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BACKGROUND: Numerous studies indicate that natural polysaccharides have immune-enhancing effects as a host defense potentiator. Few reports are available on hormetic effects of natural polysaccharides, and the underlying mechanisms remain unclear. PURPOSE: AELP-B6 (arabinose- and galactose-rich pectin polysaccharide) from Aralia elata (Miq.) Seem was taken as a case study to clarify the potential mechanism of hormetic effects of natural polysaccharides. METHODS: The pharmacodynamic effect of AELP-B6 was verified by constructing the CTX-immunosuppressive mouse model. The hormetic effects were explored by TMT-labeled proteomics, energy metabolism analysis, flow cytometry and western blot. The core-affinity target of AELP-B6 was determined by pull down, nanoLC-nanoESI+-MS, CETSA, immunoblot and SPR assay. The RAW264.7Clec4G-RFP and RAW264.7Rab1A-RFP cell lines were simultaneously constructed to determine the affinity difference between AELP-B6 and targets by confocal laser scanning live-cell imaging. Antibody blocking assays were further used to verify the mechanism of hormetic effects. RESULTS: AELP-B6 at low and medium doses may maintain the structural integrity of thymus and spleen, increase the concentrations of TNF-α, IFN-γ, IL-3 and IL-8, and alleviate CTX-induced reduction of immune cell viability in vivo. Proteomics and energy metabolism analysis revealed that AELP-B6 regulate HIF-1α-mediated metabolic programming, causing Warburg effects in macrophages. AELP-B6 at low and medium doses promoted the release of intracellular immune factors, and driving M1-like polarization of macrophages. As a contrast, AELP-B6 at high dose enhanced the expression levels of apoptosis related proteins, indicating activation of the intrinsic apoptotic cascade. Two highly expressed transmembrane proteins in macrophages, Clec4G and Rab1A, were identified as the primary binding targets of AELP-B6 which co-localized with the cell membrane and directly impacted with immune cell activation and apoptosis. AELP-B6 exhibits affinity differences with Clec4G and Rab1A, which is the key to the hormetic effects. CONCLUSION: We observed hormesis of natural polysaccharide (AELP-B6) for the first time, and AELP-B6 mediates the hormetic effects through two dose-related targets. Low dose of AELP-B6 targets Clec4G, thereby driving the M1-like polarization via regulating NF-κB signaling pathway and HIF-1α-mediated metabolic programming, whereas high dose of AELP-B6 targets Rab1A, leading to mitochondria-dependent apoptosis.
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Pectinas , Animales , Ratones , Pectinas/farmacología , Lectinas Tipo C/metabolismo , Células RAW 264.7 , Metabolismo Energético/efectos de los fármacos , Polisacáridos/farmacologíaRESUMEN
BACKGROUND: Gallbladder cancer (GBC) poses a significant risk to human health. Its development is influenced by numerous factors, particularly the homeostasis of reactive oxygen species (ROS) within cells. This homeostasis is crucial for tumor cell survival, and abnormal regulation of ROS is associated with the occurrence and progression of many cancers. Dihydrotanshinone I (DHT I), a biologically effective ingredient isolated from Salvia miltiorrhiza, has exhibited cytotoxic properties against various tumor cells by inducing apoptosis. However, the precise molecular mechanisms by which dht I exerts its cytotoxic effects remain unclear. PURPOSE: To explore the anti-tumor impact of dht I on GBC and elucidate the potential molecular mechanisms. METHODS: The proliferation of GBC cells, NOZ and SGC-996, was assessed using various assays, including CCK-8 assay, colony formation assay and EdU staining. We also examined cell apoptosis, cell cycle progression, ROS levels, and alterations in mitochondrial membrane potential to delve into the intricate molecular mechanism. Quantitative PCR (qPCR), immunofluorescence staining, and Western blotting were performed to evaluate target gene expression at both the mRNA and protein levels. The correlation between nuclear factor erythroid 2-related factor 2 (Nrf2) and kelch-like ECH-associated protein 1 (Keap1) were examined using co-immunoprecipitation. Finally, the in vivo effect of dht I was investigated using a xenograft model of gallbladder cancer in mice. RESULTS: Our research findings indicated that dht I exerted cytotoxic effects on GBC cells, including inhibiting proliferation, disrupting mitochondrial membrane potential, inducing oxidative stress and apoptosis. Our in vivo studies substantiated the inhibition of dht I on tumor growth in xenograft nude mice. Mechanistically, dht I