Advances in intestinal flora metabolites deoxycholic acid and digestive diseases in children / 国际儿科学杂志

It is the hotspot that studying the interplay and mechanism between intestinal flora metabolites and diseases.Deoxycholic acid, one of the intestinal flora metabolites, is one of the most abundant secondary bile acids in human intestinal tract, which is corelated with many diseases, while the mechanisms remain unclear.The imbalance of deoxycholic acid is connected with the intestinal flora disorder and high fat diet, which could result in several immunoreaction and inflammatory reaction.In this review, the interaction between deoxycholic acid and digestive diseases in children, such as non-alcoholic fatty liver disease, inflammatory bowel disease and irritable bowel syndrome, is discussed to explore their related mechanism, so as to clarify the direction of further study on the influence of intestinal microbiota metabolites deoxycholic acid on the human body.

Efficacy, safety, and potential industry bias in using deoxycholic acid for submental fat reduction - A systematic review and meta-analysis of randomized clinical trials

Abstract Lipolytic substance injections to reduce localized fat have been extensively used because it is a low-invasive method. This review aimed to evaluate the efficacy and safety of deoxycholic acid in submental fat reduction compared to a placebo and investigate the potential industry sponsorship bias in the results of randomized clinical trials on this topic. Ten electronic databases were extensively searched for randomized clinical trials without restriction on language and year of publication. Two reviewers extracted the data and assessed the individual risk of bias in the studies with the RoB 2.0 tool. The industry sponsorship bias was evaluated according to citations in the articles regarding industry funding/sponsorship throughout the texts. Fixed and random effects meta-analyses were performed, and the results were reported in Risk Ratio (RR) at a 95% Confidence Interval (95% CI). The initial search provided 5756 results, of which only five were included. Only two studies had a low risk of bias. All studies showed a potential industry bias. The meta-analysis showed that patients treated with deoxycholic acid had significant positive results for all efficacy outcomes and a higher risk of fibrosis, pain, erythema, numbness, swelling, edema, pruritus, nodules, headache, and paresthesia. The low to moderate certainty of evidence found allows concluding that deoxycholic acid is effective in submental fat reduction, causing well-tolerated adverse effects. However, all eligible studies showed a potential industry bias.

Efecto del ácido deoxicólico sobre la regulación del transporte iónico intestinal en la rata / Deoxycholic acid efect on intestinal ionic transport regulation in the rat

The intestine has a very important role in the homeostasis of the internal medium. Bile acids play a regulatory role in the digestion and absorption of nutrients. Among them, deoxycholic acid, when its luminal concentration increases due to bacterial overgrowth, modifies hydroelectrolytic transport, producing an increase in the volume of water and electrolytes in stools.

El intestino tiene un papel muy importante en la homeostasis del medio interno. Los ácidos biliares cumplen una función reguladora en la digestión y absorción de nutrientes. Entre ellos el ácido deoxicólico, cuando aumenta su concentración luminal por sobrecrecimiento bacteriano, modifica el transporte hidroelectrolítico produciendo aumento del volumen de agua y electrolitos en las deposiciones.

Perda de definição do contorno do submento: correto diagnóstico e algoritmo de tratamento / Loss of definition of the submental contouring: correct diagnosis and treatment algorithm

A busca por procedimentos estéticos voltados para a perda de definição do submento é crescente. Um correto diagnóstico é imperativo para o sucesso do tratamento e redução das complicações. Adiposidade localizada, flacidez cutânea e perda da estrutura óssea são os principais achados. Um algoritmo de tratamento foi discutido nesta revisão, lembrando-se, claro, da possibilidade de tratamentos combinados e sequenciais para melhores resultados

The search for aesthetic procedures aimed at the loss of submental definition is increasing. A correct diagnosis is imperative for successful treatment and the reduction of complications. Localized adiposity, skin flaccidity, and loss of bone structure are the main findings. A treatment algorithm was discussed in this review, remembering, of course, the possibility of combined and sequential treatments for better results.

