RESUMEN
Aortic dissection (AD), caused by tearing of the intima and avulsion of the aortic media, is a severe threat to patient life and organ function. Iron is closely related to dissection formation and organ injury, but the mechanism of iron ion transport disorder in endothelial cells (ECs) remains unclear. We identified the characteristic EC of dissection with iron overload by single-cell RNA sequencing data. After intersecting iron homeostasis and differentially expressed genes, it was found that hypoxia-inducible factor-1α (HIF-1α) and divalent metal transporter 1 (DMT1) are key genes for iron ion disorder. Subsequently, IL-6R was identified as an essential reason for the JAK-STAT activation, a classical iron regulation pathway, through further intersection and validation. In in vivo and in vitro, both high IL-6 receptor expression and elevated IL-6 levels promote JAK1-STAT3 phosphorylation, leading to increased HIF-1α protein levels. Elevated HIF-1α binds explicitly to the 5'-UTR sequence of the DMT1 gene and transcriptionally promotes DMT1 expression, thereby increasing Fe2+ accumulation and endoplasmic reticulum stress (ERS). Blocking IL-6R and free iron with deferoxamine and tocilizumab significantly prolonged survival and reduced aortic and organ damage in dissection mice. A comparison of perioperative data between AD patients and others revealed that high free iron, IL-6, and ERS levels are characteristics of AD patients and are correlated with prognosis. In conclusion, activated IL-6/JAK1/STAT3 signaling axis up-regulates DMT1 expression by increasing HIF-1α, thereby increasing intracellular Fe2+ accumulation and tissue injury, which suggests a potential therapeutic target for AD.
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Disección Aórtica , Proteínas de Transporte de Catión , Células Endoteliales , Interleucina-6 , Sobrecarga de Hierro , Transducción de Señal , Animales , Interleucina-6/metabolismo , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Ratones , Células Endoteliales/metabolismo , Humanos , Disección Aórtica/metabolismo , Sobrecarga de Hierro/metabolismo , Masculino , Ratones Endogámicos C57BL , Factor de Transcripción STAT3/metabolismo , Regulación hacia Arriba , Hierro/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genéticaRESUMEN
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/metabolismoRESUMEN
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.
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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/metabolismoRESUMEN
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 EnfermedadRESUMEN
OBJECTIVE: To investigate the protective effects of an anti-inflammatory mixture on acute lung injury (ALI) induced by sepsis in rats, as well as its possible mechanisms. METHODS: A total of 40 Sprague-Dawley (SD) rats were randomly divided into the sham group, septic ALI model group (model group), 3-methyladenine (3-MA) control group, and anti-inflammatory mixture pretreatment group, with 10 rats in each group. Cecal ligation and perforation (CLP) was performed to reproduce a septic ALI model. The rats in the sham group only underwent opening and closing the abdomen without perforation and ligation. Both groups were given saline gavage and intraperitoneal injection for 3 consecutive days before surgery. The 3-MA control group was given intraperitoneal injection of saline and autophagy inhibitor 3-MA 15 mg/kg for 3 consecutive days before modeling. The anti-inflammatory mixture pretreatment group was given 8.8 mL/kg of anti-inflammatory mixture by gavage [the composition of anti-inflammatory mixture: rhubarb 15 g (after the next), coptis chinensis 15 g, baical skullcap root 12 g, magnoliae cortex 12 g, dahurian patrinia herb 30 g] and saline intraperitoneal injection for 3 consecutive days before modeling. The rats in each group were anesthetized 24 hours after surgery and died due to abdominal aortic blood collection. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of serum inflammatory cytokines interleukins (IL-1ß and IL-6). Lung tissue was taken and then the bronchoalveolar lavage fluid (BALF) was collected, and the levels of IL-1ß and IL-6 were detected by ELISA. Lung wet/dry weight (W/D) ratio was measured. After hematoxylin-eosin (HE) staining, the histopathological changes of the lungs were observed under light microscopy. Western blotting was used to detect the expression of autophagy markers microtubule-associated protein 1 light chain 3- II/I (LC3- II/I) and Beclin-1 protein in lung tissue. Autophagosomes in lung tissue were observed with transmission electron microscopy. RESULTS: Compared with the sham group, the rats in the model group exhibited severe destruction of lung tissue structure, with significant infiltration of inflammatory cells, the lung W/D ratio and the levels of IL-1ß and IL-6 in serum and BALF were significantly increased, the expressions of LC3- II/I and Beclin-1 protein were down-regulated, the autophagosomes were more. The rats in the 3-MA control group exhibited more severe lung tissue injury as compared with the model group, the lung W/D ratio and the levels of inflammatory cytokines in serum and BALF were further increased, the expressions of LC3- II/I and Beclin-1 protein still showed a decrease tendency as compared with the sham group, and the autophagosomes were less than that in the model group. Compared with the model group, the anti-inflammatory mixture pretreatment group showed milder lung tissue injury with a minimal amount of inflammatory cell infiltration, the lung W/D ratio was significantly reduced (7.07±1.02 vs. 11.33±1.85, P < 0.05), the levels of IL-1ß and IL-6 in both serum and BALF were significantly decreased [IL-1ß (ng/L): 26.04±3.86 vs. 40.83±5.46 in serum, 17.75±2.02 vs. 26.86±4.32 in BALF; IL-6 (ng/L): 91.28±10.15 vs. 129.44±13.05 in serum, 76.06±7.51 vs. 120.91±7.47 in BALF, all P < 0.05], and the ratio of LC3- II/I and Beclin-1 protein expression were significantly increased [LC3- II/I ratio: 1.23±0.02 vs. 0.60±0.02, Beclin-1 protein (Beclin-1/GAPDH): 2.37±0.33 vs. 0.62±0.05, both P < 0.05]. Furthermore, an increase in the number of autophagosomes was observed. CONCLUSIONS: The anti-inflammatory mixture improves lung injury in rats with sepsis induced by CLP and reduce inflammation levels, potentially through upregulation of Beclin-1-mediated autophagy.
