Enhancing mechanism of intestinal absorption of highly lipophilic compounds using microemulsion e Quantitative analysis of the partitioning to the mesenteric lymph in intestinal cells

The purpose of this study was to quantify the effect of the fatty acid alkyl-chain length of a polyethylene glycol(PEG)glyceryl ester,which was used as a microemulsion oil component,on the partitioning of highly lipophilic compounds to the mesenteric lymph after oral administration.Oil blue N,a highly lipophilic anthraquinone derivative,was orally administered to lymph duct-cannulated and untreated rats in two kinds of different microemulsions.Gelucire®50/13 and Gelucire®44/14 were used as the oil component with long chain and medium chain fatty acid portions,respectively,of PEG glyceryl esters in microemulsions.The cumulative amount of oil blue N in lymph fluid was almost the same between the two microemulsions,although the transferred amount of oil component(triglyceride)in the lymph after administration of the Gelucire®50/13 microemulsion was significantly higher than that of the Gelucire®44/14 microemulsion.On the other hand,the solubility of oil blue N in Gelucire®44/14 was much higher than that in Gelucire®50/13.No significant differences were observed between microemulsions in the bioavailability of oil blue N.From these data,the partitioning of oil blue N to the lymph was calculated using a mathematical model,showing that the partitioning ratios of oil blue N to the lymph fluid were almost the same for both microemulsions.The solubility of oil blue N to the oil component of the microemulsions and the transfer of triglycerides to the lymph after administration of the microemulsions counteract each other,leading to similar partitioning ratios of oil blue N to the lymph.

Effect and molecular mechanism research of Astragalus membranaceus on inhibiting intestinal absorption of six alkaloids of Aconitum carmichaelii in spleen deficiency rats

Objective:To investigate the effect and the mechanism of Astragalus membranaceus(Huangqi in Chinese,HQ)extract on the intestinal absorption of six alkaloids of Aconitum carmichaelii(Fuzi in Chinese,FZ)in rats with spleen deficiency and provide novel insights into the application of HQ on modulating intestinal barrier.Methods:Four-week-old male Sprague-Dawley rats were fed with Xiaochengqi Decoction to induce the spleen deficiency model for 40 d.Single-pass intestinal perfusion model were used to study the effects of HQ extract on the absorption of alkaloids.Protein expression and mRNA levels of MRP2 and BCRP and tight junction proteins(TJ,including Claudin-1,Occludin and ZO-1)were measured using Western blot and real-time PCR,respectively.The location and expression of TJ protein was also investigated by the immunofluorescence method.Results:Compared with the normal group,the protein expression of MRP2,BCRP and TJ proteins in the model group were significantly down-regulated.After oral administration of HQ,the alkaloid absorption in intestinal villi was inhibited,MRP2,BCRP and TJ proteins were up-regulated,the green fluorescence staining of Claudin-1,Occludin,and ZO-1 was enhanced,and a thick layer of mucus was deposited on the surface of the epithelium of the intestinal cavity.Conclusion:HQ as an intestinal barrier modulator improves the physiological changes of the intestinal environment of spleen deficiency to reduce the absorption of toxic components,leading to a decrease in the absorption of drug-like molecules.

Traditional Chinese herbal medicine Astragalus Radix and its effects on intestinal absorption of aconite alkaloids in rats

Objective:Astragalus Radix(AR,Huangqi in Chinese) has been widely used as a qi(energy) restoring herb that is thought to act through reinvigorating the spleen and lung.Aconite is used to rebalance the body temperature during illness and played an irreplaceable role in disease control since ancient times,but it is limited by its strong neuro and cardiotoxicity.Since the Song Dynasty(1227),the two herbs have been commonly used as herbal pairs including in the famous Qifu Decotion,from the "Wei's Family Prescription".However,many ancient texts also record that they are not compatible using together,suggesting they can have negative outcomes when mixed.This study investigated whether Astragali Radix had either positive or negative effects on absorption of six different active alkaloids derived from aconite.Methods:Single intestinal perfusion model was used to study the effects of Astragali Radix on aconite alkaloids absorption.Response of ABC transporters and distribution of three tight junction proteins on the surface of intestinal enothelium were assessed by Reverse Transcription-Polymerase Chain Reaction(RT-PCR),Western blot and immunofluorescence microscopy,respectively.Results:The results showed that aconite alkaloids absorption could be inhibited,and different concentrations of Astragali Radix considerably increased the expression levels of the ABC transporters and tight junction proteins with Astragali Radix treatment.Conclusion:These results suggest that Astragali Radix can block absorption of aconite alkaloids through the upregulation expression of ATP-binding cassette transporters(ABC transporters) and tight junction proteins.It demonstrates that co-administration of Astragali Radix with other drugs might change the absorption profile of the second drug which is important to know in clinic therapy.