primarily targeted Nrf2 by promoting Keap1 mediated Nrf2 degradation and inhibiting protein kinase C (PKC) induced Nrf2 phosphorylation. This leads to the suppression of Nrf2 nuclear translocation and reduction of its target gene expression. Moreover, Nrf2 overexpression effectively counteracted the anti-tumor effects of dht I, while Nrf2 knockdown significantly enhanced the inhibitory effect of dht I on GBC. Meanwhile, PKC inhibitors and nuclear import inhibitors increased the sensitivity of GBC cells to dht I treatment. Conversely, Nrf2 activators, proteasome inhibitors, antioxidants and PKC activators all antagonized dht I induced apoptosis and ROS generation in NOZ and SGC-996 cells. CONCLUSION: Our findings indicated that dht I inhibited the growth of GBC cells by regulating the Keap1-Nrf2 signaling pathway and Nrf2 phosphorylation. These insights provide a strong rationale for further investigation of dht I as a potential therapeutic agent for GBC treatment.
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Apoptosis , Proliferación Celular , Neoplasias de la Vesícula Biliar , Proteína 1 Asociada A ECH Tipo Kelch , Ratones Desnudos , Factor 2 Relacionado con NF-E2 , Fenantrenos , Especies Reactivas de Oxígeno , Transducción de Señal , Animales , Humanos , Ratones , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Furanos/farmacología , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos BALB C , Factor 2 Relacionado con NF-E2/metabolismo , Fenantrenos/farmacología , Fosforilación/efectos de los fármacos , Quinonas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Salvia miltiorrhiza/química , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
ETHNIC PHARMACOLOGICAL RELEVANCE: "Yin-Jing" medicine (YJM) has been widely used by both ancient and modern Chinese medicine practitioners during long-term clinical practice. However, it remains unclear how to best guide other medicines to the targeted organs in a traditional Chinese medicine (TCM) prescription. Here, in an attempt to explain the scientific connotation of the YJM property (YJMP) attributed to a basic TCM theory, Platycodon grandiflorum (PG) was chosen as a case study to reveal the mystery of YJMP theory. AIM OF THE STUDY: The main purpose of this study is to employ modern chemical and molecular biology methods to confirm the "Yin-Jing" effect of PG, and further clarify its material basis and related possible mechanism. MATERIALS AND METHODS: The ammonia-induced lung injury rat model was utilized to determine the optimal dosage of traditional prescription Hui Yan Zhu Yu decoction (HYZYD) using Wright Giemsa staining, HE staining, Masson staining, and TUNEL analysis. With the same way, PG was confirmed to have potentiating therapeutic effect (PTE) by comparison with HYZYD and [HYZYD-PG]. TMT proteomics was used to reveal the "Yin-Jing" mechanism of action. Western blot assay (WB) was employed for verification of differentially expressed proteins. Additionally, four non-crossing fragmentations (Fr. A-D) were characterized by RPLC/SEC-ELSD and HILIC-ESI--Q-OT-IT-MS techniques. The PTE and guidance property assays were utilized to evaluate "Yin-Jing" functions by a compatible combination of hydroxysafflor yellow A (HYA) using qPCR, FCM, WB, HPLC, high content cell imaging (HCI) and high-resolution live-cell imaging (HRLCI) techniques. RESULTS: The HYZYD-M (medium dose group) significantly improved the lung injury level in a pneumonia model of rats. PG enhanced the therapeutic effect of HYZYD ascribed to Yin-Jing PTE functions. TMT proteomics revealed a category of differentially expressed proteins ascribed to Golgi-ER between HYZYD and [HYZYD-PG]. Fr. C (i.e., saponins) and Fr. D (i.e., lipids) were determined as therapeutic fragmentations via the LPS-induced A549 cell injury model; however, Fr. B (fructooligosaccharides and small Mw fructans) had no therapeutic effect. Further compatibility PTE assays confirmed Fr. B significantly improved efficiency by a combination of HYA. The guidance assays showed Fr. B could significantly increase the uptake and distribution of HYA into lung cells and tissues. HCI assays showed that Fr. B increased uptake of HYA accompanied by significant activation of Golgi-ER. Unlike Fr. B, HRLCI showed that Fr. A, C and D were not only unobvious activations of Golgi-ER but also insignificant facilitation of colocalizations between HYA and Golgi-ER. CONCLUSIONS: Fr. B is believed to be a key YJMP material basis of PG attributed to Yin-Jing PTE with characteristic of lung-oriented guidance property, whereas another abound Fr. C was determined to have synergistic effects rather than Yin-Jing material basis.
