Intragastric Research Articles

Assessment of the Smartpill, a Wireless Sensor, as a Measurement Tool for Intra-Abdominal Pressure (IAP).

Background: The SmartPill, a multisensor ingestible capsule, is marketed for intestinal motility disorders. It includes a pressure sensor, which could be used to study intra-abdominal pressure (IAP) variations. However, the validation data are lacking for this use. Material and Methods: An experimental study was conducted on anesthetized pigs with stepwise variations of IAP (from 0 to 15 mmHg by 3 mmHg steps) generated by laparoscopic insufflation. A SmartPill, inserted by endoscopy, provided intragastric pressure data. These data were compensated to take into account the intrabdominal temperature. They were compared to the pressure recorded by intragastric (IG) and intraperitoneal (IP) wired sensors by statistical Spearman and Bland-Altmann analysis. Results: More than 4500 pressure values for each sensor were generated on two animals. The IG pressure values obtained with the SmartPill were correlated with the IG pressure values obtained with the wired sensor (respectively, Spearman ρ coefficients 0.90 ± 0.08 and 0.72 ± 0.25; bias of -28 ± -0.3 mmHg and -29.2 ± 0.5 mmHg for pigs 1 and 2). The intragastric SmartPill values were also correlated with the IAP measured intra-peritoneally (respectively, Spearman ρ coefficients 0.49 ± 0.18 and 0.57 ± 0.30; bias of -29 ± 1 mmHg and -31 ± 0.7 mmHg for pigs 1 and 2). Conclusions: The SmartPill is a wireless and painless sensor that appears to correctly monitor IAP variations.

Protein Extract of a Probiotic Strain of Hafnia alvei and Bacterial ClpB Protein Improve Glucose Tolerance in Mice

A commercial strain of Hafnia alvei (H. alvei) 4597 bacteria was shown to reduce food intake and promote weight loss, effects possibly induced by the bacterial protein ClpB, an antigen-mimetic of the anorexigenic α-melanocyte-stimulating hormone. A decrease in the basal plasma glucose levels was also observed in overweight fasted humans and mice receiving H. alvei. However, it is not known whether H. alvei influences sweet taste preference and whether its protein extract or ClpB are sufficient to increase glucose tolerance; these are the objectives tested in the present study. C57BL/6J male mice were kept under standard diet and were gavaged daily for 17 days with a suspension of H. alvei (4.5 × 107 CFU/animal) or with H. alvei total protein extract (5 μg/animal) or saline as a control. Sweet taste preference was analyzed via a brief-access licking test with sucrose solution. Glucose tolerance tests (GTT) were performed after the intraperitoneal (IP) or intragastric (IG) glucose administration at the 9th and 15th days of gavage, respectively. The expression of regulatory peptides’ mRNA levels was assayed in the hypothalamus. In another experiment performed in non-treated C57BL/6J male mice, effects of acute IP administration of recombinant ClpB protein on glucose tolerance were studied by both IP- and IG-GTT. Mice treated with the H. alvei protein extract showed an improved glucose tolerance in IP-GTT but not in IG-GTT. Both groups treated with H. alvei bacteria or protein extract showed a reduction of pancreatic tissue weight but without significant changes to basal plasma insulin. No significant effects of H. alvei bacteria or its total protein extract administration were observed on the sweet taste preference, insulin tolerance and expression of regulatory peptides’ mRNA in the hypothalamus. Acute administration of ClpB in non-treated mice increased glucose tolerance during the IP-GTT but not the IG-GTT, and reduced basal plasma glucose levels. We conclude that both the H. alvei protein extract introduced orally and the ClpB protein administered via IP improve glucose tolerance probably by acting at the glucose postabsorptive level. Moreover, H. alvei probiotic does not seem to influence the sweet taste preference. These results justify future testing of both the H. alvei protein extract and ClpB protein in animal models of diabetes.

Dose and route of administration determine the efficacy of prophylactic immunotherapy for peanut allergy in a Brown Norway rat model.

