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1.
PLoS One ; 15(1): e0228093, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31971961

RESUMO

Multiple organ dysfunction induced by sepsis often involves kidney injury. Extracellular histones released in response to damage-associated molecular patterns are known to facilitate sepsis-induced organ dysfunction. Recombinant human soluble thrombomodulin (rhTM) and its lectin-like domain (D1) exert anti-inflammatory effects and neutralize damage-associated molecular patterns. However, the effects of rhTM and D1 on extracellular histone H3 levels and kidney injury remain poorly understood. Our purpose was to investigate the association between extracellular histone H3 levels and kidney injury, and to clarify the effects of rhTM and D1 on extracellular histone H3 levels, kidney injury, and survival in sepsis-induced rats. Rats in whom sepsis was induced via cecal ligation and puncture were used in this study. Histone H3 levels, histopathology of the kidneys, and the survival rate of rats at 24 h after cecal ligation and puncture were investigated. Histone H3 levels increased over time following cecal ligation and puncture. Histopathological analyses indicated that the distribution of degeneration foci among tubular epithelial cells of the kidney and levels of histone H3 increased simultaneously. Administration of rhTM and D1 significantly reduced histone H3 levels compared with that in the vehicle-treated group and improved kidney injury. The survival rates of rats in rhTM- and D1-treated groups were significantly higher than that in the vehicle-treated group. The results of this study indicated that rhTM and its D1 similarly reduce elevated histone H3 levels, thereby reducing acute kidney injury. Our findings also proposed that rhTM and D1 show potential as new treatment strategies for sepsis combined with acute kidney injury.


Assuntos
Espaço Extracelular/metabolismo , Histonas/metabolismo , Rim/patologia , Proteínas Recombinantes/uso terapêutico , Sepse/tratamento farmacológico , Trombomodulina/uso terapêutico , Animais , Ceco/patologia , Creatinina/sangue , Histonas/sangue , Humanos , Rim/efeitos dos fármacos , Ligadura , Masculino , Domínios Proteicos , Punções , Ratos Wistar , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Sepse/sangue , Análise de Sobrevida , Trombomodulina/administração & dosagem , Trombomodulina/química
2.
Eur J Histochem ; 64(1)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31941266

RESUMO

The tissue inflammatory response can influence the outcome of anastomotic healing. Anastomotic leakage represents a dreadful complication after gastrointestinal surgery, in particular sepsis and intra-abdominal infections impair the restorative process of colic anastomoses. It has been debated whether the administration of non-steroidal anti-inflammatory drugs (NSAIDs) is a risk factor for dehiscence, since many patients receive NSAIDs in the early postoperative period. Our aim was, for the first time, to analyze the morpho-functional effects of postoperative administration of two commonly used NSAIDs, Diclofenac and Ketorolac, on the healing process of colo-colic anastomoses constructed under condition of fecal peritonitis in a rat model. Sixty adult male rats underwent two surgical procedures: peritonitis induction and colo-colic anastomosis, and were divided into three groups: 20 rats received saline; 20 rats 4 mg/kg Diclofenac and 20 rats 5 mg/kg Ketorolac. We assessed anastomosis strength, morphological features of tissue wound healing, immunohistochemical metalloproteinase 9 (MMP9) expression and collagen deposition and content by Sirius red staining and hydroxyproline level. We found no significant difference in bursting pressure, collagen content and organization and morphological features between the groups, except a significantly reduced presence of inflammatory cells and MMP9 expression in the groups treated with NSAIDs. Our findings showed that Diclofenac and Ketorolac administration did not affect post-surgical healing and did not increase the leakage risk of colo-colic anastomoses during peritonitis.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ceco/cirurgia , Diclofenaco/farmacologia , Cetorolaco/farmacologia , Peritonite/cirurgia , Cicatrização/efeitos dos fármacos , Anastomose Cirúrgica , Fístula Anastomótica/etiologia , Fístula Anastomótica/patologia , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Ceco/metabolismo , Ceco/patologia , Diclofenaco/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/patologia , Cetorolaco/uso terapêutico , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Peritonite/metabolismo , Peritonite/patologia , Ratos Wistar , Fatores de Risco , Deiscência da Ferida Operatória/etiologia , Deiscência da Ferida Operatória/patologia
3.
Ecotoxicol Environ Saf ; 188: 109920, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31733937