Carbachol promotes gastrointestinal function during oral resuscitation of burn shock

AIM: To investigate the effect of carbachol on gastrointestinal function in a dog model of oral resuscitation for burn shock. METHODS: Twenty Beagle dogs with intubation of the carotid artery, jugular vein and jejunum for 24 h were subjected to 35% total body surface area fullthickness burns, and were divided into three groups: no fluid resuscitation (NR, n = 10), in which animals did not receive fluid by any means in the first 24 h postburn; oral fluid resuscitation (OR, n = 8), in which dogs were gavaged with glucose-electrolyte solution (GES) with volume and rate consistent with the Parkland formula; and oral fluid with carbachol group (OR/CAR, n = 8), in which dogs were gavaged with GES containing carbachol (20 μg/kg), with the same volume and rate as the OR group. Twenty-four hours after burns, all animals were given intravenous fluid replacement, and 72 h after injury, they received nutritional support. Hemodynamicand gastrointestinal parameters were measured serially with animals in conscious and cooperative state. RESULTS: The mean arterial pressure, cardiac output and plasma volume dropped markedly, and gastrointestinal tissue perfusion was reduced obviously after the burn injury in all the three groups. Hemodynamic parameters and gastrointestinal tissue perfusion in the OR and OR/CAR groups were promoted to pre-injury level at 48 and 72 h, respectively, while hemodynamic parameters in the NR group did not return to pre-injury level till 72 h, and gastrointestinal tissue perfusion remained lower than pre-injury level until 120 h post-burn. CO 2 of the gastric mucosa and intestinal mucosa blood flow of OR/CAR groups were 56.4 ± 4.7 mmHg and 157.7 ± 17.7 blood perfusion units (BPU) at 24 h postburn, respectively, which were significantly superior to those in the OR group (65.8 ± 5.8 mmHg and 127.7 ± 11.9 BPU, respectively, all P < 0.05). Gastric emptying and intestinal absorption rates of GES were significantly reduced to the lowest level (52.8% and 23.7% of pre-injury levels) in the OR group at about 2 and 4 h post-burn, and did not return to 80% of pre-injury level until 24 h. In the first 24 h postburn, the rate of gastric emptying and intestinal water absorption were elevated by a mean 15.7% and 11.5%, respectively, in the OR/CAR group compared with the OR group. At 5 days, the mortality in the NR group was 30% (3/10), 12.5% in the OR group (1/8), and none in the OR/CAR group. CONCLUSION: Carbachol had a beneficial effect on oral resuscitation of burn shock by promoting gastric emptying and intestinal absorption in our canine model.

Transepithelial transport of putrescine across monolayers of the human intestinal epithelial cell line, Caco-2

AIM: To study the transepithelial transport characteristics of the polyamine putrescine in human intestinal Caco-2 cell monolayers to elucidate the mechanisms of the putrescine intestinal absorption. METHODS: The transepithelial transport and the cellular accumulation of putrescine was measured using Caco-2 cell monolayers grown on permeable filters. RESULTS: Transepithelial transport of putrescine in physiological concentrations (】 0.5 mM) from the apical to basolateral side was linear. Intracellular accumulation of putrescine was higher in confluent than in fully differentiated Caco-2 cells, but still negligible (less than 0.5%) of the overall transport across the monolayers in apical to basolateral direction.EGF enhanced putrescine accumulation in Caco-2 cells by four fold, as well as putrescine conversion to spermidine and spermine by enhancing the activity of S adenosylmethionine decarboxylase. However, EGF did not have any significant influence on putrescine flux across the Caco-2 cell monolayers. Excretion of putrescine from Caco-2 cells into the basolateral medium did not exceed 50 picomoles, while putrescine passive flux from the apical to the basolateral chamber, contributed hundreds of micromoles polyamines to the basolateral chamber. CONCLUSION :Transepithelial transport of putrescine across Caco2 cell monolayers occurs in passive diffusion, and is not influenced when epithelial cells are stimulated to proliferate by a potent mitogen such as EGF.

