RESUMO
Non-alcoholic fatty liver disease (NAFLD) is the most common among lipid metabolism disorders. Autophagy plays an important role in lipid metabolism in NAFLD. Pueraria flavonoids, the main active ingredients of Pueraria lobata, exert antioxidant and anti-inflammatory effects. Herein, we report the potential lipid-lowering and anti-inflammatory effects of Pueraria flavonoids on NAFLD induced by a high-fat diet. In vivo and in vitro experiments showed that Pueraria flavonoids reduced intracellular lipid deposition by inhibiting lipid synthesis and the release of pro-inflammatory cytokines. We analyzed the autophagy flux by mRFP-GFP-LC3 plasmid transfection to assess the role of autophagy in intracellular scavenging. After treating mice fed on high fat and HepG2 cells with Pueraria flavonoids, the number of autophagosomes increased significantly, along with the level of autophagy. The autophagy loss after siRNA transfection aggravated lipid deposition and the release of inflammatory cytokines. Mechanistically, Pueraria flavonoids trigger autophagy through PI3K/Akt/mTOR signaling pathway to reduce lipid deposition and inflammation. In summary, our results showed that Pueraria flavonoids stimulated autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway, thereby reducing intracellular lipid accumulation and inflammation levels and alleviating NAFLD.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Pueraria , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos Obesos , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Camundongos Endogâmicos C57BL , Autofagia , Transdução de Sinais , Inflamação/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Lipídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Study objective: Postoperative pulmonary complications (PPCs) are common and associated with adverse outcomes impairing long-term survival and quality of recovery. This single-centered retrospective study aimed to examine factors associated with PPCs in patients receiving elective colorectal surgery aged ≥60 years. Methods: Between January 2019 and December 2019, 638 patients at the Shanghai Changhai Hospital who had received elective surgery for colorectal cancer were enrolled in this study. Patients were divided into the PPC group (n=38) and non-PPC group (n=600). Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), red blood cell distribution width (RDW), and systemic inflammatory index (SII) were selected and caculated to indicate preoperative and postoperative inflammatory status. Receiver operating characteristic curve and bivariate correlation analyses were performed to evaluate the identified risk factors. Main results: The overall incidence of PPCs was approximately 5.96%. Multivariate regression analysis identified age (OR = 1.094, 95%CI 1.038-1.153, P = 0.001), preoperative RDW (OR = 1.159, 95%CI 1.025-1.309, P = 0.018), and preoperative SII (OR = 1.001, 95%CI 1.000-1.003, P = 0.035) as independent risk factors for PPCs. The cut-off values of age, preoperative RDW, and preoperative SII for predicting PPCs were 69.5 (sensitivity 0.658, specificity 0.653), 13.2 (sensitivity 0.789, specificity 0.552) and 556.1 (sensitivity 0.579, specificity 0.672), respectively. Conclusions: Age, preoperative RDW, and preoperative SII were identified as independent risk factors for PPC occurrence in elderly patients receiving elective colorectal surgery. Further studies are warranted to evaluate whether normalization of preoperative RDW and SII, as modifiable risk factors, are associated with improved surgical outcomes.
RESUMO
Atherosclsis is a critical actuator causing cardiac-cerebral vascular disease with a complicated pathogeneon, refered to the disorders of intestinal flora and persistent inflammation. Gastrodin (4-(hydroxymethyl) phenyl-ß-D- Glucopyranoside) is the most abundant glucoside extracted from the Gastrodiaelata, which is a traditional Chinese herbal medicine for cardiac-cerebral vascular disease, yet its mechanisms remain little known. In the present study, the gastrodia extract and gastrodin attenuate the lipid deposition and foam cells on the inner membrane of the inner membrane of the thoracic aorta in the early atherosclerosis mice. Blood lipid detection tips that TC and LDL-C were reduced in peripheral blood after treatment with the gastrodia extract and gastrodin. Furthermore, unordered gut microbes are remodeled in terms of bacterial diversity and abundance at family and genus level. Also, the intestinal mucosa damage and permeability were reversed, accompaniedwith the reducing of inflammatory cytokines. Our findings revealed that the functions of gastrodia extract and gastrodin in cardiac-cerebral vascular disease involved to rescued gut microbes and anti-inflammation may be the mechanismof remission lipid accumulation.
