Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor / 中西医结合学报

OBJECTIVE@#This study was conducted to explore the mechanism of intestinal inflammation and barrier repair in Crohn's disease (CD) regulated by moxibustion through bile acid (BA) enterohepatic circulation and intestinal farnesoid X receptor (FXR).@*METHODS@#Sprague-Dawley rats were randomly divided into control group, CD model group, mild moxibustion group and herb-partitioned moxibustion group. CD model rats induced by 2,4,6-trinitrobenzene sulfonic acid were treated with mild moxibustion or herb-partitioned moxibustion at Tianshu (ST25) and Qihai (CV6). The changes in CD symptoms were rated according to the disease activity index score, the serum and colon tissues of rats were collected, and the pathological changes in colon tissues were observed via histopathology. Western blot, immunohistochemistry (IHC) and immunofluorescence were used to evaluate the improvement of moxibustion on intestinal inflammation and mucosal barrier in CD by the BA-FXR pathway.@*RESULTS@#Mild moxibustion and herb-partitioned moxibustion improved the symptoms of CD, inhibited inflammation and repaired mucosal damage to the colon in CD rats. Meanwhile, moxibustion could improve the abnormal expression of BA in the colon, liver and serum, downregulate the expression of interferon-γ and upregulate the expression of FXR mRNA, and inhibit Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA. The IHC results showed that moxibustion could upregulate the expression of FXR and mucin2 and inhibit TLR4 expression. Western blot showed that moxibustion inhibited the protein expression of TLR4 and MyD88 and upregulated the expression of FXR. Immunofluorescence image analysis showed that moxibustion increased the colocalization sites and intensity of FXR with TLR4 or nuclear factor-κB p65. In particular, herb-partitioned moxibustion has more advantages in improving BA and upregulating FXR and TLR4 in the colon.@*CONCLUSION@#Mild moxibustion and herb-partitioned moxibustion can improve CD by regulating the enterohepatic circulation stability of BA, activating colonic FXR, regulating the TLR4/MyD88 pathway, inhibiting intestinal inflammation and repairing the intestinal mucosal barrier. Herb-partitioned moxibustion seems to have more advantages in regulating BA enterohepatic circulation and FXR activation. Please cite this article as: Shen JC, Qi Q, Han D, Lu Y, Huang R, Zhu Y, Zhang LS, Qin XD, Zhang F, Wu HG, Liu HR. Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor. J Integr Med. 2023; 21(2): 194-204.

Aspectos biomoleculares de la prevención de la litogénesis biliar de colesterol / Biomolecular aspects of biliary cholesterol lithogenesis prevention

Introducción: La litogénesis biliar, proceso de sobresaturación de colesterol en la bilis vesicular, es prevenible. Objetivo: Describir las nuevas evidencias biomoleculares de la litogénesis biliar de colesterol como base de la futura terapia preventiva de la litiasis vesicular. Método: Se realizó una revisión sistemática y crítica de las evidencias de impacto sobre la litogénesis biliar. Se consultaron artículos publicados entre 2015-2020 en las bases de datos PubMed, Medline, SciELO, LILACS y Elsevier. Resultados: Se recuperaron evidencias actuales de los mecanismos biomoleculares relacionados con las futuras terapias preventivas de la litiasis vesicular, propuestos como fundamentos teóricos. Conclusiones: La descripción actualizada de la litogénesis biliar de colesterol, con los nuevos conceptos biomoleculares incorporados, aporta a su comprensión el papel de los genes de receptores nucleares, la intervención de estos últimos y de los transportadores de la secreción biliar. Dirigida a médicos generales, cirujanos, gastroenterólogos y fisiólogos, la descripción actualizada de La litogénesis biliar impacta como nuevo paradigma con los conceptos biomoleculares que intervienen en pro de su prevención(AU)

