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We report a case of autoimmune gastritis (AIG) in which gastric mucosal atrophy improved with Helicobacter pylori eradication. Based on endoscopic findings (advanced gastric atrophy with vascular visibility and diffuse redness in remnant oxyntic mucosa), a woman in her 40s was suspected of having AIG coexisting with an active H. pylori infection. This was confirmed by a positive anti-parietal cell antibody (PCA, 1:160), an elevated serum gastrin level (638 pg/mL), and positive anti-H. pylori antibody (Hp Ab, 15.5 U/mL) and H. pylori stool antigen tests. Seven months after eradication, reduced vascular visibility and disappearance of diffuse redness on endoscopy and reduced PCA (1:40) and Hp Ab (5.1 U/mL) titers were observed, although histopathological findings (basal-predominant lymphocytic infiltration, destruction of parietal and chief cells, pseudopyloric metaplasia, and enterochromaffin-like cell hyperplasia) were consistent with AIG. Endoscopy 26 months after eradication showed further improvement in atrophic findings in the gastric corpus and histopathological recovery of parietal and chief cells in fundic glands. Serum gastrin levels returned to normal (64 pg/mL), and the PCA titer fell further (1:20). [ABSTRACT FROM AUTHOR]

The knowledge of normal microscopical peculiarities of the digestive system in mammals is essential, but information regarding certain structures is still scarce in numerous species. Our study aims to highlight the normal morphological features of the cardia region in domestic rabbits, as regards the overall appearance, structure, and dimensions of the gastric pits, including a description of the cells located in gastric glands. The cardia region of five domestic rabbits underwent tissue sampling, followed by fixation in 10% buffered formalin, paraffin embedding, and later sectioned at 5 µm in thickness. Eventually, the samples were stained by Goldner's trichrome method. The microscopical examination has revealed the presence of gastric pits and glands in the entire cardia region of the rabbit, with a different morphological appearance from one zone to another. Gastric pits have the smallest depth immediately after the oesophagogastric junction, which gradually increases and decreases afterwards as it approaches the fundic zone. The gastric glands contain basically four cell types in various proportions, including serous cells, mucous cells, parietal cells, and chief cells. Other peculiarities of the gastric mucosa in the cardia region in rabbits include a thick mucosa with a loose and prominent lamina propria, and an ill-defined muscularis mucosae that is not organized in distinct layers as in other species. The detailed microanatomical structure of the cardia region of the stomach is necessary for understanding the digestion processes in rabbits, species used as a model in diverse fields of research including the pathology of the digestive system. [ABSTRACT FROM AUTHOR]

Oral submucous fibrosis (OSF) is a progressive fibrotic oral mucosal disease associated with betel quid chewing. This study evaluated whether Taiwanese male OSF patients with vitamin B12 deficiency (the serum vitamin B12 level ≤ 450 pg/mL, B12-deficient OSF patients) had high frequencies of blood hemoglobin (Hb) and serum iron and folic acid deficiencies, and serum gastric parietal cell antibody (GPCA) positivity. The blood Hb and serum iron, vitamin B12, folic acid, and GPCA concentrations in 66 Taiwanese male B12-deficient OSF patients were measured and compared with the corresponding data in 132 age-matched healthy male control subjects. We found that 6 (9.1%), 19 (28.8%), 35 (53.0%), and 9 (13.6%) of the 66 B12-deficient OSF patients had blood Hb (<13 g/dL) and serum iron (≤70 μg/dL), and folic acid (≤6 ng/mL) deficiencies, and serum GPCA positivity, respectively. Furthermore, 66 OSF patients had significantly higher frequencies of blood Hb and serum iron and folic acid deficiencies, and serum GPCA positivity than 132 healthy control subjects (all P -values < 0.05). Of the 6 anemic B12-deficient OSF patients, one had macrocytic anemia, two normocytic anemia, and three thalassemia trait-induced anemia. Taiwanese male B12-deficient OSF patients have high frequencies of blood Hb, serum iron and folic acid deficiencies, and serum GPCA positivity. The anemia and hematinic deficiencies in B12-deficient OSF patients are likely due to OSF symptoms and signs-caused insufficient intake, poor chewing, and malabsorption of hematinic elements from ingested food stuffs rather than the GPCA positivity. [ABSTRACT FROM AUTHOR]

Background and Aims: Stomach cells can be converted to insulin-producing cells by Neurog3, MafA, and Pdx1 overexpression. Enteroendocrine cells can be similarly made to produce insulin by the deletion of FOXO1. Characteristics and functional properties of FOXO1-expressing stomach cells are not known. Methods: Using mice bearing a FOXO1-GFP knock-in allele and primary cell cultures, we examined the identity of FOXO1-expressing stomach cells and analyzed their features through loss-of-function studies with red-to-green fluorescent reporters. Results: FOXO1 localizes to a subset of Neurog3 and parietal cells. FOXO1 deletion ex vivo or in vivo using Neurog3-cre or Atp4b-cre increased numbers of parietal cells, generated insulin- and C-peptide-immunoreactive cells, and raised Neurog3 messenger RNA. Gene expression and ChIP-seq experiments identified the cell cycle regulator cyclin E1 (CCNE1) as a FOXO1 target. Conclusion: FOXO1 is expressed in a subset of stomach cells. Its ablation increases parietal cells and yields insulin-immunoreactive cells, consistent with a role in lineage determination.

This article discusses a case study of a 63-year-old woman who was referred to a medical center after a mass was detected during a screening gastroscopy. The woman tested negative for Helicobacter pylori but had positive serum parietal cell antibodies. Further evaluation revealed a giant mass adjacent to the cardia, which was consistent with autoimmune gastritis. The mass was removed successfully through endoscopic submucosal dissection, and the final diagnosis was gastric pyloric gland adenoma with high-grade dysplasia. The article emphasizes the importance of magnifying narrowband imaging in examining high-risk lesions like this one. [Extracted from the article]