Assuntos
Aterosclerose/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Gastrodia/química , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/tratamento farmacológico , Ácido Acético/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Aterosclerose/microbiologia , Aterosclerose/patologia , Álcoois Benzílicos/farmacologia , Álcoois Benzílicos/uso terapêutico , Ácido Butírico/metabolismo , Modelos Animais de Doenças , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/genética , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Inflamação/microbiologia , Molécula 1 de Adesão Intercelular/sangue , Interleucina-1beta/sangue , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Lipídeos/sangue , Camundongos Endogâmicos C57BL , Propionatos/metabolismo , Proteínas de Junções Íntimas/metabolismo , Fator de Necrose Tumoral alfa/sangueRESUMO
Cigarette smoking-related lung injury is one of the most common and fatal etiologies of many respiratory diseases, for which no effective interventions are available. Astragaloside â £ (ASâ £) is an active component extracted from Astragalus membranaceus. It is prescribed as a treatment for upper respiratory tract infections. Here, we report the potential anti-inflammatory effects and mechanisms of ASâ £ on cigarette smoking extract- (CSE)-exposed RAW264.7 cells. Murine macrophages were exposed to CSE, followed by administration of ASâ £ at 25-100 µg/mL for 24 h. ASâ £ significantly rescued CSE-induced cell death by inhibition of release pro-inflammatory cytokines. We measured autophagy as an intracellular scavenger by analyzing autophagic flux using tandem mRFP-GFP-LC3 fluorescence microscopy. Following administration with ASâ £ in CSE-exposed RAW264.7 cells, there was a notable increase in autophagosomes and a range of autophagic vacuoles were generated, as seen with transmission electron microscopy. Loss of autophagy following transfection siRNA aggravated inflammatory injury and release of inflammatory cytokines. Mechanistically, ASâ £-triggered autophagy is mediated by the TLR4/NF-κB signaling pathway to reduce inflammation. Taken together, our findings suggest that ASâ £ acts stimulates autophagy, and that ASâ £ induces autophagy by inhibiting the TLR4/NF-κB signaling pathway, contributing to alleviation of inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Inflamação/prevenção & controle , Macrófagos/efeitos dos fármacos , NF-kappa B/metabolismo , Saponinas/farmacologia , Receptor 4 Toll-Like/metabolismo , Triterpenos/farmacologia , Animais , Citocinas/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/ultraestrutura , Camundongos , Fosforilação , Células RAW 264.7 , Transdução de SinaisRESUMO
The number of regulatory T cells (Treg cells) and the expression of ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; also known as CD39) and 5'-ectonucleotidase (NT5E; also known as CD73) on the Treg cell surface are increased during sepsis. In this study, to determine the factors leading to the high expression of CD39 and CD73, and the regulation of the CD39/CD73/adenosine pathway in Treg cells under septic conditions, we constructed a mouse model of sepsis and separated the Treg cells using a flow cytometer. The Treg cells isolated from the peritoneal lavage and splenocytes of the mice were treated with adenosine or the specific adenosine A2A receptor agonist, CGS21680, and were transfected with specific siRNA targeting E2F transcription factor 1 (E2F-1) or cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), which are predicted transcription regulatory factors of CD39 or CD73. The regulatory relationships among these factors were then determined by western blot analysis and dual-luciferase reporter assay. In addition, changes in adenosine metabolism were measured in the treated cells. The results revealed that adenosine and CGS21680 significantly upregulated CD39 and CD73 expression (P<0.01). E2F-1 and CREB induced CD39 and CD73 expression, and were upregulated by adenosine and CGS21680. Adenosine triphosphate (ATP) hydrolysis and adenosine generation were inhibited by the knockdown of E2F-1 or CREB, and were accelerated in the presence of CGS21680. Based on these results, it can be inferred that adenosine, the adenosine A2A receptor agonist, E2F-1 and CREB are the possible factors contributing to the high expression of CD39 and CD73 on the Treg cell surface during sepsis. Adenosine and its A2A receptor agonist served as the signal transducer factors of the CD39/CD73/adenosine pathway, accelerating adenosine generation. Our study may benefit further research on adenosine metabolism for the treatment of sepsis.