Introduction: Biliary lithogenesis is a preventable process of cholesterol supersaturation in gallbladder bile. Objective: Describe the new biomolecular evidence of biliary cholesterol lithogenesis serving as a basis for future preventive therapy for gallbladder lithiasis. Methods: A systematic critical review was conducted of impact evidence about biliary lithogenesis. The papers consulted were published in the databases PubMed, Medline, SciELO, LILACS and Elsevier from 2015 to 2020. Results: Current evidence was retrieved of biomolecular mechanisms proposed as theoretical foundations for future preventive therapies for gallbladder lithiasis. Conclusions: Intended for general practitioners, surgeons, gastroenterologists and physiologists, the updated description of biliary lithogenesis including the role of nuclear receptors, biliary lipid transporters and the biological value of enterohepatic circulation in the integrity and functioning of the hepatobiliary system as regulators of the cholesterol mechanism, makes an impact as a new paradigm with the biomolecular concepts involved in biliary lithogenesis prevention(AU)

New Generation Laxatives / 대한내과학회지

A significant proportion of chronic constipation patients are dissatisfied with their treatment. Recently, a number of new medications have been introduced for patients refractory to conventional laxatives, such as prucalopride, lubiprostone, linaclotide, and elobixibat. Prucalopride is a novel gastrointestinal prokinetic agent that acts as a 5-hydroxytryptamine type 4 (5-HT4) agonist. Compared with older nonselective 5-HT4 agonists, the higher selectivity of prucalopride for 5-HT4 receptors can reduce the risk of significant adverse cardiovascular events. Prucalopride improves stool frequency and consistency, and reduces the need for rescue medications. Lubiprostone, a chloride channel activator, increases the secretion of intestinal fluid, improves the stool frequency and consistency, and reduces straining. Linaclotide, a guanylate cyclase-C agonist, is effective in treating patients with chronic constipation and its effect on visceral sensitivity, as shown mainly in animal studies, provides an attractive pharmaceutical option for patients with irritable bowel syndrome with constipation. Elobixibat is an ileal sodium-dependent bile acid transporter inhibitor that blocks the enterohepatic circulation of bile acids, increasing the bile acid concentration in the intestine, which accelerates colonic transit and softens the stool. A phase III trial of the treatment of chronic constipation and irritable bowel syndrome with constipation is underway. The clinical application of new-generation laxatives will contribute to the management of chronic constipation refractory to conventional laxatives.

Bile acids and bariatric surgery / 中华胃肠外科杂志

As an essential metabolic molecule, bile acids regulate triglyceride, cholesterol, energy metabolism. Bariatric surgery offers a treatment that can reduce weight and induce metabolic syndrome, but the mechanism is still unclear. New researches reveal that serum bile acids are elevated after surgery, as well as the improvement of metabolic disease. The surgery changes gastrointestinal tract, resulting in a short circuiting of the enterohepatic circulation of bile acids. Here we review the bile acids metabolism and their effect after bariatric surgery.

Advent of Novel Phosphatidylcholine-Associated Nonsteroidal Anti-Inflammatory Drugs with Improved Gastrointestinal Safety

The mucosa of the gastrointestinal (GI) tract exhibits hydrophobic, nonwettable properties that protect the underlying epithelium from gastric acid and other luminal toxins. These biophysical characteristics appear to be attributable to the presence of an extracellular lining of surfactant-like phospholipids on the luminal aspects of the mucus gel layer. Phosphatidylcholine (PC) represents the most abundant and surface-active form of gastric phospholipids. PC protected experimental rats from a number of ulcerogenic agents and/or conditions including nonsteroidal anti-inflammatory drugs (NSAIDs), which are chemically associated with PC. Moreover, preassociating a number of the NSAIDs with exogenous PC prevented a decrease in the hydrophobic characteristics of the mucus gel layer and protected rats against the injurious GI side effects of NSAIDs while enhancing and/or maintaining their therapeutic activity. Bile plays an important role in the ability of NSAIDs to induce small intestinal injury. NSAIDs are rapidly absorbed from the GI tract and, in many cases, undergo enterohepatic circulation. Thus, NSAIDs with extensive enterohepatic cycling are more toxic to the GI tract and are capable of attenuating the surface hydrophobic properties of the mucosa of the lower GI tract. Biliary PC plays an essential role in the detoxification of bile salt micelles. NSAIDs that are secreted into the bile injure the intestinal mucosa via their ability to chemically associate with PC, which forms toxic mixed micelles and limits the concentration of biliary PC available to interact with and detoxify bile salts. We have worked to develop a family of PC-associated NSAIDs that appear to have improved GI safety profiles with equivalent or better therapeutic efficacy in both rodent model systems and pilot clinical trials.