Allergen-specific immunotherapy (IT) is emerging as a viable option for treatment of peanut allergy. Yet, prophylactic IT remains unexplored despite early introduction of peanut in infancy was shown to prevent allergy. There is a need to understand how allergens interact with the immune system depending on the route of administration, and how different dosages of allergen may protect from sensitisation and a clinical active allergy. Here we compared peanut allergen delivery via the oral, sublingual (SL), intragastric (IG) and subcutaneous (SC) routes for the prevention of peanut allergy in Brown Norway (BN) rats. BN rats were administered PBS or three different doses of peanut protein extract (PPE) via either oral IT (OIT), SLIT, IGIT or SCIT followed by intraperitoneal (IP) injections of PPE to assess the protection from peanut sensitisation. The development of IgE and IgG1 responses to PPE and the major peanut allergens were evaluated by ELISAs. The clinical response to PPE was assessed by an ear swelling test (EST) and proliferation was assessed by stimulating splenocytes with PPE. Low and medium dose OIT (1 and 10 mg) and all doses of SCIT (1, 10, 100 µg) induced sensitisation to PPE, whereas high dose OIT (100 mg), SLIT (10, 100 or 1000 µg) or IGIT (1, 10 and 100 mg) did not. High dose OIT and SLIT as well as high and medium dose IGIT prevented sensitisation from the following IP injections of PPE and suppressed PPE-specific IgE levels in a dose-dependent manner. Hence, administration of peanut protein via different routes confers different risks for sensitisation and protection from peanut allergy development. Overall, the IgE levels toward the individual major peanut allergens followed the PPE-specific IgE levels. Collectively, this study showed that the preventive effect of allergen-specific IT is determined by the interplay between the specific site of PPE delivery for presentation to the immune system, and the allergen quantity, and that targeting and modulating tolerance mechanisms at specific mucosal sites may be a prophylactic strategy for prevention of peanut allergy.

HIF-PHIs for Anemia Management in CKD: Potential and Uncertainty ASCEND.

<h3>Abstract</h3> The outbreak of Corona Virus Disease 2019 caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) is highly transmitted. The potential extra-respiratory transmission routes remain uncertain. Five rhesus macaques were inoculated with 1×10⁶ TCID₅₀ of SARS-CoV-2 via conjunctival (CJ), intratracheal (IT), and intragastric (IG) routes, respectively. Remarkably, the CJ inoculated-macaques developed mild interstitial pneumonia and viral load was detectable in the conjunctival swabs at 1 days post-inoculation (dpi). Only via IT inoculation, viral load was detected in the anal swab at 1-7 dpi and macaque showed weight loss. However, viral load was undetectable after IG inoculation. Comparatively, viral load was higher in the nasolacrimal system but lesions of lung were relatively mild and local via CJ inoculation compared with that via IT inoculation, demonstrating distinct characteristics of virus dispersion. Both the two routes affected the alimentary tract. Therefore the clinicians need to protect eye while working with patients.

The entrance route: Oral, mucous, cutaneous, or systemic has a marked influence on the outcome of Trypanosoma cruzi experimental infection

In recent decades, the oral infection of Trypanosoma cruzi has gathered increased attention due to frequent outbreaks that can lead to more severe clinical signs than those usually found in the areas of vector transmission. This study addresses the main routes of infection using metacyclic trypomastigotes (MT) and blood trypomastigotes (BT). Herein, BALB/c mice were infected with the Colombian (TcI) strain via intraperitoneal (IP), oral, intragastric (IG), ocular (OC) and cutaneous (CT) routes with 106 culture-derived MT or BT. Parasitemia was intermittent and low in animals inoculated with MT, in contrast, high parasitemia levels were found in BT-mice. A tropism for the muscles was observed in oral or IG infection with BT. Differently, the parasite was widely distributed in the tissues of mice infected with MT. However, the intensity of the inflammation infiltrating the tissues was higher in oral or IG infection with BT. Animals inoculated with BT via the IG route had similar serum levels of IFN-γ and smaller IL-10 compared to those infected with MT via the IG route. TNF-α levels were higher in the serum from BT-animals, which could explain the higher intensity of heart inflammation in these animals. Our results suggest that the infective form and the route of infection differentially modulated the outcome of Trypanosoma cruzi mice infection.

Administration Routes as Modulators of the Intrahepatic Distribution and Anti-Anemic Activity of Salicylic Acid/Fe3O4 Nanoparticles.

