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Pulmonary fibrosis (PF) is a pathological change caused by repeated injuries and repair dysfunction of the alveolar epithelium. Our previous study revealed that the residues Asn3 and Asn4 of peptide DR8 (DHNNPQIR-NH2) could be modified to improve stability and antifibrotic activity, and the unnatural hydrophobic amino acids α-(4-pentenyl)-Ala and d-Ala were considered in this study. DR3penA (DHα-(4-pentenyl)-ANPQIR-NH2) was verified to have a longer half-life in serum and to significantly inhibit oxidative damage, epithelial-mesenchymal transition (EMT) and fibrogenesis in vitro and in vivo. Moreover, DR3penA has a dosage advantage over pirfenidone through the conversion of drug bioavailability under different routes of administration. A mechanistic study revealed that DR3penA increased the expression of aquaporin 5 (AQP5) by inhibiting the upregulation of miR-23b-5p and the mitogen-activated protein kinase (MAPK) pathway, indicating that DR3penA may alleviate PF by regulating MAPK/miR-23b-5p/AQP5. Safety evaluation showed that DR3penA is a peptide drug without obvious toxicity or acute side effects and has significantly improved safety compared to DR8. Thus, our findings suggest that DR3penA, as a novel and low-toxic peptide, has the potential to be a leading compound for PF therapy, which provides a foundation for the development of peptide drugs for fibrosis-related diseases.
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Objective To investigate the effects of intestinal microbiota of patients with chronic constipation on the expression of serotonin transporter (SERT) and the bowel movement in mice.Methods Fecal samples of patients with slow transit constipation met Rome Ⅲ criteria and healthy normal controls were collected and made into fecal microbiota solution.Twenty specfic pathogen free (SPF) mice were divided into experiment group and control group.The mice of two groups were both pre-treated with streptomycin to establish the germ-free mice model.The mice of control group were gavaged with mixed fecal microbiota solution of healthy normal controls and the mice of experiment group were gavaged with mixed fecal microbiota solution of patients with chronic constipation.Mice were sacrificed after fed for 15 days.Defecation parameters and ink discharge time of mice were detected.The expressions of SERT mRNA and SERT protein in mice intestinal tissues were detected with real time-polymerase chain reaction and Western blotting.The 5-hydroxytryptamine (5-HT) levels of mice intestinal tissues were evaluated by enzyme-linked immunosorbent assay (ELISA) and double immunofluorescent staining.The methods of t test and Chi-square test were performed for statistical analysis.Results On the 15th day,the total number of the feces within 2 h of the experiment group and control group was 8.55±1.83 and 12.14±2.90,respectively,and the difference was statistically significant (t=3.33,P＜0.05).The weight of feces were (151.90 ± 32.42) mg and (246.72 ± 64.01) mg,respectively,and the difference was statistically significant (t=4.18,P＜0.01).The dry weight of feces were (65.52±11.76) mg and (92.93±23.07) mg,respectively,and the difference was statistically significant (t=3.37,P＜0.05).The water content of feces were (56.63 ± 3.01) ％ and (61.95 ± 3.70) ％,respectively,and the difference was statistically significant (t=3.57,P＜0.05).The defecating time of first black feces of the experiment group and control group were (83.24±11.31) min and (69.06±2.72) min,respectively,and the difference was statistically significant (t=-2.74,P＜0.05).The expressions of SERT mRNA and SERT protein levels in mice intestine tissues of the experiment group were significantly higher than those of the control group (t =2.61,-6.89;both P＜0.05).5-HT level of mice intestinal tissues of the experimental group and control group were (151.69± 10.18) ng/mL and (198.77 ± 25.99) ng/mL,respectively,and the difference was statistically significant (t=-4.13,P＜0.01).Conclusion Intestinal microbiota of patients with chronic constipation may influence the expression of SERT in the mice intestinal tissues,and then decrease the level of 5-HT,slowing the bowel movement in mice.
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Objective To explore the necessity of colonoscopy in young patients with chronic constipation.Methods Data of patients aged 18-50 underwent colonoscopy at Tianjin Medical University General Hospital with chronic constipation as the sole indication between April 2003 and May 2014 were analyzed.Endoscopic and pathologic reports were analyzed.Results During the study period,a total of 563 patients were included,who were aged 18-50 with chronic constipation as the sole indication,of which 260 patients were aged 18-35,and 303 patients were aged 36-50.No lesion was found during colonoscopy in 167 (29.7％) patients,whereas in other 396 (70.3 ％) patients positive findings were reported,including polyps in 45 patients (of which 13 were with multiple polyps),adenomas in 20(17 in distal colon,3 in proximal colon).In patients aged 18-35,3 cases of adenomas(3/260,1.2％) were found,of which 1 patient (1/260,0.4％)had advanced adenoma.In patients aged 36-50,17 cases of adenomas(17/303,5.6％) were found,of which 4 (4/303,1.3％) were advanced ones.Colorectal cancers were found in 2 patients (0.7％,2/303),both in patients aged 36-50.The detection rate for colorectal neoplasms (including adenoma and cancer) in patients with chronic constipation aged 18-35 was significantly lower than that in patients aged 36-50[1.2％(3/260) VS 6.3％(19/303),P=0.002,95％CI:0.05-0.60].Conclusion The detection rate for colorectal neoplasms in patients aged 18-35 years with chronic constipation is relatively low,and colonoscopy is not recommended for them.