Bile Acid Inhibition of N-type Calcium Channel Currents from Sympathetic Ganglion Neurons

Under some pathological conditions as bile flow obstruction or liver diseases with the enterohepatic circulation being disrupted, regurgitation of bile acids into the systemic circulation occurs and the plasma level of bile acids increases. Bile acids in circulation may affect the nervous system. We examined this possibility by studying the effects of bile acids on gating of neuronal (N)-type Ca2+ channel that is essential for neurotransmitter release at synapses of the peripheral and central nervous system. N-type Ca2+ channel currents were recorded from bullfrog sympathetic neuron under a cell-attached mode using 100 mM Ba2+ as a charge carrier. Cholic acid (CA, 10(-6) M) that is relatively hydrophilic thus less cytotoxic was included in the pipette solution. CA suppressed the open probability of N-type Ca2+ channel, which appeared to be due to an increase in null (no activity) sweeps. For example, the proportion of null sweep in the presence of CA was ~40% at +40 mV as compared with ~8% in the control recorded without CA. Other single channel properties including slope conductance, single channel current amplitude, open and shut times were not significantly affected by CA being present. The results suggest that CA could modulate N-type Ca2+ channel gating at a concentration as low as 10(-6) M. Bile acids have been shown to activate nonselective cation conductance and depolarize the cell membrane. Under pathological conditions with increased circulating bile acids, CA suppression of N-type Ca2+ channel function may be beneficial against overexcitation of the synapses.

Breast Feeding and Jaundice / 한양의대학술지

Even though there is a strong link between breast feeding and jaundice, it is natural and it may have a partially beneficial role in the neonate. There are two types of jaundice associated with breast feeding. First, insufficient caloric intake during the first week of life may increase serum unconjugated bilirubin concentration, which is known as "breast feeding jaundice (BFJ)". This increased severity of physiologic jaundice results from the increased enterohepatic circulation (EHC) of bilirubin, but not because of a factor in breast milk. Second, prolongation of unconjugated hyperbilirubinemia into the third and later weeks of life in the healthy newborn is a regularly occurring extension of physiologic jaundice, which is known as "breast milk jaundice (BMJ)". This is caused by a factor in breast milk inhibits the glucuronyl transferase in the liver and/or increases the EHC of bilirubin. The acceptable bilirubin level in the full-term healthy breast-fed infant needs to be discussed not only to prevent unnecessary interruption of breast feeding, but also to prevent kernicterus. Optimal breast feeding practices are crucial to prevent the BFJ and to minimize the intensity of BMJ. Further research is needed to clarify the benefit of bilirubin in relation to adaptation of extrauterine life.

Effect of ganciclovir on pharmacokinetics of mycophenolic mofetil, in kidney transplant patients