The placenta plays various roles in a healthy pregnancy, and abnormalities in the placenta result in adverse outcomes. Adequate differentiation of trophoblast subtypes is necessary for placental function, but the molecular mechanisms that determine trophoblast cell fate remain unclear. Here, we screened small molecular compound (SMC) libraries (1904 SMCs) to identify particular SMCs which regulate trophoblast differentiation in mouse trophoblast stem cells (mTSCs) to understand the molecular mechanisms underlying cell fate decision in trophoblast cells. The two-step screening revealed a novel effect of N -oleoyldopamine (OLDA), an endogenic vanilloid, to promote differentiation into parietal trophoblast giant cells (P-TGCs) and repress them into spongiotrophoblast cells in mTSCs. Analyses by gene deletion and inhibitor treatments indicated that transient receptor potential cation channel subfamily V member 3 (Trpv3), one of the candidates for targeting by OLDA, was involved in maintaining stem status and P-TGC differentiation in mTSCs. Finally, transcriptome analysis revealed that Fosl1 , a key regulatory factor in differentiation into P-TGCs, was upregulated by OLDA treatment, suggesting that OLDA promoted the differentiation of mTSCs into P-TGCs via regulation of Fosl1 expression. • Three compounds modulate the differentiation of mouse trophoblast stem cell (mTSC). • N -Oleoyldopamine (OLDA) promotes the differentiation of mTSC into a prietal trophoblast giant cells (P-TGCs). • Trpv3 inhibition induces a P-TGC like gene expression pattern. • OLDA induces acute Fosl1 expression in mTSC at the early stage of differentiation. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is one of the most common worldwide chemicals involved in the industry of polycarbonate plastics, medical devices, and pharmaceuticals. Forty three-month-old albino rats were randomly classified into four groups. Group Ӏ received a daily corn oil dose (5 mL/kg/ body weight, BW) through a gastric tube for one month, Group ӀӀ received a daily dose of Curcumin (200 mg/kg body weight (B.W.) through a gastric tube for one month, Group ӀӀӀ received a daily dose of BPA (0.5 μg/kg B.W.) through a gastric tube for one month and Group ӀV received concomitant daily doses of Bisphenol A and Curcumin as the regimen described in groups ӀӀ and ӀӀӀ. The rats were sacrificed, and glandular portion of stomach was dissected and processed for light, immunohistochemical and ultrastructural study. BPA induced destructed gastric glands, dilated congested blood vessels, submucosal oedema, decreased PAS-positive reactivity, increased collagen fibres deposition, decrease in the positive BCL2 immunoexpression, increased positive PCNA immunoexpression, reduction in the gastric mucosal height and destructive changes in the enteroendocrine, chief and parietal cells. Curcumin coadministration provoked an obvious improvement in the gastric structure. BPA exposure has toxic effects on the glandular portion of the stomach in rats. Otherwise, Curcumin coadministration has exhibited protective impact on the architecture of the stomach. [ABSTRACT FROM AUTHOR]

Accumulating evidence has shown that Parkinson's disease (PD) is a systemic disease other than a mere central nervous system (CNS) disorder. One of the most important peripheral symptoms is gastrointestinal dysfunction. The enteric nervous system (ENS) is regarded as an essential gateway to the environment. The discovery of the prion-like behavior of α-synuclein makes it possible for the neurodegenerative process to start in the ENS and spread via the gut-brain axis to the CNS. We first confirmed that synucleinopathies existed in the stomachs of chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid (MPTP/p)-induced PD mice, as indicated by the significant increase in abnormal aggregated and nitrated α-synuclein in the TH-positive neurons and enteric glial cells (EGCs) of the gastric myenteric plexus. Next, we attempted to clarify the mechanisms in single MPTP-injected mice. The stomach naturally possesses high monoamine oxidase-B (MAO-B) activity and low superoxide dismutase (SOD) activity, making the stomach susceptible to MPTP-induced oxidative stress, as indicated by the significant increase in reactive oxygen species (ROS) in the stomach and elevated 4-hydroxynonenal (4-HNE) in the EGCs after MPTP exposure for 3 h. Additionally, stomach synucleinopathies appear before those of the nigrostriatal system, as determined by Western blotting 12 h after MPTP injection. Notably, nitrated α-synuclein was considerably increased in the EGCs after 3 h and 12 h of MPTP exposure. Taken together, our work demonstrated that the EGCs could be new contributors to synucleinopathies in the stomach. The early-initiated synucleinopathies might further influence neighboring neurons in the myenteric plexus and the CNS. Our results offer a new experimental clue for interpreting the etiology of PD. [ABSTRACT FROM AUTHOR]

Hypoalbuminemia (HA) is frequently observed in systemic inflammatory diseases and in liver disease. However, the influence of HA on the pharmacokinetics and toxicity of compounds with high plasma albumin binding remained insufficiently studied. The 'lack-of-delivery-concept' postulates that HA leads to less carrier mediated uptake of albumin bound substances into hepatocytes and to less glomerular filtration; in contrast, the 'concept-of-higher-free-fraction' argues that increased concentrations of non-albumin bound compounds facilitate hepatocellular uptake and enhance glomerular filtration. To address this question, we performed intravital imaging on livers and kidneys of anesthetized mice to quantify the spatio-temporal tissue distribution of the mycotoxin ochratoxin A (OTA) based on its auto-fluorescence in albumin knockout and wild-type mice. HA strongly enhanced the uptake of OTA from the sinusoidal blood into hepatocytes, followed by faster secretion into bile canaliculi. These toxicokinetic changes were associated with increased hepatotoxicity in heterozygous albumin knockout mice for which serum albumin was reduced to a similar extent as in patients with severe hypoalbuminemia. HA also led to a shorter half-life of OTA in renal capillaries, increased glomerular filtration, and to enhanced uptake of OTA into tubular epithelial cells. In conclusion, the results favor the 'concept-of-higher-free-fraction' in HA; accordingly, HA causes an increased tissue uptake of compounds with high albumin binding and increased organ toxicity. It should be studied if this concept can be generalized to all compounds with high plasma albumin binding that are substrates of hepatocyte and renal tubular epithelial cell carriers. [ABSTRACT FROM AUTHOR]

Simple Summary: The prenatal development of equine stomach has been rarely elaborated. The majority of accessible literature focused on the embryonal period (ca. to the 45–50th day of gestation). The histological study of the stomach wall, including the metric measurements and the gastric gland development, filled the lack of detailed information about the processes taking place in more advanced periods of pregnancy (the foetal period). The achieved results showed that the growth rate of subsequent layers of the stomach wall provided differences comparing with the isometric growth rate of whole foetus length (CRL). The blind ventricular sac, the plicated edge margin, and the pyloric part growth rates were lower than CRL increase. The body of stomach showed a higher growth rate than the whole foetus length. The non-glandular and glandular part of gastric mucosa was distinguishable from the beginning of foetal period. The gastric glands developed the most rapidly in the body of stomach, especially in the late pregnancy. The parietal cells were visible in the gastric glands in the middle of foetal period and the chief cells could be identified in the late pregnancy. The dynamic processes occurring in the prenatal life did not finish in the moment of birth, but postnatally. Histological and morphometrical analysis of the stomach wall was performed during the foetal period divided into three age groups (4th–11th month of gestation). The material was taken from non-glandular (the blind ventricular sac) and glandular parts (the plicated edge margin/cardiac part, the body of stomach and the pyloric part) of the stomach. It was preserved and prepared according to the standard protocol. The histological slides were stained (H-E, Masson-Goldner and PAS). The analyses were performed using the light microscope. All measurements were statistically elaborated. The crown-rump length growth rate was estimated as isometric. The blind ventricular sac growth rate was lower than CRL (negative allometric) and the partition of stomach mucosa into non-glandular and glandular part occurred in the 1st age group. The plicated edge margin/cardiac part and the pyloric part shoved similar tendencies. Only the body of stomach demonstrated a higher growth rate than CRL (positive allometric), which can be explained due to the strongest development of fundic glands. Moreover, comparing the adult reference group to the three parts of the foetal period, all metric values were lower than those achieved prenatally. The blind ventricular sac was covered with the multiple plane epithelium. The glandular parts of stomach that formed the superficial concave areas were covered with the simple columnar epithelium in the 1st age group, which developed to the cardiac, fundic, and pyloric glands in the 2rd and 3rd age groups. The propria mucosae was built with the mesenchyme, which differentiated later to the loose connective tissue. The muscular layer of mucosa was not clearly distinguishable in the 1st age group. The muscular layer of the stomach wall was formed with myoblasts in the 1st age group and later in the 2nd and the 3rd age groups built with fusiform myocytes divided into internal and external layers. The non-differentiated cells of glandular epithelium transformed into the parietal and chief cells. The first were visible in the gastric glands of the 2nd age group. Both of them were present in the 3rd age group gastric mucosa. The PAS staining proved a moderate PAS-positive reaction in the 2rd age group, while it was estimated as intense Pas-positive in the gastric glands in the 3rd age group and was comparable to postnatal observation (the adult reference group). [ABSTRACT FROM AUTHOR]

