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BACKGROUND: Childhood asthma is a major global health concern. ADP-ribosylation factor 6 (ARF6) is a low-molecular-weight GTPase; however, its role in childhood asthma remains unclear. METHODS: Ovalbumin (OVA)-challenged neonatal mice and transforming growth factor-ß1 (TGF-ß1)-induced BEAS-2B cells were used as in vivo and in vitro models of childhood asthma, respectively. RESULTS: Upon OVA stimulation, ARF6 expression was upregulated in the lung tissue. Neonatal mice administered SehinH3 (an ARF6 inhibitor) exhibited improved pulmonary pathological injury, along with reduced inflammatory cell infiltration in the lungs and cytokine release in bronchial alveolar lavage fluid and serum (interleukin [IL]-3, IL-5, IL-13, IgE, and OVA-specific IgE). SehinH3 treatment restrained epithelial - mesenchymal transition (EMT) in the lungs of asthmatic mice, as evidenced by increased E-cadherin and decreased N-cadherin and α-smooth muscle actin expression. Different TGF-ß1 exposures to BEAS-2B cells induced a time- and dose-dependent increase in ARF6 expression in vitro. Upon TGF-ß1 stimulation, ARF6 knockdown repressed EMT and SehinH3 treatment caused similar results in BEAS-2B cells. The transcription factor E2F8 is involved in diverse biological functions and its increased expression was confirmed in vivo and in vitro. Dual-luciferase assays confirmed that E2F8 binds to the ARF6 promoter and promotes its transcriptional activity. In vitro results revealed that E2F8 silencing suppressed EMT, whereas rescue experiments showed that ARF6 overexpression partly reversed these phenomena. CONCLUSION: Our study showed that ARF6 is associated with childhood asthma progression and may be positively regulated by E2F8. These results provide insight into the pathogenesis and treatment of childhood asthma.
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Asma , Fator de Crescimento Transformador beta1 , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Ovalbumina , Fator 6 de Ribosilação do ADP , Transição Epitelial-Mesenquimal , Asma/metabolismo , Inflamação , Imunoglobulina E , Fatores de Transcrição E2F/metabolismo , Camundongos Endogâmicos BALB C , Modelos Animais de DoençasRESUMO
Pulmonary artery hypertension (PAH) is a common and serious disease which is characterized by pulmonary vascular remodeling. Bosentan (BST) is the first approved oral targeted drug of endothelin-1 (ET-1) receptor antagonists for the treatment of PAH. MicroRNA-27a (miR-27a) and peroxisome proliferator-activated receptor γ (PPARγ) were found to be related to the pathogenesis of PAH. To further explore the signal transduction mechanism of BST in the treatment of PAH, we examined the effects of BST on endothelin receptors, miR-27a, and PPARγ. Meanwhile, the influence of miR-27a in the formation and development of PAH was discussed. Our results demonstrated that during the pathophysiology of PAH, miR-27a, PPARγ, and ET-1 were cross-inhibited, which indicated that the miR-27a/PPARγ/ET-1 signaling pathway was dysregulated; in addition, BST could competitively bind to ET-1 receptors and inhibit the miR-27a/PPARγ/ET-1 signaling pathway, thereby delaying the proliferation of PASMCs and affecting the development of PAH. Our results give a new understanding of the pathogenesis and treatment of PAH and provide more reliable evidence for the application of BST in the treatment of PAH in the clinic.
