ABSTRACT
Biopsychosocial factors are associated with disorders of gut-brain interaction (DGBI) and exacerbate gastrointestinal symptoms. The mechanisms underlying pathophysiological alterations of stress remain unclear. Corticotropin-releasing hormone (CRH) is a central regulator of the hormonal stress response and has diverse impact on different organ systems. The aim of the present study was to investigate the effects of peripheral CRH infusion on meal-related gastrointestinal symptoms, gastric electrical activity, and gastric sensorimotor function in healthy volunteers (HVs). In a randomized, double-blinded, placebo-controlled, crossover study, we evaluated the effects of CRH on gastric motility and sensitivity. HVs were randomized to receive either peripheral-administered CRH (100 µg bolus + 1 µg/kg/h) or placebo (saline), followed by at least a 7-day washout period and assignment to the opposite treatment. Tests encompassed saliva samples, gastric-emptying (GE) testing, body surface gastric mapping (BSGM, Gastric Alimetry; Alimetry) to assess gastric myoelectrical activity with real-time symptom profiling, and a gastric barostat study to assess gastric sensitivity to distention and accommodation. Twenty HVs [13 women, mean age 29.2 ± 5.3 yr, body mass index (BMI) 23.3 ± 3.8 kg/m2] completed GE tests, of which 18 also underwent BSGM measurements during the GE tests. The GE half-time decreased significantly after CRH exposure (65.2 ± 17.4 vs. 78.8 ± 24.5 min, P = 0.02) with significantly increased gastric amplitude [49.7 (34.7-55.6) vs. 31.7 (25.7-51.0) µV, P < 0.01], saliva cortisol levels, and postprandial symptom severity. Eleven HVs also underwent gastric barostat studies on a separate day. However, the thresholds for discomfort during isobaric distensions, gastric compliance, and accommodation did not differ between CRH and placebo.NEW & NOTEWORTHY In healthy volunteers, peripheral corticotropin-releasing hormone (CRH) infusion accelerates gastric-emptying rate and increases postprandial gastric response, accompanied by a rise in symptoms, but does not alter gastric sensitivity or meal-induced accommodation. These findings underscore a significant link between stress and dyspeptic symptoms, with CRH playing a pivotal role in mediating these effects.
Subject(s)
Corticotropin-Releasing Hormone , Cross-Over Studies , Gastric Emptying , Healthy Volunteers , Stomach , Humans , Female , Male , Corticotropin-Releasing Hormone/metabolism , Corticotropin-Releasing Hormone/administration & dosage , Corticotropin-Releasing Hormone/pharmacology , Adult , Double-Blind Method , Stomach/drug effects , Stomach/physiology , Gastric Emptying/drug effects , Young Adult , Saliva/metabolismABSTRACT
Variability of the gastrointestinal tract is rarely reflected in in vitro test protocols but often turns out to be crucial for the oral dosage form performance. In this study, we present a generation method of dissolution profiles accounting for the variability of fasted gastric conditions. The workflow featured 20 biopredictive tests within the physiological variability. The experimental array was constructed with the use of the design of experiments, based on three parameters: gastric pH and timings of the intragastric stress event and gastric emptying. Then, the resulting dissolution profiles served as a training data set for the dissolution process modeling with the machine learning algorithms. This allowed us to generate individual dissolution profiles under a customizable gastric pH and motility patterns. For the first time ever, we used the method to successfully elucidate dissolution properties of two dosage forms: pellet-filled capsules and bare pellets of the marketed dabigatran etexilate product Pradaxa. We showed that the dissolution of capsules was triggered by mechanical stresses and thus was characterized by higher variability and a longer dissolution onset than observed for pellets. Hence, we proved the applicability of the method for the in vitro and in silico characterization of immediate-release dosage forms and, potentially, for the improvement of in vitro-in vivo extrapolation.
Subject(s)
Capsules , Dabigatran , Fasting , Gastric Emptying , Dabigatran/chemistry , Dabigatran/administration & dosage , Dabigatran/pharmacology , Capsules/chemistry , Gastric Emptying/physiology , Gastric Emptying/drug effects , Humans , Hydrogen-Ion Concentration , Solubility , Drug Liberation , Administration, Oral , Computer Simulation , Stomach/physiology , Stomach/drug effectsABSTRACT
Recycled cooking oil (RCO) is widely used in many small restaurants. However, the health risk posed by long-term consumption of RCO is unclear. In this study, C57 mice were treated with RCO for 34 weeks. Organ coefficients of the liver, stomach, and kidney were found to be decreased. H&E staining revealed overt lesions in the pancreas, liver, kidney, esophagus, duodenum, and ileum of RCO-treated mice. Immunohistochemistry showed significant DNA damage in the duodenum and ileum and apoptosis in the lungs of the RCO-treated mice. Immunoblotting showed elevated levels of γ-H2AX, Bcl-2/Bax, TNFα, cleaved Caspase-3 and poly ADP-ribose polymerase (PARP). Increased levels of lactate dehydrogenase (LDH) and decreased levels of succinate dehydrogenase (SDH) were also detected. These findings suggest that long-term consumption of RCO produces various toxicities in mice with important implications for humans. DNA damage followed by mitochondria-associated apoptosis, and necrosis is likely to contribute to the toxicities.
