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Objective To observe the effects of Shengxue Tongbian Granules on colonic myoelectricity and Ca2+/CaM/MLCK signaling pathway in rats with slow transit constipation(STC)of blood deficiency and intestinal dryness syndrome;To explore its mechanism for the treatment of STC.Methods The STC model of blood deficiency and intestinal dryness syndrome was established by intragastric administration of loperamide combined with tail bloodletting.The rats were divided into control group,model group,mosapride citrate group and Shengxue Tongbian Granules group,with 8 rats in each group.The administration group was given corresponding drugs by gavage for 14 days.The general condition of rats before and after treatment was observed,the fecal water content was detected,the slow wave frequency,amplitude,and coefficient of variation of colonic electromyography were detected using a biological function experimental system,and intestinal propulsion rate was detected.HE staining was used to observe the pathological changes of colon tissue,the concentration of Ca2+ in colonic smooth muscle cells was detected by colorimetry,the expression of Cx43,calmodulin(CaM),myosin light chain kinase(MLCK)and p-MLC20 in smooth muscle tissue were detected by Western blot.Results Compared with the control group,the body mass,fecal water content and intestinal propulsion rate of rats in the model group decreased(P<0.01),the slow wave frequency of colonic electromyography slowed down,the coefficient of variation of frequency increased(P<0.01),and the amplitude and coefficient of variation of slow wave increased(P<0.01);colonic mucosal structure was damaged,with visible inflammatory changes and significant erosion,and the concentration of Ca2+ and the expressions of Cx43,CaM,MLCK,p-MLC20 proteins in colonic smooth muscle cells were significantly decreased(P<0.01).Compared with the model group,the body mass,fecal water content and intestinal propulsion rate of the rats in the mosapride citrate group and the Shengxue Tongbian Granules group significantly increased(P<0.05,P<0.01),the slow wave frequency of colonic electromyography increased and the coefficient of variation of frequency decreased(P<0.01),and the slow wave amplitude and amplitude variation coefficient decreased(P<0.05,P<0.01);the colonic mucosal structure was relatively intact,the erosion situation was improved,and the Ca2+ concentration,Cx43,CaM,MLCK and p-MLC20 protein expressions in colonic smooth muscle cells significantly increased(P<0.01).Conclusion Shengxue Tongbian Granules can improve defecation symptoms and promote colonic motility in STC rats with blood deficiency and intestinal dryness syndrome,which may be related to regulating colonic myoelectric rhythm and activating Ca2+/CaM/MLCK signaling pathway.
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ObjectiveTo clarify the relationship between intestinal flora and intestinal motility in rats with slow transit constipation （STC） and qi stagnation syndrome by conducting a pseudo-sterile experiment and fecal microbiota transplantation （FMT） technology. MethodsTwenty-four Wistar rats were randomly divided into normal group （n=6）， STC with qi stagnation pattern group （n=6） and pseudo-sterile group （n=12）. In the STC group with qi stagnation pattern， 3 mg/kg of loperamide suspension by intragastric administration combined with tail clamping stimulation were performed to establish the rat model of STC with qi stagnation pattern. After successful modeling， fresh feces from the rats in the STC with qi stagnation pattern group and the normal group were collected to prepare 100 mg/ml of fecal bacterial suspension. In the pseudo-sterile group， the antibiotic cocktail method was used （a mixed antibiotic suspension containing bacitracin， streptomycin sulfate， and neomycin sulfate at 20 mg/ml each was administered intragastrically） to establish pseudo-sterile rats model. After successful modeling， the rats were randomly divided into normal fecal bacterial liquid group and STC with qi stagnation pattern fecal bacterial liquid group， with six rats in each group， and then were given 10 ml/kg of the prepared corresponding rat fecal bacterial suspension by gavage. Rats in STC with qi stagnation pattern group were given an equal volume of sterile water by gavage. All groups were administered once a day for 7 consecutive days. The small intestinal propulsion rate of the STC with qi stagnation pattern group， the normal fecal bacterial liquid group， and STC with qi stagnation pattern fecal bacterial liquid group were compared. ELISA method was used to detect serum 5-hydroxytryptamine （5-HT） levels. Immunohistochemistry was used to detect the positive expression levels of 5-hydroxytryptamine 3 receptor （5-HT3R） and 5-hydroxytryptamine 4 receptor （5-HT4R） in colon tissue. Western blot method was used to detect the protein expression levels of tryptophan hydroxylase 1 （TPH1）， tryptophan hydroxylase 2 （TPH2）， serotonin transporter （SERT）， and monoamine oxidase A （MAO-A） in colon tissue. ResultsCompared to those in the normal fecal bacterial liquid group， the small intestinal propulsion rate， serum 5-HT level， positive expression of 5-HT3R and 5-HT4R in colon tissue， and protein expression of TPH1， TPH2， SERT and MAO-A significantly decreased in the STC with qi stagnation pattern group and STC with qi stagnation pattern fecal bacterial liquid group （P＜0.05）. There was no statistically significant difference in the indicators between the STC with qi stagnation pattern group and STC with qi stagnation pattern fecal bacterial liquid group （P＞0.05）. ConclusionThe intestinal flora in STC rats with qi stagnation pattern can lead to a slowdown in intestinal transmission function， whose mechanism may be related to intestinal motility disorders affected by the synthesis， transport， metabolism and other pathways of 5-HT.