Study on the synthesis process of deoxycholic acid / 国际药学研究杂志

Objective: To optimize the synthesis process of deoxycholic acid according to the concept of the quality-based design(QBD)to ensure the safety and quality of the product. Methods： Based on a large number of literature and the referenced original patents, the plant sourced 9-hydroxyandrostenedione was selected and used as the starting material for the deoxycholic acid synthesis, in view of the advantages and disadvantages of each of the reported synthetic routes, and the synthesis process of the key intermediate 7 was investigated systematically with the particular attention. For the process impurities and optical isomer impurities generated in each reaction, the key parameters of the synthetic process were investigated and optimized in detail. At the same time, each step of post-reaction treatment and refining process was systematically investigated to provide the quality standard for the key intermediate 7. Results： Under the guidance of QBD, the reaction process parameters were optimized based on the single factor design experiments, by which the content of chiral isomers was reasonably controlled and the reaction yield was largely improved. Based on the results, a quality standard was designed for the key intermediate 7, and the reasonability and feasibility of the quality standard was proved by the successful synthesis of deoxychloic acid from 7 to obtain multiple batches of qualified deoxycholic acid samples. Conclusion： The whole process is stable and simply operable, and well matches the industrial requirement for the raw material deoxycholic acid synthesis.

Ursodeoxycholic acid combined with bezafibrate in the treatment of refractory primary biliary cholangitis: a meta-analysis / 中华肝脏病杂志

Objective@#To evaluate the efficacy, safety and remission rates of pruritus of bezafibrate and UDCA combination therapy in the treatment of refractory PBC.@*Methods@#PubMed, Embase, The Cochrane Library databases, Science direct, Web of Science, CBM, WangFang Data, CNKI, VIP databases were searched to collect randomized controlled trials, crossover trials and self-control clinical trials of combination therapy of UDCA and bezafibrate with UDCA monotherapy for PBC up to June, 2018. RevMan 5.3 software was used for meta-analysis. Two evaluators independently screened the literature, extracted the data, and evaluated the risk of bias of relevant study.@*Results@#Eleven studies, including 465 patients were included. Ursodeoxycholic acid combined with bezafibrate had greatly improved liver biochemical indicators (P < 0.01) and pruritus scores in patients with refractory primary biliary cholangitis (MD = -2.97, 95% CI: -4.34~ -1.60, P < 0.01). However, there was no statistically significant differences in adverse events (RR = 1.28, 95% CI: 0.96 to 1.70, P = 0.09), and mortality rate (RR = 2.58, 95% CI: 0.57 to 11.73, P = 0.22) between the two groups.@*Conclusion@#Ursodeoxycholic acid combined with bezafibrate may improve the biochemical response and pruritus score of refractory PBC, but has no significant effect on adverse events and mortality rate.

Decellularization of Trachea With Combined Techniques for Tissue-Engineered Trachea Transplantation

OBJECTIVES: The purpose of this study is to shorten the decellularization time of trachea by using combination of physical, chemical, and enzymatic techniques. METHODS: Approximately 3.5-cm-long tracheal segments from 42 New Zealand rabbits (3.5±0.5 kg) were separated into seven groups according to decellularization protocols. After decellularization, cellular regions, matrix and strength and endurance of the scaffold were followed up. RESULTS: DNA content in all groups was measured under 50 ng/mg and there was no significant difference for the glycosaminoglycan content between group 3 (lyophilization+deoxycholic acid+de-oxyribonuclease method) and control group (P=0.46). None of the decellularized groups was different than the normal trachea in tensile stress values (P>0.05). Glucose consumption and lactic acid levels measured from supernatants of all decellularized groups were close to group with cells only (76 mg/dL and 53 mg/L). CONCLUSION: Using combination methods may reduce exposure to chemicals, prevent the excessive influence of the matrix, and shorten the decellularization time.

Mechanisms of deoxycholic acid to promote the initiation and progression of colorectal cancer / 医学研究生学报

Colorectal cancer is a malignant disease of digestive system, with increasing morbidity. As a risk factor of colorectal cancer, high fat diet changes the secretory form of hepatic bile acids and stimulates its secretion. As a result, it increases the concentration of bile acids in the large intestine. Deoxycholic acid promotes the initiation and progression of colorectal cancer through affecting various intracellular signals, modulating expression of multiple genes and influencing the balance of the gut microbiota. The article reviewes the mechanisms of deoxycholic acid to promote the initiation and progression of colorectal cancer.

