RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Mume Fructus (MF) is a well-known traditional Chinese medicine used to treat chronic cough, prolonged diarrhea, and other inflammation-related diseases. We previously confirmed the anti-colitis effect of its ethanol extract on a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced Crohn's disease (CD) rat model. However, the active ingredients and underlying mechanisms of MF remain unknown. AIM OF THE STUDY: To clarify the material basis and potential mechanism of the ethanol extract of MF (MFE) in alleviating CD and its complications, such as lung injury and intestinal obstruction. MATERIALS AND METHODS: MF was extracted with 80% ethanol aqueous solution and separated with 0, 40, and 100% ethanol aqueous solutions. MFE and its fractions were screened in a TNBS-induced CD rat model. For the bioactive fraction, the chemical composition was identified and quantified using ultrahigh-performance liquid chromatography coupled with diode-array detection and quadrupole time-of-flight tandem mass spectrometry. Interleukin (IL)-1ß, IL-6, IL-17, transforming growth factor (TGF)-ß, and lipopolysaccharide (LPS) levels in the colon, lungs, and/or plasma were detected using enzyme-linked immunosorbent assays. The expression levels of zonula occludens-1 (ZO-1) and occludin in the colon were measured using immunohistochemical staining, and the intestinal microbiota and short-chain fatty acid (SCFA) levels were analyzed using 16S rRNA gene sequencing and gas chromatography/mass spectrometry. RESULTS: The 40% ethanol fraction of MF (MFE40), which mainly contained methyl citrate, ethyl citrate, and caffeoylquinic acid ethyl esters, was identified as the active fraction that could alleviate CD in rats. MFE40 could ameliorate inflammation and fibrosis in the colon and lung tissues by inhibiting the secretion of cytokines, such as IL-1ß, IL-6, IL-17, and TGF-ß, along with intestinal obstruction and lung injury in CD rats. The possible mechanisms of MFE40 were related to increased expression of ZO-1 and occludin in the colon, reduction in plasma LPS levels, and restoration of SCFAs via reduction in the relative abundance of Adlercreutzia, Clostridium_sensu_stricto_1, Erysipelatoclostridium, Faecalibaculum, norank_f_Erysipelotrichaceae, Phascolarctobacterium Coriobacteriaceae_UGG_002, and Allobaculum and increase in the relative abundance of Escherichia shigella, Christensenella, Acetivibrio_ethanolgignens, and Butyricicoccus. MFE40 had no significant influence on the inflammatory factors in healthy rats. CONCLUSIONS: Citrate esters and hydroxycinnamate esters are the main active constituents of MFE40. MFE40 exhibited a remission effect on CD rats and inhibited intestinal obstruction and lung injury via anti-inflammatory effects and regulation of the intestinal microbiota-gut-lung homeostasis.
Assuntos
Doença de Crohn , Obstrução Intestinal , Lesão Pulmonar , Animais , Citratos/metabolismo , Colo , Doença de Crohn/induzido quimicamente , Doença de Crohn/tratamento farmacológico , Doença de Crohn/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Etanol/farmacologia , Inflamação/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Obstrução Intestinal/metabolismo , Lipopolissacarídeos/farmacologia , Lesão Pulmonar/metabolismo , Ocludina/metabolismo , RNA Ribossômico 16S , Ratos , Ácido Trinitrobenzenossulfônico/toxicidadeAssuntos
Antifibróticos/uso terapêutico , Pesquisa Biomédica , Doença de Crohn/tratamento farmacológico , Gastroenterologia , Obstrução Intestinal/prevenção & controle , Intestinos/efeitos dos fármacos , Animais , Antifibróticos/efeitos adversos , Biomarcadores/metabolismo , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Doença de Crohn/fisiopatologia , Fibrose , Humanos , Obstrução Intestinal/metabolismo , Obstrução Intestinal/patologia , Obstrução Intestinal/fisiopatologia , Intestinos/metabolismo , Intestinos/patologia , Intestinos/fisiopatologia , Valor Preditivo dos Testes , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Intestinal obstruction caused by intestinal fibrosis is a common and serious complication of Crohn's disease (CD). Intestinal fibroblasts, the main effector cells mediating gastrointestinal fibrosis, are activated during chronic inflammation. However, the mechanism of fibroblast activation in CD has not been well elucidated. METHODS: Fibroblasts isolated from stenotic and nonstenotic intestines of CD patients were used for RNA sequencing. Immunohistochemical and immunofluorescent staining was performed to evaluate the correlation between intestinal fibrosis and YAP/TAZ expression in our CD cohort and a DSS-induced chronic colitis murine model. A Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) inhibitor was used to explore the ROCK1-YAP/TAZ axis in intestinal fibroblasts in vitro and DSS-induced chronic colitis murine model in vivo. FINDINGS: The expression of YAP/TAZ was significantly upregulated in stenotic fibroblasts, which was associated with the YAP/TAZ target gene signature. YAP/TAZ knockdown suppressed the activation of intestinal fibroblasts. In intestinal fibroblasts, YAP/TAZ were activated by the Rho-ROCK1 signalling pathway. High YAP/TAZ expression was positively correlated with ROCK1 expression, which is a prognostic marker for intestinal obstruction in CD patients. INTERPRETATION: YAP/TAZ activation can lead to fibroblast activation and intestinal obstruction in CD. The effect of ROCK1 inhibitor on alleviating intestinal fibrosis is associated with YAP/TAZ inhibition. Targeted inhibition of YAP/TAZ in fibroblasts may be a potential therapeutic strategy to suppress intestinal fibrosis in CD. FUNDING: This work was supported by the National Key R&D Program of China (2019YFC1316002), the NSFC (81873547, 82073201, 81874177, 82000481) and the Shanghai Sailing Program (20YF1429400).