Asunto(s)
Lesión Pulmonar Aguda , Autofagia , Beclina-1 , Ratas Sprague-Dawley , Sepsis , Animales , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/metabolismo , Ratas , Sepsis/complicaciones , Sepsis/metabolismo , Sepsis/tratamiento farmacológico , Autofagia/efectos de los fármacos , Masculino , Beclina-1/metabolismo , Antiinflamatorios/farmacología , Proteínas Reguladoras de la Apoptosis/metabolismo , Interleucina-1beta/metabolismo , Pulmón/patología , Pulmón/metabolismo , Interleucina-6/metabolismo , Modelos Animales de EnfermedadRESUMEN
Objective: To observe the effects of targeting and blocking cannabinoid receptor 1 (CB1R) on mouse spleen immune function and inflammatory response under chronic intermittent hypoxia (CIH) conditions, and to explore its regulatory effort. Methods: Forty SPF male C57BL/6 mice aged 4 to 5 weeks,from May 2021 to August 2021 in Experimental Animal Center of the Second Hospital of Shanxi Medical University, were randomly divided into normal oxygen control group (NC), 6-week CIH group (6w CIH), 10-week CIH group (10w CIH), 6-week CIH+CB1R group (6w CIH+AM251) and 10-week CIH+CB1R group (10w CIH+AM251) according to the method of random number table. The advanced programmable intermittent low oxygen chamber was used to prepare the CIH mouse model. The morphological structure of spleen tissue of CIH mice was stained by hematoxylin-eosin (HE) staining. The expression levels of M1 and M2 macrophage surface markers CD86, CD206 were determined by immunofluorescence. The mRNA expression levels of CB1R, CD86, CD206 and the relative expression levels of RORγt and Foxp3,which are characteristic transcriptional regulators of T helper 17(Th17) and Treg cells were detected by quantitative reverse transcriptase PCR(qRT-PCR). The expression of inflammatory factors IL-6 and IL-10 was determined by ELISA. SPSS 26.0 and Graphpad prism 8.3 were used to analyze the data. Results: (1) Compared with NC group, spleen tissue structure was disordered, fibrous tissue hyperplasia, lymphocyte proliferation and disordered arrangement in periarteriole lymphatic sheath in CIH group. The expression of CB1R in CIH group was higher than that in NC group (P<0.05), and with the prolongation of CIH time, the expression of 10w CIH group was higher than that in 6w CIH group(P<0.05). The expression of CB1R in CIH+AM251 group was lower than that in the corresponding CIH group(all P<0.05). (2) Compared with NC group, the expression level of CD86 in macrophages in CIH group was higher than that in NC group(all P<0.05). The relative expression of RORγt in 6w and 10w CIH groups was 0.76±0.03 and 0.91±0.04, respectively, which was higher than that in NC group (0.65±0.06)(all P<0.05). The relative expression levels of inflammatory factor IL-6 were 10.80±1.73 and 14.86±0.01, respectively, which were higher than 6.69±0.23 in the NC group (all P<0.05). The expression level of CD206 in macrophages in the CIH+AM251 group was higher than that in the CIH group(all P<0.05). The relative expression levels of Foxp3 in 6w and 10w CIH+AM251 groups were 0.62±0.05 and 0.32±0.21, respectively, which were higher than those in 6w CIH group (0.28±0.02) and 10w CIH group (0.02±0.01)(P<0.05). The relative expression levels of anti-inflammatory factor IL-10 were 668.45±15.71 and 379.15±56.84, respectively, which were higher than those in CIH group (all P<0.05). Conclusion: Targeted sealing of CB1R may alleviate inflammatory response of mouse spleen under CIH conditions by regulating macrophage polarization and the expression of inflammatory factors, and may have some protective effect.