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ObjectiveTo observe the clinical effect of modified Jichuanjian on senile patients with slow transit constipation of spleen-kidney yang deficiency syndrome and the influence on brain-gut peptide. MethodA total of 150 senile patients with slow transit constipation were randomized into control group （75 cases） and observation group （75 cases） with the random number table method. The observation group was given modified Jichuanjian （oral， 1 dose/day， 4 weeks）， and the control group was treated with Biantong Capsules （oral， 3 capsules/time， twice/day， 4 weeks）. Data before and after treatment were recorded， including the score of major constipation symptoms， score of Patient Assessment of Constipation Quality of Life （PAC-QOL）， TCM syndrome score， spontaneous complete bowel movements （SCBM）， colonic transit test， serum 5-hydroxytryptamine （5-HT）， 5-HT 4 receptor （5-HT4R）， somatostatin （SS）， and vasoactive intestinal peptide （VIP）， and recurrence. ResultThe total effective rate of the observation group was 93.06% （67/72）， as compared with the 74.65% （53/71） in the control group （χ2=8.974 6， P<0.01）. After treatment， the scores of major constipation symptoms， scores of four dimensions of PAC-QOL， total score of PAC-QOL， and TCM syndrome score were lower than those before treatment in the two groups （P<0.01）， and lower in the observation group than in the control group （P<0.01）. The SCBM in the observation group were more than those in the control group at the 2nd， 3rd， 4th weeks after treatment （P<0.01）. The proportions of residual markers at 24， 48， 72 h after treatment were smaller than those before treatment in the two groups （P<0.01）， and smaller in the observation group than in the control group （P<0.01）. After treatment， the levels of serum 5-HT and 5-HT4R were higher （P<0.01） and the levels of serum SS and VIP were lower （P<0.01） than those before treatment in the two groups. In addition， the levels of serum 5-HT and 5-HT4R in the observation group were higher （P<0.01） and the levels of serum SS and VIP were lower （P<0.01） in the observation group than in the control group. The recurrence in the observation group was 29.85% （20/67） in comparison with the 58.49% （31/53） in the control group （χ2=9.932 4， P<0.01）. ConclusionModified Jichuanjian is effective for senile patients with slow transit constipation of spleen-kidney yang deficiency syndrome， which can alleviate clinical symptoms， improve quality of life， regulate the level of serum brain-gut peptide， improve the colonic transit function， increase SCBM， and reduce the recurrence.
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ObjectiveTo observe the effects of Aurantii Fructus Immaturus， Atractylodis Macrocephalae Rhizoma， and their combination on slow transit constipation via PTEN-induced putative kinase 1 （PINK1）/Parkin pathway-mediated mitophagy. MethodFifty-six male SD rats were randomly assigned into normal group， model group， natural recovery group， Aurantii Fructus Immaturus group， Atractylodis Macrocephalae Rhizoma group， Aurantii Fructus Immaturus combined with Atractylodis Macrocephalae Rhizoma group， and mosapride group， with 8 rats in each group. Slow transit constipation model was established by gavage with loperamide （3 mg·kg-1·d-1） for 14 days in other groups except the normal group. After successful modeling， except that the model group was continuously induced by loperamide， the normal group and the natural recovery group were administrated with 0.9% normal saline by gavage， and the rats in the Aurantii Fructus Immaturus （1.35 g·kg-1·d-1） group， the Atractylodis Macrocephalae Rhizoma （2.7 g·kg-1·d-1） group， the Aurantii Fructus Immaturus combined with Atractylodis Macrocephalae Rhizoma （4.05 g·kg-1·d-1） group， and the mosapride （1.56 mg·kg-1·d-1） group were administrated with corresponding drugs by gavage for 7 days. The amount of feces， fecal water content， and intestinal propulsion rate of rats were determined. The pathological changes of the colon were evaluated by hematoxylin-eosin （HE） staining and Alcian blue-periodic acid-Schiff （AB-PAS） staining. The activity of respiratory chain complex and the ultrastructure of the colon tissue were determined by ultraviolet spectrophotometry and observed by transmission electron microscopy， respectively. Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR） was employed to determine the mRNA levels of PINK1， Parkin， and p62， and Western blot to determine the protein levels of microtubule-associated protein 1 light chain 3 （LC3）， PINK1， and Parkin. ResultCompared with the normal group， the model group and the natural recovery group showed decreases in the amount of feces， fecal water content， intestinal propulsion rate （P<0.05，P<0.01）， and activities of mitochondrial respiratory chain complexes Ⅱ， Ⅲ， and Ⅳ in the colon tissue （P<0.05，P<0.01）. Further， the mRNA levels of PINK1 and Parkin and the protein levels of PINK1， Parkin， and LC3 were up-regulated （P<0.01） and the mRNA level of p62 was down-regulated in the model group （P<0.05） and the natural recovery group. Compared with the model group and the natural recovery group， the Aurantii Fructus Immaturus combined with Atractylodis Macrocephalae Rhizoma group showed increased amount of feces， fecal water content， intestinal propulsion rate， and activities of mitochondrial respiratory chain complexes Ⅱ， Ⅲ， and Ⅳ （P<0.05，P<0.01）. Moreover， the combination meliorated the degree of mitochondrial swelling in the colon tissue， down-regulated the mRNA levels of PINK1 and Parkin and the protein levels of PINK1， Parkin， and LC3 （P<0.05，P<0.01）， and up-regulated the mRNA level of p62 （P<0.05）. ConclusionAurantii Fructus Immaturus and Atractylodis Macrocephalae Rhizoma， and their combination may remedy the colonic motility disorders in rats with slow transit constipation by blocking PINK1/Parkin signaling pathway to inhibit the excessive mitophagy in interstitial cells of Cajal in the colon tissue.