Inhibitory effect and mechanism of acarbose combined with gymnemic acid on maltose absorption in rat intestine

AIM: To compare the combinative and individual effect of acarbose and gymnemic acid (GA) on maltose absorption and hydrolysis in small intestine to determine whether nutrient control in diabetic care can be improved by combination of them. METHODS: The absorption and hydrolysis of maltose were studied by cyclic perfusion of intestinal loops in situ and motility of the intestine was recorded with the intestinal ring in vitro using Wistar rats. RESULTS: The total inhibitory rate of maltose absorption was improved by the combination of GA (0.1g/L-1.0 g/L) and acarbose (0.1 mmol/L-2.0 mmol/L) throughout their effective duration (P 【0.05, U test of Mann-Whitney), although the improvement only could be seen at a low dosage during the first hour. With the combination, inhibitory duration of acarbose on maltose absorption was prolonged to 3h and the inhibitory effect onset of GA was fastened to 15 min. GA suppressed the intestinal mobility with a good correlation (r = 0.98) to the inhibitory effect of GA on maltose absorption and the inhibitory effect of 2 mmol/L (high dose) acarbose on maltose hydrolysis was dual modulated by 1g/L GA in vivo indicating that the combined effects involved the functional alteration of intestinal barriers. CONCLUSION: There are augmented effects of acarbose and GA,which involve pre-cellular and paracellular barriers. Diabetic care can be improved by employing the combination.

AN ANALYTICAL SOLUTION FOR THE MODEL OF DRUG DISTRIBUTION AND ABSORPTION IN SMALL INTESTINE

According to the physiological and anatomical characteristics of small intestine,neglecting the effect of its motility on the distribution and absorption of drug and nutrient,Y.Miyamoto et al.proposed a model of two-dimensional laminar flow in a circular porous tube with permeable wall and calculated the concentration profile of drugby numerical analysis.In this paper,we give a steady-state analytical solution of the above model including deactivationterm.The obtained results are in agreement with the results of their numerical analysis. Moreover the analytical solution presented in this paper reveals the relation among the physiological parameters of the model and describes the basic absorption rule of drug and nutrient through the intestinal wall and hence pro- vides a theoretical basis for determining the permeability and reflection coefficient through in situ experiments.

Mechanical regulation of lipid and sugar absorption by Piezo1 in enterocytes

Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid.Postprandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients.The response of intestinal epithelial cells to mechanical stimulation is not fully understood.Piezo1,a mechanosensitive ion channel,is widely expressed throughout the digestive tract.However,its function in intestinal nutrient absorption is not yet clear.In our study,excessive lipid deposition was observed in the duodenum of obese patients,while duodenal Piezo1-CaMKK2-AMPKa was decreased when compared to normal-weight individuals.Under high-fat diet condition,the Piezo1iKO mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver.These phenotypes were mainly caused by the inhibition of duodenal CaMKK2-AMPKa and the upregulation of SGLT1 and DGAT2.In contrast,Yoda1,a Piezo1 agonist,was found to reduce intestinal lipid absorption in diet induced obese mice.Overexpression of Piezo1,stretch and Yoda1 inhibited lipid accumulation and the expression of DGAT2 and SGLT1,whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells.Our study reveals a previously unexplored mechanical regulation of nutrient absorption in intestinal epithelial cells,which may shed new light on the therapy of obesity.

Effects of octreotide on glucose transporter type 2expression in obese rat small intestine