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Bosentana/farmacologia , Antagonistas dos Receptores de Endotelina/farmacologia , PPAR gama/efeitos dos fármacos , Animais , Humanos , MicroRNAs/metabolismo , PPAR gama/metabolismo , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: B cell-activating factor (BAFF) has been proposed to be a regulator of B cell and T cell immune responses and be associated with inflammatory processes in autoimmunity and B cell malignancies. No study has reported the role of BAFF in inflammatory bowel disease (IBD). AIMS: The purpose of this study was to investigate expression and concentrations of BAFF in IBD and determine its value to discriminate patients with IBD. METHODS: Seventy-eight ulcerative colitis (UC) patients, 37 Crohn's disease (CD) patients, 12 irritable bowel syndrome (IBS) patients and 44 healthy controls were recruited. We examined serum and faecal BAFF levels using enzyme-linked immunosorbent assay. Intestinal BAFF expression was analysed in biopsies obtained from IBD patients. Intestinal mucosa localization of BAFF was conducted by immunofluorescence. RESULTS: The median (25th-75th percentile) serum BAFF concentration (pg/ml) was 1430 (1105-1624) in CD patients, 1472 (1018-1772) in UC patients and 977 (482-1345) in healthy controls. Serum BAFF was 64 % sensitive and 93 % specific for identifying active IBD from healthy controls. The BAFF expression was significantly increased in biopsy specimens from IBD patients. Fecal BAFF concentration was 369 (326-493) pg/ml in CD patients, 542 (358-1758) pg/ml in UC patients, 294 (287-299) pg/ml in IBS patients and 295 (284-309) pg/ml in healthy controls. Fecal BAFF was 90 % sensitive and 96 % specific for identifying active IBD from healthy controls and IBS patients. CONCLUSION: The novel association between BAFF and IBD seems to identify that BAFF might regulate the inflammatory process in these diseases and it appears to be a potential marker of IBD.
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Fator Ativador de Células B/metabolismo , Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Mucosa Intestinal/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores/metabolismo , Estudos de Casos e Controles , Colite Ulcerativa/diagnóstico , Doença de Crohn/diagnóstico , Ensaio de Imunoadsorção Enzimática , Fezes/química , Feminino , Imunofluorescência , Humanos , Síndrome do Intestino Irritável/metabolismo , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto JovemRESUMO
CONTEXT: Although it is recognized that thrombin plays a key role in airway remodeling during chronic asthma. In a previous study, we have proved that thrombin promotes airway remodeling via PAR-1 in OVA-allergic rats, but little is known about intracellular signaling pathway involved in the event. OBJECTIVE: In this study, we intend to explore the impact of pERK1/2 signaling pathway on the process of thrombin-induced airway remodeling in OVA-allergic rats. MATERIALS AND METHODS: A rat model of chronic asthma was set up by systemic sensitization and repeated challenge to OVA. The doses of thrombin, recombinant hirudin, PAR-1 inhibitor ER-112780-06, and pERK1/2 inhibitor PD98059 varied for different groups. The expression of pERK1/2 was analyzed by western blot and RT-PCR. Secretion of TGF-ß1 and IL-6 was detected by ELISA. RESULTS: The expression of pERK1/2 was higher in the airway of asthmatic rats than those of normal rats, and was significantly increased by thrombin treatment but decreased by thrombin-inhibitor treatment. Airway remodeling was enhanced by thrombin but weakened by pERK1/2 inhibitor. Expression of growth factors and IL-6 in asthmatic rats was significantly increased by thrombin treatment and decreased by thrombin-inhibitor treatment and pERK1/2 inhibitor treatment. CONCLUSION: These results suggest that ERK1/2 signaling pathway may play an important role in the process of thrombin-promoting airway remodeling in OVA-allergic rats, and pERK1/2 inhibitor effectively inhibits the process.
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Remodelação das Vias Aéreas/imunologia , Asma/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Trombina/fisiologia , Administração por Inalação , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Antitrombinas/farmacologia , Asma/enzimologia , Modelos Animais de Doenças , Feminino , Hirudinas/farmacologia , Interleucina-6/genética , Sistema de Sinalização das MAP Quinases/imunologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Ratos Wistar , Receptor PAR-1/antagonistas & inibidores , Trombina/antagonistas & inibidores , Trombina/farmacologia , Fator de Crescimento Transformador beta1/genéticaRESUMO
Lonicera japonica flos is widely used as a pharmaceutical resource and a commonly-employed ingredient in healthy food, soft beverages and cosmetics in China. Sometimes, sulfur fumigation is used during post-harvest handling. In this study, a comprehensive comparison of the chemical profile between sun-dried and sulfur-fumigated samples was conducted by HPLC fingerprints and simultaneous quantification of nine constituents, including secologanic acid, along with another eight usually-analyzed markers. Secologanic acid was destroyed, and its sulfonates were generated, whereas caffeoylquinic acids were protected from being oxidized. The residual sulfur dioxide in sulfur-fumigated samples was significantly higher than that in sun-dried samples, which might increase the potential incidence of toxicity to humans. Meanwhile, compared with sun-dried samples, sulfur-fumigated samples have significantly stronger antioxidant activity, which could be attributed to the joint effect of protected phenolic acids and flavonoids, as well as newly-generated iridoid sulfonates.