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Crohn/metabolismo , Fibroblastos/metabolismo , Obstrução Intestinal/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Animais , Células Cultivadas , Doença de Crohn/complicações , Doença de Crohn/patologia , Feminino , Fibrose , Humanos , Obstrução Intestinal/etiologia , Obstrução Intestinal/patologia , Intestinos/citologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fatores de Transcrição/genética , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAP , Quinases Associadas a rho/metabolismoRESUMO
Acute small bowel obstruction remains one of the most challenging nosologies in emergency surgery, leading to a pronounced imbalance between lipid peroxidation and the antioxidant defense system. We aimed to study changes in the anti- and prooxidant status of serum and small intestine wall in an experiment modeling acute small bowel obstruction. The control group included 11 rats, and the main group included 42 rats (simulation of mechanical bowel obstruction on day 1 was conducted in 14 rats, on day 2 - in 12 rats, on day 3 - in 16 rats). Acute small bowel obstruction was modeled by ligation. Serum analysis and removal of the small intestinal wall were performed on days 1, 2, and 3. Indicators of lipid peroxidation and antioxidant protection were determined by the spectrophotometric method, and the imbalance between lipid peroxidation and antioxidant protection gradually increased from 1 to 3 days of observation. On day 3, the low level of aldehyde increased 1.3 times, and the level of superoxide dismutase decreased 1.2 times compared to the control group. Pathophysiological changes in the wall of the small intestine are caused by the activation of lipid peroxidation and the exhaustion antioxidant protection, whereby the degree of their severity increases depending on the increase in time from the moment of modeling of acute obstruction of the small intestine.
Assuntos
Antioxidantes/metabolismo , Obstrução Intestinal/metabolismo , Intestino Delgado/patologia , Doença Aguda , Animais , Intestino Delgado/cirurgia , Peroxidação de Lipídeos , Masculino , Ratos , Superóxido Dismutase/metabolismoRESUMO
Rationale: Smooth muscle-motility disorders are mainly characterized by impaired contractility and functional intestinal obstruction. Some of these cases are caused by genetic mutations of smooth muscle genes ACTA2, ACTG2, MYH11, MYLK and LMOD1. Still the etiology is complex and multifactorial and the underlying pathology is poorly understood. Integrin interaction protein Kindlin-2 is widely expressed in striated and smooth muscle cells (SMC). However, the function of Kindlin-2 in the smooth muscle remains elusive. Methods: We generated two mouse models using different cre promoter transgenic mice, Kindlin-2fl/fl SM22α-cre+ (cKO mice) and Kindlin-2fl/fl; MYH-cre+ (iKO mice). Embryos and adult tissues were prepared for hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) apoptosis assay. We investigated ultrastructure changes of mouse smooth muscle using transmission electron microscopy (TEM) and measured smooth muscle contractile force in mounting aortic and intestinal rings using the multiwire myograph system (DMT 620M). In addition, cell traction force microscopy (CTFM) was applied to observe the functional change of primary SMC after Kindlin-2 depletion by RNAi. Results: Depletion of Kindlin-2 encoding gene Fermt2 in embryonic smooth muscles leads to apoptosis, downregulates the key components of SMC, impairs smooth muscle development, and finally causes embryonic death at E14.5. Tamoxifen-induced Kindlin-2-specific knockout in adult mouse smooth muscle showed decreased blood pressure, intestinal hypoperistalsis, and eventually died of intestinal obstruction. Kindlin-2 depletion also leads to downregulated Myh11, α-SMA, and CNN, shortened myofilament, broken myofibrils, and impaired contractility of the smooth muscles in iKO mice. Mechanistically, loss of Kindlin-2 decreases Ca2+ influx in primary vascular smooth muscle cells (PVSMC) by downregulating the expression of calcium-binding protein S100A14 and STIM1. Conclusion: We demonstrated that Kindlin-2 is essential for maintaining the normal structure and function of smooth muscles. Loss of Kindlin-2 impairs smooth muscle formation during embryonic development by inducing apoptosis and jeopardizes the contraction of adult smooth muscle by blocking Ca2+ influx that leads to intestinal obstruction. Mice with Kindlin-2 depletion in adult smooth muscle could be a potent animal model of intestinal obstruction for disease research, drug treatment and prognosis.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas do Citoesqueleto/deficiência , Obstrução Intestinal/patologia , Proteínas Musculares/deficiência , Músculo Liso/patologia , Animais , Movimento Celular , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Obstrução Intestinal/etiologia , Obstrução Intestinal/metabolismo , Camundongos , Camundongos Knockout , Contração Muscular , Proteínas Musculares/genética , Músculo Liso/metabolismoRESUMO