AIM： TO investigate the effects of the somatostatin analogue, octreotide, on maltose and sucrase activities and expression of glucose transporter type 2 （GLUT2） in obese rat intestinal mucosa. METHODS： We divided 49 Sprague-Dawley rats into a group of 31 high fat diet-induced obese rats and a group of 18 normal controls. The obese rats were separated into an octreotide treated group 9f 16 rats and an obese group of 15. The intervention （：jroup was injected with octreotide at 40 ±g/kg body weight every 12 h for 8 d. Rat body weight was measured weekly to calculate Lee＇s index. After euthanization, maltase and sucrase activities in the small intestine were measured by activity assays, and the fasting plasma glucose level was measured. The expression of GLUT2 in small intestinal mucosa was analyzed by immunohistochemistry, reverse transcriptase polymerase chain reaction and Western blotting assays. RESULTS： Body weight, Lee＇s index, fasting plasma glucose level, maltase activity in small intestinal mucosa, mucosa and apical GLUT2, GLUT2 mRNA and protein expression levels were all significantly higher in the obese group than in the normal control group （605.61 ± 141.00 vs 378.54 ±111.75, 337.61 ± 10.82 vs 318.73 ± 20.10, 8.60± 1.38 vs 7.33 ± 0.70, 156.01 ± 58.81 vs 50.43 ± 30.49, 390 744.2± 62 469.21 vs 170 546.50 ± 50 646.14, 26 740.18 ±3809.60 vs 354.98± 57.19, 0.26± 0.11 vs 0.07± 0.02, and 2.08 ± 0.59 vs 1.27 ± 0.38, respectively, all P 〈 0.01）. Sucrase activity did not differ between the two groups. Octreotide intervention significantly decreased the body weight and fasting plasma glucose level of obese rats （508.27 ± 94.39 vs 605.61 ± 141.00, 7.58 ± 1.51 vs 8.60±1.38, respectively, all P 〈 0.05）. The intestinal mucosa and apical GLUT2, expression of GLUT2 mRNA and protein were also significantly lower in the octreotide intervention group than in the obese group （269 975.2 ± 53 730.94 vs 390 744.2 ± 62 469.21, 3758.06 ± 364.51 vs 26 740.18 ± 3809.60, 0.08 ± 0.02 vs 0.26 ±0.11, and 1.31 ± 0.27 vs 2.08 ±0.59, respectively, all P 〈 0.01）. CONCLUSION： High fat dietinduced obesity is associated with elevated intestinal maltase activity, GLUT2 expression, and permanent apical GLUT2 in the small intestinal mucosa of rats. Octreotide can inhibit these effects.

An emerging role of vitamin D_(3) in amino acid absorption in different intestinal segments of on-growing grass carp(Ctenopharyngodon idella)

Vitamin D_(3)(VD_(3)),an essential nutrient for animals,has been demonstrated to stimulate the uptake of certain amino acids.However,the role of VD_(3) in the intestine,the primary site for digestion and absorption of nutrients,remains poorly characterized.Here,the grass carp(Ctenopharyngodon idella)was studied to assess the influence of different doses of VD_(3)(15.2,364.3,782.5,1,167.9,1,573.8,and 1,980.1 IU/kg)on growth performance,intestinal morphology,digestive absorption,amino acid transport,and potential signaling molecule levels in a feeding experiment.As a result,dietary VD_(3) improved growth performance,intestinal structure,and digestive and brush border enzyme activities.Additionally,most intestinal free amino acids and their transporters were upregulated after VD_(3) intake,except for Ala,Lys,Asp,Leu,solute carrier(SLC)7A7,SLC1A5,and SLC1A3 mRNA in different segments,Leu and SLC6A14 mRNA in the proximal intestine,and SLC7A5 mRNA in the mid and distal intestine.In the crucial target of rapamycin(TOR)signal pathway of amino acid transport,the gene and protein expression of TOR,S6 kinase 1,and activating transcription factor 4 were elevated,whereas 4E-binding protein 1 was decreased,further suggesting an advanced amino acid absorption capacity in the fish due to VD_(3) supplementation.Based on percentage weight gain,feed efficiency,and trypsin activity,the VD_(3) requirements of on-growing grass carp were estimated to be 968.33,1,005.00,and 1,166.67 IU/kg,respectively.Our findings provide novel recommendations for VD_(3) supplementation to promote digestion and absorption capacities of fish,contributing to the overall productivity of aquaculture.

Disease-specific protein corona formed in pathological intestine enhances the oral absorption of nanoparticles

Protein corona(PC)has been identified to impede the transportation of intravenously injected nanoparticles(NPs)from blood circulation to their targeted sites.However,how intestinal PC(IPC)affects the delivery of orally administered NPs are still needed to be elucidated.Here,we found that IPC exerted“positive effect”or“negative effect”depending on different pathological conditions in the gastrointestinal tract.We prepared polystyrene nanoparticles(PS)adsorbed with different IPC derived from the intestinal tract of healthy,diabetic,and colitis rats(H-IPC@PS,D-IPC@PS,C-IPC@PS).Proteomics analysis revealed that,compared with healthy IPC,the two disease-specific IPC consisted of a higher proportion of proteins that were closely correlated with transepithelial transport across the intestine.Consequently,both D-IPC@PS and C-IPC@PS mainly exploited the recycling endosome and ER-Golgi mediated secretory routes for intracellular trafficking,which increased the transcytosis from the epithelium.Together,disease-specific IPC endowed NPs with higher intestinal absorption.D-IPC@PS posed“positive effect”on intestinal absorption into blood circulation for diabetic therapy.Conversely,CIPC@PS had“negative effect”on colitis treatment because of unfavorable absorption in the intestine before arriving colon.These results imply that different or even opposite strategies to modulate the disease-specific IPC need to be adopted for oral nanomedicine in the treatment of variable diseases.