Alopecia em barba causada por desoxicolato para tratamento de gordura submentoniana / Beard alopecia caused by deoxycholic acid for the treatment of submental fat

Segundo relato de caso da literatura de alopecia em região de barba observada após terceira sessão de injeções de desoxicolato a 1% para redução de gordura submentoniana.

Second case report in the literature regarding beard alopecia observed after the third session of injections of 1% deoxycholic acid for reduction of submental fat.

Dynamic changes of taurine-conjugated bile acid levels during the development and progression of type 2 diabetes in OLETF rats / 中华内分泌代谢杂志

Objective To observe the changes of serum and fecal taurine-conjugated bile acid levels and its association with glucose metabolism during the spontaneous development of type 2 diabetes in OLETO rats.Methods Twenty male OLETF rats(4 weeks old)were included and 10 male LETO rats of the same age were used as the normal control group.OLETF rats were fed with high fat diet whereas LETO rats were fed with normal diet.Serum and fecal taurine-conjugated bile acid levels of OLETF rats were tested at different stage of diabetes including baseline, normal glucose tolerance, impaired glucose tolerance and diabetes periods, and the association of taurine-conjugated bile acid level with body weight, blood glucose, and glucose-regulating hormones were also investigated.Results Compared with LETO rats, the baseline serum levels of taurine-conjugated bile acid in OLETF rats did not change, but the levels of fecal taurine-conjugated bile acid including taurine-conjugated chenodeoxycholic acid(TCDCA), taurocholic acid(TCA)and taurine-conjugated deoxycholic acid(TDCA)were significantly decreased [(14.25±7.18 vs 0.90±0.31)mg/kg,(7.12±4.14 vs 1.30±0.35)mg/kg,(4.30±1.78 vs 1.02±0.14)mg/kg, all P<0.01].During the development of diabetes, the fecal levels of TCDCA, TCA and TDCA were still lower than those in the control rats.TDCA was negatively associated with the level of fasting blood glucose(r=-0.470, P=0.032),but positively associated with the serum level of glucagon-like peptide(GLP)-l(r=0.406, P=0.044).Conclusion The decrease of intestinal taurine-conjugated bile acid level is involved in the development of diabetes in OLETF rats.Intestinal TDCA may regulate the secretion of GLP-1 by paracrine pathway.

Research progress of decitabine in myelodysplastic syndromes / 中国医师杂志

It provides a new approach to treat myelodysplastic syndromes when decitabine comes out.In order to improve the understanding of the role of decitabine and to provide a reference for the clinical treatment of middle-risk and high-risk myelodysplastic syndromes,this article mianly summarized drug combination,prognostic molecular markers,and reviewed the mechanism of action,main medication regimen in recent 5 years for the treatment of middle-risk and high-risk myelodysplastic syndromes with decitabine.

Role of SIRT3 in dysfunction of energy metabolism induced by deoxycho-lic acid in human colon NCM460 cells / 中国病理生理杂志

AIM: To investigate the effect of deoxycholic acid (DCA) on the energy metabolism in human normal colon epithelial NCM460 cells.METHODS: NCM460 cells was treated with DCA at 10, 30 and 100 μmol/L for 5 d, or DCA at 100 μmol/L for 3, 5 and 7 d.After treated with DCA at 100 μmol/L for 3 d, the cells were treated with resveratrol, the activator of sirtuin 3 (SIRT3), for the next 4 d.Adenosine triphosphate (ATP) production in the mitochondria and lactate acid level were detected.The protein expression of SIRT3 was determined by Western blot.RESULTS: DCA inhibited the ATP production, increased lactate acid level, and downregulated the protein expression of SIRT3 in a dose-and time-dependent manner.Resveratrol at 10 μmol/L reversed the effects of DCA on the NCM460 cells.CONCLUSION: DCA induces the dysfunction of energy metabolism in NCM460 cells, and the mechanism may be related with SIRT3.