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OBJECTIVE To explore the mechanism of Kuaisong yin in the prevention and treatment of constipation. METHODS Slow transit constipation （STC） model was established with Compound difenoxylate tablet in mice and rats. Two batches of mice were divided into blank group， model group， positive control group （Maren soft capsule， 0.64 g/kg）， Kuaisong yin low-dose， medium-dose and high-dose groups （3.2， 6.4， 12.8 g/kg）， with 10 mice in each group. The effect of Kuaisong yin on constipation in mice was evaluated by intestinal propulsion experiment and defecation experiment. Rats were divided into blank group， model group， positive control group （Maren soft capsule，0.36 g/kg）， Kuaisong yin low-dose and high-dose groups （2.4， 4.8 g/kg）， with 7 or 8 rats in each group. They were given relevant medicine once a day for 1 week. The metabonomics of serum and urine of rats were analyzed by UPLC-Q-TOF-MS/MS technology. RESULTS Compared with model group， the ink propulsion rate and 5 h defecation volume of mice in Kuaisong yin high-dose group were significantly increased （P＜0.05）； the first defecation time of mice in Kuaisong yin medium-dose and high-dose groups was significantly shortened， and the quality of defecation was significantly reduced within 5 h （P＜0.05 or P＜0.01）. Serum metabonomics screened 16 compounds （such as proline， propionylcarnitine， hemolytic phosphatidylcholine， etc.） and 6 metabolic pathways （such as sphingomyelin metabolism， arginine and proline metabolism， sphingolipid biosynthesis-lactose and neolactone series）. Urine metabonomics screened 20 different metabolites （such as prostaglandin A2， L-valine， phosphatidylcholine， sphingomyelin， etc.） and 8 metabolic pathways （such as valine， leucine and isoleucine biosynthesis， sphingomyelin metabolism， pyruvate metabolism， etc.）. CONCLUSIONS Kuaisong yin can play a role in improving constipation by regulating different metabolites such as hemolytic phosphatidylcholine， phosphatidylcholine， prostaglandin A2， L-valine， proline， and regulating metabolic pathways such as multiple amino acid metabolism， sphingomyelin metabolism， etc.
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ObjectiveTo investigate the effect and mechanism of Aconiti Lateralis Radix Praeparata-Cinnamomi Cortex in regulating the intestinal function in the rat model of slow transit constipation （STC） due to yang deficiency via the vasoactive intestinal peptide （VIP）/cathelicidin antimicrobial peptide （cAMP）/protein kinase A （PKA）/aquaporin （AQP） pathway. MethodSD rats were randomized into 6 groups （n=6）， including a control group， a model group， high-， medium-， and low-dose Aconiti Lateralis Radix Praeparata-Cinnamomi Cortex groups， and a prucalopride group. Other groups except the control group were treated with loperamide hydrochloride combined with ice water by gavage for the modeling of STC due to yang deficiency. The number of fecal pellets， time to the first black stool defecation， fecal water content， intestinal propulsion rate， and score of fecal properties were recorded in each group. At the end of the treatment， the colon was stained with hematoxylin-eosin （HE） to reveal the histopathological changes and Alcian blue/periodic acid-Schiff （AB-PAS） to reveal the secretion of colonic mucus. The enzyme-linked immunosorbent assay （ELISA） was employed to measure the level of VIP in the serum. The mRNA level of AQP in the colon was measured by polymerase chain reaction （Real-time PCR）. Immunohistochemical staining was performed to observe the expression of AQPs in the colon and kidney tissues. Western blot was performed to determine the protein levels of cAMP， PKA， and VIP in the colon tissue. ResultCompared with the control group, the model group had longer time to the first black stool defecation, reduced fecal pellets and water content, reduced Bristol Stool Form Scale score and intestinal propulsion rate, and constipation aggravated（P<0.01）. Moreover, increased the intestinal lesions, reduced the mucus secretion, reduce the serum VIP level, up-regulated the expression levels of AQP1 in the colon and kidney tissues, inhibited the expression of AQP3 and AQP9（P<0.01）., and down-regulated the protein levels of cAMP, PKA, and VIP in the colon tissue. Compared with the model group， the high-dose Aconiti Lateralis Radix Praeparata-Cinnamomi Cortex group had shortened time to the first black stool defecation， increased fecal pellets and water content， increased Bristol Stool Form Scale score and intestinal propulsion rate， and alleviated constipation symptoms. Moreover， high-dose Aconiti Lateralis Radix Praeparata-Cinnamomi Cortex reduced the intestinal lesions， increased the mucus secretion， elevated the serum VIP level（P<0.01）.， down-regulated the expression levels of AQP1 in the colon and kidney tissues， promoted the expression of AQP3 and AQP9（P<0.05，P<0.01）， and up-regulated the protein levels of cAMP， PKA， and VIP in the colon tissue. The medium- and low-dose groups had weaker effect than the high-dose group（P<0.01）. ConclusionHigh-dose Aconiti Lateralis Radix Praeparata-Cinnamomi Cortex can improve the intestinal motility and balance the intestinal water and fluid metabolism by up-regulating the VIP/cAMP/PKA/AQP pathway， thereby mitigating the constipation symptoms in the rat model of slow transit constipation due to yang deficiency.