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Lesión Pulmonar , Platycodon , Ratas , Animales , Platycodon/química , Medicina Tradicional China , Cromatografía Líquida de Alta Presión/métodos , PulmónRESUMEN
The study of facile-synthesis and low-cost X-ray scintillators with high light yield, low detection limit and high X-ray imaging resolution plays a vital role in medical and industrial imaging fields. However, the optimal balance between X-ray absorption, decay lifetime and excitonic utilization efficiency of scintillators to achieve high-resolution imaging is extremely difficult due to the inherent contradiction. Here two thermally activated delayed fluorescence (TADF)-actived coinage-metal clusters M6 S6 L6 (M=Ag or Cu) were synthesized by simple solvothermal reaction, where the cooperation of heavy atom-rich character and TADF mechanism supports strong X-ray absorption and rapid luminescent collection of excitons. Excitingly, Ag6 S6 L6 (SC-Ag) displays a high photoluminescence quantum yield of 91.6 % and scintillating light yield of 17420â photons MeV-1 , as well as a low detection limit of 208.65â nGy s-1 that is 26â times lower than the medical standard (5.5â µGy s-1 ). More importantly, a high X-ray imaging resolution of 16â lp/mm based on SC-Ag screen is demonstrated. Besides, rigid core skeleton reinforced by metallophilicity endows clusters M6 S6 L6 strong resistance to humidity and radiation. This work provides a new view for the design of efficient scintillators and opens the research door for silver clusters in scintillation application.
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Anisotropic charge transport plays a pivotal role in clarifying the conductivity mechanism in direct X-ray detection to improve the detection sensitivity. However, the anisotropic photoelectric effect of semiconductive single crystal responsive to X-ray is still lacking of theoretical and experimental proof. The semiconductive coordination polymers (CPs) with designable structures, adjustable functions, and high crystallinity provide a suitable platform for exploring the anisotropic conductive mechanism. Here,the study first reveals a 1D conductive transmission path for direct X-ray detection from the perspective of structural chemistry. The semiconductive copper(II)-based CP 1 single crystal detector exhibits unique anisotropic X-ray detection performance. Along the 1D π-π stacking direction, the single crystal device (1-SC-a) shows a superior sensitivity of 2697.15 µCGyair -1 cm-2 and a low detection limit of 1.02 µGyair s-1 among CPs-based X-ray detectors. This study provides beneficial guidance and deep insight for designing high-performance CP-based X-ray detectors.
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Luminescent metal halides have been exploited as a new class of X-ray scintillators for security checks, nondestructive inspection, and medical imaging. However, the charge traps and hydrolysis vulnerability are always detrimental to the three-dimensional ionic structural scintillators. Here, the two zero-dimensional organic-manganese(II) halide coordination complexes 1-Cl and 2-Br were synthesized for improvements in X-ray scintillation. The introduction of a polarized phosphine oxide can help to increase the stabilities, especially the self-absorption-free merits of these Mn-based hybrids. The X-ray dosage rate detection limits reached up to 3.90 and 0.81 µGyair/s for 1-Cl and 2-Br, respectively, superior to the medical diagnostic standard of 5.50 µGyair/s. The fabricated scintillation films were applied to radioactive imaging with high spatial resolutions of 8.0 and 10.0 lp/mm, respectively, holding promise for use in diagnostic X-ray medical imaging.