RESUMO

This study aimed to investigate the influences of mercuric chloride (HgCl2, 250 ppm, drink water) on the growth performance, cecal morphology and microbiota of chickens (n = 60) after 30, 60, and 90 days of exposure. A control group of sixty chickens received water free of HgCl2. Our results suggested that mercury exposure reduced the body weight and changed the cecal morphology of chickens after the 90-day treatment. Furthermore, sequence analysis of 16 S rRNA gene revealed that the diversity and composition of cecal microbiota in chickens differed between the control and exposure group. At the phylum level, Proteobacteria and Tenericutes phyla both significantly increased in mercury exposure groups on day 30 while only Tenericutes phyla significantly increased on day 60. At the genus level, we observed that the change in microbial populations are most dramatic on day 30. Besides, compared with the control group, the genus Prevotellaceae_UCG-001 significantly increased in exposure group on day 30 but showed no significant difference on day 60, whereas there was a significant decrease on day 90. PICRUSt analysis revealed potential metabolic changes, such as Bacterial invasion of epithelial cells and Metabolism of xenobiotics, associated with mercury exposure in chickens. Taken together, the data show that subchronic exposure to mercury not only affected the growth and development but also caused the dysbiosis of gut microbiota, which may further induced metabolic disorders in chickens.


Assuntos
Ceco/efeitos dos fármacos , Galinhas , Poluentes Ambientais/toxicidade , Microbioma Gastrointestinal , Cloreto de Mercúrio/toxicidade , Microbiota , Animais , Bacteroidetes/isolamento & purificação , Ceco/microbiologia , Ceco/patologia , Galinhas/microbiologia , Relação Dose-Resposta a Droga , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Masculino , Microbiota/genética , Proteobactérias/isolamento & purificação , RNA Ribossômico 16S/genética
4.
J. bras. nefrol ; 41(3): 440-444, July-Sept. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1040241

RESUMO

Abstract Hyperkalemia is one of the most common electrolyte disorders, responsible for a high number of adverse outcomes, including life-threatening arrhythmias. Potassium binders are largely prescribed drugs used for hyperkalemia treatment but unfortunately, there are many adverse events associated with its use, mostly gastrointestinal. Identification of patients at highest risk for the serious complications associated with the current potassium binders, such as colon necrosis and perforation, could prevent fatal outcomes. The authors present a case of a 56-year-old man with secondary diabetes and chronic renal disease that was treated for hyperkalemia with Calcium Polystyrene Sulfonate (CPS). He later presented with acute abdomen due to cecum perforation and underwent ileocecal resection but ultimately died from septic shock a week later. During surgery, a solid white mass was isolated in the lumen of the colon. The mass was identified as a CPS bezoar, a rare drug-mass formed in the gastrointestinal tract that contributed to the perforation. A previous history of partial gastrectomy and vagothomy was identified as a probable risk factor for the CPS bezoar development. Hopefully, the two new potassium binders patiromer and (ZS-9) Sodium Zirconium Cyclosilicate will help treat such high-risk patients, in the near future.


Resumo A hipercalemia é um dos distúrbios eletrolíticos mais comuns, responsável por um grande número de desfechos adversos, incluindo arritmias potencialmente fatais. Quelantes de potássio são amplamente prescritos para o tratamento da hipercalemia, mas infelizmente são muitos os eventos adversos associados ao seu uso, em particular os gastrointestinais. A identificação de pacientes com risco mais elevado para complicações graves associadas aos quelantes de potássio atualmente em uso, como necrose e perfuração do cólon, pode evitar desfechos fatais. O presente artigo descreve o caso de um homem de 56 anos com diabetes secundário e doença renal crônica em tratamento por hipercalemia com poliestirenossulfonato de cálcio (PSC). Posteriormente o paciente apresentou abdômen agudo devido a perfuração do ceco e foi submetido a uma ressecção ileocecal, mas acabou indo a óbito por choque séptico uma semana mais tarde. Durante a cirurgia, uma massa branca sólida foi isolada no lúmen do cólon. A massa foi identificada como um bezoar de PSC, uma massa de fármaco de rara ocorrência formada no trato gastrointestinal que contribuiu para a perfuração. História pregressa de gastrectomia parcial e vagotomia foi identificada como provável fator de risco para o desenvolvimento do bezoar de PSC. Espera-se que os dois novos quelantes de potássio - patiromer e ciclossilicato de zircônio sódico - ajudem a tratar pacientes de alto risco em um futuro próximo.