Ferula sinkiangensis is a perennial herb, producing fruits only once through its life history, and exclusively habitated in Xinjiang being in the list of state rare and endangered plants Level 2. Besides andromonoecy, usually found in Umbelliferae, plants of male sterility were observed in their populations. Aimed to male sterility and the factors inducing it, comparative observation on morphology of male sterility individuals and functional female flowers were executed through field investigation, and study on cytology of the process of the anther degeneration in female flowers were made from paraffin sections. The results were as follows:(1)Female plants germinated at the end of March and blossomed in the middle of April, and their fruits matured at the end of May; Phenological phases of them were the same as those of andromonoecy.(2)The average height and diameter of plant, and number of the first level branch of female individuals were(71.00±10.92)cm,(71.67±17.64)cm, and(23.83±2.04), separately; The average length and width of basal leaves were(33.41±11.63)cm and(24.47±8.60)cm; The female and the andromonoecy were the same in size of both the plant and the leaf.(3)On female plants, inflorescences on the first and the second level branches were all female, which could bear fruits wholly; The number of umbels in the inflorescence(13.22±4.70)and number of flowers in the umbel(12.03±2.30)and number of total flowers in the inflorescence(159.08)were higher than those in individuals of hermaphrodite; Female plants produced more flowers which could set fruits and bore out-crossing seeds of heterosis.(4)In female umbels flowers located tightly and the distance among flowers were shorter than those in both hermaphrodite and male umbels; Female flowers opened slightly in the whole flowering stage, while petals of both hermaphrodite and male flowers folded reversely.(5)There were no differences in morphological characteristics of petals and pistils among different sexual flowers. But the length(1.79±0.39 mm)and width(1.10±0.21 mm)of petals, and the length of stamens(0.6-1.3 mm)in the functional female flower were the smallest, where anthers degenerated and no pollen stain well developed.(6)Abnormal development of the anther on the degenerated stamen appeared in both of parietal cells and male gametophytes from sporogenous cell stage to microspore tetrad stage. In conclusion, the nutrients productivity in plants of male sterility is similar as andromonoecy, but patterns of resource distribution are quite different; there are significant differences between female and hermaphrodite/male flowers in both the morphology and the function; abnormal development of parietal cells, especially because of the lack of tapetum, caused abortion of microspores in the functional female flower. [ABSTRACT FROM AUTHOR]

Simple Summary: The bottlenose dolphin (Tursiops truncatus) is the most represented species housed in zoological settings in Western countries, while Risso's dolphin (Grampus griseus) is usually kept under human care as a result of the rehabilitation process in rescue centers. Although they belong to the same family, Delphinidae, these two species present remarkably different feeding habits. Risso's dolphin is strictly teutophagous, and its diet is particularly based on cephalopods such as mesopelagic squid, which is poor in histamine. The bottlenose dolphin is mainly ichthyophagous and primarily prefers blue fish, which is rich in histamine as a degradation product and stimulates the parietal cells of the stomach to secrete hydrochloric acid (HCl). These different eating habits are usually correlated to habitat, behavior and physiological needs related to the specific morpho-functional conditions of the species. Despite these dietary differences, in captivity, the two species are fed in the same way through the administration of several kilograms of bony fish (such as capelin or herring) per day. While this diet appears to be optimal for the bottlenose dolphin, Risso's dolphin appears to be more sensitive, presenting gastrointestinal discomfort when ingesting bony fish for a few consecutive days. To histologically evaluate the gastric compartments of Risso's (Grampus griseus) and bottlenose dolphins (Tursiops truncatus) and provide suggestions for the diet of Risso's dolphins in captivity, we examined 12 stomachs from both species. While slight differences in keratinization were observed in the forestomach, significant differences came to light in the second stomach's mucosa. At this level, in Risso's dolphin, the principal cells are markedly reduced in size and located externally to the parietal cells, not interspersed between them, compared to bottlenose dolphins; differences were also observed in the structure and concentration of the parietal and principal cells of the gastric body glands (p < 0.0001). The quantitative results of G- and D-cell counts in the gastric mucosa show a clear difference, with a higher concentration of G cells in the mucosa of Risso's dolphin (t = 7.334; p < 0.0001) and a higher level of D cells in bottlenose dolphin mucosa (t = 3.123; p = 0.0049). These results suggest that parietal cells undergo greater stimulation by gastrin produced by G cells, with greater acid secretion in G. griseus. Further studies are needed to understand whether an inappropriate diet could lead to severe clinical signs due to gastric acidity in Risso's dolphin. [ABSTRACT FROM AUTHOR]

ObjectivesMicrovillus inclusion disease (MVID) is a severe form of neonatal diarrhea, caused mainly by mutations in MYO5B. Inactivating mutations in MYO5B causes depolarization of enterocytes in the small intestine, which gives rise to chronic, unremitting secretory diarrhea. While the pathology of the small intestine in MVID patients is well described, little is known about extraintestinal effects of MYO5B mutation.MethodsWe examined stomach, liver, pancreas, colon, and kidney in Navajo MVID patients, who share a single homozygous MYO5B-P660L (1979C>T p.Pro660Leu, exon 16). Sections were stained for markers of the apical membrane to assess polarized trafficking.ResultsNavajo MVID patients showed notable changes in H/K-ATPase-containing tubulovesicle structure in the stomach parietal cells. Colonic mucosa was morphologically normal, but did show losses in apical ezrin and Syntaxin 3. Hepatocytes in the MVID patients displayed aberrant canalicular expression of the essential transporters MRP2 and BSEP. The pancreas showed small fragmented islets and a decrease in apical ezrin in pancreatic ducts. Kidney showed normal primary cilia.ConclusionsThese findings indicate that the effects of the P660L mutation in MYO5B in Navajo MVID patients are not limited to the small intestine, but that certain tissues may be able to compensate functionally for alterations in apical trafficking.