The liver is a key organ in the pharmacokinetics of iron oxide nanoparticles (IONPs). This paper examined how the intravenous (IV) or intragastric (IG) route of administration influenced the intrahepatic distribution or therapeutic effects of IONPs. Wistar rats, some with bleeding-induced anemia, and iron oxide nanoparticles functionalized with salicylic acid (SaIONPs), with an average hydrodynamic diameter of 73 nm, compatible with rat sinusoid fenestrations, were used in this study. Light microscopy and multispectral camera analysis of Prussian blue labeled SaIONPs allowed mapping of intrahepatic nanoparticle deposits and revealed intrahepatic distribution patterns specific to each route of administration: loading of Kupffer cells and periportal hepatocytes when the IV route was used and predominant loading of hepatocytes when the IG route was used. Reducing the time to return to baseline values for hemoglobin (HGB) in rats with bleeding-induced anemia with IV or IG therapy has proven the therapeutic potential of SaIONPs in such anemias. The long-term follow-up showed that IV therapy resulted in higher HGB values. Proper use of the administration routes may modulate intrahepatic distribution and therapeutic effects of nanoparticles. These results may be beneficial in theragnosis of liver disease.

Assessment of the Route of Exposure to Ovalbumin and Cow's Milk Proteins on the Induction of IgE Responses in BALB/c Mice.

Simple SummaryThe mouse model is very valuable to scientists, mainly because many reagents are commercially available for conducting research in this animal model. In the search for a standardized mouse model of food allergy, the route of administration of the proteins of interest is a determinant to successfully sensitizing the mice. Our aim was to evaluate the IgE allergen-specific response to food proteins after their administration by the intragastric or intraperitoneal routes in BALB/c mice. The results show that the intraperitoneal administration of the allergens ovalbumin or cow’s milk protein triggered more robust and consistent immunoglobulin E responses than the intragastric administration of the proteins, whether Sucralfate is used or not (an antacid that can promote sensitization in mice and an allergic response similar to the one triggered in human beings). It is concluded that the intraperitoneal administration of food proteins is better than the intragastric one to sensitize BALB/c mice, even after gastric-acid suppression. We have generated scientific evidence to pave the way in the search for a reproducible mouse model of immunoglobulin E-mediated food allergy to evaluate the safety of crops derived from modern biotechnology, such as genetic engineering, or the safety and effectiveness of new food allergy therapies.BALB/c mice can be orally sensitized to food proteins under acid suppressive medication, mimicking human exposure and triggering a human-like allergic immune response. However, the reproducibility of such an oral food allergy model remains questionable. Our aim was to evaluate the IgE responses triggered against ovalbumin (OVA) and cow’s milk proteins (CMP) after intragastric (IG), either under gastric-acid suppression or not, or intraperitoneal (IP) sensitization in BALB/c mice. OVA (0.2 mg) and different concentrations of CMP were administered with/without the antacid sucralfate by the IG route. For IP sensitization, OVA or CMP (0.5 mg) were administered. ELISA was used to evaluate IgE responses. The IP sensitization protocols triggered more robust and consistent anti-OVA or anti-CMP IgE responses than the intragastric ones (with/without sucralfate) (p < 0.05). 2.7% (1/36), and 5.5% (3/54) of the mice that underwent the sucralfate-assisted IG protocol triggered IgE responses against OVA or CMP, respectively. All the mice were administered OVA or CMP via IP triggered detectable IgE responses. The IP sensitization model is more reliable than the IG one for evaluating the intrinsic sensitizing and/or allergenic potential of food proteins, even if IG immunizations are carried out under gastric-acid suppression.

Quinine Effects on Gut and Pancreatic Hormones and Antropyloroduodenal Pressures in Humans-Role of Delivery Site and Sex.