Subject(s)
Cell Death , Cooking/standards , Plant Oils/toxicity , Animals , Caspase 3/genetics , Caspase 3/metabolism , Cells, Cultured , DNA Damage , Female , Histones/genetics , Histones/metabolism , Intestines/drug effects , Kidney/drug effects , L-Lactate Dehydrogenase/genetics , L-Lactate Dehydrogenase/metabolism , Liver/drug effects , Lung/drug effects , Male , Mice , Mice, Inbred C57BL , Plant Oils/administration & dosage , Plant Oils/standards , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Stomach/drug effects , Succinate Dehydrogenase/genetics , Succinate Dehydrogenase/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Neuronal aggregates of misfolded alpha-synuclein protein are found in the brain and periphery of patients with Parkinson's disease. Braak and colleagues have hypothesized that the initial formation of misfolded alpha-synuclein may start in the gut, and then spread to the brain via peripheral autonomic nerves hereby affecting several organs, including the heart and intestine. Age is considered the greatest risk factor for Parkinson's disease, but the effect of age on the formation of pathology and its propagation has not been studied in detail. We aimed to investigate whether propagation of alpha-synuclein pathology from the gut to the brain is more efficient in old versus young wild-type rats, upon gastrointestinal injection of aggregated alpha-synuclein. Our results demonstrate a robust age-dependent gut-to-brain and brain-to-gut spread of alpha-synuclein pathology along the sympathetic and parasympathetic nerves, resulting in age-dependent dysfunction of the heart and stomach, as observed in patients with Parkinson's disease. Moreover, alpha-synuclein pathology is more densely packed and resistant to enzymatic digestion in old rats, indicating an age-dependent maturation of alpha-synuclein aggregates. Our study is the first to provide a detailed investigation of alpha-synuclein pathology in several organs within one animal model, including the brain, skin, heart, intestine, spinal cord and autonomic ganglia. Taken together, our findings suggest that age is a crucial factor for alpha-synuclein aggregation and complete propagation to heart, stomach and skin, similar to patients. Given that age is the greatest risk factor for human Parkinson's disease, it seems likely that older experimental animals will yield the most relevant and reliable findings. These results have important implications for future research to optimize diagnostics and therapeutics in Parkinson's disease and other age-associated synucleinopathies. Increased emphasis should be placed on using aged animals in preclinical studies and to elucidate the nature of age-dependent interactions.
Subject(s)
Aging/pathology , Primary Dysautonomias/etiology , alpha-Synuclein/toxicity , Aging/metabolism , Animals , Autonomic Nervous System/drug effects , Autonomic Nervous System/metabolism , Autonomic Nervous System/pathology , Brain/pathology , Duodenum/drug effects , Duodenum/pathology , Kidney/pathology , Muscle, Skeletal/pathology , Myocardium/pathology , Parkinson Disease/metabolism , Parkinson Disease/pathology , Primary Dysautonomias/metabolism , Primary Dysautonomias/pathology , Protein Aggregation, Pathological/pathology , Rats, Inbred F344 , Skin/pathology , Spinal Cord/pathology , Stomach/drug effects , Stomach/pathologyABSTRACT
Dried ginger is a commonly used stomachic. Dried ginger is often used as a gastric protector to treat stomach-related diseases. However, the effect of dried ginger on energy metabolism in stomach tissue of rats under physiological condition has not been studied. In this study, different doses of water extract of dried ginger were given to rats for 4â weeks. The activity of Na+ -K+ -ATPase, Ca2+ -Mg2+ -ATPase, SDH (succinate dehydrogenase) enzyme, ATP content, mitochondrial metabolic rate and mitochondrial number in stomach tissue of rats were measured. Analysis of potential biomarkers related to the effect of dried ginger on energy metabolism in stomach tissue of rats by metabonomics, and their metabolic pathways were also analyzed. The results revealed that there was no significant difference in Na+ -K+ -ATPase in high-dose group (GJH), medium-dose group (GJM) and low-dose group (GJL) compared to the Control group. The Ca2+ -Mg2+ -ATPase activity was significantly increased in stomach tissue of GJH group and GJM group, but there were no significant changes in stomach tissue of GJL group. The SDH activity and the ATP levels were significantly increased in stomach tissue of GJH group, GJM group and GJL group. The mitochondrial metabolic rate was significantly increased in GJL group, but there was no significant change in GJM group and was inhibited in GJH group. These effects might be mediated by arginine biosynthesis, glutathione metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, arginine and proline metabolism, purine metabolism pathway.
