Distal Part Of Small Intestine Research Articles

Development of Novel Oral Formulations of Disulfide Antioxidants Based on Porous Silica for Controlled Release of the Drugs.

Powerful antioxidant α-lipoic acid (LA) exhibits limited therapeutic efficiency due to its pharmacokinetic properties. Therefore, the purpose of this work was to evaluate the ability of silica-based composites of LA as well as its amide (lipoamide, LM), as new oral drug formulations, to control their release and maintain their therapeutic concentration and antioxidant activity in the body over a long time. The composites synthesized at different sol–gel synthesis pH and based on silica matrixes with various surface chemistry were investigated. The release behavior of the composites in media mimicking pH of digestive fluids (pH 1.6, 6.8, and 7.4) was revealed. The effects of chemical structure of the antioxidants, synthesis pH, surface chemistry of the silica matrixes in the composites as well as the pH of release medium on kinetic parameters of the drug release and mechanisms of the process were discussed. The comparative analysis of the obtained data allowed the determination of the most promising composites. Using these composites, modeling of the release process of the antioxidants in accordance with transit conditions of the drugs in stomach, proximal, and distal parts of small intestine and colon was carried out. The composites exhibited the release close to the zero order kinetics and maintained the therapeutic concentration of the drugs and antioxidant effect in all parts of the intestine for up to 24 h. The obtained results showed that encapsulation of LA and LM in the silica matrixes is a promising way to improve their bioavailability and antioxidant activity.

Gut as an emerging organ for the treatment of diabetes: focus on mechanism of action of bariatric and endoscopic interventions.

Increasing worldwide prevalence of type 2 diabetes mellitus and its accompanying pathologies such as obesity, arterial hypertension and dyslipidemia represents one of the most important challenges of current medicine. Despite intensive efforts, high percentage of patients with type 2 diabetes does not achieve treatment goals and struggle with increasing body weight and poor glucose control. While novel classes of antidiabetic medications such as incretin-based therapies and gliflozins have some favorable characteristics compared to older antidiabetics, the only therapeutic option shown to substantially modify the progression of diabetes or to achieve its remission is bariatric surgery. Its efficacy in the treatment of diabetes is well established, but the exact underlying modes of action are still only partially described. They include restriction of food amount, enhanced passage of chymus into distal part of small intestine with subsequent modification of gastrointestinal hormones and bile acids secretion, neural mechanisms, changes in gut microbiota and many other possible mechanisms underscoring the importance of the gut in the regulation of glucose metabolism. In addition to bariatric surgery, less-invasive endoscopic methods based on the principles of bariatric surgery were introduced and showed promising results. This review highlights the role of the intestine in the regulation of glucose homeostasis focusing on the mechanisms of action of bariatric and especially endoscopic methods of the treatment of diabetes. A better understanding of these mechanisms may lead to less invasive endoscopic treatments of diabetes and obesity that may complement and widen current therapeutic options.

The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is a form of non-alcoholic fatty liver disease (NAFLD) characterized by steatosis, inflammation, and fibrosis often associated with metabolic syndrome. Fibroblast growth factor 15 (FGF15), an endocrine factor mainly produced in the distal part of small intestine, has emerged to be a critical factor in regulating bile acid homeostasis, energy metabolism, and liver regeneration. We hypothesized that FGF15 alters the development of each of the listed features of NASH. To test this hypothesis, four-week old male Fgf15−/− and their corresponding wild-type (WT) mice were fed either a high fat diet (HFD) or a control chow diet for six months. The results confirmed that HFD feeding for six months in WT mice recapitulated human NASH phenotype, including macrovesicular steatosis, inflammation, and fibrosis. Whereas FGF15 deficiency had no effect on the severity of liver steatosis or inflammation, it was associated with decreased liver fibrosis. Furthermore, FGF15 deficiency resulted in abnormal bile acid homeostasis, increased insulin resistance, increased HFD-induced serum triglycerides, decreased inductions of hepatic cholesterol content by HFD, and altered gene expression of lipid metabolic enzymes. These data suggest that FGF15 improves lipid homeostasis and reduces bile acid synthesis, but promotes fibrosis during the development of NASH.