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OBJECTIVE@#To explore the possible effects and mechanism of Zhizhu Decoction (ZZD) on the pathophysiology of slow transit constipation (STC).@*METHODS@#A total of 54 C57BL/6 mice was randomly divided into the following 6 groups by a random number table, including control, STC model (model), positive control, and low-, medium- and high-doses ZZD treatment groups (5, 10, 20 g/kg, namely L, M-, and H-ZZD, respectively), 9 mice in each group. Following 2-week treatment, intestinal transport rate (ITR) and fecal water content were determined, and blood and colon tissue samples were collected. Hematoxylin-eosin and periodic acid-Schiff staining were performed to evaluate the morphology of colon tissues and calculate the number of goblet cells. To determine intestinal permeability, serum levels of lipopolysaccharide (LPS), low-density lipoprotein (LDL) and mannose were measured using enzyme-linked immunosorbent assay (ELISA). Western blot analysis was carried out to detect the expression levels of intestinal tight junction proteins zona-occludens-1 (ZO-1), claudin-1, occludin and recombinant mucin 2 (MUC2). The mRNA expression levels of inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-4, IL-10 and IL-22 were determined using reverse transcription-quantitative reverse transcription reaction. Colon indexes of oxidative stress were measured by ELISA, and protein expression levels of colon silent information regulator 1/forkhead box O transcription factor 1 (SIRT1/FoxO1) antioxidant signaling pathway were detected by Western blot.@*RESULTS@#Compared with the model group, ITR and fecal moisture were significantly enhanced in STC mice in the M-ZZD and H-ZZD groups (P<0.01). Additionally, ZZD treatment notably increased the thickness of mucosal and muscular tissue, elevated the number of goblet cells in the colon of STC mice, reduced the secretion levels of LPS, LDL and mannose, and upregulated ZO-1, claudin-1, occludin and MUC2 expressions in the colon in a dose-dependent manner, compared with the model group (P<0.05 or P<0.01). In addition, ZZD significantly attenuated intestinal inflammation and oxidative stress and activated the SIRT1/FoxO1 signaling pathway (P<0.05 or P<0.01).@*CONCLUSION@#ZZD exhibited beneficial effects on the intestinal system of STC mice and alleviated intestinal inflammation and oxidative stress via activating SIRT1/FoxO1 antioxidant signaling pathway in the colon.
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Ratones , Animales , Sirtuina 1/genética , Antioxidantes , Ocludina , Lipopolisacáridos , Claudina-1 , Manosa , Ratones Endogámicos C57BL , Estreñimiento/tratamiento farmacológico , Inflamación , Transducción de SeñalRESUMEN
The differences in dryness between raw Aurantii Fructus Immaturus(AFI) and bran-fried products were investigated based on a slow-transit constipation(STC) model. Seventy healthy SPF-grade rats were randomly divided into a blank group(K), a positive drug group(Y), a model group(M), low-and high-dose raw AFI groups(SD and SG), and low-and high-dose bran-fried AFI groups(FD and FG). During the experiment, it was found that compared with the K group, the groups with drug treatment had little effect on the daily body weight of the STC rats. The first defecation time of black stool in the M group was significantly higher than that in the K group, and the 24-hour fecal output significantly decreased starting from the 13th day, indicating successful modeling. The SG group showed a significant increase in the first defecation time, fecal water content, urine output, and water intake than other groups with drug treatment. The FG group had the highest fecal output than other groups with drug treatment. The FD group had the highest salivary secretion than other groups with drug treatment. The levels of cAMP/cGMP, VIP, 5-HT, AQP1, and AQP5 were measured in each group with drug treatment, and the expression of c-Kit and SCF mRNA in gastric antrum tissue and AQP3 mRNA in the kidney and colon were detected by RT-PCR. The results showed that the SD and SG groups had a more significant impact on AQP1, AQP5, and other water channel indexes in STC rats than the FD and FG groups. The FD and FG groups had a more significant impact on c-Kit, SCF, VIP, 5-HT, and other gastrointestinal motility indicators than the SD and SG groups. This study, through in vitro biological observations, immunological detection, and gene expression analysis, found that raw AFI had strong dryness property, while bran-fried AFI could alleviate its dryness property.
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Ratas , Animales , Serotonina , Estreñimiento/tratamiento farmacológico , Medicamentos Herbarios Chinos , ARN MensajeroRESUMEN
ObjectiveTo explore the therapeutic effect and mechanism of Yiqi Huoxue Tongbian prescription on slow transit constipation （STC） in rats. MethodThe rat model of STC was established by gavage of loperamide hydrochloride. Rats were assigned into control， model， mosapride， low-， medium-， and high-dose （3.51， 7.02， and 14.04 g·kg-1， respectively） Yiqi Huoxue Tongbian prescription groups. The changes of general signs， fecal moisture content， and intestinal propulsion rate were measured after model establishment and drug administration. The colonic mucosal changes were observed by hematoxylin eosin staining. Enzyme-linked immunosorbent assay was employed to determine the content of substance P （SP） and vasoactive intestinal peptide （VIP） in the colon of rats in each group. The gray values of aquaporin （AQP） 3， AQP4， AQP8， and c-Kit in rat colon tissue were measured by immunohistochemistry and Western blot， and the changes of intestinal flora were detected by 16S rRNA high-throughput sequencing. ResultCompared with the model group， 10 days of treatment with Yiqi Huoxue Tongbian prescription increased the fecal moisture content and intestinal propulsion rate （P<0.01）. The medium- and high-dose Yiqi Huoxue Tongbian prescription groups and the mosapride group showed no obvious mucosal inflammation and neat arrangement of goblet cells with a large number in the colon tissue. Moreover， the three groups showed increased SP content （P<0.01） and decreased VIP content （P<0.01） in the serum. The medium- and high-dose Yiqi Huoxue Tongbian prescription groups showed down-regulated protein levels of AQP3， AQP4， and AQP8 （P<0.01） and up-regulated protein level of c-Kit （P<0.01）. The drug administration groups presented slightly increased observed species， Chao1， ACE， and Shannon， Simpson， and PD whole tree. The principal component analysis showed that the control group had a short distance with the high- and medium-dose Yiqi Huoxue Tongbian prescription groups， indicating that high- and medium-dose Yiqi Huoxue Tongbian prescription can recover the intestinal flora to that in the control group. ConclusionYiqi Huoxue Tongbian prescription can alleviate the defecation status of rats with slow transit constipation by down-regulating the expression of AQP3， AQP4， and AQP8 to reduce the absorption of water in the intestine， up-regulating the expression of c-Kit to increase the number and distribution of Cajal interstitial cells， and regulating the balance of flora in the colon tissue.