Subject(s)
Energy Metabolism , Zingiber officinale , Animals , Rats , Adenosine Triphosphatases/metabolism , Adenosine Triphosphate/metabolism , Arginine/metabolism , Energy Metabolism/drug effects , Zingiber officinale/chemistry , Stomach/drug effects , Stomach/metabolism , MetabolomicsABSTRACT
Bitter tastants are recently introduced as potential hunger-suppressive compounds, the so-called "Bitter pill." However, the literature about bitter administration lacks consistency in methods and findings. We want to test whether hunger ratings and hormone plasma levels are affected by: 1) the site of administration: intragastrically (IG) or intraduodenally (ID), 2) the bitter tastant itself, quinine hydrochloride (QHCl) or denatonium benzoate (DB), and 3) the timing of infusion. Therefore, 14 healthy, female volunteers participated in a randomized, placebo-controlled six-visit crossover study. After an overnight fast, DB (1 µmol/kg), QHCl (10 µmol/kg), or placebo were given IG or ID via a nasogastric feeding tube. Blood samples were taken 10 min before administration and every 10 min after administration for a period of 2 h. Hunger was rated at the same time points on a visual analogue scale. ID bitter administration did not affect hunger sensations, motilin, or acyl-ghrelin release compared with its placebo infusion. IG QHCl infusion tended to suppress hunger increase, especially between 50 and 70 min after infusion, simultaneously with reduced motilin values. Here, acyl-ghrelin was not affected. IG DB did not affect hunger or motilin, however acyl-ghrelin levels were reduced 50-70 minutes after infusion. Plasma values of glucagon-like peptide 1 and cholecystokinin were too low to be properly detected or to have any physiological relevance. In conclusion, bitter tastants should be infused into the stomach to reduce hunger sensations and orexigenic gut peptides. QHCl has the best potential to reduce hunger sensations, and it should be infused 60 min before food intake.NEW & NOTEWORTHY Bitter tastants are a potential new weight-loss treatment. This is a noninvasive, easy approach, which should be received with considerable enthusiasm by the public. However, literature about bitter administration lacks consistency in methods and findings. We summarize how the compound should be given based on: the site of administration, the best bitter compound to use, and at what timing in respect to the meal. This paper is therefore a fundamental step to continue research toward the further development of the "bitter pill."
Subject(s)
Duodenum/drug effects , Hunger/drug effects , Peptide Hormones/blood , Quaternary Ammonium Compounds/administration & dosage , Quinine/administration & dosage , Stomach/drug effects , Cholecystokinin , Cross-Over Studies , Female , Ghrelin/blood , Glucagon-Like Peptide 1 , Humans , Intubation, Gastrointestinal , Motilin/blood , Placebos , Single-Blind Method , Taste , Weight Loss , Young AdultABSTRACT
INTRODUCTION: Gastrointestinal bleeding is a morbid complication of dual antiplatelet therapy (DAPT). We evaluated the extent to which contemporary trials of DAPT included steps to ensure appropriate use of proton pump inhibitor (PPI) gastroprotection and reported rates of PPI use. METHODS: A methodological review of randomized trials comparing varying durations of DAPT after percutaneous coronary intervention. RESULTS: Among 21 trials, none incorporated protocol procedures or guidance for prescribing PPIs. Five reported rates of PPI use (range 25.6-69.1%). DISCUSSION: PPI gastroprotection is overlooked in major trials of DAPT. Appropriate use of PPI gastroprotection represents an important opportunity to improve patient safety.