A 21-year-old Man with Delayed Puberty

Delayed puberty is defined clinically by the absence or incomplete development of secondary sexual characteristics bounded by an age at which 95 percent of children of that sex and culture have initiated sexual maturation. The upper 95th percentile in the for age for boys is 14 (an increase in testicular size being the first sign) and for girls is 12 (breast development being the first sign). Delayed puberty pathophysiologically is classified according to the circulating levels of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in to two groups of high serum LH/FSH and low or normal serum LH/FSH concentrations which are related to primary hypogonadism and hypothalamic dysfunction respectively. Patient Presentation. A 21 year old boy presented with severe respiratory distress syndrome due to pneumonia and generalized edema. Laboratory studies showed pancytopenia which made clinicians work up for hematologic disorders, leading to bone marrow aspiration and biopsy which was consistent with megaloblastic anemia resulting from vit B12 deficiency. Another manifestation of this patient was delayed puberty which had been ignored over these years. Evaluation of delayed puberty revealed a low serum LH/FSH concentration. Accompaniment of delayed puberty resulting from hypothalamic origin with edema and hypoalbuminemia made clinicians work up for a malabsorption syndrome. Therefore upper endoscopy and colonoscopy were done and duodenal biopsies were consistent with celiac sprue. The unusual symptom of this patient was vit B12 deficiency which is rare in celiac disease. Conclusion. Neglected celiac sprue can be accompanied by vit B12 deficiency probably because of involvement of more distal parts of small intestine over the time.

The relationship between DNA adduct formation by benzo[a]pyrene and expression of its activation enzyme cytochrome P450 1A1 in rat

Benzo[a]pyrene (BaP) is a human carcinogen requiring metabolic activation prior to reaction with DNA. Cytochrome P450 (CYP) 1A1 is the most important hepatic and intestinal enzyme in both BaP activation and detoxification. CYP1A2 is also capable of oxidizing BaP, but to a lesser extent. The induction of CYP1A1/2 by BaP and/or β-naphthoflavone in liver and small intestine of rats was investigated. Both BaP and β-naphthoflavone induced CYP1A expression and increased enzyme activities in both organs. Moreover, the induction of CYP1A enzyme activities resulted in an increase in formation of BaP–DNA adducts detected by 32P-postlabeling in rat liver and in the distal part of small intestine in vivo. The increases in CYP1A enzyme activity were also associated with bioactivation of BaP and elevated BaP–DNA adduct levels in ex vivo incubations of microsomes of both organs with DNA and BaP. These findings indicate a stimulating effect of both compounds on BaP-induced carcinogenesis.

Oat β-Glucan Increased ATPases Activity and Energy Charge in Small Intestine of Rats

Dietary oat or oat products may potentially help to fight against high risk of cardiovascular diseases and β-glucan in oat was considered as a central player. The present study aimed to investigate the effects of dietary oat whole meal or β-glucan on insulin sensitivity and energy metabolism of rats. Rats were fed with control diet, oat whole meal based diet, or control diet with supplemented β-glucan for 4 weeks. Oat whole meal and β-glucan increased insulin sensitivity index. Interestingly, supplementation of oat whole meal or β-glucan induced increases in intestinal Na(+)K(+)-ATPase activity, Ca(2+)Mg(2+)-ATPase activity, and energy charge, particularly in the distal part of small intestine (ileum). Furthermore, amounts of Bifidobacterium and Lactobacillus in colon contents were elevated by oat whole meal or β-glucan. These findings provide an insight into that β-glucan increased insulin sensitivity and benefited intestinal health.

Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: a study on enzyme knockout mice

Alkaline sphingomyelinase (alk-SMase) hydrolyses sphingomyelin (SM) to ceramide in the gut. To evaluate the physiological importance of the enzyme, we generated alk-SMase knockout (KO) mice by the Cre-recombinase-Locus of X-over P1(Cre-LoxP) system and studied SM digestion. Both wild-type (WT) and KO mice were fed ³H-palmitic acid labeled SM together with milk SM by gavage. The lipids in intestinal content, intestinal tissues, serum, and liver were analyzed by TLC. In KO mice, nondigested ³H-SM in the intestinal content increased by 6-fold and the formation of ³H-ceramide decreased markedly, resulting in 98% reduction of ³H-ceramide/³H-SM ratio 1 h after gavage. The absorbed ³H-palmitic acid portion was decreased by 95%. After 3 h, a small increase in ³H-ceramide was identified in distal intestine in KO mice. In feces, ³H-SM was increased by 243% and ceramide decreased by 74% in the KO mice. The KO mice also showed significantly decreased radioactivity in liver and serum. Furthermore, alkaline phosphatase activity in the mucosa was reduced by 50% and histological comparison of two female littermates preliminarily suggested mucosal hypertrophy in KO mice. This study provides definite proof for crucial roles of alk-SMase in SM digestion and points to possible roles in regulating mucosal growth and alkaline phosphatase function.