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Antioxidantes/farmacologia , Lonicera/química , Extratos Vegetais/farmacologia , Ácido Quínico/análogos & derivados , Enxofre/farmacologia , China , Cromatografia Líquida de Alta Pressão , Flavonoides/farmacologia , Fumigação/métodos , Glicosídeos Iridoides/farmacologia , Lonicera/efeitos dos fármacos , Extratos Vegetais/química , Ácido Quínico/química , Ácido Quínico/farmacologia , Dióxido de Enxofre/químicaRESUMO
To investigate formation mechanism of secologanic acid sulfonates in sulfur-fumigated buds of Lonicera japonica, secologanic acid was enriched and purified from the sun-dried buds of L. japonica by various column chromatography on macroporus resin HPD-100, silica gel and ODS. The stimulation experiments of sulfur-fumigation process were carried out using secologanic acid reacted with SO2 in the aqueous solution. The reaction mechanism could be involved in the esterification or addition reaction. The present investigation provides substantial evidences for interpreting formation pathway of secologanic acid sulfonates in sulfur-fumigated buds of L. japonica.
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Alcanossulfonatos/química , Flores/química , Lonicera/química , Enxofre/química , Ácidos Carboxílicos/química , Cromatografia Líquida de Alta Pressão , Flores/efeitos dos fármacos , Lonicera/efeitos dos fármacos , Modelos Químicos , Estrutura Molecular , Enxofre/farmacologia , Dióxido de Enxofre/química , Água/químicaRESUMO
High expression of the zinc finger X-chromosomal protein (ZFX) correlates with proliferation, aggressiveness, and development in many types of cancers. In the current report, we investigated the efficacy of ZFX in mouse pulmonary artery smooth muscle cells (PASMCs) proliferation during pulmonary arterial hypertension (PAH). PASMCs were cultured in hypoxic conditions. Real-time PCR and western blotting were conducted to detect the expression of ZFX. Cell proliferation, apoptosis, migration, and invasion were, respectively, measured by CCK-8, flow cytometry, wound scratchy, and transwell assays. Glycolytic ability was validated by the extracellular acidification rate and oxygen consumption rate. Transcriptome sequencing technology was used to explore the genes affected by ZFX knockdown. Luciferase and chromatin immunoprecipitation assays were utilized to verify the possible binding site of ZFX and YAP1. Mice were subjected to hypoxia for 21 days to induce PAH. The right ventricular systolic pressure (RVSP) was measured and ratio of RV/LV + S was calculated. The results show that ZFX was increased in hypoxia-induced PASMCs and mice. ZFX knockdown inhibited the proliferation, migration, and invasion of PASMC. Using RNA sequencing, we identify glycolysis and YAP as a key signaling of ZFX. ZFX knockdown inhibited Glycolytic ability. ZFX strengthened the transcription activity of YAP1, thereby regulating the YAP signaling. YAP1 overexpression reversed the effect of ZFX knockdown on hypoxia-treated PASMCs. In conclusion, ZFX knockdown protected mice from hypoxia-induced PAH injury. ZFX knockdown dramatically reduced RVSP and RV/(LV + S) in hypoxia-treated mice.