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Poliestirenos/uso terapêutico , Bezoares/complicações , Ceco/patologia , Hiperpotassemia/tratamento farmacológico , Perfuração Intestinal/etiologia , Silicatos/uso terapêutico , Evolução Fatal , Diabetes Mellitus/etiologia , Hiperpotassemia/etiologia
5.
Gastroenterology ; 157(6): 1572-1583.e8, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31470007

RESUMO

BACKGROUND & AIMS: Transgenic mice (HBUS) that express the epidermal growth factor receptor (EGFR) ligand HBEGF (heparin-binding epidermal growth factor-like growth factor) and a constitutively active G protein-coupled receptor (US28) in intestinal epithelial cells develop serrated polyps in the cecum. Development of serrated polyps depends on the composition of the gut microbiota and is associated with bacterial invasion of the lamina propria, accompanied by induction of inflammation and up-regulation of interleukin 1 beta (IL1B) and matrix metalloproteinase (MMP) 3 in the cecum. We investigated the mechanisms by which these changes contribute to development of serrated polyps. METHODS: We performed studies with C57BL/6 (control) and HBUS mice. To accelerate polyp development, we increased the exposure of the bacteria to the lamina propria by injecting HBUS mice with diphtheria toxin, which binds transgenic HBEGF expressed by the epithelial cells and causes apoptosis. Mice were given injections of IL1B-neutralizing antibody and the MMP inhibitor N-isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid. Intestinal tissues were collected from mice and analyzed by histology, reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence, and flow cytometry. We examined fibroblast subsets in polyps using single-cell RNA sequencing. RESULTS: Administration of diphtheria toxin to HBUS mice accelerated development of serrated polyps (95% of treated mice developed polyps before 100 days of age, compared with 53% given vehicle). IL1B stimulated subsets of platelet-derived growth factor receptor alpha+ (PDGRFA+) fibroblasts isolated from cecum, resulting in increased expression of MMP3. Neutralizing antibodies against IL1B or administration of the MMP inhibitor reduced the number of serrated polyps that formed in the HBUS mice. Single-cell RNA sequencing analysis showed subsets of fibroblasts in serrated polyps that express genes that regulate matrix fibroblasts and inflammation. CONCLUSIONS: In studies of mice, we found that barrier breakdown and expression of inflammatory factors contribute to development of serrated polyps. Subsets of cecal PDGFRA+ fibroblasts are activated by release of IL1B from myeloid cells during the early stages of serrated polyp development. MMP3 produced by PDGFRA+ fibroblasts is important for serrated polyp development. Our findings confirm the functions of previously identified serrated polyp-associated molecules and indicate roles for immune and stromal cells in serrated polyp development.


Assuntos
Pólipos do Colo/imunologia , Receptores ErbB/metabolismo , Interleucina-1beta/metabolismo , Mucosa Intestinal/patologia , Metaloproteinase 3 da Matriz/metabolismo , Animais , Apoptose/imunologia , Ceco/citologia , Ceco/imunologia , Ceco/patologia , Toxina Diftérica/administração & dosagem , Toxina Diftérica/imunologia , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/patologia , Receptores ErbB/antagonistas & inibidores , Fibroblastos/imunologia , Fibroblastos/metabolismo , Gefitinibe/farmacologia , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Interleucina-1beta/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Metaloproteinase 3 da Matriz/imunologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Camundongos Transgênicos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Sulfonamidas/farmacologia
6.
Nat Commun ; 10(1): 3494, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375667

RESUMO

Necrotizing enterocolitis (NEC) is an idiopathic, inflammatory bowel necrosis of premature infants. Clinical studies have linked NEC with antecedent red blood cell (RBC) transfusions, but the underlying mechanisms are unclear. Here we report a neonatal murine model to investigate this association. C57BL/6 mouse pups rendered anemic by timed phlebotomy and then given RBC transfusions develop NEC-like intestinal injury with prominent necrosis, inflammation, and submucosal edema/separation of the lamina propria in the ileocecal region and colon within 12-24 h. The anemic intestine is infiltrated by inflammatory macrophages, which are activated in situ by RBC transfusions via a Toll-like receptor (TLR)-4-mediated mechanism and cause bowel injury. Chelation of RBC degradation products with haptoglobin, absence of TLR4, macrophage depletion, and inhibition of macrophage activation is protective. Intestinal injury worsens with increasing severity and the duration of anemia prior to transfusion, indicating a need for the re-evaluation of current transfusion guidelines for premature infants.