ContextThe bitter substance quinine modulates the release of a number of gut and gluco-regulatory hormones and upper gut motility. As the density of bitter receptors may be higher in the duodenum than the stomach, direct delivery to the duodenum may be more potent in stimulating these functions. The gastrointestinal responses to bitter compounds may also be modified by sex.BackgroundWe have characterized the effects of intragastric (IG) versus intraduodenal (ID) administration of quinine hydrochloride (QHCl) on gut and pancreatic hormones and antropyloroduodenal pressures in healthy men and women.Methods14 men (26 ± 2 years, BMI: 22.2 ± 0.5 kg/m2) and 14 women (28 ± 2 years, BMI: 22.5 ± 0.5 kg/m2) received 600 mg QHCl on 2 separate occasions, IG or ID as a 10-mL bolus, in randomized, double-blind fashion. Plasma ghrelin, cholecystokinin, peptide YY, glucagon-like peptide-1 (GLP-1), insulin, glucagon, and glucose concentrations and antropyloroduodenal pressures were measured at baseline and for 120 minutes following QHCl.ResultsSuppression of ghrelin (P = 0.006), stimulation of cholecystokinin (P = 0.030), peptide YY (P = 0.017), GLP-1 (P = 0.034), insulin (P = 0.024), glucagon (P = 0.030), and pyloric pressures (P = 0.050), and lowering of glucose (P = 0.001) were greater after ID-QHCl than IG-QHCl. Insulin stimulation (P = 0.021) and glucose reduction (P = 0.001) were greater in females than males, while no sex-associated effects were found for cholecystokinin, peptide YY, GLP-1, glucagon, or pyloric pressures.ConclusionID quinine has greater effects on plasma gut and pancreatic hormones and pyloric pressures than IG quinine in healthy subjects, consistent with the concept that stimulation of small intestinal bitter receptors is critical to these responses. Both insulin stimulation and glucose lowering were sex-dependent.

Differential fructose and glucose appetition in DBA/2, 129P3 and C57BL/6 × 129P3 hybrid mice revealed by sugar versus non-nutritive sweetener tests

Inbred mouse strains differ in their postoral appetite stimulating response (appetition) to fructose as demonstrated in intragastric (IG) sugar conditioning and oral sugar vs. nonnutritive conditioning experiments. For example, FVB and SWR strains show experience-induced preferences for 8% fructose over a 0.1% sucralose + 0.1% saccharin (S + S) solution, whereas C57BL/6 (B6) and BALB/c strains do not. All strains, however, learn to prefer 8% glucose to S + S after experience, which is attributed to the potent appetition actions of this sugar. The present study extended this analysis to DBA/2 (DBA) and 129P3 (129) inbred mice. In Experiment 1A, ad libitum fed DBA and 129 mice preferred S + S to fructose before and after separate experience with the two sweeteners, indicating an indifference to the postoral nutrient effects of the sugar. When food restricted (Experiment 1B), 129 mice continued to prefer S + S to fructose while DBA mice showed equal preference for the sweeteners after experience, indicating some sensitivity to fructose appetition. In Experiment 1C, both strains acquired significant preferences for glucose over S + S after experience, confirming their sensitivity to postoral glucose appetition. Experiment 2 revealed that C57BL/6 × 129P3 (B6:129) hybrid mice responded like inbred B6 mice and 129 mice in acquiring a preference for glucose but not fructose over S + S. This is of interest because sweet "taste-blind" P2 × 2 / P2 × 3 double-knockout (DKO) mice on a B6:129 genetic background prefer fructose to water in 24 h tests, which is indicative of fructose appetition. Whether differences in the genetic makeup of DKO and B6:129 hybrid mice or other factors explain the fructose appetition of the DKO mice remains to be determined.

Comparative Effects of Intragastric and Intraduodenal Administration of Quinine on the Plasma Glucose Response to a Mixed-Nutrient Drink in Healthy Men: Relations with Glucoregulatory Hormones and Gastric Emptying.