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Two examples of efficient cathode-ray scintillation coordination polymers with good stability at high voltage were prepared by conjugating luminescent groups with d10 metal ions. The synergistic effect of inorganic metal and organic ligand suppresses the self-quenching of the conjugated luminescent groups and enhances the scintillation performance. This work provides new ideas for the design of new field-emission displays and cathode-ray scintillation materials.
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BACKGROUND: A two- to three-fold increased risk of venous thrombotic events (VTE) has been demonstrated in patients with inï¬ammatory bowel disease (IBD) compared to the general population, but less is known about the risk of VTE in child- and pediatric-onset IBD. In recent years, several studies have reported the rising incidence rate of VTE in juvenile patients with IBD, and the related risk factors have been explored. AIM: To evaluate the risk of VTE in children and adolescents with IBD. METHODS: Articles published up to April 2021 were retrieved from PubMed, Embase, Cochrane Library, Web of Science, SinoMed, CNKI, and WANFANG. Data from observational studies and clinical work were extracted. The outcome was the occurrence of VTE according to the type of IBD. The available odds ratio (OR) and the corresponding 95% confidence interval (CI) were extracted to compare the outcomes. Effect size (P), odds ratio (OR), and 95%CI were used to assess the association between VTE risk and IBD disease. Subgroup analyses stratified by subtypes of VTE and IBD were performed. RESULTS: Twelve studies (7450272 IBD patients) were included in the meta-analysis. Child and adolescent IBD patients showed increased VTE risk (P = 0.02, 95%CI: 0.01-0.03). Subgroup analyses stratified by IBD (ulcerative colitis (UC): P = 0.05, 95%CI: 0.03-0.06; Crohn's disease (CD): P = 0.02, 95%CI: 0.00-0.04) and VTE subtypes (portal vein thrombosis: P = 0.04, 95%CI: 0.02-0.06; deep vein thrombosis: P = 0.03, 95%CI: 0.01-0.05; central venous catheter-related thrombosis: P = 0.23, 95%CI: 0.00-0.46; thromboembolic events: P = 0.02, 95%CI: 0.01-0.03) revealed a significant correlation between VTE risk and IBD. Patients with IBD were more susceptible to VTE risk than those without IBD (OR = 2.99, 95%CI: 1.45-6.18). The funnel plot was asymmetric, suggesting the presence of significant publication bias. Pediatric and adolescent IBD patients have an increased VTE risk. UC and CD patients exhibited a high risk of VTE. The risk of VTE subtypes was increased in IBD patients. CONCLUSION: The current meta-analysis showed that the incidence and risk of VTE are significantly increased in pediatric and adolescent IBD patients. Thus, IBD might be a risk factor for VTE in children and young adults. High-quality prospective cohort studies are necessary to confirm these findings.
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Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Tromboembolia Venosa , Adolescente , Niño , Colitis Ulcerosa/complicaciones , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/epidemiología , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/epidemiología , Estudios Prospectivos , Factores de Riesgo , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiología , Adulto JovenRESUMEN
The detection of X-rays has always been a frontier of scientific research. An Eu-MOF with both X-ray-induced photochromic and scintillation properties has been synthesized through the combination of a photochromism-active viologen ligand and rare earth Eu element with high-efficiency absorption of X-rays. In a bright environment, Eu-MOF exhibits different color changes under high-energy X-rays and low-energy X-rays, which can effectively distinguish X-rays. Eu-MOF can also be used for X-ray detection by scintillation properties in dark environments. This work provides a new perspective on the design of multifunctional materials that can perform simple X-ray detection in different environments.