Assuntos
Anemia/complicações , Enterocolite Necrosante/etiologia , Transfusão de Eritrócitos/efeitos adversos , Doenças do Recém-Nascido/etiologia , Anemia/terapia , Animais , Animais Recém-Nascidos , Ceco/patologia , Colo/patologia , Modelos Animais de Doenças , Enterocolite Necrosante/patologia , Humanos , Íleo/patologia , Recém-Nascido , Doenças do Recém-Nascido/patologia , Recém-Nascido Prematuro , Mucosa Intestinal/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo
7.
Med Sci Monit ; 25: 5986-5991, 2019 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-31401645

RESUMO

BACKGROUND Sepsis is a devastating medical condition. In the USA, about 745 000 people are diagnosed with sepsis annually. Although many anti-inflammatory drugs have been used to manage sepsis, the treatment success rate is very low. This study was undertaken to examine the protective effects of naringenin on sepsis-induced kidney injury in rats. MATERIAL AND METHODS Sepsis was induced in Wistar albino rats by cecal ligation and puncture methods. Histological analysis was performed with hematoxylin and eosin (HE) staining. Reactive oxygen species (ROS) levels were determined by flow cytometery. TUNEL assay was used to demonstrate apoptosis. Sandwich ELISA method was used for the determination of urinary angiotensinogen, and protein expression was determined by Western blot analysis. RESULTS We found that naringenin decreased atrophy in the glomerulus and enabled maintenance of the capsule area and normal tubular cavity of the septic rats. Admistration of naringenin at the dosage of 10 and 20 mg/kg to sepsis rats caused significant reduction in the sepsis-induced apoptosis of kidney cells, accompanied by decrease in Bax and increase in Bcl-2 expression. Moreover, naringenin also decreased the ROS levels in septic rats and downregulated the expression of SOD, CAT, and APX. The effects of naringenin were also examined on the levels of urinary angiotensinogen in sepsis rats. We found that naringenin caused a significant decrease in urinary angiotensinogen levels of septic rats. CONCLUSIONS Naringenin appears to have potential in the treatment of sepsis.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Flavanonas/farmacologia , Sepse/tratamento farmacológico , Angiotensinogênio/urina , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Ceco/patologia , Modelos Animais de Doenças , Rim/patologia , Glomérulos Renais/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Sepse/complicações , Sistema Urinário/patologia
8.
Ecotoxicol Environ Saf ; 183: 109588, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31450035

RESUMO

Lead (Pb) is one of the most hazardous metals to human and wildlife and it also has multiple negative impacts on birds. However, its influences on bird gut morphology and intestinal microbiota were still unclear. We used female Japanese quails (Coturnix japonica) to examine the effects of chronic lead exposure (0, 50 ppm and 1000 ppm) on cecal histology, microbial communities and immune function. The results showed 50 ppm lead exposure caused subtle damages of cecum cell structure. However, 1000 ppm lead exposure caused severe cecum histopathological changes characterized by mucosa abscission, Lieberkühn glands destruction and lymphocyte proliferation. Moreover, both lead concentrations induced ultrastructural damages featured by nucleus pyknosis, mitochondrial vacuolation and microvilli contraction. Meanwhile, microbial community structure, species diversity, taxonomic compositions and taxa abundance in the cecum were affected by lead exposure. Furthermore, the mRNA relative expression of immunity-related genes such as interleukin 2 (IL-2) and gamma interferon (IFN-γ) was significantly downregulated while that of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) and natural killer kappa B (NF-κB) was significantly upregulated in the cecum of 50 and 1000 ppm lead exposure groups. We concluded that lead exposure may cause gut health impairment of female Japanese quails by inducing cecal histopathological changes, microbiota dysbiosis and cecal immune disorder.


Assuntos
Ceco/efeitos dos fármacos , Coturnix/imunologia , Coturnix/microbiologia , Disbiose/induzido quimicamente , Exposição Ambiental , Microbioma Gastrointestinal/efeitos dos fármacos , Chumbo/toxicidade , Animais , Ceco/imunologia , Ceco/microbiologia , Ceco/patologia , Citocinas/genética , Modelos Animais de Doenças , Feminino
9.
Int J Colorectal Dis ; 34(9): 1585-1590, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31377853