Relationship between the incidence of non-hepatic hyperammonemia and the prognosis of patients in the intensive care unit

BACKGROUND Ammonia is a normal constituent of body fluids and is found mainly through the formation of urea in the liver.Blood levels of ammonia must remain low as even slightly elevated concentrations(hyperammonemia)are toxic to the central nervous system.AIM To examine the relationship between the incidence of non-hepatic hyperammonemia(NHH)and the prognosis of patients who were admitted to the intensive care unit(ICU).METHODS This is a prospective,observational and single-center study.A total of 364 patients who were admitted to the ICU from November 2019 to February 2020 were initially enrolled.Changes in the levels of blood ammonia at the time of ICU admission and after ICU admission were continuously monitored.In addition,factors influencing the prognosis of NHH patients were analyzed.RESULTS A total of 204 patients who met the inclusion criteria were enrolled in this study,including 155 NHH patients and 44 severe-NHH patients.The incidence of NHH and severe-NHH was 75.98% and 21.57%,respectively.Patients with severe-NHH exhibited longer length of ICU stay and higher Acute Physiologic Assessment and Chronic Health Evaluation and Sequential Organ Failure Assessment scores compared to those with mild-NHH and non-NHH.Glasgow Coma Scale scores of patients with severe-NHH were than those of non-NHH patients.In addition,the mean and initial levels of ammonia in the blood might be helpful in predicting the prognosis of NHH.CONCLUSION High blood ammonia level is frequent among NHH patients admitted to the ICU,which is related to the clinical characteristics of patients.Furthermore,the level of blood ammonia may be helpful for prognosis prediction.

A new strategy of enhancing absorptivity and safety for evodiamine: polyamidoamine derivatives modified by polyethylene glycol chain

Background:Traditional Chinese medicine involves complex ingredients and mixtures of ingredients that often exhibit low bioavailability,and excipients are often lacking to increase the absorption-enhancing effects.This study modified the generation 4 polyamidoamine dendrimer with polyethylene glycol of different molecular weights(5000,2000,1000)to form a series of polyamidoamine-co-polyethylene glycol(PAMAM-co-PEG)as a novel class of oral absorption enhancers.Evodiamine,the major alkaloid found in the traditional Chinese medicine Wu Zhu Yu(Fructus Evodiae),was used as a model drug to verify the absorption-enhancing effects and the safety of this alkaloid.Methods:This study utilized the solubility determination method documented in the Pharmacopoeia of the People’s Republic of China(2015 edition)and the D0 values recommended in the US FDA guidelines to comprehensively evaluate the solubility of evodiamine.The permeability of evodiamine was assessed using the apparent permeability coefficient in experiments based on in vitro cell models.Multiple aspects of the biological safety of PAMAM-co-PEG were explored using the MTT assay,LDH assay,and total protein release of the rat intestinal tract.Moreover,the absorption-enhancing effects of PAMAM-co-PEG at different molecular weights on evodiamine were verified via the use of in vitro cell models and in vivo intestinal loop circulation experiments with rats.Results:Evodiamine exhibited low solubility and permeability and was classified into class IV compounds using the biopharmaceutical classification system.PAMAM-co-PEG 2000 demonstrated improvement in the biosafety and absorption-enhancement effect of evodiamine at a specific concentration.This study showed that 0.05%(w/v)of PAMAM-co-PEG 2000 increased the cumulative penetration of evodiamine via cell transport by 1.32 times,and 0.10%(w/v)of PAMAM-co-PEG 2000 increased the area under curve value of evodiamine by 1.31 times.Conclusion:Evodiamine possesses low solubility and permeability and leads to poor oral bioavailability and a certain degree of cytotoxicity.PAMAM-co-PEG 2000 was found to be a potentially safe and efficient oral absorption enhancer.The results of this study might create a foundation for the development of novel excipients suitable for the complex active ingredients of traditional Chinese medicine.