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Albicanol is a natural terpenoid derived from Dryopteris fragrans. Herein, we assessed the ability of Albicanol to protect against oxidative stress-induced senescence. Using a murine model of D-galactose (D-gal)-induced aging, we determined that Albicanol treatment can reverse D-gal-mediated learning impairments and behavioral changes, while also remediating brain tissue damage in treated mice. We found that serum SOD, CAT, GSH-Px, and T-AOC levels were significantly decreased in aging mice, and that Albicanol treatment significantly increased the serum levels of these antioxidant enzymes. We additionally evaluated the impact of Albicanol treatment on the Keap1/Nrf2/ARE signaling pathway, and found that it was able to decrease Keap1 expression while increasing the expression of Nrf2, thereby activating this signaling pathway, suppressing oxidative damage, and enhancing the expression of downstream target genes including SOD, GSH, GST, HO-1, and NQO1 in this murine aging model system. Albicanol treatment also inhibited the secretion of inflammatory TNF-a and IL-1b. Together, these data indicated that Albicanol can activate Nrf2 pathway-related genes, thereby inhibition of delayed aging by alleviating oxidative stress-induced damage.
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Envejecimiento/efectos de los fármacos , Antioxidantes/uso terapéutico , Galactosa/farmacología , Naftalenos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Sesquiterpenos/uso terapéutico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/patología , Expresión Génica/efectos de los fármacos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ratones , Prueba del Laberinto Acuático de Morris/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacos , Memoria Espacial/efectos de los fármacosRESUMEN
In order to investigate efficacy of FGF21 combine dexamethasone (Dex) on rheumatoid arthritis (RA) meanwhile reduce side effects of dexamethasone. We used combination therapy (Dex 15 mg/kg + FGF21 0.25 mg/kg, Dex 15 mg/kg + FGF21 0.5 mg/kg or Dex 15 mg/kg + FGF21 1 mg/kg) and monotherapy (Dex 15 mg/kg or FGF21 1 mg/kg) to treat CIA mice induced by chicken type II collagen, respectively. The effects of treatment were determined by arthritis severity score, histological damage, and cytokine production. The levels of oxidative stress parameters, liver functions, and other blood biochemical indexes were detected to determine FGF21 efficiency to side effects of dexamethasone. Oil red O was performed to detect the effects of FGF21 and dexamethasone on fat accumulation in HepG2 cells. The mechanism of FGF21 improves the side effects of dexamethasone which was analyzed by Western blotting. This combination proved to be therapeutically more effective than dexamethasone or FGF21 used singly. FGF21 regulates oxidative stress and lipid metabolism by upregulating dexamethasone-inhibited SIRT-1 and then activating downstream Nrf-2/HO-1and PGC-1. FGF21 and dexamethasone are highly effective in the treatment of arthritis; meanwhile, FGF21 may overcome the limited therapeutic response and Cushing syndrome associated with dexamethasone.
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Antiinflamatorios/administración & dosificación , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Dexametasona/administración & dosificación , Factores de Crecimiento de Fibroblastos/administración & dosificación , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Pollos , Dexametasona/efectos adversos , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Células Hep G2 , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/fisiología , Ratones , Ratones Endogámicos C57BL , Resultado del TratamientoRESUMEN
The synergy of unusual X-aggregation induced luminescent chromophores and heavy Pb(ii) ions has facilitated excellent X-ray scintillation of two structurally similar Pb-SMOFs, which are heat-resistant due to solvent-free lattices. Owing to their higher Pb(ii) contents, Pb-SMOFs with larger X-ray absorption coefficients are more sensitive for X-ray dosage detection than powdered CsPbBr3.
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Efficient cathode-ray scintillating metal-organic frameworks are constructed from a π-conjugated luminescent motif and light Ca(ii) ions. The luminescence self-quenching pathway has been effectively hindered through coordination. In situ vacuum ultraviolet fluorescent spectra have shown the excitons recombining in the scintillation process for the first time.