RESUMO

PURPOSES: Bowel resection in patients with Crohn's disease (CD) has a high reported rate of postoperative complications and surgical recurrence. A macroscopically normal resection margin is recommended in CD surgery as wider margins do not translate in reduced recurrence rates. The aim of this study was to evaluate the association between resection margin status and anastomotic complications following ileocaecal resection for primary CD. METHODS: All patients treated with ileocaecal resection for primary CD from 2010 to 2018 were included in this retrospective observational study. Emergency operations and recurrent CD were excluded. Patients in whom an anastomosis was not fashioned at the time of the surgery were also excluded. Histopathology data collected included macroscopic description, presence of macroscopic and microscopic involvement of the proximal and distal resection margins. The primary outcome was the rate of positive resection margin in patients who developed anastomotic complications (anastomotic leaks and intra-abdominal collections), and the secondary outcomes were overall complications rate, length of hospital stay, reoperations and rehospitalisation within 30 days. RESULTS: A total of 104 patients were included. The proximal resection margin was microscopically involved in 19 patients (18.2%). Ten patients (9.6%) developed intra-abdominal anastomotic related complications, with 5 patients out of 10 (50%) in the group of postoperative anastomotic complications having a positive microscopic proximal margin at histology, compared to 14 patients (14.9%) in the group that did not develop anastomotic complications (p < 0.0001). CONCLUSIONS: Microscopic involvement of the proximal resection margin is more frequent in patients who develop postoperative anastomotic complications following elective ileocaecal resection for primary CD.


Assuntos
Ceco/cirurgia , Doença de Crohn/cirurgia , Íleo/cirurgia , Margens de Excisão , Complicações Pós-Operatórias/etiologia , Adulto , Anastomose Cirúrgica/efeitos adversos , Ceco/patologia , Doença de Crohn/patologia , Feminino , Humanos , Íleo/patologia , Masculino , Resultado do Tratamento
11.
Biomed Pharmacother ; 116: 109002, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154270

RESUMO

Berberine (BBR) is a non-prescription drug to treat various bacteria-associated diarrheas. However, BBR has also been reported to cause diarrhea in clinic, with underlying mechanisms poorly understood. Because altered gut microbial ecology is a potential basis for diarrhea, this study was conducted to investigate the impact of BBR on gut microbiota of treatment-emergent diarrhea. BBR treatment (200 mg/kg, i.g.) in normal rats exhibited no significant changes in serum biochemical parameters but mild diarrhea occurred, accompanied with the decreased gastrointestinal transit time and increased fecal moisture, suggestive of the local effects of BBR in the intestine. Colon histology revealed the decreased abundance of mucus-filled goblet cells in BBR group. Although BBR-treated rats had the enlarged cecum with watery caecal digesta, short-chain fatty acids concentration was significantly lower than control group. Additionally, BBR caused gut microbiota dysbiosis by evaluating the decreased observed species number and Shannon index. BBR increased the relative abundances of families Porphyromonadaceae and Prevotellaceae as well as genera Parabacteroides, Prevotellaceae_UCG-001 and Prevotellaceae_NK3B31_group. Spearman's correlation analysis revealed family Prevotellaceae and genus Prevotellaceae_UCG-001 as the most prominent drivers of the BBR treatment-emergent diarrhea, correlating positively with fecal moisture but negatively with gastrointestinal transit time. This study therefore demonstrated that the treatment-emergent mild diarrhea of BBR was most likely due to the dysbiosis of the gut microbiota.


Assuntos
Berberina/efeitos adversos , Diarreia/induzido quimicamente , Diarreia/microbiologia , Disbiose/complicações , Disbiose/microbiologia , Microbioma Gastrointestinal , Animais , Biodiversidade , Ceco/patologia , Colo/efeitos dos fármacos , Colo/patologia , Colo/fisiopatologia , Diarreia/fisiopatologia , Disbiose/fisiopatologia , Ácidos Graxos/metabolismo , Fezes/química , Microbioma Gastrointestinal/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Masculino , Tamanho do Órgão , Ratos Wistar , Estatísticas não Paramétricas
13.
Chemosphere ; 234: 409-418, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31228844