Liver-gut axis in the regulation of iron homeostasis

The human body requires about 1-2 mg of iron per day for its normal functioning, and dietary iron is the only source for this essential metal. Since humans do not possess a mechanism for the active excretion of iron, the amount of iron in the body is determined by the amount absorbed across the proximal small intestine and, consequently, intestinal iron absorption is a highly regulated process. In recent years, the liver has emerged as a central regulator of both iron absorption and iron release from other tissues. It achieves this by secreting a peptide hormone called hepcidin that acts on the small intestinal epithelium and other cells to limit iron delivery to the plasma. Hepcidin itself is regulated in response to various systemic stimuli including variations in body iron stores, the rate of erythropoiesis, inflammation and hypoxia, the same stimuli that have been known for many years to modulate iron absorption. This review will summarize recent findings on the role played by the liver and hepcidin in the regulation of body iron absorption.

Preparation and characterization of intestinal transporter-targeted polymeric micelles

The intestinal epithelium is the main barrier to the oral delivery of poorly water-soluble drugs. Based on the specific transporters expressed on the apical membrane of the intestinal epithelium, novel polymer micelles targeting to the organic cation transporter 2（OCTN2） were constructed by combining carnitine conjugated poly（2-ethyl-2-oxazoline）-poly（D,L-lactide）（Car-PEOz-PLA） with monomethoxy poly（ethylene glycol）-poly（D,L-lactide）（mP EG-PLA）. The structure of the synthesized Car-PEOz-PLA was confirmed by -1H NMR, TLC and ammonium reineckate precipitation reaction, and the number-average molecular weight determined by GPC was 7260 g/mol with a low PDI of 1.44. Coumarin 6-loaded carnitine modified polymeric micelles prepared by film hydration method were characterized to have a nano-scaled size of about 31 nm in diameter, uniform spherical morphology, high drug loading content of 0.098%±0.03% and encapsulation efficiency of 92.67%±2.80%. Moreover, the carnitine-modified micelles exhibited the similar in vitro release behavior in SGF and SIF, and evidently enhanced intestinal absorption of poorly water-soluble agent. Therefore, the designed OCTN2-targeted micelles might have a promising potential for oral delivery of poorly water-soluble drugs.

Mixed nanomicelles loaded with thymopeptides-sodium deoxycholate/phospholipid improve drug absorption

AIM: To improve the absorption of thymopeptides(TH) by preparing sodium deoxycholate/phospholipid-mixed nanomicelles(SDC/PL-MMs). METHODS: TH-SDC/PL-MMs were prepared by a film dispersion method, and then evaluated using photon correlation spectroscopy(PCS), zeta potential measurement, as well as their physical stability after storage for several days. Furthermore, in situ intestinal single-pass perfusion experiments and pharmacodynamics in immunodeficient mice were performed to make a comparison with TH powders and the control drug in absorption properties. RESULTS: A narrow size distribution of nanomicelles, with a mean particle size of(149 ± 8.32) nm and a zeta potential of(-31.05 ± 2.52) mV, was obtained. The in situ intestine perfusion experiments demonstrated a significant advantage in absorption characteristics for TH compared to the other formulations, and oral administration of TH-SDC/PL-MMs potentiated an equivalent effect with i.h. TH in pharmacodynamic studies in immunodeficient mice. CONCLUSIONS: TH-SDC/PL-MMs prepared by a film dispersion method are able to improve the absorption of TH. SDC/PL-MMs might be a good approach for the more effective delivery of drugs like TH.

Self-assembled aggregations in Coptidis Rhizoma decoction dynamically regulate intestinal tissue permeability through Peyer's patch-associated immunity