Preparation and pharmacokinetic study of asiatic acid loaded chitosan-deoxycholic acid polymeric micelles in rats / 中草药

Objective To prepare asiatic acid (AA) loaded chitosan-deoxycholic acid self-assembled micelles (AA-CS-DCA PMs) adopting chitosan-deoxycholic acid (CS-DCA) as carriers and investigate its pharmacokinetic characteristics in rats. Methods AA-CS-DCA PMs were prepared by ultrasonic dispersion method. The characteristics of micelles were evaluated by the distribution of particle size, Zeta potential, drug loading, encapsulation efficiency, and in vitro release. Model of bile drainage was established in conscious rats and pre-column derivatization HPLC method was used to determine the concentration of AA in bile. Moreover, the pharmacokinetics characteristics of AA-CS-DCA PMs in vivo was evaluated by tmax, Cmax and AUC0-t. Results The particle size was (70.5 ± 9.8) nm, the Zeta potential was (38.4 ± 0.8) mV, and encapsulation efficiency and drug loading were (77.8 ± 1.2)% and (11.7 ± 0.2)%, respectively. The in vitro release profile showed a sustained release property. In vivo study showed that Cmax of AA-CS-DCA group (26.05 ± 3.04) μg/h was 2.8 times higher than that of the control group (9.19 ± 1.12) μg/h; The tmax of AA-CS-DCA PMs group prolonged significantly (P < 0.05) in biliary excretion (2 h vs 1 h) and the elimination half-life t1/2 was 1.8 times of the control group [(2.68 ± 1.71) h vs (1.49 ± 0.38 h)]. In addition, the AUC0-24 h which reflected the degree of drug absorption increased by 200% compared with the control group [(99.05 ± 12.83) μg vs (33.56 ± 8.33) μg]. Conclusion The chitosan- deoxycholic acid self-assembled micelles can raise the concentration of AA and prolong the retention time in vivo, which effectively improve the oral bioavailability of AA.

The Effect of Deoxycholic Acid on Secretion and Motility in the Rat and Guinea Pig Large Intestine

BACKGROUND/AIMS: Bile acid is an important luminal factor that affects gastrointestinal motility and secretion. We investigated the effect of bile acid on secretion in the proximal and distal rat colon and coordination of bowel movements in the guinea pig colon. METHODS: The short-circuit current from the mucosal strip of the proximal and distal rat colon was compared under control conditions after induction of secretion with deoxycholic acid (DCA) as well as after inhibition of secretion with indomethacin, 1,2-bis (o-aminophenoxy) ethane-N,N,N′,N′-tetra-acetic acid (an intracellular calcium chelator; BAPTA), and tetrodotoxin (TTX) using an Ussing chamber. Colonic pressure patterns were also evaluated in the extracted guinea pig colon during resting, DCA stimulation, and inhibition by TTX using a newly developed pressure-sensing artificial stool. RESULTS: The secretory response in the distal colon was proportionate to the concentration of DCA. Also, indomethacin, BAPTA, and TTX inhibited chloride secretion in response to DCA significantly (P < 0.05). However, these changes were not detected in the proximal colon. When we evaluated motility, we found that DCA induced an increase in luminal pressure at the proximal, middle, and distal sensors of an artificial stool simultaneously during the non-peristaltic period (P < 0.05). In contrast, during peristalsis, DCA induced an increase in luminal pressure at the proximal sensor and a decrease in pressure at the middle and distal sensors of the artificial stool (P < 0.05). CONCLUSIONS: DCA induced a clear segmental difference in electrogenic secretion. Also, DCA induced a more powerful peristaltic contraction only during the peristaltic period.

High Bile Acid-induced by High-fat Diet Impairs Intestinal Mucosa by Down-regulating Stem Cell Function / 胃肠病学