Asunto(s)
Hipoxia , Inflamación , Receptor Cannabinoide CB1 , Bazo , Animales , Masculino , Ratones , Modelos Animales de Enfermedad , Hipoxia/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Ratones Endogámicos C57BL , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/metabolismo , Bazo/metabolismo , Linfocitos T Reguladores/inmunologíaRESUMEN
Obesity has emerged as a worldwide health concern due to its increasing prevalence. Adipocytes have the ability to express angiotensin-converting enzyme 2 receptors (ACE2) and several adipocytokines. These expressions could lead to the activation of a cytokine storm, which in turn promotes the development of cardiovascular diseases. The aim of this study was to investigate the impact of perindopril and losartan exposure on the ACE2 and interleukin 6 (IL-6) levels in adipocyte cells. This study used an in vivo true experimental design utilizing a post-test-only control group. A total of 24 adult male albino rats were divided into four groups, one group served as the non-obese (negative control), while the other three groups were obese: (1) the positive control (untreated obese rats); (2) perindopril group (2 mg/kg BW/day orally for 4 weeks); and (3) losartan group (20 mg/kg BW/day for 4 weeks). Afterwards, the rats were euthanized, and the visceral fat tissue were obtained during dissection. The levels of ACE2 and IL-6 were measured using the enzyme-linked immunosorbent assay (ELISA). Losartan administration in obese rats resulted in a notable elevation in ACE2 levels compared to both the perindopril group (losartan vs perindopril, p=0.011) and the positive control (p=0.004). In addition, the treatment of perindopril and losartan in obese rats resulted in a significant reduction in IL-6 levels when compared to the positive control (perindopril vs positive control, p=0.020; losartan vs positive control, p=0.002, respectively). This study provides insight into the administration of perindopril and losartan, which could suppress the pro-inflammatory (IL-6) but increase the ACE2 levels in adipose tissue.
Asunto(s)
Enzima Convertidora de Angiotensina 2 , Modelos Animales de Enfermedad , Interleucina-6 , Losartán , Obesidad , Perindopril , Animales , Losartán/farmacología , Perindopril/farmacología , Perindopril/uso terapéutico , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Ratas , Interleucina-6/metabolismo , Masculino , Enzima Convertidora de Angiotensina 2/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismoRESUMEN
BACKGROUND: Currently, creating more effector T cells and augmenting their functions is a focal point in pancreatic ductal adenocarcinoma (PDAC) treatment research. T cell immunoglobulin domain and mucin domain molecule 4 (TIM-4), known for promoting cancer progression in various malignancies, is implicated in the suppressive immune microenvironment of tumors. Analyzing of the role of TIM-4 in the immune regulation of PDAC can offer novel insights for immune therapy. METHODS: We analyzed the TIM-4 expression in tumor specimens from PDAC patients. Meanwhile, multiple fluorescent immunohistochemical staining was used to study the distribution characteristics of TIM-4, and through tissue microarrays, we explored its correlation with patient prognosis. The influence of TIM-4 overexpression on cell function was analyzed using RNA-seq. Flow cytometry and ELISA were used for verification. Finally, the relationship between TIM-4 and T lymphocytes was analyzed by tissue microarray, and the impacts of TIM-4 on T cell subsets were observed by cell coculture technology and a mouse pancreatic cancer in situ model. RESULTS: In PDAC, TIM-4 is mainly expressed in tumor cells and negatively correlated with patient prognosis. TIM-4 influences the differentiation of Treg by inhibiting IL-6 secretion in pancreatic cancer cells and facilitates the proliferation of pancreatic cancer in mice. Additionally, the mechanism may be through the CD8+ effector T cells (CD8+Tc). CONCLUSION: TIM-4 has the potential to be an immunotherapeutic target or to improve the efficacy of chemotherapy for PDAC.
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Carcinoma Ductal Pancreático , Factores de Transcripción Forkhead , Interleucina-6 , Neoplasias Pancreáticas , Linfocitos T Reguladores , Microambiente Tumoral , Humanos , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Microambiente Tumoral/inmunología , Interleucina-6/metabolismo , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Ratones , Factores de Transcripción Forkhead/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Línea Celular Tumoral , Pronóstico , Femenino , Masculino , Proliferación Celular , Proteínas de la MembranaRESUMEN
BACKGROUND: The AGEs levels in tissues of diabetics and elderly tend to be higher than in normal individuals. This study aims to determine the effects of AGEs on Achilles tendon repair. MATERIALS AND METHODS: Thirty-six male eight-week-old Sprague Dawley rats were selected in this study. The rats were randomly divided into two experimental groups and a control group after the transection of the Achilles tendon. During the tendon repair, the experimental groups were injected around the Achilles tendon with 350mmol/L (low dose group) and 1000mmol/L (high dose group) D-ribose 0.2 ml respectively to increase the AGEs level, while in the control group were given the same amount of PBS. The injections were given twice a week for six weeks. Collagen-I, TNF-α, and IL-6 expression in the healed Achilles tendon was assessed. Additionally, macroscopic, pathological, and biomechanical evaluations of Achilles tendon repair were conducted. RESULTS: The repaired Achilles tendons in the high dose group showed severe swelling and distinctive adhesions. The histological score went up with the increase of the AGEs in the Achilles tendon (p<0.001). TNF- α and IL-6 in the Achilles tendon increased (p<0.001, p<0.001), and the production of collagen-I decreased with the accumulation of AGEs in the repaired Achilles tendon (p<0.001). The tensile strength of Achilles tendon in the high dose group was impaired significantly. CONCLUSION: In current study, the compromised tendon repair model induced by AGEs was successfully established in rat. The study demonstrated that AGEs significantly impair Achilles tendon repair.