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Fatores de Transcrição Kruppel-Like , Hipertensão Arterial Pulmonar , Remodelação Vascular , Proteínas de Sinalização YAP , Animais , Camundongos , Movimento Celular/genética , Proliferação de Células , Células Cultivadas , Hipóxia/complicações , Pulmão/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/prevenção & controle , Hipertensão Arterial Pulmonar/metabolismo , Artéria Pulmonar/metabolismo , Proteínas de Sinalização YAP/genética , Proteínas de Sinalização YAP/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismoRESUMO
Foot-and-mouth disease virus (FMDV) is a highly contagious pathogen that has caused significant economic losses in the livestock industry. Peptide vaccines engineered with the protective epitopes of FMDV have provided a safer alternative for disease prevention than the traditional inactivated vaccines. However, the immunogenicity of the peptide is usually poor and therefore an adjuvant is required. Here, we showed that recombinant T4 phages displaying the B-cell epitope of the FMDV VP1 protein (VP1130-158), without additional adjuvants, induced similar levels of antigen-specific IgG1 but higher levels of IgG2a compared to the peptide vaccine. Incorporation of a CD4+ T cell epitope, either 3A21-35 of FMDV 3A protein or P2830-844 of tetanus toxoid, further enhanced the immunogenicity of VP1-T4 phage nanoparticles. Interestingly, the extrinsic adjuvant cannot enhance the immunogenicity of the nanoparticles, indicating the intrinsic adjuvant activities of T4 phage. Furthermore, the recombinant T4 phage can be produced on a large scale within a short period of time at a relatively low-cost using Escherichia coli, heralding its potential in the development of a safe and effective FMDV vaccine.
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Vírus da Febre Aftosa , Febre Aftosa , Vacinas Virais , Animais , Bacteriófago T4 , Febre Aftosa/prevenção & controle , Nanovacinas , Anticorpos Antivirais , Epitopos de Linfócito B , Adjuvantes Imunológicos , Proteínas do CapsídeoRESUMO
BACKGROUND: Protease-activated receptor-1 (PAR-1) is widely distributed in platelets and involved in coagulation cascade activated by thrombin. In this study, we intend to explore the role of PAR-1 in the process of thrombin-inducing transforming growth factor-ß1 (TGF-ß1) to promote airway remodeling in ovalbumin (OVA)-allergic rats. MATERIALS AND METHODS: A rat model of chronic asthma was set up by systemic sensitization and repeated challenge to OVA. The doses of thrombin, recombinant hirudin, PAR-1 inhibitor ER-112780-06 varied for different groups. We evaluated the bronchoalveolar lavage fluid (BALF) concentration of thrombin in these groups. The protein and gene expression of PAR-1 was assessed and the expression of TGF-ß1 was also detected. RESULTS: The PAR-1 mRNA level and the protein level were higher in the airway of asthmatic rats than those of normal rats, and were significantly increased by thrombin treatment but decreased by thrombin-inhibitor treatment. Airway remodeling was strengthened by thrombin but weakened by thrombin inhibitor and PAR-1 antagonist. Expression of TGF-ß1 protein in asthmatic rats was significantly increased by thrombin treatment and decreased by thrombin-inhibitor treatment and PAR-1 antagonist treatment. CONCLUSION: The expression of PAR-1 is regulated by thrombin that induces the expression of TGF-ß1 to promote airway remodeling via PAR-1 in OVA-allergic rats.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Ovalbumina/imunologia , Receptor PAR-1/metabolismo , Trombina/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Asma/induzido quimicamente , Asma/patologia , Líquido da Lavagem Broncoalveolar , Colágeno/metabolismo , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/fisiologia , Hirudinas/farmacologia , Muco , Ratos , Ratos Wistar , Receptor PAR-1/genética , Trombina/antagonistas & inibidores , Trombina/metabolismo , Fator de Crescimento Transformador beta1/genéticaRESUMO
A 66-year-old male patient receiving maintenance hemodialysis with arteriovenous fistula of the right upper limb was admitted to the hospital because of intermittent syncope, dizziness, and distension. Central venography indicated occlusion of the right brachiocephalic vein (RBV), and the contrast agent flowed from the right internal jugular vein into the intracranial vein, then into the contralateral internal jugular vein, and finally returned into the superior vena cava. Percutaneous transluminal angioplasty was performed to dilate the RBV. Postoperatively, the contrast agent flowed smoothly into the right atrium through the RBV and the superior vena cava. Craniocerebral magnetic resonance angiography and magnetic resonance venography indicated that the intracranial venous reflux disappeared. The patient did not experience syncope again; moreover, dizziness and distention improved, as well as right facial swelling and right eye congestion, and he was discharged 2 days later. Two months later, the patient complained of dizziness. Venography under digital subtraction angiography showed severe stenosis at the RBV and percutaneous transluminal angioplasty was performed; moreover, stent placement was performed. The contrast agent flowed smoothly into the right atrium through the RBV and the superior vena cava again. Ultimately, the headaches and dizziness improved significantly postoperatively. Hence, if hemodialysis patients present with neurological symptoms, intracranial venous congestion should be monitored; nonetheless, most patients have a good prognosis when treated appropriately.