Subject(s)
Clinical Trials as Topic , Dual Anti-Platelet Therapy/standards , Percutaneous Coronary Intervention/methods , Platelet Aggregation Inhibitors/therapeutic use , Postoperative Care/methods , Practice Guidelines as Topic , Stomach Diseases/prevention & control , Humans , Platelet Aggregation Inhibitors/adverse effects , Stomach/drug effectsABSTRACT
OBJECTIVE AND DESIGN: Montelukast, a cysteinyl leukotriene receptor antagonist, exhibits antiinflammatory action. We tested whether exposure to montelukast plus nonsteroidal antiinflammatory drugs (NSAIDs) elicits better control of paw inflammation in the rat formalin test and improves associated gastric damage. MATERIALS: A total of 46 adult male rats were used in the study. TREATMENTS: We evaluated separate and combined effects of montelukast (20 mg/kg), celecoxib (COX2 inhibitor, 10 mg/kg), and diclofenac (nonselective COX1/COX2 inhibitor, 10 mg/kg) on paw and gastric damage in the rat formalin test. RESULTS: Individual pretreatments of rats with montelukast, diclofenac, or celecoxib partly reduced formalin-induced increases in (i) paw edema, fibrosis, and inflammatory cells, (iii) serum interleukin-6 (IL-6) and leukotrienes (LTB4 and LTD4), and (iv) paw expressions of inducible nitric oxide synthase (iNOS) and COX2. These effects were accentuated in rats treated with montelukast plus diclofenac or montelukast plus celecoxib. Alternatively, montelukast or celecoxib, but not diclofenac, alleviated formalin-evoked gastric damage and increments in tumor necrosis factor-α and decrements in prostaglandin-E2. These advantageous gastric influences were potentiated in rats treated with montelukast plus celecoxib. CONCLUSIONS: While montelukast equally enhances antiinflammatory action of diclofenac or celecoxib via downregulating iNOS/COX2/LTs/IL-6 signaling, its gastroprotective action is preferentially potentiated by celecoxib.
Subject(s)
Acetates/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Cyclopropanes/administration & dosage , Formaldehyde/chemistry , Inflammation/drug therapy , Quinolines/administration & dosage , Stomach/drug effects , Sulfides/administration & dosage , Animals , Celecoxib/administration & dosage , Cyclooxygenase 2/metabolism , Diclofenac/administration & dosage , Male , Nitric Oxide Synthase Type II/metabolism , Rats , Rats, Wistar , Risk , Signal TransductionABSTRACT
Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause gastric mucosal damage, in which gastric hypermotility has been reported to play a primary role. The antipyretic analgesic drug ethenzamide (ETZ) is widely used in combination with other NSAIDs and, in a recent study, was found to possess 5-hydroxytriptamine (5HT)2B receptor antagonistic activity. Therefore, the inhibition of gastric contraction via 5HT2B receptor blockade by ETZ might contribute to ETZ's protective effect against NSAIDs-induced gastric mucosal damage. In the present study, we examined the effects of ETZ on gastric contraction and ibuprofen (IBP)-induced gastric mucosal damage in rats. We found that ETZ suppressed both 5HT- and α-methyl-5HT (5HT2 receptor agonist)-induced contractions of rat-isolated gastric fundus in a concentration-dependent manner. This suppressive effect of ETZ was not seen for either high-KCl- or acetylcholine-induced contractions. Furthermore, ETZ was confirmed to decrease ibuprofen-induced gastric mucosal damage in a dose-dependent manner in rats. Similarly, clonidine is known to reduce gastric motility, and methysergide (a 5HT2 receptor antagonist) is known to inhibit 5HT-induced contractions of the gastric fundus, which also decreases IBP-induced gastric mucosal damage, respectively. Although further research on other possible sites or mechanisms of action would be needed, these results suggest that ETZ exerts a protective effect against IBP-induced gastric mucosal damage and that suppressing the gastric contraction may play an important role in the gastroprotective effect of ETZ.
Subject(s)
Analgesics, Non-Narcotic/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal , Ibuprofen , Protective Agents/therapeutic use , Salicylamides/therapeutic use , Stomach/drug effects , Acetylcholine/pharmacology , Analgesics, Non-Narcotic/pharmacology , Animals , Male , Muscle Contraction/drug effects , Potassium Chloride/pharmacology , Protective Agents/pharmacology , Rats, Sprague-Dawley , Salicylamides/pharmacology , Serotonin/pharmacology , Serotonin 5-HT2 Receptor Agonists/pharmacology , Stomach/pathology , Stomach/physiologyABSTRACT
This study was conducted to investigate the potential toxicity of repeated oral dose of SUNACTIVE Zn-P240, a new type of zinc supplement, in Sprague-Dawley rats. SUNACTIVE Zn-P240 was administered once daily by gavage at doses of 0, 500, 1000, and 2000 mg/kg/day for each group over a 28-day period. At 2000 mg/kg/day, there were increases in serum alkaline phosphatase (ALP) and alanine aminotransferase, liver weight, histopathological changes in stomach, liver, and pancreas and decreases in body weight, food consumption, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration, total protein (TP), and albumin. At 1000 mg/kg/day, there was an increase in the serum ALP level and there were decreases in the MCV, MCH, and TP. There were no treatment-related adverse effects in the 500 mg/kg/day group. Under the present experimental conditions, the target organs in rats were determined to be the stomach, pancreas, liver, and erythrocyte and the no-observed-adverse-effect level (NOAEL) in rats was considered to be 500 mg/kg/day.