Assuntos
5'-Nucleotidase/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Antígenos CD/metabolismo , Apirase/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fator de Transcrição E2F1/metabolismo , Fenetilaminas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , 5'-Nucleotidase/genética , Adenosina/metabolismo , Agonistas do Receptor A2 de Adenosina/farmacologia , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Antígenos CD/genética , Apirase/genética , Western Blotting , Células Cultivadas , Meios de Cultivo Condicionados/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Fator de Transcrição E2F1/genética , Camundongos Endogâmicos BALB C , Interferência de RNA , Receptor A2A de Adenosina/metabolismo , Sepse/sangue , Linfócitos T Reguladores/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
OBJECTIVES: Forkhead/winged helix transcription factor p3 (Foxp3) increases in CD4(+)CD25(+)Treg cells during sepsis; however, related mechanisms are unclear. Our study aimed to explore the possible molecular mechanisms of high expression of Foxp3 in Treg cells during sepsis. METHODS: Sepsis was induced by cecal ligation and puncture (CLP) method. CD4(+)CD25(+)Treg cells were isolated from peripheral blood and identified by flow cytometry (FCM). Treg cells were cultured with or without adenosine, adenosine agonist, adenosine antagonist, SMAD family member 3 (Smad3) agonist (transforming growth factor (TGF)-ß1), or C-Jun N-Terminal Kinase (JNK) inhibitor. Expression levels of Foxp3 and activator protein 1 (AP-1) were determined. The binding of c-Fos or c-Jun to the Foxp3 promoter was then evaluated by the chromatin immunoprecipitation (ChIP) assay and quantified by quantitative real-time PCR (qRT-PCR). The mRNA and protein levels of Foxp3 were determined after transfection with siRNA against c-Fos, Fra-2, c-Jun or JunD. RESULTS: Pharmacological inhibition of both adenosine and JNK reduced Foxp3 protein levels. JNK/AP-1 activation was involved in increased levels of Foxp3 protein in CD4(+)CD25(+)Treg cells. AP-1 regulated activity of Foxp3 promoter in Treg cells, and the induction of c-Fos or c-Jun activity leads to elevated transcription of Foxp3 gene. Knockdown of c-Fos, Fra-2, c-Jun, or JunD levels also reduced Foxp3 expression. CONCLUSION: We confirm that adenosine plays significant roles in the high expression of Foxp3. Adenosine promotes Foxp3 expression in Treg cells during sepsis via JNK/AP-1 pathway.
RESUMO
BACKGROUND: Tracheal intubation with conventional laryngoscopy requires many trials until beginners are sufficiently skilled in intubating patients safely. To facilitate intubation, the authors used retrograde light-guided laryngoscopy (RLGL) and compared its feasibility with conventional direct laryngoscopy (DL). METHODS: Twenty operators participated in a prospective, randomized, open-label, parallel-arm study. These operators intubated 205 patients randomly according to a computer-generated procedure by using either DL or RLGL (five intubations with each technique). The primary outcome was the success rate of tracheal intubation. The authors evaluated the success rate of tracheal intubation, the time to glottic exposure and tracheal intubation, and the Cormack and Lehane grades. RESULTS: Compared with DL, the success rate was greater in the RLGL group for all five intubations (72% vs. 47%; rate difference, 25%; 95% CI [11.84-38.16%], P < 0.001). This was associated with a shorter time to glottic exposure (median [25th and 75th percentile]; 27 [15; 42] vs. 45 [30; 73] s, P < 0.001), shorter intubation time (66 [44; 120] vs. 120 [69; 120] s, P < 0.001), and decreased throat soreness (mean ± SD; visual analog scale, 2.1 ± 0.9 vs. 3.7 ± 1.0 cm, P = 0.001) in the RLGL group compared to the DL group. CONCLUSION: RLGL is an alternative intubation technique. In our study, it enables beginners to intubate patients more successfully and quickly than conventional DL.