Time and/or site specific drug delivery of floating pulsatile release delivery system

Pharmaceutical invention and research are increasingly focusing on delivery systems which enhance desirable therapeutic objectives while minimizing side effects. Recent trends indicate that drug delivery systems are especially suitable for achieving controlled or delayed release oral formulations with low risk of dose dumping, flexibility of blending to attain desirable release patterns with less inter- and intra-subject variability. A blend of floating and pulsatile principles of drug delivery system seems to present the advantage that a drug can be released in the upper GI tract after a definite time period of no drug release. Floating pulsatile drug delivery system (FPDDS) concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. Diseases wherein FPDDS are promising include asthma, peptic ulcer, cardiovascular diseases, arthritis, and attention deficit syndrome in children. To overcome limitations of various approaches for imparting, buoyancy and lag controlling were prepared by floating pulsatile delivery systems, for which time-controlling system like swelling and rupturable membranes, soluble or erodible coating, capsule-shaped system, and multiparticulate system are primarily involved in the control of release. FPDDS showed excellent lag phase followed by burst release in distal part of small intestine which gives site- and time-specific release of drugs acting as per chronotherapy of the diseases. The current article focuses on the diseases requiring FPDDS, methodologies involved for the existing systems, recent update.

Differences in Intraepithelial Lymphocytes in the Proximal, Middle, Distal Parts of Small Intestine, Cecum, and Colon of Mice

We have previously reported the regional differences in the intraepithelial lymphocytes (IELs) present in the small intestine of mice. In this study, we further investigated these differences on the basis of our previous findings and studied the entire intestine, including the cecum and colon. Most of the significant differences in phenotypic compositions were found between the small and large intestines, although some differences were found among the different parts of the small and large intestines. In particular, the composition of the subsets in αβ T cells and γδ T cells clearly differed between the small and large intestines. For example, in αβ T cells, the percentages of double negative (DN) and CD8αα+ cells were higher in the large intestine, that of CD8αβ+ cells was higher in the small intestine, and those of CD4+ and CD4+ CD8αα+ double positive (DP) cells were higher in the distal part of the small intestine. In γδ T cells, the percentage of CD8αα+ cells was higher in the small intestine and that of DN cells was higher in the large intestine. These results indicate that the differences between IELs in the small and large intestines are discontinuous.

Eudragit ® and hydrotalcite-like anionic clay composite system for diclofenac colonic delivery

In this paper, the microencapsulation of the MgAl-hydrotalcite (HTlc) and diclofenac (DIK) intercalation product (HTlc-DIK) was realized in order to obtain a composite system for colonic drug delivery. Eudragit ® S or Eudragit ® L were used as polymers for preparation of microparticles (MPs). MPs were prepared by using a properly modified oil-in-oil solvent evaporation method. A 1:5 or 1:10 w/w HTlc-DIK/polymer ratios were employed. An experimental design was applied in order to assess the preparation variable effects on the qualitative MP appearance. Improved MP preparations were achieved when 7–13 ml of acetone-ethanol solution was employed at both HTlc-DIK/polymer ratios. The MPs were tested for in vitro drug release. DIK release from Eudragit ® L MPs at pH 6.8 reached 26–35% within 25–30 min at both HTlc-DIK/polymer ratios and no further increase was observed when the pH was shifted to 7.5. DIK release from Eudragit ® S MPs at pH 7.5 reached for both ratios 70% after 6–8 h. The obtained results showed that hydrotalcite intercalation compound can be microencapsulated without missing the intercalated compound and the resulted composite MPs showed good characteristics. Besides HTlc-DIK/Eudragit ® S MPs possess improved features with respect to HTlc-DIK/Eudragit ® L MPs. For this reason, HTlc-DIK/Eudragit ® S MPs could be promising for drug delivery either to the distal part of small intestine or to the colon.