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Tendón Calcáneo , Productos Finales de Glicación Avanzada , Ratas Sprague-Dawley , Traumatismos de los Tendones , Cicatrización de Heridas , Animales , Masculino , Tendón Calcáneo/lesiones , Tendón Calcáneo/patología , Tendón Calcáneo/metabolismo , Tendón Calcáneo/cirugía , Tendón Calcáneo/efectos de los fármacos , Productos Finales de Glicación Avanzada/metabolismo , Traumatismos de los Tendones/metabolismo , Traumatismos de los Tendones/patología , Traumatismos de los Tendones/fisiopatología , Ratas , Cicatrización de Heridas/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Colágeno Tipo I/metabolismo , Interleucina-6/metabolismo , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Mineralocorticoid receptor (MR) induces cardiac inflammation cooperatively with nuclear factor-κB and signal transducer and activator of transcription 3 (STAT3); MR blockers exert anti-inflammatory effects. However, the underlying mechanism remains unclear. We investigated the anti-inflammatory effect of esaxerenone, a novel MR blocker, in experimental myocardial infarction (MI) and its underlying mechanisms. METHODS AND RESULTS: Male C57BL/6J mice subjected to ligation of the left anterior descending artery were randomly assigned to either the vehicle or esaxerenone group. Esaxerenone was provided with a regular chow diet. The mice were euthanized at either 4 or 15 days after MI. Cardiac function, fibrosis, and inflammation were evaluated. Esaxerenone significantly improved cardiac function and attenuated cardiac fibrosis at 15 days after MI independently of its antihypertensive effect. Inflammatory cell infiltration, inflammatory-related gene expression, and elevated serum interleukin-6 levels at 4 days after MI were significantly attenuated by esaxerenone. In vitro experiments using mouse macrophage-like cell line RAW264.7 cells demonstrated that esaxerenone- and spironolactone-attenuated lipopolysaccharide-induced interleukin-6 expression without altering the posttranslational modification and nuclear translocation of p65 and STAT3. Immunoprecipitation assays revealed that MR interacted with both p65 and STAT3 and enhanced the p65-STAT3 interaction, leading to a subsequent increase in interleukin-6 promoter activity, which was reversed by esaxerenone. CONCLUSIONS: Esaxerenone ameliorated postinfarct remodeling in experimental MI through its anti-inflammatory properties exerted by modulating the transcriptional activity of the MR-p65-STAT3 complex. These results suggest that the MR-p65-STAT3 complex can be a novel therapeutic target for treating MI.
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Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Antagonistas de Receptores de Mineralocorticoides , Infarto del Miocardio , Receptores de Mineralocorticoides , Factor de Transcripción STAT3 , Sulfonas , Factor de Transcripción ReIA , Animales , Factor de Transcripción STAT3/metabolismo , Masculino , Receptores de Mineralocorticoides/metabolismo , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/genética , Antagonistas de Receptores de Mineralocorticoides/farmacología , Ratones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/prevención & control , Infarto del Miocardio/genética , Factor de Transcripción ReIA/metabolismo , Células RAW 264.7 , Sulfonas/farmacología , Transducción de Señal/efectos de los fármacos , Fibrosis , Transcripción Genética/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Antiinflamatorios/farmacología , Interleucina-6/metabolismo , Interleucina-6/genética , PirrolesRESUMEN
Heyndrickxia coagulans (formerly Bacillus coagulans) has been increasingly utilized as an immunomodulatory probiotics. Oral administration of H. coagulans HOM5301 significantly boosted both innate and adaptive immunity in mice, particularly by increasing the phagocytic capacity of monocytes/macrophages. Lipoteichoic acid (LTA), a major microbe-associated molecular pattern (MAMP) in Gram-positive bacteria, exhibits differential immunomodulatory effects due to its structural heterogeneity. We extracted, purified, and characterized LTA from H. coagulans HOM5301. The results showed that HOM5301 LTA consists of a glycerophosphate backbone. Its molecular weight is in the range of 10-16 kDa. HOM5301 LTA induced greater productions of nitric oxide, TNFα, and IL-6 in RAW 264.7 macrophages compared to Staphylococcus aureus LTA. Comparative transcriptome and proteome analyses identified the differentially expressed genes and proteins triggered by HOM5301 LTA. KEGG analyses revealed that HOM5301 LTA transcriptionally and translationally activated macrophages through two immune-related pathways: cytokine-cytokine receptor interaction and phagosome formation. Protein-protein interaction network analysis indicated that the pro-inflammatory response elicited by HOM5301 LTA was TLR2-dependent, possibly requiring the coreceptor CD14, and is mediated via the MAPK and NF-kappaB pathways. Our results demonstrate that LTA is an important MAMP of H. coagulans HOM5301 that boosts immune responses, suggesting that HOM5301 LTA may be a promising immunoadjuvant.