RESUMO

Intestinal microflora play an important role in maintaining the homeostasis of the intestinal microenvironment, but fluoride-induced changes in intestinal mechanical barrier and intestinal microflora have not been well studied. Given this paucity of information, this study aims to determine the effects of high fluoride level on intestinal mechanical barrier and intestinal microflora in the cecum of mice. Seventy-two female 21-day-old Kunming mice were randomly assigned to three groups and raised for 70 days. Changes in intestinal pathomorphology and intestinal epithelial cell proliferation were observed by haematoxylin and eosin-staining and Brdu measurement, respectively. The distribution of goblet cells, glycoproteins and mast cells was analysed through Alcian blue and periodic acid-Schiff (AB-PAS) staining, Periodic Acid-Schiff (PAS) staining, and toluidine blue staining. Results showed that excessive fluoride damaged the structure of the cecal tissues, inhibited epithelial cell proliferation and decreased the relative distribution of goblet cells, glycoproteins and mast cells that are involved in defense responses. Intestinal microflora sequencing analysis revealed that the composition of the diversity and composition of intestinal microflora was altered by excessive fluoride based on 16S rRNA amplicon sequencing. The relative abundance of Firmicutes (P = 0.03174), Bacteroidetes (P = 0.04462), Actinobacteria (P = 0.01085) and Spirochacteria (P = 0.04084) was significantly changed in the fluoride group as compared with the control group. In conclusion, excessive fluoride intake induced intestinal barrier damage, leading to changes in cecal composition, epithelium secretion and intestinal microflora.


Assuntos
Ceco/efeitos dos fármacos , Epitélio/patologia , Fluoretos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/patologia , Animais , Bactérias/genética , Bactérias/isolamento & purificação , Ceco/microbiologia , Ceco/patologia , Epitélio/efeitos dos fármacos , Feminino , Intestinos/microbiologia , Camundongos , RNA Ribossômico 16S/genética
14.
Infect Immun ; 87(9)2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31235639

RESUMO

Salmonella enterica serovar Typhimurium (S. Typhimurium) induces inflammatory changes in the ceca of streptomycin-pretreated mice. In this mouse model of colitis, the type III secretion system 1 (T3SS-1) has been shown to induce rapid inflammatory change in the cecum at early points, 10 to 24 h after infection. Five proteins, SipA, SopA, SopB, SopD, and SopE2, have been identified as effectors involved in eliciting intestinal inflammation within this time range. In contrast, a T3SS-1-deficient strain was shown to exhibit inflammatory changes in the cecum at 72 to 120 h postinfection. However, the effectors eliciting T3SS-1-independent inflammation remain to be clarified. In this study, we focused on two T3SS-2 phenotypes, macrophage proliferation and cytotoxicity, to identify the T3SS-2 effectors involved in T3SS-1-independent inflammation. We identified a mutant strain that could not induce cytotoxicity in a macrophage-like cell line and that reduced intestinal inflammation in streptomycin-pretreated mice. We also identified five T3SS-2 effectors, SifA, SpvB, SseF, SseJ, and SteA, associated with T3SS-1-independent macrophage cytotoxicity. We then constructed a strain lacking T3SS-1 and all the five T3SS-2 effectors, termed T1S5. The S. Typhimurium T1S5 strain significantly reduced cytotoxicity in macrophages in the same manner as a mutant invA spiB strain (T1T2). Finally, the T1S5 strain elicited no inflammatory changes in the ceca of streptomycin-pretreated mice. We conclude that these five T3SS-2 effectors contribute to T3SS-1-independent inflammation.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/fisiologia , Colite/microbiologia , Salmonella enterica/patogenicidade , Estreptomicina/farmacologia , Sistemas de Secreção Tipo III/fisiologia , Animais , Ceco/patologia , Colite/patologia , Modelos Animais de Doenças , Macrófagos/patologia , Camundongos , Proteínas dos Microfilamentos/fisiologia , Salmonella enterica/metabolismo
15.
Biomed Pharmacother ; 117: 109163, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31238257

RESUMO

Xuebijing (XBJ) injection, a Chinese traditional medicine injection, is widely used in the treatment of sepsis in China, and shows a promising clinical therapeutic effect. However, its impacts on the metabolic changes of sepsis have not yet been reported. We established a septic rat model using cecal ligation and puncture (CLP) and treated with XBJ or placebo (saline). The survival rates were monitored for 7d, the effects of XBJ on liver and kidney tissue morphology, serum biochemistry [alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine (Cr)] and cytokines [tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6)] production were assessed. Plasma samples were profiled by gas chromatography/mass spectrometer (GC/MS) and analyzed to evaluate the metabolites changes. We found that XBJ can increase the survival rate of septic rats by reducing multi-organ dysfunctions shown as decrease in serum biochemistry indicators, cytokines, and morphologic changes. A Partial Least-Squares Discriminant Analysis (PLS-DA) score plot indicated that rats undergo significant metabolic changes between the three groups. 21 distinct metabolites with VIP>1.5 and p<0.05 were were identified between these group. These metabolites primarily reflected disorders in energy metabolism, glucose metabolism and amino acid metabolism. This study established the foundation for further research of the mechanisms and therapeutic targets of sepsis.