Autoimmune gastritis is a corpus-dominant type of gastritis with positive serum anti-parietal cell antibodies (APCA) and/or anti-intrinsic factor antibodies. Serum APCA and pepsinogen (PG) assays were performed in subjects with corpus-dominant gastritis detected by endoscopy. Serum APCA was positive in five patients. All these patients were postmenopausal women (four Koreans and one Caucasian from the Russian Federation) with a mean age of 59.0±3.2 years. They displayed low PG I levels ranging from 8.1 to 18.8 ng/mL (mean, 11.4±4.8 ng/mL) and low PG I/II ratios ranging from 0.7 to 2.4 (mean, 1.2±0.7). Three of the patients were being treated for autoimmune thyroiditis. Multiple gastric neuroendocrine tumors were observed in two Helicobacter pylori (H. pylori)-naive patients with high serum gastrin levels exceeding 700 pg/mL and serum chromogranin A levels exceeding 1,000 ng/mL. In the remaining three patients, intestinal metaplasia was observed in the biopsied specimens from the antrum, suggesting a history of H. pylori infection. Our findings indicate the value of positive serum APCA findings, low serum PG I levels, and low serum PG I/II ratios in confirming autoimmune gastritis in patients showing corpus-dominant atrophy, regardless of their H. pylori infection status.

Background/Aims Ménétrier’s disease (MD) is a rare premalignant disorder of the stomach with thickened gastric folds associated with protein-losing enteropathy and H Pylori infection. The clinical presentation of MD might cause diagnostic difficulty and can be mistaken for malignancy, hence tissue acquisition technique is very crucial for diagnosis and to date, there is no universally established method for tissue collection specifically for MD. We describe a case of MD in a 59-year-old, Filipino Female presenting as gastric outlet obstruction mimicking Linitis Plastic with tissue acquisition using band-ligation endoscopic mucosal resection (EMR). Case Presentation A 59-year-old Filipino female presented with 1 week history of vomiting and early satiety with no weight loss, edema and diarrhea. She has no comorbidities, with normal CBC, electrolytes and serum albumin. Esophagogastroduodenoscopy revealed a poorly distensible stomach with poor contractility with multiple giants’ folds seen from the proximal stomach to the antrum with narrowing at the pre pyloric area. Rapid urease test was negative for H. pylori infection. Endoscopic ultrasonography showed thickened gastric wall (16 mm) with intact five-wall layers. A band ligation device (Boston Scientific) was attached to the endoscope and suction was applied to the thickened gastric fold creating a pseudopolyp and electrocautery snare was then used to resect the pseudopolyp above the band and multiple biopsies were taken above the exposed mucosa using cold forceps . Histopathology revealed foveolar hyperplasia and significant parietal cell loss clinching the diagnosis of MD. Multidisciplinary team was gathered and patient underwent near total gastrectomy, gastro-jejunostomy secondary to the obstructive symptoms. Conclusion Tissue acquisition is crucial for accurate diagnosis especially in premalignant lesions like MD. This case report may accentuate the importance of tissue acquisition in diagnosing MD and illustrate how band-ligation EMR can facilitate full-thickness biopsy, potentially offering opportunities for earlier intervention. [ABSTRACT FROM AUTHOR]

The mesothelium is a non-adhesive protective surface that lines the serosal cavities and organs within the body. The glycocalyx is a complex structure that coats the outer layer of the mesothelium. However, due to the limitations of conventional fixation techniques, studies on glycans are limited. In this study, lectin staining of frozen tissues was performed to investigate the diversity of glycans in the glycocalyx of mesothelial cells in mice. Datura stramonium lectin (DSL), which recognizes lactosamine and binds to Galectin-3 and −1, was broadly bound to the mesothelial cells of the visceral and parietal peritoneum but not to the pancreas, liver, intestine, or heart. Furthermore, human mesothelial cells in the omentum and parietal peritoneum were positive for DSL. Erythrina cristagalli lectin binding was specific to mesothelial cells in the parietal peritoneum, that is, the pleura, diaphragm, and peritoneum. Intriguingly, surface sialylation, the key element in reducing peritoneal dissemination and implantation, and promoting ascites formation by ovarian carcinoma cells, was much higher in the parietal peritoneum than in the omentum. These findings revealed slight differences in the glycans of mesothelial cells of different organs, which may be related to clinical diseases. These results also suggest that there may be differences in the functions of parietal and visceral mesothelial cells. [ABSTRACT FROM AUTHOR]

Background: The scattered tubular cells (STCs) are a population of resident progenitor tubular cells with expansion, self-renewal and epithelial differentiation abilities. Although these cells are localized within the proximal (PTs) and distal (DTs) tubules in a normal adult kidney, their presence has never been demonstrated in human macula densa (MD). The purpose of the present study is to describe the presence of STCs in MD using specific markers such as prominin-1 (CD133), cytokeratin 7 (KRT7) and vimentin (VIM). Methods: We analyzed two sets of three consecutive serial sections for each sample. The first sections of each set were immunostained for nNOS to identify MD, the second sections were immune-stained for CD133 (specific STCs marker) while the third sections were analyzed for KRT7 (another STCs specific marker) and VIM (that stains the basal pole of the STCs) in the first and second sets, respectively, in order to study the co-expression of KRT7 and VIM with the CD133 marker. Results: CD133 was localized in some MD cells and in the adjacent DT cells. Moreover, CD133 was detected in the parietal epithelial cells of Bowman's capsule and in some proximal tubules (PT). KRT7-positive cells were identified in MD and adjacent DT cells, while KRT7 positivity was mostly confined in both DT and collecting ducts (CD) in the other areas of the renal parenchyma. CD133 and KRT7 were co-expressed in some MD and adjacent DT cells. Some of the latter cells were positive both for CD133 and VIM. CD133 was always localized in the apical part of the cells, whereas the VIM expression was evident only in the cellular basal pole. Although some cells of MD expressed VIM or CD133, none of them co-expressed VIM and CD133. Conclusions: The presence of STCs was demonstrated in human adult MD, suggesting that this structure has expansion, self-renewal and epithelial differentiation abilities, similar to all other parts of renal tubules. [ABSTRACT FROM AUTHOR]