In vitro evaluation of feed-grade enzyme activity at pH levels simulating various parts of the avian digestive tract

The activities of β-glucanase, xylanase, amylase, α-galactosidase and protease were measured at their published optimum pH levels and at pH levels of 3.0, 6.0, 6.5, 7.0 and 7.5 to simulate pH levels of the gizzard, the diet, the crop, and the proximal and distal parts of small intestine, respectively. The activity of β-glucanase was determined by measuring reducing sugars after incubation of β-glucan. Xylanase activity was assayed by measuring xylose after hydrolysis of xylan. The activity of amylase was measured through hydrolysis of soluble starch. The assay of α-galactosidase was based on a hydrolysis of p-nitrophenyl-α- d-galactoside followed by measurement of liberated p-nitrophenol. The activity of protease was assayed by measuring tyrosine after enzymatic hydrolysis of casein. β-Glucanase had high activity at pH levels of 3.0–7.0. Xylanase had no enzyme activity at pH 3.0, but had high activity at pH levels of 6.0–7.0. Amylase had high activity at pH levels of 6.0 and 6.5 but had no or very low activity at pH 3.0, 7.0 and 7.5. α-Galactosidase had high activity at pH 6, but not at other pH levels tested. Protease had either no or very low activity at all pH levels except at pH 3.0. These results suggest that the pH levels commonly found in the avian digestive tract may be a limiting factor for maximum activity of the exogenous enzymes, such as amylase, α-galactosidase and protease.

Content of carbohydrates in enteral medium of various parts of digestive tract of the reindeer rangifer tarandus during winter

It has been established that cellulose concentration in dry matter of manifold chymus in female reindeers Rangifer tarandus is increased in comparison with rumen and reticulum, while the reducing sugar concentration is decreased. There is oppositely directed change of the carbohydrate concentration at transit from manifold to the medial part of jejunum—a decrease of cellulose and an increase of sugars. In the distal part of small intestine as well as in large intestine, the cellulose content increases again, whereas the sugar level decreases. The maximal rise of the content of aldoses and ketoses in chymus of the reindeer jejunum proximal part indicates that the high assimilation of reindeer moss polysaccharides is achieved not only due to adaptive alimentary possibilities of rumen, but also owing to intensive hydrolysis of exogenous and mostly endogenous polysaccharides of the secondary microbial origin in small intestine. Comparison of the total amount of reducing sugars in the reindeer digestive tract with the total amount of glucose in blood allows suggesting that alongside with gluconeogenesis the absorption of monosugars from digestive tract plays an essential role in maintenance of the high glycemic level that is especially necessary during winter season to provide the elevated energy demands of the animal organism.

Influence of various fiber supplements on quantity of microbial biomass in digestive tract of piglets determined by ATP-luciferase assay

Dietary fibre has positive effects on digestion and on gastrointestinal tract of pigs. Pigs do not possess indigenous enzymes for its digestion. Fibre is fermented by gastrointestinal microflora. The influence of different fibre sources on quantity of microbial biomass in gastrointestinal tract (GIT) of weaned piglets was studied in our experiment. First we introduced ATP-luciferase assay with pure E. coli culture, mixture of E. coli and somatic cells and samples from small and large intestine. The proper protocol for preparation of samples from GIT for ATP-luciferase assay was established. Twenty four weaned piglets, divided into four groups, were fed the same feed except the included fibre: carboxymethylcellulose (group CMC), lignified cellulose (group LIG) and pure cellulose (group CEL). The control group received starch instead of fibre (group KON). Piglets were sacrificed after 13 days of feeding and digesta samples were taken from: stomach, proximal part of small intestine, distal part of small intestine, caecum, colon and rectum together. The quantity of microorganisms in different parts of GIT was estimated by ATP-luciferase assay. The highest concentration (conc.) of microbial ATP was found in large intestine in all groups. Statistically significant effect of different fibres on conc. of microbial ATP in different parts of GIT was not demonstrated. The experiment did not provide evidence that the soluble dietary fibre (carboxymethylcellulose) would enable more intensive microbial fermentation in weaned pigs than insoluble fiber. The reason was probably in big variability and nonhomogenity of samples from GIT.

