighting the complex pathophysiology of this condition. METHODS: A systematic review and meta-analysis through PubMed, Scopus, Embase, Web of Science, and Virtual Health Library were conducted to address this complexity, analyzing and comparing published data on various laboratory parameters, including circulating ammonia, blood creatinine, albumin, sodium, and inflammation markers in cirrhotic patients, both with and without HE. RESULTS: This comprehensive review, which included 81 studies from five reputable databases until June 2024, revealed a significant increase in circulating ammonia levels in cirrhotic patients with HE, particularly those with overt HE. Notably, significant alterations were observed in the circulating creatinine, albumin, sodium, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα) in HE patients. CONCLUSIONS: These findings suggest an association between ammonia and HE and underscore the importance of considering other blood parameters such as creatinine, albumin, sodium, and pro-inflammatory cytokines when devising new treatment strategies for HE.

Asunto(s)

Amoníaco , Encefalopatía Hepática , Cirrosis Hepática , Encefalopatía Hepática/sangre , Humanos , Amoníaco/sangre , Cirrosis Hepática/sangre , Cirrosis Hepática/complicaciones , Biomarcadores/sangre , Creatinina/sangre , Interleucina-6/sangre , Factor de Necrosis Tumoral alfa/sangre , Sodio/sangre , Hiperamonemia/sangre , Albúmina Sérica/análisis