The prevalence of autoimmune atrophic gastritis (AAG) in vitiligo patients was estimated at about 15%. In both conditions, a release of specific antibodies and an autoimmune destruction of target cells (melanocytes in vitiligo, parietal cells (PC) in AAG) mediated by CD8‐T lymphocytes was demonstrated to perform a comparative histological study of vitiligo skin and AAG mucosa. In two patients with concomitant vitiligo and AAG, biopsies from the vitiligo lesions and gastric mucosa from corpus fundus were performed. Sections were immunostained with E‐cadherin, Coll IV, CD8, CD20, CD4 antibodies. The skin sections also were stained with HES, HMB45, MITF. Common histological findings were found in both diseases. Adhesivity impairment with down expression of E‐cadherin and Coll IV was objectivated. The protruding MITF+melanocytes and the detached PC were surrounded by an infiltrate including CD8 and CD4. CD8 was infiltrating the epidermis in close contact with the remaining melanocytes and the gastric glands around the remaining PC. In both diseases, the autoimmune process could be preceded by a detachment of either melanocytes in vitiligo or PC in AAG possibly in relation to an initial adhesivity impairment of these cells. Common autoimmune mechanisms could be suggested for both diseases. The autoimmune process could be preceded by a cell adhesivity impairment leading to a detachment of either melanocytes in vitiligo or PC in AAG. [ABSTRACT FROM AUTHOR]

The article discusses research on how kidney podocytes regenerate foot processes of the filtration apparatus following injury. It mentions that sarcomere-like structures (SLSs) with periodically spaced myosin IIA and synaptopodin appeared in injured podocytes in vivo. Results show that SLSs in podocytes that migrated from isolated kidney glomeruli presented periodic synaptopodin-positive clusters, suggesting SLSs as mechanobiological mediators of podocyte recovery.

Purpose: Type 1 diabetes mellitus (T1DM) is an autoimmune condition characterised by the presence of antipancreatic antibodies. The autoimmune process is also directed against other organs, most frequently against the thyroid gland, intestinal mucosa, and gastric parietal cells. Methods: Our investigation included 121 children with T1DM with a mean age±standard deviation of 11.99±4.63 years (range, 2.0-20.0 years). We explored the frequency of associated autoimmunity; the presence of predictive factors such as current age, sex, and severity at diabetes diagnosis; T1DM duration; and family history of autoimmunity. Results: Associated autoimmunity was present in 28.9% of T1DM patients. Children with associated autoimmunity were older at diabetes diagnosis (P=0.009) and had a longer diabetes duration compared to children without associated autoimmunity (P=0.044). Adolescents aged 12-20 years had a statistically significant higher chance of developing thyroid autoimmunity compared to children aged 1-5 years (P=0.019). Multiple autoimmunity (MA), T1DM, and 2 or more autoimmune diseases were present in 5.8% of the study population. All children with MA presented with ketoacidosis at diabetes diagnosis and had a higher percentage of familial autoimmunity (P=0.042). The familial autoimmunity of these patients most frequently affected =3 relatives (P=0.026) and was more frequently diagnosed before 5 years of age (P=not significant). Conclusion: Associated autoimmunity was present in almost one-third of T1DM patients. Significant associations with associated autoimmunity were longer diabetes duration, female sex, older age at diabetes diagnosis, and glutamic acid decarboxylase positivity. Predictors of MA were age <5 years at T1DM diagnosis, the presence of diabetic ketoacidosis at diagnosis, and a significant family history of autoimmunity. [ABSTRACT FROM AUTHOR]

Background: Pantoprazole is a protein pump inhibitor (PPI) used to treat acute duodenal ulcers, acute benign gastric ulcers, gastroesophageal reflux disease (GERD), and as a preventative measure for duodenal ulcer. It has a local effect on the stomach and works by competitively inhibiting the enzyme H+/K+ ATP, which is found in the gastric parietal cells. For acute duodenal ulcers, acute benign gastric ulcers, and gastroesophageal reflux disease (GERD), the usual oral dosage recommendation is 45 mg, and it is taken for 8-12 weeks. Objectives: The preparation of pantoprazole floating tablets was attempted in the current investigation and optimize the formulation using different excipients like Hydroxy ethyl cellulose (HEC), cyclodextrin, sodium bicarbonate, citric acid and microcrystalline cellulose were used in the direct compression method to create pantoprazole floating tablets (250 mg). Methods: The direct compression method has been used in the current effort to create floating tablets. The active ingredient, sodium bicarbonate, citric acid, microcrystalline cellulose, and hydroxy ethyl cellulose were sieved through sieve no. 60 and blended uniformly with a mortar and pestle. Using a Rotary tablet punch machine, the powder was compacted into tablets after talc and magnesium stearate were added as lubricants Results: Preformulation studies were conducted to select suitable excipients, drug/polymer interactions were validated by the FTIR investigation. The manufactured floating tablets were assessed for hardness, weight fluctuation, thickness, friability, drug content homogeneity, floating lag time, and in vitro dissolution experiment studies was conducted. The results were within the limit and were compared with the marketed formulation. Conclusion: According to the observations of the current investigation, a floating pantoprazole tablet increases the stomach residence time and bioavailability, increasing therapeutic efficacy. Formulations F1, F2, F4, F5, F7, and F8 showed good floating, but Formulations F3, and F6 showed moderate floating throughout all 8 formulations. The stability analyses that were done for all the formulations showed that the F7 and F8 formulations had good stability. [ABSTRACT FROM AUTHOR]

Crescentic glomerulonephritis is characterized by vascular necrosis and parietal epithelial cell hyperplasia in the space surrounding the glomerulus, resulting in the formation of crescents. Little is known about the molecular mechanisms driving this process. Inducing crescentic glomerulonephritis in two Pax2Cre reporter mouse models revealed that crescents derive from clonal expansion of single immature parietal epithelial cells. Preemptive and delayed histone deacetylase inhibition with panobinostat, a drug used to treat hematopoietic stem cell disorders, attenuated crescentic glomerulonephritis with recovery of kidney function in the two mouse models. Three-dimensional confocal microscopy and stimulated emission depletion superresolution imaging of mouse glomeruli showed that, in addition to exerting an anti-inflammatory and immunosuppressive effect, panobinostat induced differentiation of an immature hyperplastic parietal epithelial cell subset into podocytes, thereby restoring the glomerular filtration barrier. Single-cell RNA sequencing of human renal progenitor cells in vitro identified an immature stratifin-positive cell subset and revealed that expansion of this stratifin-expressing progenitor cell subset was associated with a poor outcome in human crescentic glomerulonephritis. Treatment of human parietal epithelial cells in vitro with panobinostat attenuated stratifin expression in renal progenitor cells, reduced their proliferation, and promoted their differentiation into podocytes. These results offer mechanistic insights into the formation of glomerular crescents and demonstrate that selective targeting of renal progenitor cells can attenuate crescent formation and the deterioration of kidney function in crescentic glomerulonephritis in mice. A drug that turns crescents into podocytes: Severe immune-mediated disorders often lead to kidney failure resulting from formation of glomerular crescents, which are regions of parietal epithelial hyperplasia around the glomeruli. Melica et al. show that crescents derive from clonal expansion of a subset of parietal epithelial cells that represent renal progenitor cells. Panobinostat reduced crescent formation and improved proteinuria and kidney function in a mouse model of crescentic glomerulonephritis by enhancing renal progenitor cell differentiation into podocytes. Expansion of a renal progenitor cell subset in human crescents correlated with end-stage kidney disease. These results support the concept that crescentic glomerulonephritis represents a clonal disease that can be treated with panobinostat. [ABSTRACT FROM AUTHOR]