Assuntos
Ceco/patologia , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Cromatografia Gasosa-Espectrometria de Massas , Metabolômica , Punções , Sepse/tratamento farmacológico , Sepse/metabolismo , Animais , Medicamentos de Ervas Chinesas/farmacologia , Ligadura , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma , Análise Multivariada , Ratos Sprague-Dawley , Sepse/sangue , Síndrome de Resposta Inflamatória Sistêmica/patologia
16.
Biomed Pharmacother ; 117: 109150, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31234024

RESUMO

Sepsis, a life-threatening disease with high morbidity and mortality in critically ill patients, usually leads to serious complications including liver damage and dysregulated metabolic homoeostasis. The aim of this study was to evaluate the therapeutic potential of melatonin in rats with caecal ligation and puncture (CLP)-induced sepsis, which mimics critical infections in humans and explore the underlying molecular mechanisms. Male Sprague-Dawley rats received CLP surgery under anaesthesia to induce polymicrobial sepsis. Melatonin (20 mg/kg) was intraperitoneally (i.p.) injected every 12 h for 7 days after CLP, with or without intraperitoneal injection of the SIRT1 inhibitor EX527 (5 mg/kg). Markers of glucose metabolism, inflammation, liver function and associated signaling pathway were measured. Septic rats exhibited marked inhibition of the hepatic SIRT1/STAT3 pathway, along with increased blood glucose levels and hepatic gluconeogenesis. Melatonin administration efficiently attenuated liver dysfunction and glucose metabolism disorders by promoting hepatic SIRT1 expression and STAT3 phosphorylation. Furthermore, inhibition of SIRT1 by EX527 significantly diminished the protective effects of melatonin on sepsis induced liver injury, hyperglycaemia and STAT3 inactivation. These results emphasize that melatonin is a potential therapeutic agent for sepsis-associated liver injury and glucose metabolism disorders, possibly acting by targeting SIRT1-mediated STAT3 activation in the liver.


Assuntos
Gluconeogênese , Fígado/lesões , Melatonina/farmacologia , Substâncias Protetoras/farmacologia , Fator de Transcrição STAT3/metabolismo , Sepse/complicações , Transdução de Sinais , Sirtuína 1/metabolismo , Acetilação , Animais , Carbazóis/farmacologia , Ceco/patologia , Citocinas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Gluconeogênese/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Ligadura , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Punções , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Biomed Pharmacother ; 116: 109012, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146107

RESUMO

The bioactive phenylethanoid 3,4-dihydroxyphenylethyl alcohol glycoside (DAG) is a component isolated from Sargentodoxa cuneata. The effects of DAG on acute lung injury (ALI) are largely unknown. Here, the effects of DAG on sepsis-induced ALI were investigated, and the related mechanisms were explored. Male C57BL/6 mice were used to establish a sepsis-induced ALI model. Levels of inflammatory cytokines were determined using real-time quantitative reverse transcription PCRs (qRT-PCR) and enzyme-linked immunosorbent assays (ELISAs). Pathological changes in the lung tissues were evaluated using haematoxylin and eosin (HE) staining. Mouse survival was quantified, and macrophage polarization was analyzed using flow cytometry. Our results showed that, in septic mice, pretreatment with DAG significantly improved survival, reduced histological damage in the lung, and suppressed the inflammatory response by inhibiting the activation of the NF-κB, STAT3, and p38 MAPK signaling pathways. Moreover, DAG treatment reduced the percentage of M1 macrophages in the bronchoalveolar lavage fluid (BALF) and spleen. In addition, DAG treatment decreased the production of pro-inflammatory cytokines and suppressed the activation of the NF-κB, STAT3, and p38 MAPK signaling pathways in LPS-induced MH-S cells. DAG treatment also reduced the relative abundances of M1 macrophages and M1 macrophage markers by suppressing the activation of the Notch1 signaling pathway. Thus, our results provided new insights for the development of drugs to treat ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Polaridade Celular , Glicosídeos/uso terapêutico , Inflamação/patologia , Macrófagos/patologia , Sepse/tratamento farmacológico , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/patologia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Ceco/patologia , Polaridade Celular/efeitos dos fármacos , Citocinas/metabolismo , Glicosídeos/química , Glicosídeos/farmacologia , Mediadores da Inflamação/metabolismo , Ligadura , Lipopolissacarídeos , Pulmão/irrigação sanguínea , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Peroxidase/metabolismo , Fenótipo , Punções , Fator de Transcrição STAT3/metabolismo , Sepse/complicações , Sepse/patologia , Análise de Sobrevida
18.
Int J Surg Pathol ; 27(6): 693-696, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31006344