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Background: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease with increasing rates globally. Patients with type 2 diabetes mellitus have higher risk of developing NAFLD. Patients with a higher degree of liver fibrosis in NAFLD are at an increased risk for liver-related mortality, but get missed easily during the referral process. This project aims to improve early detection and linkage-to-care of fibrotic NAFLD patients. Methods: We utilized a combination of automated electronic health record (EHR)-based fibrosis (FIB)-4 score and directed provider education. A health-system wide FIB-4 score calculator that providers can easily add to their workflow for NAFLD patient triaging. Data were analyzed at 6 and 12 months after implementation. Results: Postimplementation, there was an increase in patients referred to hepatology with higher degree of liver fibrosis and decreased referral to hepatology with low risk of liver fibrosis, measured by FIB-4 score. At baseline, â¼55% of referred patient to hepatology had FIB-4 score <1.3 compared to 38% at 12 months postimplementation. There was an increase in referral of patients with FIB-4 scores >1.3 when compared to preinterventions, 62% versus 45%. This is most pronounced in patients with severe fibrotic disease with FIB-4 score >2.67, 30% versus 12%. Conclusions: Automated FIB-4 score in EHR can improve appropriate linkage-to-care for at-risk fibrotic NAFLD, especially when coupled with targeted provider education. The durability of such improvement is essential to study along with the need to increase broad acceptance across health systems.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patologia , Fígado/patologia , Fibrose , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologiaRESUMO
Physiological cardiac hypertrophy is associated with mitochondrial adaptations that are characterized by activation of PGC-1alpha and increased fatty acid oxidative (FAO) capacity. It is widely accepted that phosphatidylinositol 3-kinase (PI3K) signaling to Akt1 is required for physiological cardiac growth. However, the signaling pathways that coordinate physiological hypertrophy and metabolic remodeling are incompletely understood. We show here that activation of PI3K is sufficient to increase myocardial FAO capacity and that inhibition of PI3K signaling prevents mitochondrial adaptations in response to physiological hypertrophic stimuli despite increased expression of PGC-1alpha. We also show that activation of the downstream kinase Akt is not required for the mitochondrial adaptations that are secondary to PI3K activation. Thus, in physiological cardiac growth, PI3K is an integrator of cellular growth and metabolic remodeling. Although PI3K signaling to Akt1 is required for cellular growth, Akt-independent pathways mediate the accompanying mitochondrial adaptations.
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Cardiomegalia/enzimologia , Mitocôndrias/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Condicionamento Físico Animal , Proteínas Proto-Oncogênicas c-akt/fisiologia , Adaptação Fisiológica , Animais , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Isoenzimas/antagonistas & inibidores , Camundongos , Camundongos Mutantes , Miócitos Cardíacos/enzimologia , Oxirredução , Fosfatidilinositol 3-Quinases/genética , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Proteína Quinase C/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de SinaisRESUMO
BACKGROUND: Stromal cell-derived factor-1 (SDF-1) plays a critical role in adult brain injury repair including neurogenesis and vasculogenesis. However, the effects of recombinant SDF-1(rSDF-1) treatment on hypoxic-ischemic (HI) brain injury in neonatal mice are not clear. MATERIALS AND METHODS: Seven-day-old (P7) C57BL/6J mice were divided into sham group, control group, and rSDF-1 group. Mice brains were collected to determine histopathological damage and the expression level of SDF-1, caspase-3, and Ki67 on P8, P10, P14, and P21. Passive avoidance and elevated plus-maze tests were also assessed on P20 and P21. RESULTS: Compared with control group, rSDF-1 treatment increased the weight ratio of left and right brain hemisphere (p < 0.05), reduced the number of electric foot shocks (p < 0.05) and the percentage of time spent in the open arms (p < 0.05), meanwhile, increased the retention latency (p < 0.05) and the percentage of time spent in the enclosed arms (p < 0.05) on P20 and P21. High expression of Ki67 and low expression of caspase-3 were also observed. DISCUSSION: This study showed that rSDF-1 treatment effectively alleviated brain injury shown by reducing in caspase-3 expression and increasing in Ki67 expression. Moreover, rSDF-1 treatment significantly improved behavioral performances in juvenile mice after HI.