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Objective:To observe the clinical effect of modified Zengyetang in treating slow transit constipation （STC） due to Qi-Yin deficiency and its effect on gastrointestinal function. Method:One hundred and thirty eligible patients were randomly divided into a control group （<italic>n</italic>=65， 6 cases dropped out or were lost to follow-up and 59 completed the trial） and a treatment group （<italic>n</italic>=65， 3 cases dropped out or were lost to follow-up and 62 completed the trial）. Patients in the control group received oral mosapride citrate dispersible tablets， 5 mg per time， three times per day， while those in the treatment group were treated with modified Zengye Tang， one bag per day， for four successive weeks. The main symptom constipation， the Patient Assessment of Constipation Symptoms （PAC-SYM）， and traditional Chinese medicine （TCM） syndrome scores， colonic transit， as well as motilin （MTL）， vasoactive intestinal peptide （VIP）， and substance P （SP） levels before and after treatment were recorded， together with the frequency of spontaneous complete bowel movements （SCBMs） per week and STC recurrence during treatment. Result:The clinical efficacy （95.16%） of the treatment group was higher than that （81.36%） of the control group （<italic>χ</italic><sup>2</sup>=5.631 4， <italic>P</italic><0.05）， whereas the recurrence rate （30.65%） of the treatment group was significantly lower than that （57.63%） of the control group （<italic>χ</italic><sup>2</sup>=8.941 1， <italic>P</italic><0.01）. After treatment， the main symptom constipation， three sub-scale and total PAC-SYM， and TCM syndrome scores in the treatment group were obviously decreased as compared with those in the control group （<italic>P</italic><0.01）. The proportions of residual markers at 24， 48， and 72 h in the treatment group declined in contrast to those in the control group （<italic>P</italic><0.01）. The frequency of SCBMs per week in the 2<sup>nd</sup>， 3<sup>rd</sup>， and 4<sup>th</sup> weeks of the treatment group was higher than that in the control group （<italic>P</italic><0.01）. Compared with the control group after treatment， the treatment group exhibited significantly elevated MTL and SP but lowered VIP （<italic>P</italic><0.01）. Conclusion:Modified Zengyetang relieves the clinical symptoms， regulates gastrointestinal hormone secretion， increases the frequency of SCBMs， enhances colonic transit， and decreases the recurrence of patients with STC due to Qi-Yin deficiency.
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Shouhui Tongbian Capsules was used to explore the therapeutic effect and potential mechanism on slow transit constipation model mice induced by loperamide hydrochloride. In the experiment, loperamide hydrochloride-induced ICR mice were used as the model of slow transit constipation. Fifty ICR mice were divided into the blank group, model group and high, medium and low dose groups of Shouhui Tongbian Capsules extract(100, 200 and 400 mg·kg~(-1)). The model group and the administration groups were then modeled using loperamide hydrochloride intragastrically to obtain slow transit constipation. After successful modeling, high, medium and low doses of drugs were given to each drug group by intragastric administration. After 14 days of administration, the first defecation time, 6 h defecation grain number, 6 h defecation wet weight and dry weight, black feces discharged within 6 h and the fecal water content were measured. Intestinal tissues were taken for c-Kit and SCF immunohistochemical sections to detect the expression of c-Kit and SCF in the blank group, model group and high, medium and low dose groups of the medicinal extract of Shouhui Tongbian Capsules. The tissue changes in the intestinal wall of mice were detected by HE staining. At the same time, partial intestinal tissues were taken to test the activity of ATP synthase and isocitrate dehydrogenase in intestinal tissues of mice. RESULTS:: showed that Shouhui Tongbian Capsules effectively improved the symptoms of slow transit constipation in ICR mice and promoted intestinal movement. Shouhui Tongbian Capsules obviously shortened the time of discharging black stool for the first time, improved the intestinal propulsion rate, increased the water content and amount of feces, and improved the constipation symptoms. Mechanism study revealed that Shouhui Tongbian Capsules increased ATP synthase activity and mitochondrial isocitrate dehydrogenase activity in intestinal tissue, and up-regulated c-Kit/SCF signaling pathway to promote interstitial Cajal cells proliferation, intestinal nerve transmission, intestinal motility and transport capacity.