In preclinical studies, bitter compounds, including quinine, stimulate secretion of glucoregulatory hormones [e.g., glucagon-like peptide-1 (GLP-1)] and slow gastric emptying, both key determinants of postprandial glycemia. A greater density of bitter-taste receptors has been reported in the duodenum than the stomach. Thus, intraduodenal (ID) delivery may be more effective in stimulating GI functions to lower postprandial glucose. We compared effects of intragastric (IG) and ID quinine [as quinine hydrochloride (QHCl)] administration on the plasma glucose response to a mixed-nutrient drink and relations with gastric emptying, plasma C-peptide (reflecting insulin secretion), and GLP-1. Fourteen healthy men [mean±SD age: 25±3y; BMI (in kg/m2): 22.5±0.5]received, on 4 separate occasions, in double-blind, randomly assigned order, 600 mgQHCl or control, IG or ID, 60min (IG conditions) or 30min (IG conditions) before a mixed-nutrient drink. Plasma glucose (primary outcome) and hormones were measured before, and for 2 h following, the drink. Gastric emptying of the drink was measured using a 13C-acetate breath test. Data were analyzed using repeated-measures 2-way ANOVAs (factors: treatment and route of administration) to evaluate effects of QHCl alone and 3-way ANOVAs (factors: treatment, route-of-administration, and time) for responses to the drink. After QHCl alone, there were effects of treatment, but not route of administration, on C-peptide, GLP-1, and glucose (P<0.05); QHCl stimulated C-peptide and GLP-1 and lowered glucose concentrations (IG control: 4.5±0.1; IG-QHCl: 3.9±0.1; ID-control: 4.6±0.1; ID-QHCl: 4.2±0.1 mmol/L)compared with control. Postdrink, there were treatment×time interactions for glucose, C-peptide, and gastric emptying, and a treatment effect for GLP-1 (all P<0.05), but no route-of-administration effects. QHCl stimulated C-peptide and GLP-1, slowed gastric emptying, and reduced glucose (IG control: 7.2±0.3; IG-QHCl: 6.2±0.3; ID-control: 7.2±0.3; ID-QHCl: 6.4±0.4 mmol/L) compared with control. In healthy men, IG and ID quinine administration similarly lowered plasma glucose, increased plasma insulin and GLP-1, and slowed gastric emptying. These findings have potential implications for lowering blood glucose in type 2 diabetes. This study was registered as a clinical trial with the Australian New Zealand Clinical Trials at www.anzctr.org.au as ACTRN12619001269123.

Antimetastatic and Antitumor Activities of Orally Administered NAX014 Compound in a Murine Model of HER2-Positive Breast Cancer.

The natural isoquinoline alkaloid Berberine (BBR) has been shown to possess several therapeutic effects, including anticancer activity. Different BBR derivatives have been designed and synthesized in order to obtain new compounds with enhanced anticancer efficacy. We previously showed that intraperitoneal (IP) administration of the BBR-derived NAX014 compound was able to counteract HER-2 overexpressing mammary tumors onset and progression in transgenic mice. However, the IP administration was found to induce organ toxicity at doses higher than 2.5 mg/Kg. In this study, we evaluated the effect of intragastric (IG) administration of 20 mg/kg of NAX014 on both safety and anticancer efficacy in HER-2/neu transgenic mice. Furthermore, cancer cell dissemination and migration, tumor cell senescence and immunological changes were examined. Our results demonstrated that IG NAX014 administration delayed the onset of mammary tumors with no negative effects on health and survival. NAX014 reduced HER-2 overexpressing BC cells migration in vitro and the frequency of lung metastasis in HER-2/neu transgenic mice. A statistically significant increase of senescence-associated p16 expression was observed in tumors from NAX014-treated mice, and the induction of cell senescence was observed in HER-2 overexpressing BC cells after in vitro treatment with NAX014. Although NAX014 did not modulate the presence of tumor-infiltrating lymphocytes, the level of circulating TNF-α and VEGF was found to be reduced in NAX014-treated mice. The overall results address the NAX014 compound as potential tool for therapeutic strategies against HER-2 overexpressing breast cancer.

Immunosuppressive effect of PLGA-FK506-NPs in treatment of acute cardiac rejection via topical subcutaneous injection

FK506, a first-line immunosuppressant, is routinely administered orally and intravenously to inhibit activation and proliferation of T cells after heart transplantation (HT). Current administration route is not conducive enough to exert its efficacy in lymphatic system. Herein, we proposed that subcutaneous (SC) administration of FK506-loaded nanoparticles (PLGA-FK506-NPs) would be valuable for treating acute rejection after HT. The biodistribution and pharmacokinetic study revealed that it could effectively deliver FK506 to the lymph nodes (LNs) due to their suitable particle size, especially in inguinal LNs. Subsequently, the therapeutic efficacy of PLGA-FK506-NPs on the HT model was evaluated using intravenous (IV), intragastric (IG), or SC injection. Histopathological analysis revealed that 80% of allografts exhibited only grade 1R rejection with negligible lymphocyte infiltration in the SC group. The IV group exhibited 40% 1R rejection with mild lymphocyte infiltration and 20% grade 3R that require further intervention, and the IG group exhibited grades 40% 3R rejection with more lymphocyte infiltration. Moreover, the infiltration of T cells and the secretion of IL-2 and IFN-γ were significantly reduced in the SC group compared with the IG or IV group. The mean survival time (MST) further revealed that 50% of grafts treated with PLGA-FK506-NPs via SC injection survived longer than IG and IV groups. Moreover, the MST of single-dose SC injection of PLGA-FK506-NPs demonstrated that it would effectively reduce the required dose for a similar therapeutic effect. Overall, these results indicate that SC administration of PLGA-FK506-NPs is a more effective route for chronic FK506 treatment.