Subject(s)
Dietary Supplements/toxicity , Zinc/pharmacology , Animals , Dose-Response Relationship, Drug , Erythrocytes/drug effects , Female , Liver/drug effects , Male , Nanotechnology , No-Observed-Adverse-Effect Level , Pancreas/drug effects , Rats , Rats, Sprague-Dawley , Stomach/drug effectsABSTRACT
Ethyl acrylate (EA) was classified by IARC as a Group-2B Carcinogen based, in part, on data suggesting increased incidence of thyroid neoplasia in rats and mice exposed chronically to EA vapors. We examined chronic exposure of rats and mice to EA vapors, evaluated the data on the incidence of thyroid follicular neoplasia, and determined the relevance of thyroid tumors to human health risk. The data revealed a small statistically significant increase in thyroid tumors in EA-exposed male rats and mice. The tumor incidences were within the range of historical controls and were not consistently dose-dependent. Most thyroid tumors in exposed animals were benign. Chronic exposure of EA to rats and mice (drinking water or gavage) and dogs (capsules) had no evidence of thyroid neoplasia. Results from chronic studies, in vivo and in vitro data, and ToxCastTM/Tox 21 HTPS did not support genotoxic/mutagenic potential for EA. This suggests that the associations between EA exposure and thyroid neoplasia represent chance or random observations rather than a compound-mediated effect. Due to species-specific physiological differences, the hypothalamic-pituitary-thyroid axis of rodents is more sensitive to endocrine disruptive chemicals than that of humans which further suggests that findings in rodents have questionable relevance to human health.
Subject(s)
Acrylates/toxicity , Carcinogens/toxicity , Neoplasms, Experimental/chemically induced , Stomach Neoplasms/chemically induced , Thyroid Neoplasms/chemically induced , Animals , Dogs , Female , Humans , Male , Mice , Neoplasms, Experimental/blood , Neoplasms, Experimental/pathology , Rats , Species Specificity , Stomach/drug effects , Stomach/pathology , Stomach Neoplasms/pathology , Thyroid Gland/drug effects , Thyroid Gland/metabolism , Thyroid Gland/pathology , Thyroid Hormones/blood , Thyroid Hormones/metabolism , Thyroid Neoplasms/blood , Thyroid Neoplasms/pathology , Toxicity Tests, Chronic/statistics & numerical dataABSTRACT
Huangqi Jianzhong Tang (HQJZ) is a representative prescription used for clinical treatment of chronic atrophic gastritis (CAG) in Chinese medicine. Our previous study had revealed that energy regulation was one of the important mechanisms of HQJZ action against CAG. In this study, ultra-high-performance liquid chromatography coupled with quadrupole-Exactive mass spectrometry (UHPLC-Q-Exactive MS) based metabonomics was used to find the potential mitochondrial biomarkers and metabolic pathways of HQJZ in CAG rats, which focused on a specific organelle (mitochondria) isolated from gastric tissue samples. A total of 16 biomarkers from CAG tissues were identified with 11 of these significantly regulated by HQJZ treatment. These biomarkers was mainly involved in glycine, serine, and threonine metabolism; aminoacyl-tRNA biosynthesis metabolism; and taurine and hypotaurine metabolism. Our results show that HQJZ could protect from CAG by altering the mitochondrial function. These findings deepen our understanding of the mitochondrial metabolic changes that occur with CAG and shine a light on the mechanism of HQJZ.