BACKGROUND: This study aimed to evaluate the safety and feasibility of self-expanding metallic stent (SEMS) followed by neoadjuvant chemotherapy prior to elective surgery for obstructing left-sided colon cancer. METHODS: Eleven consecutive patients with obstructing left-sided colon cancer between May 2014 and November 2015 were included retrospectively. All patients received SEMS followed by neoadjuvant chemotherapy. The primary outcome measure was stoma and laparoscopic surgery. RESULTS: Chemotherapy was with two cycles of CAPOX (54.5%) or three cycles mFOLFOX6 (45.5%). Median serum albumin and hemoglobin levels before surgery were significantly higher than before neoadjuvant chemotherapy (p = 0.01 and p = 0.008 respectively) and before SEMS (p = 0.01 and p = 0.003 respectively). Median bowel wall thickness proximal to the upper edge of tumor was significantly more before neoadjuvant chemotherapy than before stent (p = 0.003), and significantly less before surgery than before neoadjuvant chemotherapy (p = 0.003). No patient underwent stoma creation. Laparoscopic surgery was performed in nine (81.8%) patients. No local recurrence or metastases developed over median cancer-specific follow-up of 44 months (range, 37-55 months). CONCLUSION: SEMS followed by neoadjuvant chemotherapy prior to elective surgery appears to be safe and well tolerated in patients with obstructing left-sided colon cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/cirurgia , Obstrução Intestinal/cirurgia , Laparoscopia/instrumentação , Stents Metálicos Autoexpansíveis/efeitos adversos , Adulto , Idoso , Capecitabina/uso terapêutico , Neoplasias do Colo/metabolismo , Tratamento Farmacológico , Estudos de Viabilidade , Feminino , Fluoruracila , Humanos , Obstrução Intestinal/metabolismo , Leucovorina , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Compostos Organoplatínicos , Oxaliplatina/uso terapêutico , Estudos Retrospectivos , Albumina Sérica Humana/metabolismo , Resultado do TratamentoRESUMO
The objective was to study the effect of mechanical intestinal obstruction in rats on the phenotype of interstitial cells of Cajal (ICC). Healthy Wistar rats were randomly divided into sham-operation group (C), one day obstruction group (M1), two days obstruction group (M2), and three days obstruction group (M3), with 10 rats in each group. The expression of SCF mRNA and c-Kit protein in intestinal tissue was investigated by RT-PCR and immunohistochemistry. Compared with the sham-operation group, the relative expression of SCF mRNA and the expression of c-Kit protein in intestinal tissue were significantly decreased in both obstruction groups. Levels decreased gradually with the prolongation of obstruction time, and significantly decreased on the 3rd day after obstruction (P<0.05). Immunohistochemical staining of the small intestine showed that the number of ICC in the sham-operation group was the highest, and they were gradually decreased with the extension of obstruction time in the M1 to M3 groups. There was a significant difference between groups (P<0.05). Intestinal obstruction caused a decrease in the concentrations of SCF mRNA and c-Kit protein in ICC. With the prolongation of intestinal obstruction, the number of ICCs gradually decreased.
Assuntos
Células Intersticiais de Cajal/metabolismo , Obstrução Intestinal/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , RNA Mensageiro/metabolismo , Fator de Células-Tronco/metabolismo , Animais , Modelos Animais de Doenças , Imuno-Histoquímica , Células Intersticiais de Cajal/patologia , Obstrução Intestinal/patologia , Masculino , Fenótipo , Ratos , Ratos WistarRESUMO
OBJECTIVES: Intestinal obstruction has a high mortality rate when therapeutic treatment is delayed. Resuscitation in intestinal obstruction requires a large volume of fluid, and fluid combinations have been studied. Therefore, we evaluated the effects of hypertonic saline solution (HS) with pentoxifylline (PTX) on apoptosis, oxidative stress and survival rate. METHODS: Wistar rats were subjected to intestinal obstruction and ischemia through a closed loop ligation of the terminal ileum and its vessels. After 24 hours, the necrotic bowel segment was resected, and the animals were randomized into four groups according to the following resuscitation strategies: Ringer's lactate solution (RL) (RL-32 ml/kg); RL+PTX (25 mg/kg); HS+PTX (HS, 7.5%, 4 ml/kg), and no resuscitation (IO-intestinal obstruction and ischemia). Euthanasia was performed 3 hours after resuscitation to obtain kidney and intestine samples. A malondialdehyde (MDA) assay was performed to evaluate oxidative stress, and histochemical analyses (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling [TUNEL], Bcl-2 and Bax) were conducted to evaluate kidney apoptosis. Survival was analyzed with another series of animals that were observed for 15 days. RESULTS: PTX in combination with RL or HS reduced the MDA levels (nmol/mg of protein), as follows: kidney IO=0.42; RL=0.49; RL+PTX=0.31; HS+PTX=0.34 (p<0.05); intestine: IO=0.42; RL=0.48; RL+PTX=0.29; HS+PTX=0.26 (p<0.05). The number of labeled cells for TUNEL and Bax was lower in the HS+PTX group than in the other groups (p<0.05). The Bax/Bcl-2 ratio was lower in the HS+PTX group than in the other groups (p<0.05). The survival rate on the 15th day was higher in the HS+PTX group (77%) than in the RL+PTX group (11%). CONCLUSION: PTX in combination with HS enhanced survival and attenuated oxidative stress and apoptosis. However, when combined with RL, PTX did not reduce apoptosis or mortality.