Effects of ethyl hexanoate on activities of sympathetic nerves innervating the brown and white adipose tissues, body temperature, and plasma fatty acids

The autonomic nervous system (ANS) is implicated in maintaining homeostasis of the internal environment in mammals. Therefore, changes occurring in the ANS can cause alterations of physiological phenomena. Ethyl hexanoate (EH) is known as the aroma component of apples. To study the action of ethyl hexanoate on physiological phenomena, we examined the effect of an intragastric (IG) injection of 1 mL/kg body weight of 0.1 ppm EH solution on sympathetic nerve activity innervating the brown adipose tissue (BAT) and white adipose tissue (WAT) in anesthetized rats. Consequently, IG administration of EH increased activity of the sympathetic nerves innervating both the BAT and WAT. In addition, the effects of the IG injection on body temperature above the interscapular BAT and plasma free fatty acid (FFA) concentration were also examined in conscious rats. In this attempt IG injection of EH elevated both the body temperature and plasma FFA levels. Furthermore, subdiaphragmatic vagotomy eliminated the effects of EH on sympathetic nerves innervating BAT and WAT. These findings suggest that EH causes excitations of sympathetic nerves innervating BAT and WAT, and enhances thermogenesis and lipolysis via the afferent vagus nerve. Thus, these present findings also suggest the possibility that EH might have anti-obesity effects.

Nutrient-conditioned intake stimulation does not require a distinctive flavor cue in rats

The postoral actions of nutrients in rodents can stimulate intake and condition flavor preferences through an appetition process. Appetition is revealed in rodents by their increased intake of and preference for a flavored solution paired with intragastric (IG) nutrient infusions. Here we determined if IG 16% maltodextrin (MD) infusions can stimulate intake and preference in the absence of a distinctive flavor cue. Rats implanted with IG catheters were given chow and water 2 h/day followed, 2 h later, by 20-h oral access to water paired with IG MD infusions. Other rats were given bitter sucrose octaacetate solution (SOA) paired with IG MD infusions 20 h/day. Over 8 test days, the SOA rats increased their total 20-h fluid intake (oral + IG) from 26 to 119 g/20 h and Water rats increased their intake from 31 to 96 g/20 h. When infused IG with water instead of MD in a 4-day extinction test, the SOA and Water groups reduced their fluid intakes to 45–48 g/20 h. When oral fluids were again paired with IG MD infusions, the SOA and Water groups increased their intakes to 115 and 109 g/20 h, respectively. In two-bottle tests, the SOA rats drank more SOA paired with IG MD than water paired with IG water. Water rats given the choice of a water bottle paired with IG MD and water bottle paired with IG water did not consistently prefer the H2O/ID MD bottle. Instead they displayed side or sipper tube preferences although neither cue was consistently paired with IG MD during one-bottle training.

The Role of Post-Ingestive Feedback in the Development of an Enhanced Appetite for the Orosensory Properties of Glucose over Fructose in Rats.

The simple sugars glucose and fructose share a common “sweet” taste quality mediated by the T1R2+T1R3 taste receptor. However, when given the opportunity to consume each sugar, rats learn to affectively discriminate between glucose and fructose on the basis of cephalic chemosensory cues. It has been proposed that glucose has a unique sensory property that becomes more hedonically positive through learning about the relatively more rewarding post-ingestive effects that are associated with glucose as compared to fructose. We tested this theory using intragastric (IG) infusions to manipulate the post-ingestive consequences of glucose and fructose consumption. Food-deprived rats with IG catheters repeatedly consumed multiple concentrations of glucose and fructose in separate sessions. For rats in the “Matched” group, each sugar was accompanied by IG infusion of the same sugar. For the “Mismatched” group, glucose consumption was accompanied by IG fructose, and vice versa. This condition gave rats orosensory experience with each sugar but precluded the differential post-ingestive consequences. Following training, avidity for each sugar was assessed in brief access and licking microstructure tests. The Matched group displayed more positive evaluation of glucose relative to fructose than the Mismatched group. A second experiment used a different concentration range and compared responses of the Matched and Mismatched groups to a control group kept naïve to the orosensory properties of sugar. Consistent with results from the first experiment, the Matched group, but not the Mismatched or Control group, displayed elevated licking responses to glucose. These experiments yield additional evidence that glucose and fructose have discriminable sensory properties and directly demonstrate that their different post-ingestive effects are responsible for the experience-dependent changes in the motivation for glucose versus fructose.