Objective:To investigate the dynamic regulation of self-assembled aggregations(SAA)in Coptidis Rhizoma decoction on the permeability of intestinal tissue and the mechanism underlying.Methods:The effects of SAA on berberine(Ber)absorption were respectively analyzed in an in situ intestinal perfusion model and in an Ussing Chamber jejunum model with or without Peyer’s patches(PPs).The expression levels of ZO-1,Occludin and Claudin-1 were detected by immunofluorescence to evaluate the tight junction(TJ)between intestinal epithelium cells.The expression levels of T-box-containing protein expressed in T cells,signal transducers and activators of tranion-6,retinoic acid receptor-related orphan receptor ct and forkhead box P3 in PPs were detected by the reverse transcription-polymerase chain reaction and the secretions of interferon-c(IFN-c),interleukin-4(IL-4),interleukin-17(IL-17)and transforming growth factor-b(TGF-b)in PPs were evaluated by immunohistochemistry,to reflect the differentiation of T lymphocyte in PPs to helper T(Th)cell 1,Th2,Th17 and regulatory T(Treg)cell.To confirm the correlation between SAA in Coptidis Rhizoma decoction,PPs-associated immunity and intestinal epithelium permeability,SAA were administrated on an Ussing Chamber jejunum model with immunosuppressed PPs and evaluated its influences on intestinal tissue permeability and TJ proteins expression.Results:SAA in Coptidis Rhizoma decoction could dose-dependently promote Ber absorption in jejunum segment,with the participation of PPs.The dose-dependent and dynamical regulations of SAA on permeability of intestinal tissue and TJ proteins expression level between intestinal epithelium cells occurred along with the dynamically changed T lymphocyte differentiation and immune effectors secretion in PPs.The administration of SAA on immunosuppressed PPs exhibited dose-dependent PPs activation,inducing dynamic promotion on intestinal tissue permeability and inhibition on TJ proteins expression.Conclusion:SAA can improve the Ber absorption in small intestine,through the PPs-associated immunity induced dynamic regulation on intestinal tissue permeability and TJ proteins expression.These findings might enlighten the research of traditional Chinese medicine decoction.

Rehabilitation therapy for short bowel syndrome

OBJECTIVE: To investigate the effect of rehabilitation therapy for short bowel syndrome on patient nutritional status and intestinal adaptation. METHODS: The rehabilitation therapy included enteral or parenteral nutrition, glutamine, recombinant human growth hormone and rehabilitative diet. From January 1997 to July 2000, twenty - seven patients with short bowel syndrome received the treatment. The average age of the patients was 38.5 +/- 19.3 years, and the length of residual small intestine ranged from 15 to 80 cm, with an average of 46.8 +/- 23.4 cm. The ileocecal valve was preserved in 14 cases, and the average time between the onset of short bowel syndrome and the rehabilitation therapy was 86 +/- 105 days. RESULTS: After the treatment, nutritional status of the patients improved markedly, and intestinal absorptive capacity improved. Eight patients were followed up for more than 2 years, among whom 4 (50%) were weaned from total parenteral nutrition. Thirteen patients were followed up for more than 1 year, and 10 patients (76.9%) were weaned from total parenteral nutrition. CONCLUSIONS: Rehabilitation therapy for short bowel syndrome can improve patient nutritional status effectively and promote intestinal adaptation, providing a new hope for these patients. The therapeutic effects are related to the length of the residual small intestine, patients age and duration between massive intestinal resection and start of the treatment. Early initiation of rehabilitation therapy promotes intestinal adaptation and increases patients ability to wean from total parenteral nutrition.

Preparation and characterization of intestine PepT1-targeted calcium carbonate nanoparticles

To improve the oral absorption of poorly water-soluble drugs by overcoming the intestinal epithelium barrier, calcium carbonate nanoparticles targeting to intestine peptide transporter 1（Pep T1） were fabricated by modification of the surface of calcium carbonate nanoparticles with Gly-Sar. Gly-Sar-conjugated TPGS was successfully synthesized and characterized, and coumarin 6-loaded Gly-Sar modified calcium carbonate nanoparticles were then prepared and characterized to have a nano-scaled size of about 193 nm in diameter, cracked surface morphology under a scanning electron microscope, and high drug loading efficiency（60.5±5.9）%. Moreover, the Gly-Sar-modified calcium carbonate nanoparticles exhibited better drug loading stability during the process of their transcellular transport, and evidently enhanced intestinal absorption of poorly water-soluble agents. Therefore, the designed intestine Pep T1-targeted calcium carbonate nanoparticles might have a promising potential for oral delivery of poorly water-soluble drugs.

Metabolism of Chinese Materia Medica in Gut Microbiota and Its Biological Effects

The drug metabolism in gut microbiota draws increasing attentions. After interacting with the gut bacteria, the biological effects of drugs might be altered, leading to toxicity or detoxification, production of potential bioactivities, regulating intestinal absorption, etc. In this review, we will focus on the metabolism of Chinese materia medica（CMM） in mammal gut microbiota and its biological effects to learn the interaction between gut bacteria and drugs through oral route in CMM.