Assuntos
Apoptose/efeitos dos fármacos , Obstrução Intestinal/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pentoxifilina/farmacologia , Ressuscitação/métodos , Solução Salina Hipertônica/farmacologia , Animais , Modelos Animais de Doenças , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Obstrução Intestinal/mortalidade , Obstrução Intestinal/prevenção & controle , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Estimativa de Kaplan-Meier , Rim/efeitos dos fármacos , Rim/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/análise , Distribuição Aleatória , Ratos Wistar , Reprodutibilidade dos TestesRESUMO
The objective was to study the effect of mechanical intestinal obstruction in rats on the phenotype of interstitial cells of Cajal (ICC). Healthy Wistar rats were randomly divided into sham-operation group (C), one day obstruction group (M1), two days obstruction group (M2), and three days obstruction group (M3), with 10 rats in each group. The expression of SCF mRNA and c-Kit protein in intestinal tissue was investigated by RT-PCR and immunohistochemistry. Compared with the sham-operation group, the relative expression of SCF mRNA and the expression of c-Kit protein in intestinal tissue were significantly decreased in both obstruction groups. Levels decreased gradually with the prolongation of obstruction time, and significantly decreased on the 3rd day after obstruction (P<0.05). Immunohistochemical staining of the small intestine showed that the number of ICC in the sham-operation group was the highest, and they were gradually decreased with the extension of obstruction time in the M1 to M3 groups. There was a significant difference between groups (P<0.05). Intestinal obstruction caused a decrease in the concentrations of SCF mRNA and c-Kit protein in ICC. With the prolongation of intestinal obstruction, the number of ICCs gradually decreased.
Assuntos
Animais , Masculino , Ratos , RNA Mensageiro/metabolismo , Fator de Células-Tronco/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Intersticiais de Cajal/metabolismo , Obstrução Intestinal/metabolismo , Fenótipo , Imuno-Histoquímica , Ratos Wistar , Modelos Animais de Doenças , Células Intersticiais de Cajal/patologia , Obstrução Intestinal/patologiaRESUMO
OBJECTIVES: Intestinal obstruction has a high mortality rate when therapeutic treatment is delayed. Resuscitation in intestinal obstruction requires a large volume of fluid, and fluid combinations have been studied. Therefore, we evaluated the effects of hypertonic saline solution (HS) with pentoxifylline (PTX) on apoptosis, oxidative stress and survival rate. METHODS: Wistar rats were subjected to intestinal obstruction and ischemia through a closed loop ligation of the terminal ileum and its vessels. After 24 hours, the necrotic bowel segment was resected, and the animals were randomized into four groups according to the following resuscitation strategies: Ringer's lactate solution (RL) (RL-32 ml/kg); RL+PTX (25 mg/kg); HS+PTX (HS, 7.5%, 4 ml/kg), and no resuscitation (IO-intestinal obstruction and ischemia). Euthanasia was performed 3 hours after resuscitation to obtain kidney and intestine samples. A malondialdehyde (MDA) assay was performed to evaluate oxidative stress, and histochemical analyses (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling [TUNEL], Bcl-2 and Bax) were conducted to evaluate kidney apoptosis. Survival was analyzed with another series of animals that were observed for 15 days. RESULTS: PTX in combination with RL or HS reduced the MDA levels (nmol/mg of protein), as follows: kidney IO=0.42; RL=0.49; RL+PTX=0.31; HS+PTX=0.34 (p<0.05); intestine: IO=0.42; RL=0.48; RL+PTX=0.29; HS+PTX=0.26 (p<0.05). The number of labeled cells for TUNEL and Bax was lower in the HS+PTX group than in the other groups (p<0.05). The Bax/Bcl-2 ratio was lower in the HS+PTX group than in the other groups (p<0.05). The survival rate on the 15th day was higher in the HS+PTX group (77%) than in the RL+PTX group (11%). CONCLUSION: PTX in combination with HS enhanced survival and attenuated oxidative stress and apoptosis. However, when combined with RL, PTX did not reduce apoptosis or mortality.