Intranasal delivery of berberine via in situ thermoresponsive hydrogels with non-invasive therapy exhibits better antidepressant-like effects.

The efficacy of antidepressant therapy is frequently limited by challenges related to the potential to reach the brain. The development of new strategies to deliver more antidepressants to the brain so as to bypass the blood-brain barrier (BBB) is beneficial for the treatment of nervous system diseases, especially depression. Here, we have reported an unconventional strategy by the intranasal delivery of berberine with an in situ thermoresponsive hydrogel as the holder in the nasal cavity to improve its antidepressant-like activity. A berberine/hydroxylpropyl-β-cyclodextrin (HP-β-CD) inclusion complex was first prepared to improve the solubility of berberine and loaded into a thermoresponsive hydrogel system of poloxamers. A radioactive tracer of 125I-labeled berberine was used to investigate brain targeting. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to study the pharmacokinetic change in the hippocampus. Monoamine neurotransmitters were analyzed in a reserpine-induced depression model, and metabolomic analysis of the hippocampus was performed in a chronic unpredictable mild stress (CUMS)-induced depression model. The radioactive tracer analysis manifested that the thermoresponsive hydrogel administered intranasally could maintain a high concentration gradient of berberine to the brain, and the relative bioavailability of berberine was enhanced approximately by 110 times that of the oral berberine/HP-β-CD inclusion complex in the hippocampus. The thermoresponsive hydrogel system resulted in similar or better antidepressant-like efficacy even with a lower dosage in reserpine and CUMS-induced depression in rats. The pharmacometabolomics analysis revealed that in addition to increasing the hippocampal monoamine levels, berberine via intranasal administration exhibited a unique mechanism by restoring the mitochondrial dysfunction as well as phospholipid and sphingolipid abnormalities as compared to intragastric (IG) administration. We consider this a safer and more effective strategy with a lower dosage than traditional oral drugs for the treatment of depression.

Capsaicin-induced visceral deafferentation does not attenuate flavor conditioning by intragastric fat infusions in mice

The postoral actions of sugar and fat can rapidly stimulate the intake of and preference for flavors associated with these nutrients via a process known as appetition. Prior findings revealed that postoral glucose appetition is not attenuated following capsaicin-induced visceral deafferentation. The present experiment determined if capsaicin treatment altered fat appetition in C57BL/6 mice. Following capsaicin (Cap) or control (Con) treatment, mice were fitted with chronic intragastric (IG) catheters. They were then given 1-h sessions with a flavored saccharin solution (CS-) paired with IG water infusion or a different flavor (CS+) paired with IG 6.4% fat infusion. IG fat stimulated CS+ intakes in both Cap and Con mice, and the groups displayed similar preferences for CS+ over CS- in two-choice tests. These results confirm prior reports of normal fat conditioning in rats exposed to capsaicin or vagal deafferentation surgery. In contrast, other recent findings indicate that total or selective vagotomy alters the preference of mice for dilute vs. concentrated fat sources.

Efficacy and synergistic evaluation of compound allantoin in the treatment of mice infected with Helicobacter pylori