Rapidly progressive crescentic glomerulonephritis associated with anti-neutrophil cytoplasmic antibodies (ANCA-GN) is a major cause of renal failure. Current immunosuppressive therapies are associated with severe side effects, intensifying the need for new therapeutic strategies. The activation of Mas receptor/Angiotensin-(1-7) axis exerted renoprotection in chronic kidney disease. Here, we investigated the effect of adding the lanthionine-stabilized cyclic form of angiotensin-1-7 [cAng-(1-7)] to cyclophosphamide in a rat model of ANCA-GN. At the onset of proteinuria, Wistar Kyoto rats with ANCA-GN received vehicle or a single bolus of cyclophosphamide, with or without daily cAng-(1-7). Treatment with cAng-(1-7) plus cyclophosphamide reduced proteinuria by 85% vs. vehicle, and by 60% vs. cyclophosphamide, and dramatically limited glomerular crescents to less than 10%. The addition of cAng-(1-7) to cyclophosphamide protected against glomerular inflammation and endothelial rarefaction and restored the normal distribution of parietal epithelial cells. Ultrastructural analysis revealed a preserved GBM, glomerular endothelium and podocyte structure, demonstrating that combination therapy provided an additional layer of renoprotection. This study demonstrates that adding cAng-(1-7) to a partially effective dose of cyclophosphamide arrests the progression of renal disease in rats with ANCA-GN, suggesting that cAng-(1-7) could be a novel clinical approach for sparing immunosuppressants. [ABSTRACT FROM AUTHOR]

Background and aim: Local GABAergic signaling in the dorsal vagal complex (DVC) is essential to control gastric function. While the inhibitory GABAA receptor action on motility in the DVC is well-documented, the role of the GABAB receptor on gastric function is less well-established. Microinjection of baclofen, a selective GABAB receptor agonist, in the dorsal motor nucleus of the vagus (DMV) increases gastric tone and motility, while the effect on motility in the nucleus tractus solitarius (NTS) needs to be investigated. Previous in vitro studies showed that GABAB receptors exert a local inhibitory effect in unidentified NTS neurons. Since the NTS and DMV nuclei have differential control of gastric motility, we compared GABAB receptor activation in the NTS to that reported in the DMV. We microinjected baclofen unilaterally in the NTS while monitoring intragastric pressure and compared its action to optogenetic activation of somatostatin (SST) neurons in transgenic sst-Cre::channelrhodopsin-2 (ChR2) mice. We also performed patch-clamp recordings from SST and DMV neurons in brainstem slices from these mice. Methods: In vivo drug injections and optogenetic stimulation were performed in fasted urethane/a-chloralose anesthetized male mice. Gastric tone and motility were monitored by an intragastric balloon inserted in the antrum and inflated with warm water to provide a baseline intragastric pressure (IGP). Coronal brainstem slices were obtained from the sst-Cre::ChR2 mice for interrogation with optogenetics and pharmacology using electrophysiology. Results: The unilateral microinjection of baclofen into the NTS caused a robust increase in gastric tone and motility that was not affected by ipsilateral vagotomy. Optogenetic activation of SST neurons that followed baclofen effectively suppresses the gastric motility in vivo. In brain slices, baclofen suppressed spontaneous and light-activated inhibitory postsynaptic currents in SST and gastrointestinal-projection DMV neurons and produced outward currents. Conclusion: Our results show that GABAB receptors in the NTS strongly increase gastric tone and motility. Optogenetic stimulation in vivo and in vitro suggests that these receptors activated by baclofen suppress the glutamatergic sensory vagal afferents in the NTS and also inhibit the interneurons and the inhibitory neurons that project to the DMV, which, in turn, increase motility via a cholinergic excitatory pathway to the stomach. [ABSTRACT FROM AUTHOR]

During human kidney development, cells of the proximal nephron gradually differentiate into podocytes and parietal epithelial cells (PECs). Podocytes are terminally differentiated cells that play a key role in both normal and pathological kidney function. Therefore, the potential of podocytes to regenerate or be replaced by other cell populations (PECs) is of great interest for the possible treatment of kidney diseases. In the present study, we analyzed the proliferation and differentiation capabilities of podocytes and PECs, changes in the expression pattern of nestin, and several early proteins including WNT4, Notch2, and Snail, as well as Ki-67, in tissues of developing, postnatal, and pathologically changed human kidneys by using immunohistochemistry and electron microscopy. Developing PECs showed a higher proliferation rate than podocytes, whereas nestin expression characterized only podocytes and pathologically changed kidneys. In the developing kidneys, WNT4 and Notch2 expression increased moderately in podocytes and strongly in PECs, whereas Snail increased only in PECs in the later fetal period. During human kidney development, WNT4, Notch2, and Snail are involved in early nephrogenesis control. In kidneys affected by congenital nephrotic syndrome of the Finnish type (CNF) and focal segmental glomerulosclerosis (FSGS), WNT4 decreased in both cell populations, whereas Notch2 decreased in FSGS. In contrast, Snail increased both in CNF and FSGS, whereas Notch2 increased only in CNF. Electron microscopy revealed cytoplasmic processes spanning the urinary space between the podocytes and PECs in developing and healthy postnatal kidneys, whereas the CNF and FSGS kidneys were characterized by numerous cellular bridges containing cells with strong expression of nestin and all analyzed proteins. Our results indicate that the mechanisms of gene control in nephrogenesis are reactivated under pathological conditions. These mechanisms could have a role in restoring glomerular integrity by potentially inducing the regeneration of podocytes from PECs. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the role of dexmedetomidine in gastric ischemia/reperfusion injury using gastric mucosal epithelial cell (GES-1) model. Methods: GES-1 were subjected to oxygen-glucose deprivation conditions, followed by increasing dexmedetomidine concentrations (0.5, 1.0, or 1.5 μM) for 4 h of reoxygenation. Cell viability and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide and flow cytometry, respectively. Oxidative stress and inflammation were analyzed by enzyme-linked immunosorbent assay (ELISA). Results: Oxygen-glucose deprivation conditions induced cytotoxicity in GES-1 by decreasing cell viability and increasing apoptosis. Dexmedetomidine treatment significantly increased the cell viability of hypoxia/reoxygenation-induced GES-1 (p < 0.01) but reduced apoptosis. Dexmedetomidine also attenuated the hypoxia/reoxygenation-induced increase in malondialdehyde and myeloperoxidase, but the decrease in superoxide dismutase and glutathione in GES-1. Moreover, upregulated tumor necrosis factor-α, interleukin (IL)-1β, and IL-18 in hypoxia/reoxygenation-induced GES-1 was downregulated by dexmedetomidine treatment. Dexmedetomidine also enhanced IL-10 levels and inhibited proinflammatory factor production (p < 0.01). High-mobility group box 1 (HMGB1) protein in GES-1 was upregulated by hypoxia/reoxygenation but decreased by dexmedetomidine. HMGB1 over-expression attenuated the dexmedetomidine-induced increase in cell viability and the decrease in apoptosis, oxidative stress, and inflammation in hypoxia/reoxygenation-induced GES-1 (p < 0.01). Conclusion: Dexmedetomidine protects GES-1 against ischemia/reperfusion-induced apoptosis, inflammation, and oxidative stress by inhibiting HMGB1, thus providing a potential strategy for treating gastric ischemia/reperfusion injury. [ABSTRACT FROM AUTHOR]