Assuntos
Animais , Masculino , Pentoxifilina/farmacologia , Ressuscitação/métodos , Solução Salina Hipertônica/farmacologia , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Obstrução Intestinal/metabolismo , Imuno-Histoquímica , Peroxidação de Lipídeos/efeitos dos fármacos , Distribuição Aleatória , Reprodutibilidade dos Testes , Ratos Wistar , Marcação In Situ das Extremidades Cortadas , Modelos Animais de Doenças , Estimativa de Kaplan-Meier , Obstrução Intestinal/mortalidade , Obstrução Intestinal/prevenção & controle , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Malondialdeído/análiseRESUMO
BACKGROUND: Previous studies found that visceral sensitivity is increased in bowel obstruction (BO). We hypothesized that mechanical stress-induced expression of BDNF in smooth muscle cells (SMC) of the distended bowel plays a critical role in visceral hypersensitivity in BO by altering voltage-gated K+ channel (Kv ) activity in sensory neurons. METHODS: Partial colon obstruction was maintained in rats for 7 days. Colon-projecting neurons in the dorsal root ganglia (DRG, T13 to L2) were isolated for electrophysiological and gene expression studies. KEY RESULTS: Compared to controls, membrane excitability of colon-projecting DRG neurons was markedly enhanced in BO. The densities of total Kv and transient A-type (IA ) K+ currents, but not sustained delayed IK current, were significantly reduced in the neurons in BO. The mRNA expression of IA subtype Kv 1.4 in colon neurons was down-regulated in BO. Expression of BDNF mRNA and protein was dramatically increased in colonic smooth muscle of the distended segment, but not in the non-distended aboral segment. Mechanical stretch of colon SMC in vitro increased BDNF expression. Treatment with anti-BDNF antibody restored total Kv and IA currents of neurons from BO rats. Administration of Trk B inhibitor ANA-12 blocked BO-associated changes of neuronal excitability, Kv activity and gene expression in obstruction. CONCLUSIONS AND INFERENCES: Mechanical stress-induced expression of BDNF in colon SMC plays a critical role in visceral hypersensitivity in BO by suppressing A-type K+ currents and gene expression in sensory nerve. These findings help to identify therapeutic targets for distention-associated abdominal pain in the gut.
Assuntos
Dor Abdominal/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Obstrução Intestinal/metabolismo , Dor Abdominal/etiologia , Animais , Obstrução Intestinal/complicações , Masculino , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/metabolismo , Estresse MecânicoRESUMO
AIM: To improve the results of treatment of patients with acute small bowel obstruction. MATERIAL AND METHODS: The research is based on the results of a comprehensive survey 202 people with acute small bowel obstruction. Reamberin was used in 102 patients treatment. RESULTS: It was established that metalloenzymes take an active part in the formation of endotoxemia in people with acute small bowel obstruction. Also, in patients as a result of an imbalance between oxidant and antioxidant systems, accumulated a significant amount of lipid peroxidation products, along with it a decrease activity of enzymes of antioxidant system. reamberin application in complex treatment of acute small bowel obstruction provided the reduction in the time correction of oxidative stress by preventing the growth and activity of lipid peroxidation products with simultaneous stimulation of the antioxidant system and contributed to the normalization of microelement homeostasis.
Assuntos
Obstrução Intestinal , Intestino Delgado , Peroxidação de Lipídeos/efeitos dos fármacos , Meglumina/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Succinatos/administração & dosagem , Doença Aguda , Adulto , Antioxidantes/administração & dosagem , Feminino , Homeostase/efeitos dos fármacos , Humanos , Obstrução Intestinal/metabolismo , Obstrução Intestinal/fisiopatologia , Obstrução Intestinal/cirurgia , Intestino Delgado/patologia , Intestino Delgado/fisiopatologia , Masculino , Meglumina/administração & dosagem , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
AIM: To improve the outcomes in patients with colon cancer complicated by acute obstruction via development of combined and complex treatment strategies. MATERIAL AND METHODS: We observed 442 patients with colon cancer complicated with acute obstruction. Original classification and diagnostic algorithm were applied. RESULTS: Time of preoperative opening-up, volume and type of surgery were defined using obtained data. Also we are able to perform delayed radical surgery after correction of metabolic disorders and comorbidities, to create the conditions for combined and complex methods of treatment, to decrease the incidence of postoperative complications and mortality rate. CONCLUSION: Three-stage surgery with shortened time between interventions decreases the incidence of anastomosis failure, allows to refuse Hartmann's procedure and to avoid severe reconstructive surgical stage without prolongation of rehabilitation period.