Objective: To investigate the therapeutic effect of compound allantoin in Kunming mice infected with Helicobacter pylori (H. pylori). Methods: Eighty four male Kunming mice were randomly divided into normal control group, H. pylori infection control group, compound allantoin group, allantoin group, aluminum hydroxide group, triple therapy group, and compound allantoin combined with triple therapy group(drug combination group). The normal control group was administered with normal saline, and other groups were infected with H. pylori for 5 times by intragastric(IG) administration. After 4 weeks, mice were given corresponding drug solutions for 6 times by IG administration. H. pylori infection status was detected by rapid urease test(RUT) and immunohistochemistry assay(IHC). Mucosa damages were assessed by microscopic examination and electron microscopy. Results: The positive rates of the compound allantoin group detected by RUT and IHC were 9.1% and 0, respectively, which were significantly lower than those in the H. pylori infection control group (81.8% and 72.7%).The positive rates of aluminum hydroxide group(54.5% and 54.5%) have no significant difference with those in the allantoin group (27.3% and 18.2%), but were higher than those of compound allantoin group (P<0.05).The positive rate of both methods in the drug combination group were 0, and they were significantly lower than those in the triple therapy group (36.4%,45.5%) (P<0.05). There was no difference between the triple group and the compound allantoin group(P>0.05). The pathological and ultrastructural damage of compound allantoin group was obviously relieved than that of H. pylori infection group. Conclusion: Compound allantoin has therapeutic effect on H. pylori infection in mice, which can be further enhanced by combination with triple therapy group. In addition, compound allantoin can repair gastric mucosal injury caused by H. pylori, and its repair effect may be related to mitochondrial pathway.

Intragastric nutrient infusion reduces motivation for food in male and female rats.

The idea that gut-derived satiation signals influence food reward has recently gained traction, but this hypothesis is largely based on studies focused on neural circuitry, not the peripherally released signals. Here, we directly tested the hypothesis that intragastric (IG) nutrient infusion can suppress motivation for food. In a series of experiments, IG sucrose infusion (15 kcal) significantly and reliably reduced operant responding for a sucrose reward on a progressive ratio (PR) schedule. Moreover, food deprivation for 24 h before the test session did not prevent the suppressive effect of nutrients. The suppressive effect of IG sucrose on fixed ratio 5 (FR5) operant responding was also assessed as a comparison. The effect of IG nutrients to reduce motivation was not limited to sucrose; IG Ensure infusion (9.3 kcal) also significantly reduced PR operant responding for sucrose pellets. To verify that these effects were not secondary to the osmotic challenge of concentrated nutrients, we tested IG infusion of noncaloric saline solutions equiosmolar to 40% sucrose or Ensure and found no effect. Finally, we focused on glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) as candidate mediators for the effect of IG nutrients. Pretreatment with exendin-9, a GLP-1 receptor antagonist, delivered intraperitoneally, significantly attenuated the ability of IG nutrients to suppress PR responding and breakpoint in males, but not in females, whereas pretreatment with devazepide, a CCKA receptor antagonist, failed to do so in both sexes. Together, these data support the idea that nutrient-induced satiation signals influence food reward and may implicate GLP-1 in this process.

Preventive Potential of Resveratrol in Carcinogen-Induced Rat Thyroid Tumorigenesis.

Thyroid cancer (TC) is the most common endocrine malignancy without reliable preventive agent. Resveratrol possesses in vitro anti-TC activities; while its effect(s) on thyroid tumorigenesis remains unknown. This study aims to address this issue using DEN/MNU/DHPN-induced rat carcinogenesis model. 50 male Sprague-Dawley rats were separated into four groups as Group-1 (5 rats); normally fed; Group-2 (15 rats); DEN/MNU/DHPN treatment only; Group-3 (15 rats) and -4 (15 rats); DEN/MNU/DHPN treatment; followed by resveratrol intragastric (IG) injection and intraperitoneal (IP) injection; respectively; in two-day intervals for 30 weeks. The results revealed that the average resveratrol concentration in thyroid tissues was 1.278 ± 0.419 nmol/g in IG group and 1.752 ± 0.398 nmol/g in IP group. The final body weights of Group-3 and Group-4 were lighter than that (p > 0.05) of Group-1; but heavier than Group-2 (p < 0.05). TC-related lesions (hyperplasia and adenomas) were found in 53.3% of Group-2; 33.3% Group-3 and 26.7% Group-4. Lower serum carcino-embryonic antigen (CEA) and thyroglobulin (Tg) levels; down-regulated expression of IL-6 and cyclooxygenase-2 (COX-2); reduction of NF-κB/p65 nuclear translocation; and elevated IkBα expression were found in the thyroid tissues of Group-3 and Group-4 in comparison with that of Group-2. These results demonstrate that IG and IP administered resveratrol efficiently reduces the frequency and severity of DEN/MNU/DHPN-caused TC-related lesions and would be of values in thyroid tumor prevention.