Subject(s)
Drugs, Chinese Herbal/pharmacology , Gastritis, Atrophic/metabolism , Metabolome/drug effects , Metabolomics/methods , Mitochondria/drug effects , Animals , Chromatography, High Pressure Liquid/methods , Chronic Disease , Male , Mass Spectrometry/methods , Mitochondria/metabolism , Rats , Rats, Sprague-Dawley , Stomach/chemistry , Stomach/drug effectsABSTRACT
Among mammals, serotonin is predominantly found in the gastrointestinal tract, where it has been shown to participate in pathway-regulating satiation. For the stomach, vascular serotonin release induced by gastric distension is thought to chiefly contribute to satiation after food intake. However, little information is available on the capability of gastric cells to synthesize, release and respond to serotonin by functional changes of mechanisms regulating gastric acid secretion. We investigated whether human gastric cells are capable of serotonin synthesis and release. First, HGT-1 cells, derived from a human adenocarcinoma of the stomach, and human stomach specimens were immunostained positive for serotonin. In HGT-1 cells, incubation with the tryptophan hydroxylase inhibitor p-chlorophenylalanine reduced the mean serotonin-induced fluorescence signal intensity by 27%. Serotonin release of 147 ± 18%, compared to control HGT-1 cells (set to 100%) was demonstrated after treatment with 30 mM of the satiating amino acid L-Arg. Granisetron, a 5-HT3 receptor antagonist, reduced this L-Arg-induced serotonin release, as well as L-Arg-induced proton secretion. Similarly to the in vitro experiment, human antrum samples released serotonin upon incubation with 10 mM L-Arg. Overall, our data suggest that human parietal cells in culture, as well as from the gastric antrum, synthesize serotonin and release it after treatment with L-Arg via an HTR3-related mechanism. Moreover, we suggest not only gastric distension but also gastric acid secretion to result in peripheral serotonin release.
Subject(s)
Arginine/pharmacology , Gastric Acid/metabolism , Parietal Cells, Gastric/drug effects , Protons , Serotonin/biosynthesis , Cell Line, Tumor , Fenclonine/pharmacology , Gene Expression , Granisetron/pharmacology , Humans , Hydrogen-Ion Concentration , Parietal Cells, Gastric/cytology , Parietal Cells, Gastric/metabolism , Protease Inhibitors/pharmacology , Receptors, Serotonin, 5-HT3/genetics , Receptors, Serotonin, 5-HT3/metabolism , Serotonin Antagonists/pharmacology , Stomach/cytology , Stomach/drug effects , Tissue Culture Techniques , Tryptophan Hydroxylase/antagonists & inhibitors , Tryptophan Hydroxylase/genetics , Tryptophan Hydroxylase/metabolismABSTRACT
Resistance to anticancer therapeutics occurs in virtually every type of cancer and becomes a major difficulty in cancer treatment. Although 5-fluorouracil (5FU) is the first-line choice of anticancer therapy for gastric cancer, its effectiveness is limited owing to drug resistance. Recently, altered cancer metabolism, including the Warburg effect, a preference for glycolysis rather than oxidative phosphorylation for energy production, has been accepted as a pivotal mechanism regulating resistance to chemotherapy. Thus, we investigated the detailed mechanism and possible usefulness of antiglycolytic agents in ameliorating 5FU resistance using established gastric cancer cell lines, SNU620 and SNU620/5FU. SNU620/5FU, a gastric cancer cell harboring resistance to 5FU, showed much higher lactate production and expression of glycolysis-related enzymes, such as lactate dehydrogenase A (LDHA), than those of the parent SNU620 cells. To limit glycolysis, we examined catechin and its derivatives, which are known anti-inflammatory and anticancer natural products because epigallocatechin gallate has been previously reported as a suppressor of LDHA expression. Catechin, the simplest compound among them, had the highest inhibitory effect on lactate production and LDHA activity. In addition, the combination of 5FU and catechin showed additional cytotoxicity and induced reactive oxygen species (ROS)-mediated apoptosis in SNU620/5FU cells. Thus, based on these results, we suggest catechin as a candidate for the development of a novel adjuvant drug that reduces chemoresistance to 5FU by restricting LDHA.
Subject(s)
Catechin/pharmacology , Drug Resistance, Neoplasm/drug effects , Fluorouracil/pharmacology , Lactate Dehydrogenase 5/metabolism , Stomach Neoplasms/drug therapy , Apoptosis/drug effects , Catechin/analogs & derivatives , Cell Line, Tumor , Glycolysis/drug effects , Humans , Reactive Oxygen Species/metabolism , Stomach/drug effects , Stomach Neoplasms/metabolismABSTRACT
Polyphenols are classified as an organic chemical with phenolic units that display an array of biological functions. However, polyphenols have very low bioavailability and stability, which make polyphenols a less bioactive compound. Many researchers have indicated that several factors might affect the efficiency and the metabolism (biotransformation) of various polyphenols, which include the gut microbiota, structure, and physical properties as well as its interactions with other dietary nutrients (macromolecules). Hence, this mini-review covers the two-way interaction between polyphenols and gut microbiota (interplay) and how polyphenols are metabolized (biotransformation) to produce various polyphenolic metabolites. Moreover, the protective effects of numerous polyphenols and their metabolites against various gastrointestinal disorders/diseases including gastritis, gastric cancer, colorectal cancer, inflammatory bowel disease (IBD) like ulcerative colitis (UC), Crohn's disease (CD), and irritable bowel syndrome (IBS) like celiac disease (CED) are discussed. For this review, the authors chose only a few popular polyphenols (green tea polyphenol, curcumin, resveratrol, quercetin), and a discussion of their proposed mechanism underpinning the gastroprotection was elaborated with a special focus on clinical evidence. Overall, this contribution would help the general population and science community to identify a potent polyphenol with strong antioxidant, anti-inflammatory, anti-cancer, prebiotic, and immunomodulatory properties to combat various gut-related diseases or disorders (complementary therapy) along with modified lifestyle pattern and standard gastroprotective drugs. However, the data from clinical trials are much limited and hence many large-scale clinical trials should be performed (with different form/metabolites and dose) to confirm the gastroprotective activity of the above-mentioned polyphenols and their metabolites before recommendation.