Our previous study found that 19.0%, 16.9%, 5.3%, 2.3%, 11.9%, and 26.7% of 1064 atrophic glossitis (AG) patients have anemia, serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody (GPCA) positivity, respectively. This study evaluated the anemia, hematinic deficiencies, and hyperhomocysteinemia in 150 male and 914 female AG patients. The blood hemoglobin (Hb) and serum iron, vitamin B12, folic acid, homocysteine, GPCA levels in 150 male and 914 female AG patients were measured and compared with the corresponding levels in 75 male and 457 female healthy control subjects (HCSs), respectively. We found that 150 male AG patients had significantly lower mean blood Hb, serum iron, vitamin B12, and folic acid levels, and significantly higher mean serum homocysteine levels than 75 male HCSs. Moreover, 914 female AG patients had significantly lower mean blood Hb and serum iron levels and significantly higher mean serum homocysteine level than 457 female HCSs. In addition, 150 male AG patients had significantly higher mean blood Hb and serum homocysteine levels, significantly lower mean serum vitamin B12 and folic acid levels, and significantly higher frequencies of Hb, vitamin B12, and folic acid deficiency and hyperhomocysteinemia than 914 female AG patients. The male AG patients do have significantly higher mean blood Hb and serum homocysteine levels, significantly lower mean serum vitamin B12 and folic acid levels, and significantly higher frequencies of Hb, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia than the female AG patients. [ABSTRACT FROM AUTHOR]

Background: Proton-pump inhibitors (PPIs) block acid secretion from gastric parietal cells; however, recent studies have reported that PPIs have antioxidant and anti-inflammatory properties in various cells. Newer PPIs are stronger inhibitors of acid secretion; however, the anti-inflammatory effects of these drugs have not been assessed. We evaluated anti-inflammatory effect of PPIs on the development of asthma/asthma exacerbation (AE) in a national health screening cohort. Methods: This case-control study comprised 64,809 participants with asthma who were 1:1 matched with controls from the Korean National Health Insurance Service-Health Screening Cohort. Conditional logistic regression analysis was used to evaluate the effect of previous PPI use on an asthma diagnosis in all participants. Unconditional logistic regression was used to assess the effect of PPI use on AE in participants with asthma. These relationships were estimated in a subgroup analysis according to PPI generation. Results: Overall, PPI use increased the risk of asthma diagnosis [adjusted odds ratio (aOR) = 1.29, 95% confidence interval (CI) = 1.23–1.35, p < 0.001]. Use of the first-generation PPIs was associated with asthma (aOR = 1.34, 95% CI = 1.18–1.52, p < 0.001), while use of second-generation PPIs was not (aOR = 0.97, 95% CI = 0.82–1.15, p = 0.748). In contrast, overall PPI use decreased the risk of AE in participants with asthma (aOR = 0.79, 95% CI = 0.75–0.84, p < 0.001), although this effect was observed only for second-generation PPIs (aOR = 0.76, 95% CI = 0.65–0.89, p = 0.001). Conclusion: PPI use increased the risk for subsequent asthma diagnosis. However, this effect was confined to first-generation PPIs. Second-generation PPIs decreased the risk of AE. [ABSTRACT FROM AUTHOR]

Over one billion people globally are vitamin D (VD) deficient. Studies on the biological roles of VD are numerous but very little on the stomach. This project aims to understand how gastric homeostasis is affected by VD deficiency caused by prolonged exposure to darkness alone or combined with VD deficient diet. Three groups of C57/BL6 mice were subjected to different light exposure conditions and diets for 12 months (n = 8–12/group): control—12 h/12 h light/dark SDL (Standard Diet/Light), 24 h dark SDD (Standard Diet/Dark), and 24 h dark VDD (VD deficient diet/Dark). Stomach samples were collected for different multi-label lectin-/immuno-histochemical and qRT-PCR analyses, and the serum for LC-MS-MS. We found that the membrane VD receptor is expressed widely in the stomach when compared to nuclear VD receptors. Compared to SDL, VDD mice developed mucous cell expansion with increased mucins-mRNA (3.27 ± 2.73 (p < 0.05)) increased apoptotic cells, 15 ± 7 (p ≤ 0.001)); decreased cell proliferation, 4 ± 4 (p < 0.05)) and decreased acid secretion 33 ± 2 μEq/kg (p ≤ 0.0001)). Interestingly, mice exposed to full darkness developed mild VD deficiency with higher VD epimer levels: 11.9 ± 2.08 ng/mL (p ≤ 0.0001)), expansion in zymogenic cell number (16 ± 3 (p ≤ 0.01)), and a reduction in acid secretion (18 ± 2 μEq/kg (p ≤ 0.0001)). In conclusion, changes in light exposure or VD levels have serious physiological effects on the gastric mucosa, which should be considered during the management of gastric disorders. [ABSTRACT FROM AUTHOR]