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Lipopolisacáridos , Macrófagos , Ácidos Teicoicos , Animales , Ácidos Teicoicos/farmacología , Ratones , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Células RAW 264.7 , Bacillus , Receptor Toll-Like 2/metabolismo , Óxido Nítrico/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Probióticos/farmacologíaRESUMEN
OBJECTIVE: To investigate the mechanism of sanguinarine (SA) for alleviating ulcerative colitis (UC) induced by dextran sodium sulfate (DSS) in mice. METHODS: Male C57BL/6 mouse models of 3.5% DSS-induced UC were randomized for treatment with 1, 5 and 10 mg/kg SA by gavage, 400 mg/kg sulfasalazine by gavage, or 10 mg/kg SA combined with intraperitoneal injection of 30 mg/kg ML385 (a Nrf2 inhibitor). The changes in intestinal inflammation was assessed by monitoring weight changes, disease activity index (DAI) score, colon length measurement, and HE staining. After the treatments, the colon tissues were collected for detection of malondialdehyde (MDA) content using colorimetry, mRNA expressions of inflammatory factors using RT-qPCR, and the expressions of Nrf2, HO-1, Keap-1, p-p65, p65, occludin, and ZO-1 proteins were detected using Western blotting. RESULTS: SA treatment obviously alleviated weight loss, colon length shortening and DAI score increase and ameliorated structural destruction of the colon glands and colonic crypts in mice with DSSinduced UC. SA intervention significantly decreased the levels of TNF-α, IL-1ß and IL-6 mRNA and lowered ROS and MDA levels in the colon tissue of UC mice. The mouse models receiving SA treatment showed significantly increased expressions of Nrf2, HO-1, occludin and ZO-1 and lowered expressions of Keap-1 and P-P65 in the colon tissue without significant changes of p65 expression, and these changes were SA dose-dependent. Treatment with ML385 obviously attenuated the effect of highdose SA for improving UC in the mouse models. CONCLUSION: SA can improve UC-like enteritis in mice possibly by activating the Nrf2 pathway and inhibiting the NF-κB pathway in the colon tissue.
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Colitis Ulcerosa , Sulfato de Dextran , Modelos Animales de Enfermedad , Isoquinolinas , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2 , FN-kappa B , Transducción de Señal , Animales , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Masculino , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Colon/metabolismo , Colon/patología , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Ocludina/metabolismo , Malondialdehído/metabolismo , Interleucina-1beta/metabolismo , BenzofenantridinasRESUMEN
OBJECTIVE: To explore the mechanism underlying the protective effect of Lonicerae japonicae flos (LJF) extract against doxorubicin (DOX) -induced liver injury in mice. METHODS: Network pharmacology methods were used to obtain the intersection genes between LJF targets and disease targets, based on which the protein-protein interaction (PPI) network was constructed using STRING database for screening the core targets using Cytoscape software. DAVID database was used for bioinformatics analysis, and the core components and core targets were verified using molecular docking study. In a mouse model of DOX-induced liver injury, the effect of LJF extract on liver pathologies, serum levels of ALT and AST, and hepatic expressions of HYP, ROS, TNF-α, IL-6, COL-â £ and P53 proteins were evaluated using HE and Masson staining, ELISA, and Western blotting. RESULTS: We identified 12 core targets from 43 intersection genes involving cancer pathway, IL-17 signaling pathway, and TNF signaling pathways. Molecular docking study suggested that 10 core components of LJF could bind to different core targets. The mice with DOX-induced liver injury showed elevated serum AST and ALT levels with obvious liver injury and fibrosis, increased ROS content, and enhanced expressions of TNF-α, IL-6, HYP, COL-â £ and P53 proteins in the liver tissue. All these changes in the mouse models were significantly alleviated by treatment with LJF extract, suggesting obviously lowered levels of oxidative stress, inflammation and fibrosis in the liver tissues. CONCLUSION: LJF extract is capable of alleviating DOX-induced liver injury in mice by downregulating Trp53, TNF and IL-6 to reduce liver oxidative stress, inflammation and fibrosis.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Doxorrubicina , Interleucina-6 , Lonicera , Simulación del Acoplamiento Molecular , Factor de Necrosis Tumoral alfa , Animales , Doxorrubicina/efectos adversos , Ratones , Lonicera/química , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Extractos Vegetales/farmacología , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Proteína p53 Supresora de Tumor/metabolismo , Sustancias Protectoras/farmacología , Mapas de Interacción de Proteínas , Transducción de Señal/efectos de los fármacos , Farmacología en RedRESUMEN