Subject(s)
Gastrointestinal Diseases/drug therapy , Polyphenols/therapeutic use , Protective Agents/therapeutic use , Stomach/pathology , Animals , Gastrointestinal Diseases/microbiology , Gastrointestinal Diseases/physiopathology , Gastrointestinal Microbiome/drug effects , Humans , Metabolome/drug effects , Polyphenols/chemistry , Polyphenols/pharmacology , Stomach/drug effectsABSTRACT
Gastrointestinal side effects of donepezil, including dyspepsia, nausea, vomiting or diarrhea, occur in 20-30% of patients. The pathogenesis of these dysmotility associated disorders has not been fully clarified yet. Pharmacokinetic parameters of donepezil and its active metabolite 6-O-desmethyldonepezil were investigated in experimental pigs with and without small intestinal injury induced by dextran sodium sulfate (DSS). Morphological features of this injury were evaluated by a video capsule endoscopy. The effect of a single and repeated doses of donepezil on gastric myoelectric activity was assessed. Both DSS-induced small intestinal injury and prolonged small intestinal transit time caused higher plasma concentrations of donepezil in experimental pigs. This has an important implication for clinical practice in humans, with a need to reduce doses of the drug if an underlying gastrointestinal disease is present. Donepezil had an undesirable impact on porcine myoelectric activity. This effect was further aggravated by DSS-induced small intestinal injury. These findings can explain donepezil-associated dyspepsia in humans.
Subject(s)
Donepezil/pharmacokinetics , Gastrointestinal Tract/pathology , Gastrointestinal Tract/physiopathology , Indans/metabolism , Metabolome , Myoelectric Complex, Migrating , Piperidines/metabolism , Stomach/physiopathology , Animals , Capsule Endoscopy , Dextran Sulfate , Donepezil/chemistry , Donepezil/pharmacology , Female , Gastrointestinal Tract/drug effects , Metabolome/drug effects , Myoelectric Complex, Migrating/drug effects , Stomach/drug effects , SwineABSTRACT
This study aims to explore the mechanism of NSAID-related gastric ulcer treated by JIA WEI WU QI SAN. Clean-grade SD rats were randomly divided into four groups. Group A was assigned as the control group. Groups B, C and D were intragastrically administered with 2.5mg/kg of indomethacin solution QD after 48 hours. After 15 days of treatment, group B was administered with 0.9% sodium chloride, group C was given rabeprazole (2mg/kg), and group D was administered with JIA WEI WU QI SAN (2g/kg). Abdominal aorta sampling was performed, and gastric tissues were isolated on the 29th day. The protein expression of p-P38MAPK and COX-2 were detected by western blot, while the concentration of PGE2 and IL-1 were determined by ELISA. (1) The expression of IL-1ingroup B dramatically declined in group D (P<0.01). (2)The expression of PGE-2dramatically increased in group D(P<0.01). (3) The expression of COX-2 increased in group D (P<0.05). (4) The expression of p-P38MAPK decreased in group D (P<0.05). JIA WEI WU QI SAN has multiple functions, including the activation of the p-P38MAPK signaling pathway, which promote the activation of COX-2, induce the arachidonic acid to increase the level of PG, and decrease the concentration of IL-1, thereby inducing an inflammatory reaction, and promote gastric mucosa repair.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Dinoprostone/metabolism , Drugs, Chinese Herbal/pharmacology , Interleukin-1/metabolism , Stomach Ulcer/metabolism , Stomach/drug effects , p38 Mitogen-Activated Protein Kinases/drug effects , Animals , Arachidonic Acid/metabolism , Cyclooxygenase 2/drug effects , Cyclooxygenase 2/metabolism , Indomethacin/adverse effects , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Stomach/metabolism , Stomach Ulcer/chemically induced , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Spasmolytic polypeptide/trefoil factor 2 (TFF2)-expressing metaplasia (SPEM) is a mucous-secreting reparative lineage that emerges at the ulcer margin in response to gastric injury. Under conditions of chronic inflammation with parietal cell loss, SPEM has been found to emerge and evolve into neoplasia. Cluster-of-differentiation gene 44 (CD44) is known to coordinate normal and metaplastic epithelial cell proliferation. In particular, CD44 variant isoform 9 (CD44v9) associates with the cystine-glutamate transporter xCT, stabilizes the protein, and provides defense against reactive oxygen