Assuntos
Neoplasias do Colo , Procedimentos Cirúrgicos do Sistema Digestório , Obstrução Intestinal , Doenças Metabólicas , Complicações Pós-Operatórias , Idoso , Neoplasias do Colo/complicações , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/patologia , Comorbidade , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Feminino , Humanos , Obstrução Intestinal/classificação , Obstrução Intestinal/diagnóstico , Obstrução Intestinal/etiologia , Obstrução Intestinal/metabolismo , Masculino , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/etiologia , Doenças Metabólicas/terapia , Estadiamento de Neoplasias , Avaliação de Processos e Resultados em Cuidados de Saúde , Assistência Perioperatória/métodos , Assistência Perioperatória/normas , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/prevenção & controle , Melhoria de Qualidade , Federação Russa/epidemiologiaRESUMO
INTRODUCTION: Adhesion-related small bowel obstruction (ASBO) management is difficult if there are no signs of strangulation or peritonitis when intestinal transit has not been restored. The aim of the present study was to determine the impact of combining a procalcitonin (PCT)-based algorithm with clinical signs on the management of uncomplicated ASBO. METHOD: We performed a pilot, retrospective, single-center "before-after" study. During the "before" period (2007 to 2012), patients with uncomplicated ASBO (n=93, the Gastrografin® group) underwent a clinical examination and a Gastrografin® index. During the "after" period (2013 to 2016), patients with uncomplicated ASBO (n=70, the algorithm group) underwent a clinical examination and were assessed with the PCT-based algorithm. The study's primary outcome was the appropriateness of ASBO management. The secondary outcomes were the need for surgery and the time to surgery, the LOS, the morbidity and mortality rates, and the recurrence rate. RESULTS: The proportion of well-managed patients was higher in the algorithm group than in the Gastrografin® group (86% vs. 47%; P<0.001). The time to surgery (48h vs 72h; P=0.02) and the LOS (4 vs. 6days, P=0.02) were significantly lower in the algorithm group. The need for surgery was similar in both groups (31% vs. 37%, P=0.49). The morbidity (P=0.69), mortality (P=0.82) and recurrence rates (P=0.57) were similar in the two groups. CONCLUSION: The use of a PCT-based algorithm is of value in the routine clinical management of ASBO; it reduces the LOS and the time to surgery without increasing the need for surgery.
Assuntos
Algoritmos , Calcitonina/metabolismo , Tomada de Decisão Clínica/métodos , Obstrução Intestinal/diagnóstico , Obstrução Intestinal/terapia , Intestino Delgado , Aderências Teciduais/complicações , Doença Aguda , Adulto , Idoso , Biomarcadores/metabolismo , Feminino , Humanos , Obstrução Intestinal/etiologia , Obstrução Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos RetrospectivosRESUMO
BACKGROUND: The clinical outcomes for postoperative complications (PCs) after gastrectomy depend on early diagnosis and intensive treatment. The aim of this study was to investigate the role of C-reactive protein (CRP) as an early predictor of PCs after gastrectomy for gastric cancer. METHODS: A total of 334 consecutive patients who underwent gastrectomy for gastric cancer in 2014 were enrolled in this study. Blood samples were obtained preoperatively, and at postoperative days 1 and 4 for the measurement of inflammatory markers (white blood cell, neutrophil, and platelet counts, and CRP). Patients were classified into groups of major and minor/no PCs, which were defined as patients with PCs of more than grade III and those with grade I/II or without PCs, respectively, according to the Clavien-Dindo classification. RESULTS: Twenty-five patients developed major PCs. The CRP on postoperative day 4 provided superior diagnostic accuracy in predicting major PCs compared to the other systematic inflammatory markers. Multivariate analysis identified a CRP level of 16.8 mg/dl or greater on postoperative day 4 as a significant predictive factor for major PCs. CONCLUSIONS: Among the various systemic inflammatory markers, CRP on postoperative day 4 is the most reliable predictor of PCs after gastrectomy for gastric cancer.
Assuntos
Abscesso Abdominal/metabolismo , Fístula Anastomótica/metabolismo , Proteína C-Reativa/metabolismo , Gastrectomia , Íleus/metabolismo , Obstrução Intestinal/metabolismo , Complicações Pós-Operatórias/metabolismo , Neoplasias Gástricas/cirurgia , Abscesso Abdominal/epidemiologia , Idoso , Fístula Anastomótica/epidemiologia , Biomarcadores , Feminino , Humanos , Íleus/epidemiologia , Obstrução Intestinal/epidemiologia , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Complicações Pós-Operatórias/epidemiologia , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/patologiaRESUMO
Cystic fibrosis (CF) is a life-shortening autosomal recessive disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is an anion channel that conducts bicarbonate and chloride across cell membranes. Although defective anion transport across epithelial cells is accepted as the basic defect in CF, many of the features observed in people with CF and organs affected by CF are modulated by the nervous system. This is of interest because CFTR expression has been reported in both the peripheral and central nervous systems, and it is well known that the transport of anions, such as chloride, greatly modulates neuronal excitability. Thus it is predicted that in CF, lack of CFTR in the nervous system affects neuronal function. Consistent with this prediction, several nervous system abnormalities and nervous system disorders have been described in people with CF and in animal models of CF. The goal of this special feature article is to highlight the expression and function of CFTR in the nervous system. Special emphasis is placed on nervous system abnormalities described in people with CF and in animal models of CF. Finally, features of CF that may be modulated by or attributed to faulty nervous system function are discussed.