In Vitro Release and Intestinal Absorption of Physostigmine Salicylate from Submicron Emulsions

The in vitro release of physostigmine salicylate (PS) from a submicron emulsion and an aqueous solution was studied using the dialysis bag method. These formulations were then perfused to various locations along the rat small intestine (proximal, mid, and distal jejunum), and two lengths (10 and 55 cm). The disappearance of PS from the luminal compartment and its appearance in the blood compartment was monitored. In the in vitro drug release from emulsion experiments, a biphasic appearance of PS in the sink solution was observed, suggesting a possible sustained release from the emulsion. However, absorption data from perfusion studies did not correlate with this in vitro observation. No significant difference was found in absorption from emulsion versus solution in the mid jejunum where PS absorption was maximal. The difference between the two liquid formulations was observed only in those intestinal segments where the absorption was relatively low [absorption rate values of 4.6 ± 0.86 and 9.98 ± 2.04 (log%/min) × 10−3 in the proximal and distal parts of the small intestine, respectively, as compared with 14.0 ± 1.2-14.8 ± 1.1 (log%/min) × 10−3 in the mid jejunum]. In the distal part of the rat small intestine, PS was absorbed significantly better from solution than from the submicron emulsion. Cholinesterase activity in blood samples collected after intestinal perfusion with emulsion or solution revealed lower enzyme activity following emulsion administration.

Experimental Infection of Specific‐Pathogen‐Free Mice with Enterohemorrhagic Escherichia coli 0157: H7

By subcutaneous inoculation of 10(8) CFU of enterohemorrhagic E. coli O157:H7, specific-pathogen-free mice revealed most of the symptoms and histological changes observed in patients. The histological changes in intestine were mainly seen in the distal parts of small intestine and the cecum. Vacuolation of villi in the cecum was also observed. The histological changes in the kidneys of the infected mice were featured as the swollen epithelial cells of glomeruli and the marked thickening of glomerular capillaries with barely visible lumens. Unexpected findings in the bronchiole were characterized by sloughing of the epithelial cells of bronchiolar wall, leading to partial or complete obstruction of the lumens. Histological changes in the spleen, liver and lymphnodes were also observed. The bacteria were recovered from the feces, contents of small intestine, and samples taken from kidney, liver, heart, spleen, different parts of small intestine, cecum, and colon. By using peroxidase-antiperoxidase (PAP) assay with polyclonal antibodies against "O" antigen of E. coli O157:H7, it was observed that the samples taken from the brain, kidney, ileum, cecum, spleen, and liver gave positive reactions. Feces and contents of small intestine obtained from all of the infected animals were positive by occult blood test. These results show that the experimental infection of E. coli O157:H7 in this model is systemic in nature.

Lactase expression is controlled differently in the jejunum and ileum during development in rats

This study shows the distribution of the messenger RNA for lactase-phlorizin hydrolase during postnatal development and along the longitudinal axis of the rat small intestine. At birth, this messenger RNA was present along the whole length of small intestine, and its concentration remained elevated during the suckling period despite the concomitant decrease in enzyme activity. At weaning, the amount of lactase messenger RNA dropped specifically in the distal ileum. This decrease in lactase messenger RNA was initiated at the ileocecal junction, progressed gradually towards the jejunum, and followed the decrease in lactase activity several days later. Starvation and refeeding were also found to cause modifications of lactase activity and messenger RNA expression that were prominent in the distal part of small intestine. These data support that posttranscriptional and pretranslational levels of regulation are required to define the spatial and temporal expression of lactase in the rat small intestine.

Transglutaminase Activity along the Rat Small Bowel and Cellular Location

A recent report indicates a relationship between human transglutaminase (TG) jejunal mucosa activity and celiac disease. We investigated the enzyme distribution along six consecutive small bowel segments of mucosa and tested TG activity on brush border membranes obtained from whole mucosa homogenate in Wistar rats. TG activity was significantly present in jejunal mucosa even if mostly detected in the distal part of small intestine. Our study indicates highest enzymatic activity in the subcellular fraction containing organelles and cellular membranes (66.8%) while a 7% activity was associated with the brush border fraction.