species (ROS). xCT stabilization by CD44v9 leads to defense against ROS by cystine uptake, glutathione (GSH) synthesis, and maintenance of the redox balance within the intracellular environment. Furthermore, p38 signaling is a known downstream ROS target, leading to diminished cell proliferation and migration, two vital processes of gastric epithelial repair. CD44v9 emerges during repair of the gastric epithelium after injury, where it is coexpressed with other markers of SPEM. The regulatory mechanisms for the emergence of CD44v9 and the role of CD44v9 during the process of gastric epithelial regeneration are largely unknown. Inflammation and M2 macrophage infiltration have recently been demonstrated to play key roles in the induction of SPEM after injury. The following review proposes new insights into the functional role of metaplasia in the process of gastric regeneration in response to ulceration. Our insights are extrapolated from documented studies reporting oxyntic atrophy and SPEM development and our current unpublished findings using the acetic acid-induced gastric injury model.
Subject(s)
Gastric Mucosa/pathology , Metaplasia/pathology , Regeneration/physiology , Stomach/pathology , Stomach/physiology , Acetic Acid/adverse effects , Animals , Gastric Mucosa/drug effects , Gastric Mucosa/physiology , Humans , Stomach/drug effectsABSTRACT
The acetylcholinesterase inhibitor, acotiamide, improves gastric motility and is clinically used to treat functional dyspepsia. The present study aimed to identify the transporters involved in the distribution of acotiamide in stomach tissue. Acotiamide uptake by the gastric cancer-derived model cell line, Hs746 T, was Na+- and pH-independent. The initial uptake velocity of acotiamide was saturable with increasing concentrations of acotiamide and was inhibited by selective serotonin reuptake inhibitors, which are potent inhibitors of the plasma membrane monoamine transporter (PMAT). The uptake of acotiamide by PMAT gene-transfected HEK293 cells was saturable, with similar Km (197.9 µM) values to those of uptake by Hs 746T cells (106 µM). Moreover, immunoreactivity of PMAT was found in the gastric smooth muscle and vascular endothelial cells. These results suggest that PMAT contributes to the distribution of acotiamide in the stomach, where it exerts its pharmacological effects.
Subject(s)
Benzamides/metabolism , Biological Transport/drug effects , Equilibrative Nucleoside Transport Proteins/metabolism , Gastric Mucosa/metabolism , Stomach/drug effects , Thiazoles/metabolism , Acetylcholinesterase/metabolism , Cell Line , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/pharmacology , Dyspepsia/drug therapy , Dyspepsia/metabolism , Endothelial Cells/metabolism , HEK293 Cells , Humans , Muscle, Smooth/metabolism , Selective Serotonin Reuptake Inhibitors/metabolismABSTRACT
Protein inactivation either during the production process or along the gastrointestinal tract is the major problem associated with the development of oral delivery systems for biological drugs. This work presents an evaluation of the structural integrity and the biological activity of a model protein, catalase, after its encapsulation in glyceryl trimyristate-based solid lipid microparticles (SLMs) obtained by the spray congealing technology. Circular dichroism and fluorescence spectroscopies were used to assess the integrity of catalase released from SLMs. The results confirmed that no conformational change occurred during the production process and both the secondary and tertiary structures were retained. Catalase is highly sensitive to temperature and undergoes denaturation above 60 °C; nevertheless, spray congealing allowed the retention of most biological activity due to the loading of the drug at the solid state, markedly reducing the risk of denaturation. Catalase activity after exposure to simulated gastric conditions (considering both acidic pH and the presence of gastric digestive hydrolases) ranged from 35 to 95% depending on the carrier: increasing of both the fatty acid chain length and the degree of substitution of the glyceride enhanced residual enzyme activity. SLMs allowed the protein release in a simulated intestinal environment and were not cytotoxic against HT29 cells. In conclusion, the encapsulation of proteins into SLMs by spray congealing might be a promising strategy for the formulation of nontoxic and inexpensive oral biotherapeutic products.