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Animales , Ratones , Cápsulas , Estreñimiento/tratamiento farmacológico , Tránsito Gastrointestinal , Loperamida , Ratones Endogámicos ICRRESUMEN
Objective::To observe the clinical efficacy of modified Zhishi Daozhiwan on slow transit constipation (STC) and the effect on gastrointestinal hormones and intestinal flora. Method::One hundred and sixty patients were randomly divided into control group and observation group by random number table. Patients in control group got Maren Wan, 1-2 pills/time, 2 times/days, and mosapride citrate tablets, 1 piece/time, 3 times/days. Patients in observation group got modified Zhishi Daozhiwan, 1 dose/day. A course of treatment was 4 weeks. Before and after treatment, the main symptoms of constipation and patient assessment of constipation symptoms (PAC-SYM) were scored. And times of spontaneous complete bowel movement (SCBM) and colonic transmission test were recorded. And levels of intestinal flora and motilin (MTL), vasoactive intestinal peptide (VIP), substance P (SP) and gastrin (GAS) were detected. The 12-week follow-up of patients (SCBM≥3) was recorded, and the relapse of disease was calculated. Result::According to rank sum test analysis, the clinical efficacy in observation group was better than that in control group (Z=2.275, P<0.05). After treatment, scores of the main symptoms of constipation, PAC-SYM, and the total score of PAC-SYM were all lower than those in control group (P<0.01). At the second, third and fourth weeks after treatment, the times of SCBM were more than those in control group (P<0.01). Ratio of residual marker at 24, 48 and 72 h was lower than that in control group (P<0.01). Count of enterococcus and enterobacter were lower than those in control group (P<0.01), while counts of bifidobacterium and lactobacillus were higher than in control group (P<0.01). Levels of GAS, MTL and SP were higher than those in control group, whereas level of VIP was lower than that in control group (P<0.01). And relapse rate in observation group was 33.85%, which was lower than 57.69% in control group (χ2=6.653, P<0.05). Conclusion::Modified Zhishi Daozhiwan can alleviate constipation and other symptoms, increase the number of SCBM, regulate gastrointestinal hormones and intestinal flora, and improve colonic transit function, with a good clinical efficacy and low recurrence rate, so it is worth clinical application.
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Objective: To investigate the effect of sodium carboxymethyl starch (CMC) on constipation. Methods:The slow transit constipation model of mice was established by intragastric administration of loperamide for 3 d, and the dehydration-dryness constipation model of mice was established by water deprivation for 3 d. The effects of CMC were evaluated by total fecal grains, intestinal propulsion rate, fecal water content and intestinal fluid within 3 h after administration. Results: The total defecation granules in the slow transit constipation model group were (7.9±6.0) within 3 h after administration for 3 d. Compared with those in the model group, the total defecation granules in the three CMC dosage groups (0.45, 0.9 and 1.8 g/kg) significantly increased (18.5±5.0, 17.3±8.3 and 22.9±8.4, P<0.01), respectively. The results were better than those in mosapride group (14.3±8.4). The intestinal propulsion rate [(75.3±9.2)%, (78.7±9.6)%, and (79.4±8.0)%] in the three CMC dosage groups increased significantly (P<0.05 or P<0.01) compared with the model group (63.0±13.6)%. For dehydration and dryness constipation model, the total fecal granules in 0.9 and 1.8 g/kg CMC groups were 37.9±9.9 and 37.2±7.9, which significantly increased compared with those in model group (25.8±8.5, P<0.01). The intestinal propulsive rate (83.2±12.8)% was higher in CMC 1.8 g/kg group than in the model group [(72.6±11.5)%, P<0.05]. Mouse fecal water content [(56.0±4.1)%, (57.7±10.4)% and (60.2±6.8%)] in CMC 0.3, 0.6 and 1.2 g/kg groups were higher than in the model group [(49.0±6.8)%, P<0.05 or P<0.01]. Rat intestinal solution in CMC 0.6 and 1.2 g/kg groups was higher than that in saline group (P<0.05 or P<0.01). Conclusion: CMC can improve the defecation of constipated mice.
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Objective@#To investigate the clinical efficacy of laparoscopic subtotal colonic bypass plus colostomy with antiperistaltic cecoproctostomy (SCBCAC) in the treatment of senile slow transit constipation.@*Methods@#A retrospective cohort study was performed. Clinical data of 30 colonic slow transit constipation patients aged ≥70 years old undergoing laparoscopic SCBCAC from July 2012 to October 2016 (bypass plus colostomy group), and 28 patients undergoing laparoscopic subtotal colonic bypass with antiperistaltic cecoproctostomy (SCBAC) from February 2009 to June 2012 (bypass group) at our institute were collected. Efficacy was compared between the two procedures. Inclusion criteria: (1) meeting the Rome III diagnosis criteria for constipation; (2) confirmed diagnosis of slow transit constipation; (3) age ≥ 70 years old; (4) receiving non-surgical treatment for more than 5 years, and Wexner constipation score > 15; (5) follow-up for more than 2 years. Those with psychiatric symptoms or previous psychiatric history, obvious signs of outlet obstructive constipation, organic diseases of the colon and life-threatening cardiovascular diseases or cancer were excluded. In the bypass plus colostomy group, laparoscopy was performed via five trocars. The ileocecal junction and the ascending colon were mobilized and the ileocecal junction was pulled down to the pelvic inlet. The ascending colon was transected and the appendix was excised. The lateral peritoneum of the sigmoid colon and the rectal mesentery were dissected and the upper rectum was transected. The avil of a circular stapler was placed in the bottom of the cecum. The shaft of the stapler was placed in the rectum via the anal canal to complete end-to-side anastomosis (end rectum to lateral cecum). The end of the rectal-sigmoid colon was used for colostomy via an extraperitoneal approach to complete the operation. The following efficacy indexes were collected before surgery and 3, 6, 12, and 24 months after surgery: the number of daily bowel movements, the Wexner incontinence scale (WIS, 0-20, the lower the better), the Wexner constipation scale (WCS, 0-30, the lower the better), the gastrointestinal quality of life index (GIQLI, 0-144, the higher score, the better), abdominal pain intensity indicated by the numerical rating scale (NRS, 0-10, the lower score, the better), and the abdominal bloating score (ABS, 0-4, the lower score, the better). The complications defined as Clavien-Dindo class II or above were observed and recorded.