OBJECTIVE: To investigate the therapeutic mechanism of Tujia medicine Toddalia asiatica alcohol extract (TAAE) for synovial pannus formation in rats with college-induced arthritis (CIA). METHODS: Sixty male SD rats were randomized into normal control group, CIA model group, TGT group, 3 TAAE treatment groups at low, medium and high doses (n=10). Except for those in the normal control group, all the rats were subjected to CIA modeling using a secondary immunization method and treatment with saline, TGT or TAAE by gavage once daily for 35 days. The severity of arthritis was assessed using arthritis index (AI) score, and knee joint synovium pathologies were examined with HE staining. Serum levels of TNF-α, IL-6, and IL-1ß were detected with ELISA; the protein expressions of PI3K, Akt, p-PI3K, p-Akt, VEGF, endostatin, HIF-1α, MMP1, MMP3, and MMP9 in knee joint synovial tissues were determined using Western blotting, and the mRNA expressions of TNFα, IL-6, IL-1ß, VEGF, HIF-1α, PI3K, and Akt were detected with RT-PCR. RESULTS: Treatment of CIA rat models with TAAE and TGT significantly alleviated paw swelling, lowered AI scores, and reduced knee joint pathology, neoangiogenesis, and serum levels of inflammatory factors. TAAE treatment obviously increased endostatin protein expression, downregulated p-PI3K, p-Akt, MMP1, MMP3, MMP9, VEGF, and HIF-1α proteins, and reduced TNFα, IL-6, IL-1ß, PI3K, Akt, VEGF, and HIF-1α mRNA levels in the synovial tissues, and these changes were comparable between high-dose TAAE group and TGT group. CONCLUSION: TAAE can improve joint symptoms and inhibit synovial pannus formation in CIA rats by regulating the expressions of HIF-1α, VEGF, endostatin, MMP1, MMP3, and MMP9 via the PI3K/Akt signalling pathway.
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Artritis Experimental , Subunidad alfa del Factor 1 Inducible por Hipoxia , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Masculino , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Interleucina-6/metabolismo , Interleucina-1beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Endostatinas , Membrana Sinovial/metabolismo , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacologíaRESUMEN
BACKGROUND: Bordetella pertussis is the causative agent of whooping cough or pertussis. Although both acellular (aP) and whole-cell pertussis (wP) vaccines protect against disease, the wP vaccine, which is highly reactogenic, is better at preventing colonization and transmission. Reactogenicity is mainly attributed to the lipid A moiety of B. pertussis lipooligosaccharide (LOS). Within LOS, lipid A acts as a hydrophobic anchor, engaging with TLR4-MD2 on host immune cells to initiate both MyD88-dependent and TRIF-dependent pathways, thereby influencing adaptive immune responses. Lipid A variants, such as monophosphoryl lipid A (MPLA) can also act as adjuvants. Adjuvants may overcome the shortcomings of aP vaccines. RESULTS: This work used lipid A modifying enzymes from other bacteria to produce an MPLA-like adjuvant strain in B. pertussis. We created B. pertussis strains with distinct lipid A modifications, which were validated using MALDI-TOF. We engineered a hexa-acylated monophosphorylated lipid A that markedly decreased human TLR4 activation and activated the TRIF pathway. The modified lipooligosaccharide (LOS) promoted IRF3 phosphorylation and type I interferon production, similar to MPLA responses. We generated three other variants with increased adjuvanticity properties and reduced endotoxicity. Pyrogenicity studies using the Monocyte Activation Test (MAT) revealed that these four lipid A variants significantly decreased the IL-6, a marker for fever, response in peripheral blood mononuclear cells (PBMCs). CONCLUSION: These findings pave the way for developing wP vaccines that are possibly less reactogenic and designing adaptable adjuvants for current vaccine formulations, advancing more effective immunization strategies against pertussis.