RESUMO

Myxomas are benign mesenchymal neoplasms of unknown etiology that most commonly occur in the cardiac atrium; however, other reported sites include the skin, joints, skeletal muscles, maxillofacial bones, and sinonasal tract. Myxomas involving the gastrointestinal (GI) tract are rare and are limited to a few published case reports. We are presenting, to our knowledge, the first case report of a mucosal myxoma in the colon presenting as a colonic polyp. A 49-year-old woman underwent a screening colonoscopy and was found to have a 0.2-cm sessile polyp in the cecum. Histologically, the polyp was composed of bland spindled cells in the lamina propria set in a hypocellular, myxoid stroma. The lesion was relatively well-demarcated from the surrounding mucosa. The overlying colonic epithelium showed no dysplasia. S-100 immunohistochemical stain showed only focal nonspecific positivity, while CD34, CD117, SMA, EMA, and desmin were all negative. Alcian blue special stain showed positive staining, supporting the diagnosis of myxoma. Myxomas in the GI tract are very rare, with this being the first reported case of a polypoid colonic mucosal myxoma. Previous reports of GI myxomas are limited to examples in the stomach, small bowel, and one recently reported case in the colon, all of which were submucosal lesions and not limited to the mucosa. In some of the prior reports, the patients had synchronous cardiac atrial myxomas. Mucosal colonic myxoma represents a newly identified mesenchymal polyp of the colon and pathologists should be aware of this diagnostic entity.


Assuntos
Neoplasias do Ceco/diagnóstico , Ceco/patologia , Mucosa Intestinal/patologia , Pólipos Intestinais/diagnóstico , Mixoma/diagnóstico , Biópsia , Neoplasias do Ceco/patologia , Ceco/diagnóstico por imagem , Colonoscopia , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Pólipos Intestinais/patologia , Programas de Rastreamento , Pessoa de Meia-Idade , Mixoma/patologia
20.
Ann Clin Lab Sci ; 49(2): 257-264, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31028073

RESUMO

The aim of this study was to explore the effects of erythropoietin (EPO) in acute lung injuries in rats with sepsis. 127 male SD rats were divided into 3 groups (n=8): group Sham, group ALI (sepsis-caused lung injury), group EPO (EPO intervention). The blood gas analysis, C-reactive protein level (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-10 were detected and compared. The water content fraction and myeloperoxidase (MPO) activities, apoptosis, and expression level of nuclear factor -κB (NF-κB p65) in lung tissues were also detected. Compared to group Sham, the oxygenation index of group ALI was decreased (140.66±12.82 vs. 194.7±16.36), CRP (peak value: 2.31±0.33 mg/L vs. 1.00±0.16 mg/L), IL-10 (peak value: 711.26±84.97 ng/L vs. 51.21±11.45 ng/L), TNF-a (63.69±6.85 ng/L vs. 12.92±0.91 ng/L), and IL-6 (peak value: 1768.93±195.11 ng/L vs. 68.71±11.48 ng/L) increased (P<0.01), and the lung cell apoptosis and expression of NF-κB p65 (302.75±51.38 vs. 121.46±11.79) were also increased (P<0.01), and there was a recovery of EPO group (P<0.01). Group ALI exhibited pulmonary interstitial and alveolar edema, hemorrhage, and lung collapse, but the EPO intervention significantly reduced the above lung pathological changes (the water content was 70.36±1.24% in Sham group, 84.26±3.07% in ALI group and 75.72±1.96% in EPO group, P<0.01; MPO: 2.23±0.67, 7.56±1.02, 5.73±0.86, P<0.01; apoptotic index: 3.73±0.39, 25.69±4.54, 9.59±2.59, P<0.01). EPO could inhibit the expression of NF-κB in lung tissues, inhibit the levels of proinflammatory cytokines TNF-a and IL-6, but improve the level of anti-inflammatory cytokine IL-10, thus reducing the pathological changes of lung tissues and producing protective effects towards lung tissues.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Eritropoetina/uso terapêutico , Substâncias Protetoras/uso terapêutico , Sepse/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Gasometria , Ceco/patologia , Eritropoetina/farmacologia , Mediadores da Inflamação/metabolismo , Ligadura , Pulmão/patologia , Peroxidase/metabolismo , Substâncias Protetoras/farmacologia , Punções , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo , Água/química
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