@*Results@#No significant differences in preoperative WCS, WIS, GIQLI, NRS, and ABS were observed between bypass plus colostomy group and bypass group (all P>0.05). All the patients successfully underwent laparoscopic surgery and no patient in either group experienced postoperative fecal incontinence. WCS and GIQLI were significantly improved (all P<0.001) at 3, 6, 12, and 24 months after surgery in both groups. At 12 months after surgery, the number of bowel movements was significantly less in bypass plus colostomy group than that in bypass group [(2.4±0.7) times vs. (3.4±1.2) times, t=4.048, P<0.001]. At 3, 6, 12 and 24 months after surgery, the improvement of GIQLI in bypass plus colostomy group was significantly better than that in bypass group (all P<0.001). At 24 months after surgery, GIQLI in bypass plus colostomy group and bypass group was 122.3±5.3 and 92.8±16.6, respectively, with a significant difference (t=9.276, P<0.001). At 12 and 24 months after surgery, NRS in bypass plus colostomy group was significantly better than that in bypass group (both P<0.001). At 24 months after surgery, NRS in bypass plus colostomy group was 0.9±0.7, while that in bypass group was 3.7±2.7. There was a significant difference between two groups (t=5.585, P<0.001). At 6, 12 and 24 months after surgery, the improvement of ABS in bypass plus colostomy group was also significantly better than that in bypass group. At 24 months after surgery, ABS in bypass plus colostomy group was 0.6±0.6, while that in bypass group was 2.5±1.0, with a significant difference between two groups (t=8.797, P<0.001). At 1 year after surgery, barium enema examination was performed in all the patients of both groups. The barium emptying time was (21.2±3.8) hours and (95.8±86.2) hours in bypass plus colostomy group and bypass group respectively. The former group was significantly better than the latter group (t=4.740, P<0.001).@*Conclusions@#Laparoscopic SCBCAC is an effective and safe procedure for the treatment of senile slow transit constipation and can significantly improve prognosis. Its clinical efficacy is better than laparoscopic SCBAC.
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Objective:To explore the effect of Zhizhuwan on intestinal conduction and expressions of Phospholipase C-γ1 (PLC-γ1)/Phospholipase C-γ2 (PLC-γ2) signaling pathway of slow transit constipation (STC) with spleen deficiency syndrome. Method:Special pathogen free (SPF) healthy mice were randomly divided into normal group and model making group. Folium Sennae gavage was used to induce the spleen deficiency status, and then diet and drinking water were controlled to establish the mice model of spleen deficiency constipation. After the modeling, the mice in modelling group were randomly divided into model group, Zhizhuwan group and mosapride group. Zhizhuwan group was given drug at the dose of 9.0 g·kg-1·d-1, mosapride group was given 2.5 mg·kg-1·d-1, model group and normal group were given the equal dose of distilled water for 7 consecutive days. At the end of the treatment, the length of Indian ink in the colon was used to calculate the intestinal propulsion rate of the mice. The D-xylose kit was used to determine the content of D-xylose in serum of mice. The hematoxylin eosin (HE) staining was used to observe the pathological changes of colon tissues in mice. The immunohistochemistry and Western blot were used to detect the expression levels of PLC-γ1 and PLC-γ2 proteins in colon tissues of mice. Real-time PCR was used to detect the mRNA expression levels of PLC-γ1 and PLC-γ2. Result:Compared with normal group, the intestinal propulsive rate and the serum D-xylose value in model group were significantly decreased (Pγ1 and PLC-γ2 in colon tissues were significantly decreased (PD-xylose in Zhizhuwan group and mosapride group were significantly increased (Pγ1 and PLC-γ2 were significantly increased (PConclusion:Zhizhuwan can promote the intestinal movement in slow transit constipation model mouse with spleen deficiency syndrome, and alleviate the symptoms of constipation in mice. The related mechanism may be related to the increase of the expressions of PLC-γ1 and PLC-γ2 in colon tissues of mice with spleen deficiency and constipation.
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Objective: To explore the effect of Tongbiantang on protein kinase A(PKA) and mitogen-activated protein kinase(MAPK) signal pathway in colon tissue of slow transit constipation(STC) rats and its related mechanism. Method: Eighty SD rats were randomly divided into blank group and model group, 20 rats in blank group, 60 rats in model group, half male and half female; blank group was fed with common diet, model group was fed with compound phenylethylpiperidine, after 120 days of modeling, 10 rats in blank group and 20 rats in model group were randomly selected, and 2 rats were determined. Four-hour stool volume, water content and small intestinal charcoal powder propelling rate were observed to observe the number of stool particles retained in colon and evaluate the success of STC rat modeling. After 1 week of drug withdrawal, 40 rats in model group were randomly divided into model group(33 g·kg-1), Tongbiantang group, Tongbiantang+H89 group (PKA signaling pathway blocker,5 mg·kg-1), Tongbiantang+U0126 group (MPKA signaling pathway blocker,0.1 mg·kg-1) each. After 4 weeks of intervention with Tongbiantang, the amount of stool excretion, water content and small intestinal charcoal powder propelling rate were measured in 10 rats, and the number of stool grains in colon was observed. The protein content and mRNA expression in aquaporins 3(AQP3), AQP4, PKA and MAPKs signaling pathways in colon was determined by immunohistochemical staining (IHC), Western blot and Real-time fluorescence quantitative PCR (Real-time PCR). Result: Compared with the blank group, the 24-hour stool volume, fecal water content, small intestinal charcoal propelling rate and the number of fecal particles in colon of rats in the model group were significantly decreased (PPPPPConclusion: Tongbiantang can inhibit the PKA and MPKA signal pathways, thus down-regulate the expression of AQP3 and AQP4, increase intestinal peristalsis and intestinal water, and effectively treat STC.