Mycophenolate mofetil [MMF] is commonly administered concomitantly with ganciclovir for managing transplant recipients who infected with CMV, This study was conducted to evaluate the probable effects of ganciclovir on Mycophenolic acid [MPA] pharmacokinetic. Ten kidney transplant recipients who full field inclusion and exclusion criterias enrolled in this study. The first full profile blood sampling was taken during the combination therapy of gancyclovir and MMF. The second sampling was taken one week after discontinuation of gancyclovir. Serum concentrations of MPA and its glucuronide metabolite [MPAG] were determined by high-performance liquid chromatography [HPLC] method. The pharmacokinetic parameters of MPA were measured, in two conditions, for each patient. There was no significant difference between MPA clearance alone and in combination with ganciclovir [28.2 +/- 2L9 L/h vs 31.9 +/- 21.3 L/h, p=0.207] and also no significant difference was seen between the MPA Area Under the Curve [AUC] in two conditions [43.48 +/- 16.27 micro g/ml.h vs 39.80 +/- 20.18 micro g/ml.h, p=0.221]. MPAG AUC was increased significantly when the drugs were administrated in combination [957.8 +/- 675.2 micro g/ml.h vs 1348.6 +/- 1095.1 micro g/ml.h, p=0.036]. Also ganciclovir induced entrohepatic recirculation of MPA in two patients. The pharmacokinetic parameter of MPA was not affected by ganciclovir. But ganciclovir increased MPAG AUC and induced enterohepatic recirculation of MPA

Estudo da circulação hepatomesentérica pela angiografia por ressonância magnética com gadolínio: comparação entre doses simples e dupla no estudo de pacientes esquistossomóticos / Gadolinium-enhanced magnetic resonance angiography for hepatomesenteric vascular evaluation: single and double doses comparison in schistosomiasis patients

OBJETIVO: Determinar a freqüência de visualização dos segmentos da circulação hepatomesentérica pela angiografia por ressonância magnética (angio-RM) com contraste e comparar o valor do método, utilizando-se duas diferentes dosagens de gadolínio (doses simples e dupla). MATERIAIS E MÉTODOS: Estudo prospectivo de 36 pacientes esquistossomóticos submetidos a angio-RM. Os exames foram realizados em equipamento de RM de 1,5 T, usando-se bobina de corpo e bomba injetora para a administração endovenosa do contraste. Foram utilizadas, de maneira randomizada, dose dupla do contraste paramagnético (0,2 mmol/kg de Gd-DTPA) em 21 pacientes e dose simples (0,1 mmol/kg) em outros 15 pacientes. Os exames foram interpretados por dois observadores em consenso, que classificaram o grau de visualização de 25 segmentos vasculares estabelecidos para análise, sem conhecimento da dose de gadolínio utilizada. RESULTADOS: Os segmentos vasculares proximais e de maior calibre foram as estruturas com melhor grau de visualização na maioria da amostra em estudo. O tronco celíaco, a artéria hepática comum, a artéria esplênica, a croça e terço médio da artéria mesentérica superior, a veia porta, a veia esplênica e a veia mesentérica superior apresentaram grau 2 de visualização em mais de 70 por cento da amostra. Quanto à comparação das diferentes dosagens, não houve diferença significante (p < 0,05) no grau de visualização das diversas estruturas analisadas entre os grupos dose simples e dose dupla, com uma exceção isolada: na avaliação da artéria hepática direita (p = 0,008), o grupo dose simples apresentou maior freqüência de visualização grau 2, com valor significante. CONCLUSÃO: O grau de visualização dos segmentos vasculares hepatomesentéricos pela angio-RM com contraste é elevado, sendo maior nos segmentos proximais e de maior calibre. A comparação entre os grupos que utilizaram dose simples e dupla de contraste demonstrou resultados semelhantes.

OBJECTIVE: To evaluate the visibility of hepatomesenteric vascular segments by 3D gadolinium-enhanced magnetic resonance (MR) angiography and to compare the method effectiveness between two different gadolinium doses (single and double doses). MATERIALS AND METHODS: A prospective study was performed with 36 schistosomiasis patients who were submitted to 3D contrast-enhanced MR angiography. Scans were performed in a high-field equipment (1.5 T), with body coil and power injector for intravenous contrast administration. Contrast double doses (Gd-DTPA 0.2 mmol/kg) and single doses (0.1 mmol/kg) were randomly used respectively in 21 and 15 patients. Studies were interpreted by consensus between two observers who have rated the visualization degree of 25 proximal vascular segments without knowing the dose used. RESULTS: Proximal and calibrous vascular segments have presented higher visualization degree in the greatest part of the sample studied. The celiac trunk, common hepatic artery, splenic artery, proximal and medium third of superior mesenteric artery, portal vein, splenic vein and superior mesenteric vein have presented grade 2 visualization in more than 70 percent of the sample studied. As regards comparison between different doses, there was no significant difference (p < 0.05) in the visualization degree of several structures evaluated, between double dose and single dose groups, except for an isolate case of evaluation of right hepatic artery (p = 0.008) in which the single dose group has presented a higher frequency of grade 2 visualization with statistical significance. CONCLUSION: The visualization degree of hepatomesenteric vascular segments by 3D gadolinium-enhanced MR angiography is high, especially in the proximal and calibrous segments. The comparison between groups using single and double contrast doses has demonstrated similar results.