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Chronic pancreatitis (CP) is a progressive, irreversible inflammatory and fibrotic disease. The characteristics of this disease are progressive inflammation, acinar atrophy and fibrosis. Numerous factors are involved in CP such as inflammation, and oxidative stress. Recently, it has been noted that fibroblast growth factor 21 (FGF-21) reduced the severity of acute pancreatitis in mice. However, whether FGF-21 has effects on CP remains unclear. Thus, the present study was undertaken to detect the effects of FGF-21 on l-arginine induced chronic pancreatitis/islet fibrosis in mice. We used l-arginine to create a CP model in C57BL/6 mice and treated these mice with FGF-21. Compared to normal mice, blood glucose and intra-peritoneal glucose tolerance test (IPGTT) revealed significant impairment in CP animal model. CP mice also had acinar atrophy, loss of pancreas morphology, inflammatory cells infiltration, extensive deposition of collagen, elevated
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Factores de Crecimiento de Fibroblastos/uso terapéutico , Macrófagos Peritoneales/efectos de los fármacos , Pancreatitis Crónica/tratamiento farmacológico , Amilasas/sangre , Animales , Arginina/toxicidad , Diferenciación Celular/efectos de los fármacos , Factores de Crecimiento de Fibroblastos/farmacología , Fibrosis , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Malondialdehído/sangre , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Pancreatitis Crónica/inducido químicamente , Pancreatitis Crónica/patología , Peroxidasa/sangre , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Transducción de Señal/efectos de los fármacos , Células THP-1 , Serina-Treonina Quinasas TOR/fisiologíaRESUMEN
BACKGROUND: It is challenging to distinguish intestinal tuberculosis from Crohn's disease due to dynamic changes in epidemiology and similar clinical characteristics. Recent studies have shown that polymorphisms in genes involved in the interleukin (IL)-23/IL-17 axis may affect intestinal mucosal immunity by affecting the differentiation of Th17 cells. AIM: To investigate the specific single-nucleotide polymorphisms (SNPs) in genes involved in the IL-23/IL-17 axis and possible pathways that affect susceptibility to intestinal tuberculosis and Crohn's disease. METHODS: We analysed 133 patients with intestinal tuberculosis, 128 with Crohn's disease, and 500 normal controls. DNA was extracted from paraffin-embedded specimens or whole blood. Four SNPs in the IL23/Th17 axis (IL22 rs2227473, IL1ß rs1143627, TGFß rs4803455, and IL17 rs8193036) were genotyped with TaqMan assays. The transcriptional activity levels of different genotypes of rs2227473 were detected by dual luciferase reporter gene assay. The expression of IL-22R1 in different intestinal diseases was detected by immunohistochemistry. RESULTS: The A allele frequency of rs2227473 (P = 0.030, odds ratio = 0.60, 95% confidence interval: 0.37-0.95) showed an abnormal distribution between intestinal tuberculosis and healthy controls. The presence of the A allele was associated with a higher IL-22 transcriptional activity (P < 0.05). In addition, IL-22R1 was expressed in intestinal lymphoid tissues, especially under conditions of intestinal tuberculosis, and highly expressed in macrophage-derived Langhans giant cells. The results of immunohistochemistry showed that the expression of IL-22R1 in patients with Crohn's disease and intestinal tuberculosis was significantly higher than that in patients with intestinal polyps and colon cancer (P < 0.01). CONCLUSION: High IL-22 expression seems to be a protective factor for intestinal tuberculosis. IL-22R1 is expressed in Langhans giant cells, suggesting that the IL-22/IL-22R1 system links adaptive and innate immunity.