Background:High-fat diet leads to intestinal mucosa barrier dysfunction,but the mechanism is not clear. High-fat diet can induce increase of bile acid. Aims:To investigate whether the high bile acid induced by high-fat diet could act on intestinal stem cell to disrupt stem cell differentiation and imparing the intestinal mucosa. Methods:Twenty-four rats were divided into 3 groups:fed with regular diet,high-fat diet and high-fat diet + cholestyramine,respectively,for 2 weeks. Serum bile acid was detected by ELISA. Ileal diameter was measured and HE staining was performed to observe histology of intestinal mucosa. Expression of Lgr5 gene was determined by RT-qPCR. Ileal tissue fed with regular diet was cultured with deoxycholic acid(DCA)or DCA + cholestyramine for 24 hours in vitro,expression of Lgr5 gene was determined by RT-qPCR. Results:Compared with control group,serum bile acid was significantly increased(P < 0. 05),ileal diameter was significantly decreased,height of intestinal crypts and villus was significantly decreased(P < 0. 05),and expression of Lgr5 gene was significantly decreased in high-fat diet group(P < 0. 01). All the above-mentioned indices were significantly ameliorated in high-fat diet + cholestyramine group(P < 0. 05). In vitro study showed that expression of Lgr5 gene was significantly decreased in DCA group than in control group(P < 0. 01),and cholestyramine could significantly increase expression of Lgr5 gene(P < 0. 05). Conclusions:High-fat diet induced increasing of circulatory bile acid can cause injury of intestinal mucosa by inhibiting stem cell function,which can be ameliorated by cholestyramine.

Gut dysbacteriosis and primary liver cancer: Recent progress / 第二军医大学学报

Gut microbiota plays important roles in maintaining human body homeostasis, and its relationship with diseases is gaining increasing attention, but the exact pathophysiological mechanisms are not fully understood. Recently, studies have shown that gut dysbacteriosis also plays a part in the development and progression of liver cancer, which involves dysbacteriosis-related changes in bile acid metabolism, hepatic stellate cell senescence, endotoxin metabolic disorders and so on. This paper reviewed the mechanisms of liver cancer involving gut dysbacteriosis, casting new lights on prevention strategies of liver cancer by targeting gut dysbacteriosis and on the future research directions.

Secondary bile acids effects in colon pathology. Experimental mice study

ABSTRACTPURPOSE:To assess whether deoxycholic acid (DOC) and lithocholic acid (LCA) administered in a period of six months in a concentration of 0.25% may have a carcinogenic role in mice colon.METHODS:The study used C57BL6 female mice divided into four groups. The control group received a balanced diet and the others received diets supplemented with 0.25% DOC, 0.25% LCA and 0.125% DOC+0.125% LCA, respectively. After euthanasia, the lesions found in the resected gastrointestinal tracts were stained with hematoxylin-eosin and examined microscopically.RESULTS:No gastrointestinal tract changes were observed in the control group, while hyperplastic Peyer's patches in the small intestine, flat adenomas with mild dysplasia and chronic colitis at the level of the colon were found in all three test groups. The colonic lesions prevailed in the proximal colon. The highest number of flat adenoma lesions (8), hyperplasia of Peyer's patches (25) and chronic colitis (2) were found in mice fed with diet and LCA.CONCLUSION: Precancerous or cancerous pathological lesions could not be identified. Instead, adenomatous colonic injuries occurred in a shorter period of time (six months), compared to the reported data.

Determine the Grafting Ratio of CS-DCA by Linear Potentiometric Titration / 浙江中医药大学学报

Objective]To establish a new method for grafting ratio(GR) analysis of deoxycholic acid grafted chitosan(CS-DCA). [Methods]In this study, linear potentiometric titration(LPT) and 2,4,6-trinitrobenzenesulfonicacid(TNBS) were introduced to measure the GR of CS-DCA, using the 1H-nuclear magnetic resonance(1H-NMR) as reference, the results obtained by the two methods were analyzed to find a method to substitute H-NMR. [Results]There was no significant difference of the data determined by 1H-NMR and LPT(P>0.05), however, it didn't apply to 1H-NMR and TNBS(P<0.05), the results indicated that LPT had equivalent accuracy of 1H-NMR. Using 1H-NMR method as the standard reference, the relative error was no more than 3.8% for the method of LPT, and the maximum relative error for the method of TNBS was up to 12.8%, it meant that LPT had higher precision. [Conclusion]LPT is an economical, rapid and accurate method for the GR analysis of CS-DCA.