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Adyuvantes Inmunológicos , Bordetella pertussis , Lípido A , Receptor Toll-Like 4 , Lípido A/análogos & derivados , Lípido A/inmunología , Bordetella pertussis/inmunología , Humanos , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/inmunología , Adyuvantes Inmunológicos/farmacología , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/inmunología , Vacuna contra la Tos Ferina/inmunología , Lipopolisacáridos , Factor 3 Regulador del Interferón/metabolismo , Tos Ferina/prevención & control , Tos Ferina/inmunología , Interleucina-6/metabolismo , Interleucina-6/inmunologíaRESUMEN
Inflammation with expression of interleukin 6 (IL-6) in the central nervous system (CNS) occurs in several neurodegenerative/neuroinflammatory conditions and may cause neurochemical changes to endogenous neuroprotective systems. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are two neuropeptides with well-established protective and anti-inflammatory properties. Yet, whether PACAP and VIP levels are altered in mice with CNS-restricted, astrocyte-targeted production of IL-6 (GFAP-IL6) remains unknown. In this study, PACAP/VIP levels were assessed in the brain of GFAP-IL6 mice. In addition, we utilised bi-genic GFAP-IL6 mice carrying the human sgp130-Fc transgene (termed GFAP-IL6/sgp130Fc mice) to determine whether trans-signalling inhibition rescued PACAP/VIP changes in the CNS. Transcripts and protein levels of PACAP and VIP, as well as their receptors PAC1, VPAC1 and VPAC2, were significantly increased in the cerebrum and cerebellum of GFAP-IL6 mice vs. wild type (WT) littermates. These results were paralleled by a robust activation of the JAK/STAT3, NF-κB and ERK1/2MAPK pathways in GFAP-IL6 mice. In contrast, co-expression of sgp130Fc in GFAP-IL6/sgp130Fc mice reduced VIP expression and activation of STAT3 and NF-κB pathways, but it failed to rescue PACAP, PACAP/VIP receptors and Erk1/2MAPK phosphorylation. We conclude that forced expression of IL-6 in astrocytes induces the activation of the PACAP/VIP neuropeptide system in the brain, which is only partly modulated upon IL-6 trans-signalling inhibition. Increased expression of PACAP/VIP neuropeptides and receptors may represent a homeostatic response of the CNS to an uncontrolled IL-6 synthesis and its neuroinflammatory consequences.
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Encéfalo , Interleucina-6 , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Transducción de Señal , Péptido Intestinal Vasoactivo , Animales , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/genética , Interleucina-6/metabolismo , Interleucina-6/genética , Ratones , Péptido Intestinal Vasoactivo/metabolismo , Péptido Intestinal Vasoactivo/genética , Encéfalo/metabolismo , Astrocitos/metabolismo , Humanos , Ratones Transgénicos , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Sistema Nervioso Central/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Masculino , Ratones Endogámicos C57BLRESUMEN
Lipopolysaccharide (LPS) triggers a severe systemic inflammatory reaction in mammals, with the dimerization of TLR4/MD-2 upon LPS stimulation serving as the pivotal mechanism in the transmission of inflammatory signals. Ginsenoside Rh2 (G-Rh2), one of the active constituents of red ginseng, exerts potent anti-inflammatory activity. However, whether G-Rh2 can block the TLR4 dimerization to exert anti-inflammatory effects remains unclear. Here, we first investigated the non-cytotoxic concentration of G-Rh2 on RAW 264.7 cells, and detected the releases of pro-inflammatory cytokines in LPS-treated RAW 264.7 cells, and then uncovered the mechanisms involved in the anti-inflammatory activity of G-Rh2 through flow cytometry, fluorescent membrane localization, Western blotting, co-immunoprecipitation (Co-IP), molecular docking and surface plasmon resonance (SPR) analysis in LPS-stimulated macrophages. Our results show that G-Rh2 stimulation markedly inhibited the secretion of LPS-induced interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Additionally, G-Rh2 blocked the binding of LPS with the membrane of RAW 264.7 cells through direct interaction with TLR4 and MD-2 proteins, leading to the disruption of the dimerization of TLR4 and MD-2, followed by suppression of the TLR4/NF-κB signaling pathway. Our results suggest that G-Rh2 acts as a new inhibitor of TLR4 dimerization and may serve as a promising therapeutic agent against inflammation.