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Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Quimiocina CXCL12/uso terapêutico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Caspase 3/metabolismo , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/farmacologia , Modelos Animais de Doenças , Hipóxia-Isquemia Encefálica/metabolismo , Antígeno Ki-67/metabolismo , Camundongos , Proteínas Recombinantes/farmacologia , Resultado do TratamentoRESUMO
OBJECTIVE: To explore the significance of liraglutide combined with dapagliflozin or empagliflozin in the prevention of early diabetic nephropathy (DN) and its effects on renal function indices. METHODS: Three hundred patients with type 2 diabetes mellitus (T2DM) treated in our hospital from April 2019 to April 2020 were retrospectively included and divided into two groups according to different treatment regimens. Among them, 150 patients who received liraglutide alone were included in the single-drug group, and 150 patients treated with liraglutide combined with dapagliflozin or empagliflozin were included in the combination group. The baseline data and the improvement of inflammatory indices, blood glucose indices and renal function-related indices were compared between the two groups of patients. RESULTS: The baseline data such as age, body mass index, retinopathy, and course of disease had no significant difference between the two groups (P > 0.05). After treatment, the waist-to-hip ratio, total body fat percentage, total body fat mass, total body lean mass, and A/G ratio were significantly decreased in both groups (P < 0.05) compared with before treatment, and were significantly lower in the combination group than in the single-drug group (P < 0.05). The combination group had significantly lower urinary transferrin (Tf), neutrophil gelatinase-associated lipocalin (NGAL) and tumor necrosis factor (TNF)-α, insulin-like growth factor 1 (IGF-1), retinol-binding protein (RBP), homocysteine (Hcy), brain natriuretic peptide (BNP), 24 h urinary albumin excretion ratio (UAER), urine albumin to creatinine ratio (UACR) and urinary liver-type fatty acid binding protein (L-FABP) levels, and higher secretory frizzled-related protein 5 levels than the single-drug group after treatment (P < 0.05). CONCLUSION: Liraglutide combined with dapagliflozin or empagliflozin treatment can effectively reduce the levels of Tf, NGAL and TNF-α in patients with T2DM, and improve the renal function in terms of IGF-1, RBP, Hcy, BNP, UAER, UACR, L-FABP, showing high treatment safety.
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Background: Studies have not provided clear enough evidence on the direct association between cigarette smoking and poverty. This study aims to assess the association of householder smoking with near-poverty households, and the potential mediating effect of NCDs. Methods: A cross-sectional survey was conducted from November 2019 to October 2020 in relatively underdeveloped regions in China. In total, 2,409 households were investigated in areas under the jurisdiction of 24 primary health care (PHC) institutions of eight provinces. Pearson's χ2-test was performed, and multivariable logistic regression and extended probit regression models were fitted to examine the association between householder smoking and near-poverty households. Moreover, generalized structural equation modeling was used to explore the mediating effect of NCDs. Results: After adjusting for all other potential confounding factors, compared with households headed by never-smokers, households headed by smokers exhibited significantly elevated risks of being near poverty, with an odds ratio of 2.01 (95% CI: 0.48-0.91). We also found that living in rural areas and having a low education level both had a negative effect on being near poverty. Additionally, NCDs had a significantly positive mediating effect, with a 31.57% effect of householder smoking on near-poverty status mediated by NCDs; the indirect effect was estimated to be 0.17 (95% CI: 0.04-0.31). Conclusions: Householder smoking significantly elevated the risk of the household being near poverty, and suffering NCDs had a positive mediating effect.