Pharmacokinetic model for the enterohepatic circulation of mycophenolic acid / 药学学报

<p><b>AIM</b>To develop a pharmacokinetic model for the enterohepatic circulation of mycophenolic acid (MPA).</p><p><b>METHODS</b>Twenty healthy volunteers were orally given a single dose of 500 mg mycophenolate mofetil. Plasma samples were collected during 48 hours and MPA concentration was measured by HPLC method. Pharmacokinetic (PK) model was established based on physiological and biopharmaceutical consideration and PK parameters were obtained using nonlinear mixed effect model.</p><p><b>RESULTS</b>The proposed model included an intestinal compartment and gall bladder compartment in addition to the central compartment. The predicted time-concentration curve and AUC0-t, Cmax, Tmax estimated by the established model were in agreement with the observations.</p><p><b>CONCLUSION</b>The established model was well defined for the MPA disposition and could afford a useful approach for the further clinical investigation.</p>

A Case of Neonatal Cholelithiasis Induced by Prolonged Lack of Enteral Feeding and Total Parenteral Nutrition

Cholelithiasis in infancy is a rare disorder. A number of conditions that occur in the neonatal period predispose to the development of cholelithiasis. Cholelithiasis is more marked in the premature than adult, because of the immaturity of the enterohepatic circulation of bile acids which renders the newborn more susceptible to the cholestatic effect of total parenteral nutrition (TPN). Parenteral nutrition associated cholelithiasis is the major indication for cholecystectomy in the pediatric age group because of severe complication, but a number of recent studies report spontaneous resolution of the stones. We report a case of a female infant with cholelithiasis diagnosed by ultrasonogram at 88 days of age which is probably induced by prolonged lack of enteral feeding and TPN.

Effect of Oral Administration of Dioctahedral Smectite and Cholestyramine with Phototherapy in the Treatment of Neonatal Hyperbilirubinemia

PURPOSE: Dioctahedral smectite is an alumina silicate of phyllitic structure and absorbs bile acid in the intestine, forming a non-absorbable complex preventing enterohepatic circulation. The purpose of this study is to clarify the value of dioctahedral smectite and the adequate dosage, in combination with phototherapy, as well as to confirm whether it shortens the duration of hospitalization and to compare dioctahedral smectite with cholestyramine. METHODS: Total 45 full-term neonate with a total bilirubin level greater than 12 mg/dl were studied. The neonate were randomly divided into three groups : 1) Only phototherapy group (A) 2) 3.0 g/day dioctahedral smectite with phototherapy group (B) 3) 1.0 g/kg/day cholestyramine with phototherapy group (C). RESULTS: The mean serum bilirubin level of group B and C decreased significantly compared to group A at 48, 72 and 96 hours after the beginning of the study. The duration of phototherapy and hospitalization significantly decreased in group B and C. CONCLUSION: The data revealed that oral administration of dioctahedral smectite not only increased the efficacy of phototherapy, but also shortened the duration of phototherapy and can substitute for cholestyramine.