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Ginsenósidos , Lipopolisacáridos , Antígeno 96 de los Linfocitos , Multimerización de Proteína , Receptor Toll-Like 4 , Ginsenósidos/farmacología , Ginsenósidos/química , Animales , Receptor Toll-Like 4/metabolismo , Ratones , Antígeno 96 de los Linfocitos/metabolismo , Antígeno 96 de los Linfocitos/química , Células RAW 264.7 , Multimerización de Proteína/efectos de los fármacos , Unión Proteica , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Antiinflamatorios/farmacología , Antiinflamatorios/química , Simulación del Acoplamiento Molecular , Transducción de Señal/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Platelets play a crucial role in tissue regeneration, and their involvement in liver regeneration is well-established. However, the specific contribution of platelet-derived Transforming Growth Factor Beta 1 (TGFß1) to liver regeneration remains unexplored. This study investigated the role of platelet-derived TGFß1 in initiating liver regeneration following 2/3 liver resection. Using platelet-specific TGFß1 knockout (Plt.TGFß1 KO) mice and wild-type littermates (Plt.TGFß1 WT) as controls, the study assessed circulating levels and hepatic gene expression of TGFß1, Platelet Factor 4 (PF4), and Thrombopoietin (TPO) at early time points post-hepatectomy (post-PHx). Hepatocyte proliferation was quantified through Ki67 staining and PCNA expression in total liver lysates at various intervals, and phosphohistone-H3 (PHH3) staining was employed to mark mitotic cells. Circulating levels of hepatic mitogens, Hepatocyte Growth Factor (HGF), and Interleukin-6 (IL6) were also assessed. Results revealed that platelet-TGFß1 deficiency significantly reduced total plasma TGFß1 levels at 5 h post-PHx in Plt.TGFß1 KO mice compared to controls. While circulating PF4 levels, liver platelet recruitment and activation appeared normal at early time points, Plt.TGFß1 KO mice showed more stable circulating platelet numbers with higher numbers at 48 h post-PHx. Notably, hepatocyte proliferation was significantly reduced in Plt.TGFß1 KO mice. The results show that a lack of TGFß1 in platelets leads to an unbalanced expression of IL6 in the liver and to strongly increased HGF levels 48 h after liver resection, and yet liver regeneration remains reduced. The study identifies platelet-TGFß1 as a regulator of hepatocyte proliferation and platelet homeostasis in the early stages of liver regeneration.
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Plaquetas , Hepatectomía , Regeneración Hepática , Ratones Noqueados , Trombopoyetina , Factor de Crecimiento Transformador beta1 , Animales , Regeneración Hepática/fisiología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Ratones , Plaquetas/metabolismo , Trombopoyetina/metabolismo , Interleucina-6/metabolismo , Interleucina-6/genética , Proliferación Celular , Factor de Crecimiento de Hepatocito/metabolismo , Factor de Crecimiento de Hepatocito/genética , Hígado/metabolismo , Hepatocitos/metabolismo , Masculino , Factor Plaquetario 4/metabolismo , Factor Plaquetario 4/genética , Ratones Endogámicos C57BLRESUMEN
Glioblastoma multiforme (GBM) is one of the most aggressive and deadly forms of brain cancer, which has a very complex tumor microenvironment (TME) promoting tumor growth, immune evasion, and resistance to therapy. The main players within this environment are represented by cytokines such as Interleukin-4, Interleukin-6, and Interleukin-13, along with the costimulatory molecule CD40. The paper draws back the curtain on the complex interactions played out by these molecules in contributing to the formation of a TME within GBM. IL-4 and IL-13 induce an immunosuppressive environment through the polarization of tumor-associated macrophages (TAMs) into a pro-tumoral M2 phenotype. In contrast, IL-6 takes part in the activation of the JAK-STAT3 pathway, enhancing survival and proliferation of tumor cells. In this context, CD40 either induces anti-tumor immunity through APC activation or facilitates tumors by angiogenesis and survival pathways. The synergistic actions of these molecules create feedback loops that keep up the malignancy of GBM and present a big problem for therapy. Knowledge of these interactions opens new ways for the development of multi-targeted therapeutic strategies at the other end. This may result in the interruption of the tumor-supportive environment in GBM, reducing tumor growth and improving patient outcomes by targeting IL-4, IL-6, IL-13, and CD40 simultaneously.
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Neoplasias Encefálicas , Antígenos CD40 , Glioblastoma , Interleucina-13 , Interleucina-4 , Interleucina-6 , Microambiente Tumoral , Humanos , Antígenos CD40/metabolismo , Ensayos Clínicos como Asunto , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismoRESUMEN
Osteoarthritis (OA) is a progressive joint disease characterized by extracellular matrix (ECM) degradation and inflammation, which is involved with pathological microenvironmental alterations induced by damaged chondrocytes. However, current therapies are not effective in alleviating the progression of OA. Isoquercetin is a natural flavonoid glycoside compound that has various pharmacological effects including anticancer, anti-diabetes and blood lipid regulation. Previous evidence suggests that isoquercetin has anti-inflammatory properties in various diseases, but its effect on OA has not been investigated yet. In this study, through western bolt, qRT-PCR and ELISA, it was found that isoquercetin could reduce the increase of ADAMTS5, MMP13, COX-2, iNOS and IL-6 induced by IL-1ß, suggesting that isoquercetin could inhibit the inflammation and ECM degradation of chondrocytes. Through nuclear-plasma separation technique, western blot and immunocytochemistry, it can be found that Nrf2 and NF-κB pathways are activated in this process, and isoquercetin may rely on this process to play its protective role. In vivo, the results of X-ray and SO staining show that intra-articular injection of isoquercetin reduces the degradation of cartilage in the mouse OA model. In conclusion, the present work suggests that isoquercetin may benefit chondrocytes by regulating the Nrf2/NF-κB signaling axis, which supports isoquercetin as a potential drug for the treatment of OA.