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Características da Família , Pobreza , China/epidemiologia , Estudos Transversais , Fumar/epidemiologiaRESUMO
OBJECTIVE: This study aims to dissect the mechanism of traditional Chinese medicinal herbs against asthma; we chose to first focus on the main chemical components of licorice to investigate their contribution to asthmatic inflammation inhibition. METHODS: Production of cellular nucleotide molecules such as cAMP, cGMP, and cGAMP was examined by using enzyme-linked immunosorbent assay (ELISA). Enzyme-encoding genes were tested in vitro using quantitative real-time PCR and protein level was detected by Western blotting analysis. In addition, co-culturing of murine dendritic cells together with T cells was conducted to examine the expression of cytokine genes and host immune response. RESULTS: We found that one of the components within licorice, named liquiritigenin (LR), could efficiently enhance cAMP production in different cell lines. The augmentation of such molecules was linked to the high expression of cAMP synthesis genes and repressed expression of cAMP breaking down genes. In addition, the downstream immune response was also alleviated by the increase in cAMP levels by LR, suggesting the great potential of this molecule against inflammation. Subsequent immunological tests showed that LR could efficiently inhibit the expression of several cytokines and alter the NF-κB pathway and T cell polarization. CONCLUSION: Altogether, we have identified a promising antiasthmatic agent LR that could exhibit immunosuppressive function by elevating the cAMP level.
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Asma , AMP Cíclico/biossíntese , Células Dendríticas/imunologia , Flavanonas/farmacologia , Pterigotos , Transdução de Sinais/efeitos dos fármacos , Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Asma/imunologia , Asma/patologia , Células Cultivadas , Citocinas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/genética , Testes Imunológicos/métodos , NF-kappa B/metabolismoRESUMO
PURPOSE: Previously we showed that natural compound α-penta-galloyl-glucose (α-PGG) and its synthetic derivative 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-D-glucopyranose (6Cl-TGQ) act to improve insulin signaling in adipocytes by increasing glucose transport. In this study, we investigated the mechanism of actions of α-PGG and 6Cl-TGQ on insulin secretion. METHODS: Mouse islets and/or INS-1832/13 beta-cells were used to test the effects of our compounds on glucose-stimulated insulin secretion (GSIS), intracellular calcium [Ca2+]i using fura-2AM, glucose transport activity via a radioactive glucose uptake assay, intracellular ATP/ADP, and extracellular acidification (ECAR) and mitochondrial oxygen consumption rates (OCAR) using Seahorse metabolic analysis. RESULTS: Both compounds reduced GSIS in beta-cells without negatively affecting cell viability. The compounds primarily diminished glucose uptake into islets and beta-cells. Despite insulin-like effects in the peripheral tissues, these compounds do not act through the insulin receptor in islets. Further interrogation of the stimulus-secretion pathway showed that all the key metabolic factors involved in GSIS including ECAR, OCAR, ATP/ADP ratios, and [Ca2+]i of INS-1832/13 cells were diminished after the compound treatment. CONCLUSION: The compounds suppress glucose uptake of the beta-cells, which consequently slows down the rates of glycolysis and ATP synthesis, leading to decrease in [Ca2+]i and GSIS. The difference between adipocytes and beta-cells in effects on glucose uptake is of great interest. Further structural and functional modifications could produce new compounds with optimized therapeutic potentials for different target cells. The higher potency of synthetic 6Cl-TGQ in enhancing insulin signaling in adipocytes but lower potency in reducing glucose uptake in beta-cells compared to α-PGG suggests the feasibility of such an approach.
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Background. Fine needle aspiration (FNA) remains the first-line diagnostic in management of thyroid nodules and reduces unnecessary surgeries. However, it is still challenging since cytological results are not always straightforward. This study aimed to examine the results of thyroid FNA using the Bethesda system for reporting thyroid cytopathology (TBSRTC) to establish the level of accuracy of FNA procedures in a rural practice setting. Method. A retrospective chart review was conducted on existing thyroid FNA performed in a referral endocrine center between December 2011 and November 2015. Results. A total of 159 patients (18-88 years old) and 236 nodule aspirations were performed and submitted for evaluation. 79% were benign, 3% atypia/follicular lesion of unknown significance (AUS/FLUS), 5% follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), 4% suspicious for malignancy (one case was indeed an atypical parathyroid neoplasm by surgical pathology), 2% malignant, and 7% nondiagnostic. Two cases also had advanced molecular analysis on FNA specimens before thyroidectomy. Conclusion. The diagnostic yield of FNA cytology from our practice in a rural setting suggests that accuracy and specificity are comparable to results from larger centers.