Effect of Oral Administration of Cholestylamine with Phototherapy in the Treatment of Neonatal Hyperbilirubinemia

PURPOSE: Cholestylamine has been shown to release chloride ion and absorbs bile acid in the intestine, forming a nonabsorbable complex preventing enterohepatic circulation. The purpose of this study is to clarify the value of cholestylamine and the adequate dosage, in combination with phototherapy, as well as to confirm whether it shorten the duration of hospitalization. METHODS: Total 80 full-term neonates with a total bilirubin level greater than 12mg/dL were studied. The neonates were randomly divided into four groups : (1) Only phototherapy group (A)(2) 250mg/kg/day cholestylamine with phototherapy group (B)(3) 500mg/kg/day cholestylamine with phototherapy group (C)(4) 1000mg/kg/day cholestylamine with phototherapy group (D). RESULTS: Forty-eight hours, 72 hours and 96 hours after the beginning of the study, the mean bilirubin level among the B, C, D groups significantly diminished than A group (P<0.05). The duration of phototherapy and hospitalization significantly diminished in the D group. After phototherapy, finished mean bilirubin level was markedly diminished in the D group. CONCLUSION: The data revealed that oral administration of cholestylamine (especially 1000mg/kg/ day cholestylamine with phototherapy group : D) not only increased the efficacy of phototherapy, but also shortened the duration of phototherapy.

Oral Agar and Conventional Phototherapy Combination in the Treament of Neonatal Hyperbilirubinemia

PURPOSE: Neonatal jaundice is one of the most common problems in our country leading to hospitalization. Agar is low cost, low risk, and easily fed orally; it can bind bilirubin in the intestine, decreasing its enterohepatic circulation, thereby decreasing serum bilirubin levels. At present, however, the effectiveness of agar in the prevention and treament of neonatal jaundice is quite conflicting and controversy. Recently we have read Caglayan's 'Superiority of Oral Agar and Phototherapy Combination in the Treatment of Neonatal Hyperbilirubinemia'. The result was very hopeful and attractive enough, and which gave us a motivation to study if it was really of value. METHODS: From May 1995 to April 1996, a total 50 term neonates admitted in nursery of Dong-Eui Medical Center with the capillary serum bilirubin levels greater than 10mg/ dl were enrolled in the study. Those with pathologic causes and breast fed infants were all excluded. The neonates were randomly devided into two groups; 25 of conventional phototherapy alone (P group) and 25 of oral agar plus conventional phototherapy combination (A+P group). The study was terminated when the capillary serum bilirubins were decreased to 8mg/dl. Pastagar B (Pasteur Institute 64946) 500mg in 10ml distilled water were fed four times a day using 10ml syringes prior to bottle feeding. Capillary serum bilirubin levels were measured daily at 10:00 a.m. with heel pad samples. Daily stool frequency and adverse effects of treatment were observed closely. RESULTS: 1) The decrement of the serum bilirubin levels at first 24 hours of therapy was significantly different between P and A+P groups showing as 1.7+/-1.2 and 2.4+/-1.0mg/dl respectively (p0.05). 3) No adverse effects such as rashes or abdominal pains were observed during treatment. Differences of mean stool frequency were significant between P and A+P groups showing as 3.7+/-1.2 and 4.7+/-2.0 times per day respectively (p<0.05). CONCLUSION: The agar plus conventional phototherapy combination was superior to conventional phototherapy alone at first 24 hours of therapy in neonatal hyperbilirubinemia, but further more careful researches would be necessary for using it routinely in the treatment of neonatal hyperbilirubinemia in future.

Colecistografia oral retardada (modificada) no estudo da discinesia biliar / Oral cholecystography delayed (modified) to the study of biliary dyskinesia

A discinesia infundíbulo-colo-cística, ou discinesia biliar, traz dificuldades no seu diagnóstico e na sua conduta terapêutica. Estudamos uma modificaçäo da colecistografia oral onde se objetiva adequá-la ao estudo daquela patologia ou doença. Fez-se a colecistografia oral clássica complementada por radiografias após 24 e 48 horas. Julgamos que a retençäo do contraste apos 48 horas merece um estudo melhor da vesícula, até para possível indicaçäo cirúrgica