Assuntos
Sistema Nervoso Central/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/genética , Sistema Nervoso Periférico/metabolismo , Animais , Sistema Nervoso Autônomo/metabolismo , Sistema Nervoso Autônomo/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Tosse , Fibrose Cística/complicações , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Modelos Animais de Doenças , Insuficiência Pancreática Exócrina/etiologia , Insuficiência Pancreática Exócrina/metabolismo , Insuficiência Pancreática Exócrina/fisiopatologia , Motilidade Gastrointestinal , Trato Gastrointestinal/inervação , Coração/inervação , Humanos , Obstrução Intestinal/etiologia , Obstrução Intestinal/metabolismo , Obstrução Intestinal/fisiopatologia , Síndromes de Malabsorção/etiologia , Síndromes de Malabsorção/metabolismo , Síndromes de Malabsorção/fisiopatologia , Contração Muscular , Músculo Liso/inervação , Pâncreas/inervação , Sistema Nervoso Periférico/fisiopatologia , Sistema Respiratório/inervação , SudoreseRESUMO
AIM: To develop a new rat model we wanted to gain a better understanding of stricture formation in Crohn's disease (CD). METHODS: Chronic colitis was induced locally by the administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS). The relapsing inflammation characteristic to CD was mimicked by repeated TNBS treatments. Animals were randomly divided into control, once, twice and three times TNBS-treated groups. Control animals received an enema of saline. Tissue samples were taken from the strictured colonic segments and also adjacent proximally and distally to its 60, 90 or 120 d after the last TNBS or saline administrations. The frequency and macroscopic extent of the strictures were measured on digital photographs. The structural features of strictured gut wall were studied by light- and electron microscopy. Inflammation related alterations in TGF-beta 2 and 3, matrix metalloproteinases 9 (MMP9) and TIMP1 mRNA and protein expression were determined by quantitative real-time PCR and western blot analysis. The quantitative distribution of caspase 9 was determined by post-embedding immunohistochemistry. RESULTS: Intestinal strictures first appeared 60 d after TNBS treatments and the frequency of them increased up to day 120. From day 90 an intact lamina epithelialis, reversible thickening of lamina muscularis mucosae and irreversible thickening of the muscularis externa were demonstrated in the strictured colonic segments. Nevertheless the morphological signs of apoptosis were frequently seen and excess extracellular matrix deposition was recorded between smooth muscle cells (SMCs). Enhanced caspase 9 expression on day 90 in the SMCs and on day 120 also in myenteric neurons indicated the induction of apoptosis. The mRNA expression profile of TGF-betas after repeated TNBS doses was characteristic to CD, TGF-beta 2, but not TGF-beta 3 was up-regulated. Overexpression of MMP9 and down-regulation of TIMP1 were demonstrated. The progressive increase in the amount of MMP9 protein in the strictures was also obvious between days 90 and 120 but TIMP1 protein was practically undetectable at this time. CONCLUSION: These findings indicate that aligned structural and molecular changes in the gut wall rather than neuronal cell death play the primary role in stricture formation.
Assuntos
Colite/patologia , Colo/ultraestrutura , Doença de Crohn/patologia , Obstrução Intestinal/patologia , Animais , Apoptose , Western Blotting , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Colo/metabolismo , Constrição Patológica , Doença de Crohn/induzido quimicamente , Doença de Crohn/genética , Doença de Crohn/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Imuno-Histoquímica , Obstrução Intestinal/genética , Obstrução Intestinal/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Microscopia Eletrônica de Transmissão , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Tempo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta3/genética , Fator de Crescimento Transformador beta3/metabolismo , Ácido TrinitrobenzenossulfônicoRESUMO
BACKGROUND: Small bowel obstruction (SBO) is a potentially life-threatening condition which may be caused by a variety of pathologies such as postoperative adhesions or malignant diseases. Little is known on alterations in gut physiology during SBO, although its comprehension is essential to improve treatment which may help to prevent subsequent organ failure prior to surgical resolution. We aimed to investigate afferent nerve sensitivity and intestinal inflammatory response during SBO to identify possible targets of treatment. METHODS: C57Bl6 mice were anesthetized, and a midline laparotomy was performed. A small bowel loop was ligated 5 cm proximal to ileo-cecal valve to induce SBO. Control animals received a sham midline laparotomy. SBO animals and controls were sacrificed after 3, 9, or 24 h (each n = 6). A dilated segment of small intestine located 1.5 cm oral to the ligature was prepared for multi-unit mesenteric afferent nerve recordings in vitro. Histological assessment of leukocyte infiltration was performed by myeloperoxidase (MPO). Pro-inflammatory cytokine expression was quantified by RT-PCR. Data are mean ± SEM. KEY RESULTS: Afferent firing to serosal 5-HT (500 µM) peaked at 3.9 ± 0.2 impulse/s 24 h after induction of SBO compared to 2.4 ± 0.1 impulse/s in sham controls (p < 0.05). Serosal bradykinin (0.5 µM) led to an increase in peak afferent firing of 5.3 ± 0.5 impulse/s in 24 h SBO animals compared to 3.5 ± 0.2 impulse/s in sham controls (p < 0.05). No differences in 5-HT and BK sensitivity were observed in 3 and 9 h SBO animals compared to controls. Continuous mechanical ramp distension of the intestinal loop was followed by a pressure-dependent rise in afferent nerve discharge that was reduced in 3 h SBO animals compared to sham controls (p < 0.05). MPO stains showed a rise in leukocyte infiltration of the intestine in SBO animals at 9 and 24 h (p < 0.05). Il-6 but not TNF-a gene expression was increased at 9 and 24 h in SBO animals compared to sham controls (p < 0.05). CONCLUSIONS & INFERENCES: Afferent nerve sensitivity is increased 24 h after induction of SBO. SBO led to a delayed onset intestinal inflammatory response. Inflammatory mediators released during this inflammatory response may be responsible for a later increase in afferent sensitivity. Agents with anti-inflammatory action may, therefore, have a beneficial effect during SBO and may subsequently help to prevent possible organ dysfunction.