Secondary bile acid induced intestinal adenoma canceration and its effect on intestinal microflora in Apcmin/+ mice / 中华消化杂志

Objective To investigate secondary bile acid induced canceration process of intestinal adenoma and effects on intestinal microflora in Apcmin/+ mice.Methods Forty four-week-old mice (20 Apcmin/+mice and 20 wild-type C57BL/6J mice) were divided into four groups:wild-type control group (regular drinking water),wild-type deoxycholic acid (DOC) group (with 0.2 ％ DOC in drinking water),Apcmin/+ control group and Apcmin/+ DOC group.Fecal pellets of Apcmin/+ mice were collected at 0 week and 12 week after administration.The changes of intestinal microflora were analyzed by pyrosequencing.All mice were sacrificed after 12 weeks.The number,size and location of intestinal adenoma were observed.The pathological type of adenoma was evaluated after hematcxylin-eosin (HE) staining.Proliferating cell nuclear antigen (PCNA) was detected by immunohistochemistry.Cell apoptosis was determined by in situ terminal deoxynucleotidyl transferase mediated dUTP nick end labeling technique (TUNEL).Independent t test was used for the quantitative data comparison between two groups.Results No intestinal tumors were found in the wild-type mice.The total number of intestinal adenoma of Apcmin/+ DOC group significantly increased,compared with that of Apcmin/+ control group (57.00 ± 3.07 vs 21.50± 4.69,t=20.03,P＜0.01),the increase of the adenoma with maximum diameter between 1 to 2 mm was most significant (30.62± 7.73 vs 7.75 ± 4.59,t =8.04,P＜ 0.05),the rate of adenoma canceration also significantly increased compared with that of Apcmin/+ control group.The percentage of PCNA positive cells significantly increased compared with that of Apcmin/+ control group ((90.17 ± 2.14) ％ vs (41.97 ± 4.26) ％,t=31.97,P＜0.01).The percentage of cell apoptosis significantly declined ((1.40± 1.12) ％ vs (7.50 ± 0.65)％,t =14.90,P＜ 0.01).The diversity of intestinal flora of Apcmin/+ DOC group significantly decreased.The ratio of Firmicutes and Bacteroidetes significantly increased compared with control group (0.586 7±0.148 4 vs 0.387 3±0.013 6,t=2.36,P＜0.05).The number of pathogenic bacteria increased in Apcmin/+ DOC group and probiotics significantly decreased.Conclusion DOC can induce intestinal flora imbalance in Apcmin/+ mice and promote intestinal adenoma into adenocarcinoma through increasing tumor cell proliferation and inhibiting cell apoptosis.

The role of p38 signal transduction pathway in the pathogenesis of Barrett esophagus / 中华消化杂志

Objective To investigate the role of deoxycholic acid (DCA) in the pathogenesis of Barrett esophagus.Methods Normal human esophageal mucosal epithelial cells were cultured in vitro with defined keratinocyte serum-free media (D-KSFM).The cultured cells were treated with different concentrations of DCA and specific p38 mitogen activated protein kinase (MAPK) inhibitor. The expression of p38,phosphorylated p38 (p-p38) and caudal-related homeodomain transcription 2 (CDX2) at protein level were assessed by Western blot.The correlation between p-p38 and CDX2 was analyzed.The data were analyzed by one way ANOVA and LSD test.Results After being cultured with DCA for 24 h,the expression of p-p38 and CDX2 increased along with the increasing of DCA concentration.Compared with the control group (p-p38 was 13.7％ ± 1.0％ and CDX2 protein was 0),the difference was statistically significant (P＜ 0.05).When DCA was at 500 μmol/L,the expression of p-p38 and CDX2 reached the highest level (44.0％ ± 1.7％ and 8.59± 1.25).After pretreated with SB203580 for two hours and then 500 μmol/L DCA was added into cell culture,both expression level of p-p38 and CDX2 decreased compared with 500μmol/L DCA group (p-p38:28.3％ ±2.2％ vs50.5％±9.5％,CDX2:0.94±0.13 vs 2.31±0.41) after 24 h.Conclusions DCA can induce the expression of CDX2 in normal human esophageal mucosal epithelial cells,which is related with the activation of p38.The phosphorylation of p38 maybe involved in the pathogenesis of Barrett esophagus.