Assuntos
Intubação Intratraqueal/instrumentação , Laringoscópios , Laringoscopia/métodos , Adulto , Feminino , Glote/anatomia & histologia , Humanos , Intubação Intratraqueal/efeitos adversos , Estimativa de Kaplan-Meier , Luz , Masculino , Pessoa de Meia-Idade , Medição da Dor , Faringite/epidemiologia , Faringite/etiologia , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Traqueia/anatomia & histologia , Resultado do TratamentoRESUMO
BACKGROUND: Sepsis involves imbalance between the proinflammatory and antiinflammatory response to bacterial insults. Ulinastatin (UTI) is a serine protease inhibitor and reportedly exhibits antiinflammatory properties aside from its blocking of the protease pathway both in vitro and in vivo. This study was designed to investigate the potential therapeutic efficacy of UTI for sepsis. MATERIALS AND METHODS: Adult C57BL/6 male mice were divided into three groups: sham group, cecal ligation and puncture (CLP) group, and CLP + UTI group. Acute septic peritonitis was induced by CLP. Saline and UTI (100,000 U/kg) were intravenously injected 30 min after CLP in CLP and CLP + UTI groups, respectively. Samples were collected for further analysis 24 h after surgery. RESULTS: UTI administration significantly improved 7-d survival; ameliorated morphologic damage and weight loss in the spleen and thymus; decreased serum tumor necrosis factor α, interleukin-6, and interleukin-10 (IL-10) levels; increased the number of T and B cells in peripheral blood, spleen, and thymus; and inhibited T-cell apoptosis in the thymus and spleen in septic mice. CONCLUSIONS: UTI exerted a protective effect against sepsis by suppressing inflammatory response and lymphocyte apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Glicoproteínas/farmacologia , Linfócitos/efeitos dos fármacos , Sepse/tratamento farmacológico , Inibidores de Serina Proteinase/farmacologia , Animais , Citocinas/sangue , Contagem de Linfócitos , Linfócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/imunologia , Sepse/mortalidade , Baço/efeitos dos fármacos , Baço/imunologia , Timo/efeitos dos fármacos , Timo/imunologia , Redução de Peso/efeitos dos fármacosRESUMO
OBJECTIVE AND DESIGN: The present study aimed to investigate the combined effects of a neutrophil elastase inhibitor, sivelestat sodium, with a free radical scavenger, edaravone, on lipolysaccharide (LPS)-induced acute lung injury (ALI). MATERIALS AND METHODS: Adult male Sprague-Dawley rats were anesthetized and instilled intratracheally with 2 mg/kg LPS. Sivelestat sodium (10 mg/kg, i.p.) and/or edaravone (8 mg/kg, i.p.) were administered 1 h after LPS instillation. The severity of pulmonary injuries was evaluated 12 h after inducing acute lung injury. RESULTS: In lung tissues, either sivelestat or edaravone treatment alone showed significant protective effects against neutrophil infiltration and tissue injury, as demonstrated by myeloperoxidase activity and histopathological analysis. Sivelestat or edaravone treatment also attenuated the LPS-induced production of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) in rat lungs. However, the LPS-induced elevation of malondialdehyde levels in rat lungs was reduced only by edaravone, but not by sivelestat. In addition, combined treatment with both sivelestat and edaravone demonstrated additive protective effects on LPS-induced lung injury, compared with single treatments. CONCLUSIONS: Combination of sivelestat and edaravone shows promise as a new treatment option for ALI/acute respiratory distress syndrome patients.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Antipirina/análogos & derivados , Sequestradores de Radicais Livres/uso terapêutico , Glicina/análogos & derivados , Proteínas Secretadas Inibidoras de Proteinases/uso terapêutico , Sulfonamidas/uso terapêutico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Antipirina/uso terapêutico , Combinação de Medicamentos , Edaravone , Glicina/uso terapêutico , Interleucina-6/imunologia , Lipopolissacarídeos , Masculino , Malondialdeído/imunologia , Peroxidase/imunologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Impaired lung function is the primary contributor to most deaths associated with severe acute pancreatitis. It is widely accepted that oxidative stress plays a central role in the pathogenesis of pancreatitis and associated complications. Therefore, in the present study, we investigated whether therapeutic treatment with the free radical scavenger edaravone could protect rats against acute pancreatitis and the associated lung injury. Acute pancreatitis was induced by infusion of 1ml/kg of sodium taurocholate (3% solution) into the biliopancreatic duct. Edaravone (8mg/kg) was administered 1h and 13h after inducing pancreatitis, the severity of pancreatic and pulmonary injuries was evaluated 24h after inducing pancreatitis. Edaravone treatment significantly reduced the elevated malondialdehyde levels in rat lungs after acute pancreatitis, suggesting an important role for free radicals in acute pancreatitis-associated lung injury. In addition, edaravone showed significant protective effects against neutrophil infiltration and tissue injury in both pancreas and lung, as demonstrated by serum amylase levels, myeloperoxidase activity and histopathological analysis. Edaravone treatment also attenuated the elevated mRNA levels of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor alpha (TNF-alpha) in rat lungs after acute pancreatitis. In conclusion, edaravone protects rats against acute pancreatitis-associated lung injury, probably through its antioxidant and anti-inflammatory effects. Thus, edaravone shows promise as a treatment for lung injury in patients with acute pancreatitis.