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Enfermedad de Crohn/diagnóstico , Células Gigantes de Langhans/patología , Interleucinas/genética , Receptores de Interleucina/metabolismo , Tuberculosis Gastrointestinal/diagnóstico , Adulto , Biopsia , Estudios de Casos y Controles , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Diagnóstico Diferencial , Femenino , Predisposición Genética a la Enfermedad , Células Gigantes de Langhans/inmunología , Humanos , Interleucinas/inmunología , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Receptores de Interleucina/inmunología , Factores de Riesgo , Tuberculosis Gastrointestinal/genética , Tuberculosis Gastrointestinal/inmunología , Adulto Joven , Interleucina-22RESUMEN
BACKGROUND: Because of the similarity of intestinal tuberculosis and Crohn's disease in disease phenotype, differential diagnosis has always been a clinical problem. Arachidonic acid metabolites play an important role in the inflammatory response of intestinal tuberculosis and Crohn's disease. Recent studies have shown that the polymorphism locus in the promoter region of LTA4H gene affects LTB4 expression level and the susceptibility to extrapulmonary tuberculosis. Thus, we identified a total of 148 patients with intestinal tuberculosis, 145 with Crohn's disease, and 700 normal controls in this study. METHODS: All the study participants were local Han people from Jiangxi Province in the past eleven years. DNA was extracted from the paraffin-embedded specimens or the whole blood. The LTA4H promoter SNP (rs17525495) was genotyped with TaqMan assay. RESULTS: The T-alleles frequency was not significantly increased in patients with intestinal tuberculosis compared with healthy control group (p=0.630; OR=1.07; 95%CI=0.81-1.41), while patients with Crohn's disease have significantly increased T allele frequency compared with healthy population (p=0.032; OR=1.34; 95%CI=1.03-1.75). During treatment, the presence of the T allele significantly increased the proportion of Crohn's patients requiring glucocorticoids (p<0.05). CONCLUSIONS: The T allele of LTA4H gene SNP (rs17525495) is a risk factor for Crohn's disease instead of intestinal tuberculosis. More importantly, there may be a potential association of the different genotypes of rs17525495 with the treatment efficacy of 5-ASA and glucocorticoids in patients with Crohn's disease. The association between LTA4H polymorphism and drugs therapeutic effects might contribute to the practice of precision medicine and the prediction of clinical outcomes.
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Pueblo Asiatico/genética , Enfermedad de Crohn/genética , Epóxido Hidrolasas/genética , Etnicidad/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Tuberculosis Gastrointestinal/genética , Adulto , Enfermedad de Crohn/enzimología , Femenino , Frecuencia de los Genes/genética , Humanos , Masculino , Modelos Genéticos , Tuberculosis Gastrointestinal/enzimologíaRESUMEN
OBJECTIVE: Obesity-related, chronic, low-grade inflammation has been identified as a key factor in the development of many metabolic diseases, such as type 2 diabetes and cardiovascular diseases. Adipocytes, preadipocytes, and macrophages have been implicated in initiating inflammation in adipose tissue. This study aims to investigate the effects of fibroblast growth factor-21 (FGF-21) on obesity-related inflammation and its mechanisms in vivo and in vitro. METHODS: Monosodium glutamate (MSG) was used to induce obesity in mice and subsequently treated the mice with or without FGF-21. Primary adipocytes and stromal vascular fraction cells were isolated from MSG-obesity mice for additional experiments. RESULTS: Results obtained by ELISA and real-time polymerase chain reaction showed that FGF-21 efficiently ameliorated obesity-related inflammation in MSG-obesity mice. This study demonstrated that preadipocytes and adipocytes responded to anti-inflammatory effects of FGF-21. In vitro, 3 T3-L1 preadipocytes lacking ß-klotho did not respond to FGF-21 under glucose uptake. Interestingly, the treatment of 3 T3-L1 preadipocytes with FGF-21 significantly attenuated lipopolysaccharide-induced inflammatory response. CONCLUSIONS: Our study showed that FGF-21-induced glucose uptake and FGF-21-related anti-inflammatory effects are mediated by different signaling pathways. Moreover, FGF-21 showed anti-inflammatory effects on preadipocytes; these effects are mediated by the fibroblast growth factor receptor substrate 2/ERK1/2 signaling pathway.