RESUMO
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary arterial remodeling and right ventricular failure. Despite recent advances in pathophysiological mechanism exploration and new therapeutic approaches, PAH remains a challenging condition. In this study, we investigated the roles of the peptide fragments from proadrenomedullin (proADM) such as adrenomedullin (ADM), adrenotensin (ADT), and proadrenomedullin N-terminal 20 peptide (PAMP) during pulmonary remodeling caused by high pulmonary blood flow, and probed the possible involvement of mitogen-activated protein kinase (MAPK) signal transduction pathways. Sixteen rat models of PAH were artificially established by surgically connecting the left common carotid artery to the external jugular vein. We subcutaneously injected an extracellular signal-regulated protein kinase (ERK1/2) inhibitor, PD98059, in eight rats, treated another eight rats with an equal volume of saline. Eight rats without connections served as the control group. We observed that mRNA expression levels of ADM, stress-activated protein kinase (SAPK), and ERK1/2 were significantly elevated in the shunted rats; furthermore, ERK1/2 levels were significantly inhibited by PD98059. Protein levels of ADM, PAMP, p-SAPK, and p-ERK1/2 were significantly higher ADT was lower, and p-p38 remained unchanged in the rat models compared with the controls. However, the protein expression of both ADM and p-ERK1/2 was significantly inhibited by PD98059. Our results suggest that levels of ADM, ADT, and PAMP respond to pulmonary remodeling, and that activation of the SAPK and ERK1/2 signaling pathways is involved in pulmonary hypertension and artery remodeling caused by high pulmonary blood flow.
Assuntos
Adrenomedulina/biossíntese , Hipertensão Pulmonar/fisiopatologia , Sistema de Sinalização das MAP Quinases , Fragmentos de Peptídeos/biossíntese , Precursores de Proteínas/biossíntese , Adrenomedulina/genética , Remodelação das Vias Aéreas , Animais , Expressão Gênica , Hipertensão Pulmonar/metabolismo , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Fragmentos de Peptídeos/genética , Precursores de Proteínas/genética , Circulação Pulmonar , Ratos Wistar , Fluxo Sanguíneo Regional , Remodelação VascularRESUMO
It is well known that zinc (Zn(2+)) is required for the process of insulin biosynthesis and the maturation of insulin secretory granules in pancreatic beta (ß)-cells, and that changes in Zn(2+) levels in the pancreas have been found to be associated with diabetes. Glucose-stimulation causes a rapid co-secretion of Zn(2+) and insulin with similar kinetics. However, we do not know whether Zn(2+) regulates insulin availability and secretion. Here we investigated the effect of Zn(2+) on glucose-stimulated insulin secretion (GSIS) in isolated mouse pancreatic islets. Whereas Zn(2+) alone (control) had no effect on the basal secretion of insulin, it significantly inhibited GSIS. The application of CaEDTA, by removing the secreted Zn(2+) from the extracellular milieu of the islets, resulted in significantly increased GSIS, suggesting an overall inhibitory role of secreted Zn(2+) on GSIS. The inhibitory action of Zn(2+) was mostly mediated through the activities of KATP/Ca(2+) channels. Furthermore, during brief paired-pulse glucose-stimulated Zn(2+) secretion (GSZS), Zn(2+) secretion following the second pulse was significantly attenuated, probably by the secreted endogenous Zn(2+) after the first pulse. Such an inhibition on Zn(2+) secretion following the second pulse was completely reversed by Zn(2+) chelation, suggesting a negative feedback mechanism, in which the initial glucose-stimulated Zn(2+) release inhibits subsequent Zn(2+) secretion, subsequently inhibiting insulin co-secretion as well. Taken together, these data suggest a negative feedback mechanism on GSZS and GSIS by Zn(2+) secreted from ß-cells, and the co-secreted Zn(2+) may act as an autocrine inhibitory modulator.