Assuntos
Mediadores da Inflamação/metabolismo , Obstrução Intestinal/metabolismo , Obstrução Intestinal/fisiopatologia , Intestino Delgado/metabolismo , Intestino Delgado/fisiopatologia , Neurônios Aferentes/metabolismo , Animais , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Técnicas de Cultura de ÓrgãosRESUMO
BACKGROUND: Accumulating evidence suggests that the aryl hydrocarbon receptor (AhR) plays an important role in the maintenance of the function of the intestinal barrier in patients with inflammatory bowel disease and in mouse models. Intestinal obstruction (IO) is a clinical emergency consisting of severe dysfunction of intestinal barrier function, and whether AhR plays a role in the pathogenesis of IO remains unknown but would be highly significant. METHODS: Male C57BL/6 mice were subjected to IO and either treated with AhR endogenous agonist 6-formylindolo [3, 2-b] carbazole (FICZ) or left untreated. Intestinal tissue was harvested after 24âh. Correspondingly, Caco-2 monolayers were treated with FICZ in the absence or presence of hypoxia in vitro or left untreated. The cells were used after 12âh. RESULTS: Damage to the intestinal mucosa was anabatic and intestinal permeability was significantly higher in murine IO and hypoxia-induced Caco-2 models than in controls. Under these conditions the activity of AhR was lower and the fluorescence of zonula occludens-1 (ZO-1) was absent. The increased expression of myosin light chain kinase (MLCK) and phosphorylated MLC (pMLC) indicated that this pathway was open. However, treatment with FICZ caused retention of the tight junction protein ZO-1, alleviated the increase of intestinal permeability, and mitigated epithelial injury. Depletion of AhR by AhR small interfering RNA facilitated the unblocking of the MLCK-pMLC signaling pathway and repressed the protein expression of ZO-1 in vitro. CONCLUSION: AhR activation can ameliorate epithelial barrier dysfunction induced by IO through the suppression of MLCK-pMLC signaling, suggesting that AhR agonist may be a suitable means of addressing this condition.
Assuntos
Obstrução Intestinal/tratamento farmacológico , Obstrução Intestinal/metabolismo , Cadeias Leves de Miosina/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Células CACO-2 , Carbazóis/uso terapêutico , Modelos Animais de Doenças , Impedância Elétrica , Imunofluorescência , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , RNA Interferente Pequeno , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacosRESUMO
The igf1 gene is alternatively spliced as IGF-IEa and IGF-IEc variants in humans. In fibrostenotic Crohn's disease, the fibrogenic cytokine TGF-ß1 induces IGF-IEa expression and IGF-I production in intestinal smooth muscle and results in muscle hyperplasia and collagen I production that contribute to stricture formation. Mechano-growth factor (MGF) derived from IGF-IEc induces skeletal and cardiac muscle hypertrophy following stress. We hypothesized that increased IGF-IEc expression and MGF production mediated smooth muscle hypertrophy also characteristic of fibrostenotic Crohn's disease. IGF-IEc transcripts and MGF protein were increased in muscle cells isolated from fibrostenotic intestine under regulation by endogenous TGF-ß1. Erk5 and MEF2C were phosphorylated in vivo in fibrostenotic muscle; both were phosphorylated and colocalized to nucleus in response to synthetic MGF in vitro. Smooth muscle-specific protein expression of α-smooth muscle actin, γ-smooth muscle actin, and smoothelin was increased in affected intestine. Erk5 inhibition or MEF2C siRNA blocked smooth muscle-specific gene expression and hypertrophy induced by synthetic MGF. Conditioned media of cultured fibrostenotic muscle induced muscle hypertrophy that was inhibited by immunoneutralization of endogenous MGF or pro-IGF-IEc. The results indicate that TGF-ß1-dependent IGF-IEc expression and MGF production in patients with fibrostenotic Crohn's disease regulates smooth muscle cell hypertrophy a critical factor that contributes to intestinal stricture formation.