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Objective To observe the effect of Yang-warming and Qi-tonifying Recipe (YQP)on aquaporin 3(AQP3) and AQP8 in rats with slow transit constipation,and to explore its therapeutic mechanism. Methods Forty rats were randomly divided into modeling group(N=30)and normal control group(N = 10). After successful modeling by gastric gavage of loperamide,the modeled rats were randomly divided into model group,YQP group and Mosapride group,10 rats in each group,and were separately treated with corresponding medicine for 2 weeks. After treatment, the colonic transit function was measured by carbon propelling test. The protein levels of AQP3 and AQP8 were detected by immunohistochemistry and their mRNA expression levels were detected with real-time fluorescence polymerase chain reaction (qPCR). Results Compared with the normal control group,the propelling rate of carbon particle in the model group was decreased,and the protein and mRNA expression levels of AQP3 and AQP8 were significantly increased(P<0.05 or P<0.01). Compared with the model group,the propelling rate of carbon particle of YQP group and mosapride group was significantly increased, and the protein and mRNA expression levels of AQP3 and AQP8 were significantly decreased (P<0.05),but there was no significant difference between YQP group and mosapride group (P >0.05). Conclusion YQP had therapeutic effects on loperamide-induced constipation through decreasing the expression of AQP3 and AQP8 in the intestine,reducing the reabsorption of intestinal fluid, and increasing the fecal water content.
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Objective To evaluate the clinical and functional outcomes of Side-to-Side Ileosigmoidostomy Shunting Surgerys for the treatment of elder STC patients.Methods The clinical data of 67 patients all more than 63 years old with severe idiopathic STC treated with this novel approach between June 2010 and July 2017 were retrospectively analyzed.The perioperative complications and defection conditions were followed up by telephone and outpatient.The Wexner constipation score and gastrointestinal tract were compared before and after the operation.SPSS 19.0 software was used for statistical analysis.Independent sample t test was used for measurement data,t and x2 test were used for comparison of count data.Results All the patients received their operations successfully without deaths or serious complication.The center follow-up period (from outpatients or phone) was 12 months (6-29 months).only 16 patients developed complications including 2 and 14 total colonic exclusion.12 of the 14 got better obviously after enema and taken dynamic drugs,Only 2 patients with repeated abdominal pain and distention received jejunostomy.Six months after the operation,only 5 patients needed to take some drugs for defectation.Wexner constipation scores and Gastrointestinal Quality of Life Index (GIQLI) has improved obviously after 6 months and 12 months.Conclusions The novel surgical procedure,side-to-side ileosigmoidostomy Shunting Surgery that practised in our department,is an easy,safe and effective for the treatment of selected elderly patients with STC.Large-sample,randomized,controlled analyses are worth to investigate its clinical effects.
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The effect of bisacodyl on the treatment of rats with slow transit constipation (STC) was studied. Forty-five female Wister rats were divided into control group, STC group, and STC bisacodyl group. The immunohistochemical method was used to determine interstitial cells of Cajal (ICC) and the expression of c-Kit protein. Body mass and the number of defecations were significantly decreased in the STC group compared with the control group on the 100th day after diphenoxylate administration, while dry weight of feces was significantly increased and the intestinal transit time was prolonged. There were significant differences in the number of defecations, dry weight of feces, and intestinal transit time among the three groups. The number of defecations was higher, dry weight of feces was lower, and intestinal transit time was shorter in the STC bisacodyl group compared to the STC group. In addition, ICC basement membrane dissolution occurred in the colon wall of the STC group. The connection between ICC and surrounding cells was destroyed, and the nucleus shrunken to different degrees. Moreover, c-Kit expression in the STC group was significantly lower than the control group. The connection between ICC and surrounding cells in the STC bisacodyl group was significantly stronger than the STC group, and the number of ICC and the expression of c-Kit were increased. Bisacodyl could reduce the severity of STC in rats by increasing the number of ICC and the expression of c-Kit.
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Animales , Femenino , Ratas , Bisacodilo/uso terapéutico , Tránsito Gastrointestinal/efectos de los fármacos , Catárticos/uso terapéutico , Colon/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Estreñimiento/tratamiento farmacológico , Células Intersticiales de Cajal/efectos de los fármacos , Tránsito Gastrointestinal/fisiología , Inmunohistoquímica , Ratas Wistar , Colon/efectos de los fármacos , Colon/patología , Estreñimiento/fisiopatología , Estreñimiento/metabolismo , Células Intersticiales de Cajal/metabolismo , Células Intersticiales de Cajal/patologíaRESUMEN
Objective To observe the clinical efficacy of Runchang Xuanfei Shugan Formula in the treatment of slow transit constipation. Methods Totally 94 patients were randomly divided into treatment group and control group, with 47 patients in each group. Treatment group was given Runchang Xuanfei Shugan Formula, one dose per day, half a dose for morning and half a dose for evening, and the control group was given lactulose oral liquid, 15 mL each time, for morning and evening, and citrate moser Billy 5 mg, three times a day orally taken before meals. The treatment course for the two groups were 4 weeks, with three-month follow-up. The defecation symptom score, anxiety and depression score were observed, the colonic transit test meter was performed, and the side effects were recorded. Results The degree of defecation difficulty, defecation frequency, defecation time, abdominal distension and stool quality score of the two groups significantly decreased after treatment (P0.05). Conclusion Runchang Xuanfei Shugan Formula can improve clinical symptoms of slow transit constipation, ease anxiety and depression of patients, and promote colon transmission function.