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Tejido Adiposo/efectos de los fármacos , Antiinflamatorios/uso terapéutico , Factores de Crecimiento de Fibroblastos/uso terapéutico , Inflamación/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Factores de Crecimiento de Fibroblastos/farmacología , Humanos , RatonesRESUMEN
Macrophages are paramount to the initiation and procession of atherosclerosis, thus targeting macrophages in the progress of atherosclerosis is indispensable. Therefore, we perform in vitro experiments to investigate the effects of FGF-21 on macrophages in the progress of atherosclerosis. First, we use phorbol-12-myristate-13-acetate (PMA), a phorbol ester, to induce THP-1 cells into macrophages as macrophages model. After that we use Ox-LDL to induce macrophages into foam cells and simultaneously administrate with FGF-21 or not to determine whether FGF-21 has effects on foam cells formation and related inflammatory response. Wound healing results show that FGF-21 can inhibit macrophage migration. Oil Red-O stain, immunofluorescence and flow cytometer results show that FGF-21 can repress cholesterol accumulation in macrophages thereby inhibit foam cells formation and these effects can be abolished by FGFR inhibitor. Moreover, real-time PCR results showed that FGF-21 significantly reduces expression of inflammatory factors including IL-1α, IL-6 and TNF-α and this effect can be abolished by FGFR inhibitor. Furthermore, to determine the mechanism of FGF-21 regulates inflammatory response in Ox-LDL-induced THP-1 macrophages, western blotting results show that after treatment of Ox-LDL in macrophages, NF-κB signaling pathway is activated but FGF-21 can significantly inhibit this pathway. In addition, FGF-21 also regulates some regulators of lipid metabolism after treatment of Ox-LDL in macrophages. Above all, our findings demonstrate that FGF-21 can regulate foam cells formation, macrophage migration, inflammatory response and lipid metabolism in Ox-LDL-induced THP-1 macrophages.
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Factores de Crecimiento de Fibroblastos/farmacología , Células Espumosas/metabolismo , Células Espumosas/patología , Inflamación/patología , Lipoproteínas LDL/farmacología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Movimiento Celular/efectos de los fármacos , Colesterol/metabolismo , Células Espumosas/efectos de los fármacos , Glucuronidasa/metabolismo , Humanos , Proteínas Klotho , FN-kappa B/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptores Depuradores/metabolismo , Transducción de Señal/efectos de los fármacos , Células THP-1RESUMEN
Type 2 diabetes mellitus (T2DM) is accompanied by abnormal glucose metabolism and low-grade chronic inflammation. Fibroblast growth factor 21 (FGF-21) is a novel metabolic regulator and can function as an endocrine hormone to regulate glucose and lipid metabolism. Recently, FGF-21 was found to have anti-inflammatory effect, to our knowledge, the effect of FGF-21 on inflammatory state in diabetes has not been elucidated. Here, we use db/db mice as a Type 2 diabetes model to determine whether FGF-21 alleviates inflammatory state while improves hyperglycemia. Our results demonstrated that FGF-21 not only showed potent long lasting hypoglycemic effect, but also demonstrated strong anti-inflammatory effect in the serum and white adipose tissue. Besides, in vitro experiments, insulin resistance (IR) was induced in 3T3-L1 adipocytes by treating with TNF-α. Our results showed that TNF-α impaired glucose metabolism of 3T3-L1 adipocytes but FGF-21 repressed gene expression of inflammatory factors caused by IR and consequently improved the glucose metabolism in 3T3-L1 adipocytes. Furthermore, FGF-21 ameliorated glucose uptake of TNF-α-induced IR in 3T3-L1 adipocytes by inhibiting NF-κB signaling pathway.
Asunto(s)
Adipocitos/fisiología , Tejido Adiposo Blanco/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Glucosa/metabolismo , Inflamación/metabolismo , Animales , Línea Celular , Hiperglucemia , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , FN-kappa B/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Fibroblast growth factor 21 (FGF-21) has been previously judged as a major metabolic regulator. In this paper, we show that FGF-21 has a potential role in anti-inflammation and immunoregulation. In vivo, treatment with exogenous FGF-21 can alleviate LPS-induced inflammation. In vitro, FGF-21 inhibited LPS-induced IL-1ß expression in THP-1 cells. Furthermore, besides the NF-κB pathway, the mechanism of action of FGF-21 was observed to involve the elevation of IL-10 in the ERK1/2 pathway. This study clearly indicates that FGF21 can be used as an attractive target for the management of inflammatory disorders. This piece of research indicates that FGF-21 could have much value in the management of inflammatory disorders.