Autoimmune gastritis (AIG) is chronic atrophic gastritis caused by an autoimmune mechanism of unknown etiology and presents with various pathological conditions by causing an achlorhydria state through parietal cell damage. The most characteristic endoscopic finding in AIG is advanced corpus-dominant mucosal atrophy. A recent study that examined several cases in Japan revealed the presence of endoscopic features other than corpus-dominant advanced atrophy. Remnants of oxyntic mucosa and sticky adherent dense mucus were found in ≥30% of cases, and hyperplastic polyps were found in ≥20% of cases. In image-enhanced endoscopy (IEE), white globe appearance (WGA) was observed in 32% of AIG cases. Additionally, some reports have stated that the findings in AIG cases using IEE showed cast-off skin appearance (CSA) and foveola type mucosa; however, a consensus is yet to be achieved. These endoscopic results were found in cases of advanced-stage AIG. There have been few reports concerning early-stage AIG cases. In these few reports, all of the cases were pathologically diagnosed as early AIG. In all of the cases, the pathological findings almost always showed neither parietal cell destruction nor atrophy. Endoscopic findings such as "mosaic pattern with slight swelling of the areae gastricae", "diffuse reddened and edematous gastric fundic gland mucosa", and "pseudopolyp-like nodules" may be common characteristics of early images. In such early cases, high antibody titers, no atrophic changes, and few clinical abnormal findings were shown. Endoscopists are expected to update their knowledge regarding AIG diagnosis with the evolution of imaging equipment. [ABSTRACT FROM AUTHOR]

Malignant neuroendocrine tumors were diagnosed in the stomach of two out of sixty female Sprague-Dawley rats treated for 89 weeks with a high dose of a novel, small molecule, cannabinoid-1 antagonist. The tumors were associated with parietal cell atrophy accompanied by foveolar hyperplasia of the glandular stomach mucosa. Parietal cell atrophy/foveolar hyperplasia was considered test article related at the high dose, given the higher incidence and severity relative to untreated controls, although the precise mechanism of the parietal cell atrophy was undetermined. Spontaneous gastric neuroendocrine tumors are very rare in rats, and the current cases were considered secondary to parietal cell atrophy causing reduced gastric acid secretion and subsequent overstimulation of gastrin release through a feedback loop. [ABSTRACT FROM AUTHOR]

We previously found that short-term treatment (week 8 to 12 after injury) with high-dose angiotensin receptor blocker (ARB) induced the regression of existing glomerulosclerosis in 5/6 nephrectomy rats. We therefore assessed the effects of long-term intervention with ARB vs. nonspecific antihypertensives in this study. Adult rats underwent 5/6 nephrectomy and renal biopsy 8 weeks later. The rats were then divided into three groups with equivalent renal function and glomerular sclerosis and treated with high-dose losartan (ARB), nonspecific antihypertensive triple-therapy (TRX), or left untreated (Control) until week 30. We found that blood pressure, serum creatinine levels, and glomerulosclerosis were lower at sacrifice in ARB and TRX vs. Control. Only ARB reduced proteinuria and maintained the density of WT-1-positive podocytes. Glomerular tufts showed more double-positive cells for CD44, a marker of activated parietal epithelial cells, and synaptopodin after ARB vs. TRX or Control. ARB treatment reduced aldosterone levels. ARB-treated rats had significantly improved survival when compared with TRX or Control. We conclude that both long-term ARB and triple-therapy ameliorate progression, but do not sustain the regression of glomerulosclerosis. ARB resulted in the superior preservation of podocyte integrity and decreased proteinuria and aldosterone, linked to increased survival in the uremic environment. [ABSTRACT FROM AUTHOR]

Gastric cancer is the fourth cause of cancer death globally, and gastric adenocarcinoma is its most common type. Efforts for the treatment of gastric cancer have increased its median survival rate by only seven months. Due to the relatively low response of gastric cancer to surgery and adjuvant therapy, as well as the complex role of risk factors in its incidences, such as protein-pomp inhibitors (PPIs) and viral and bacterial infections, we aimed to study the pathological pathways involved in gastric cancer development and investigate possible medications by systems biology and bioinformatics tools. In this study, the protein–protein interaction network was analyzed based on microarray data, and possible effective compounds were discovered. Non-coding RNA versus coding RNA interaction network and gene-disease network were also reconstructed to better understand the underlying mechanisms. It was found that compounds such as amiloride, imatinib, omeprazole, troglitazone, pantoprazole, and fostamatinib might be effective in gastric cancer treatment. In a gene-disease network, it was indicated that diseases such as liver carcinoma, breast carcinoma, liver fibrosis, prostate cancer, ovarian carcinoma, and lung cancer were correlated with gastric adenocarcinoma through specific genes, including hgf, mt2a, mmp2, fbn1, col1a1, and col1a2. It was shown that signaling pathways such as cell cycle, cell division, and extracellular matrix organization were overexpressed, while digestion and ion transport pathways were underexpressed. Based on a multilevel systems biology analysis, hub genes in gastric adenocarcinoma showed participation in the pathways such as focal adhesion, platelet activation, gastric acid secretion, HPV infection, and cell cycle. PPIs are hypothesized to have a therapeutic effect on patients with gastric cancer. Fostamatinib seems a potential therapeutic drug in gastric cancer due to its inhibitory effect on two survival genes. However, these findings should be confirmed through experimental investigations. [ABSTRACT FROM AUTHOR]

Background: Solute carrier family 26 member (SLC26A9) is a Cl− uniporter with very high expression levels in the gastric mucosa. Here, we describe morphological and molecular alterations in gastric mucosa of slc26a9−/− mice and in selective parietal cell-deleted slc26a9fl/fl/Atp4b-Cre mice and correlate SLC26A9 expression levels with morphological and clinical parameters in a cohort of gastric cancer (GC) patients. Methods: The expression patterns of genes related to transport and enzymatic function, proliferation, apoptosis, inflammation, barrier integrity, metaplasia and neoplasia development were studied by immunohistochemistry (IHC), quantitative RT-PCR, in situ hybridization and RNA microarray analysis. SLC26A9 expression and cellular/clinical phenotypes were studied in primary human GC tissues and GC cell lines. Results: We found that both complete and parietal cell-selective Slc26a9 deletion in mice caused spontaneous development of gastric premalignant and malignant lesions. Dysregulated differentiation of gastric stem cells in an inflammatory environment, activated Wnt signaling, cellular hyperproliferation, apoptosis inhibition and metaplasia were observed. Analysis of human gastric precancerous and cancerous tissues revealed that SLC26A9 expression progressively decreased from atrophic gastritis to GC, and that downregulation of SLC26A9 was correlated with patient survival. Exogenous expression of SLC26A9 in GC cells induced upregulation of the Cl−/HCO3− exchanger AE2, G2/M cell cycle arrest and apoptosis and suppressed their proliferation, migration and invasion. Conclusions: Our data indicate that SLC26A9 deletion in parietal cells is sufficient to trigger gastric metaplasia and the development of neoplastic lesions. In addition, we found that SLC26A9 expression decreases during human gastric carcinogenesis, and that exogenous SLC26A9 expression in GC cells reduces their malignant behavior. [ABSTRACT FROM AUTHOR]

Podocytes, alternatively called glomerular epithelial cells, are terminally differentiated cells that wrap around glomerular capillaries and function as a part of the glomerular filtration barrier in the kidney. Therefore, podocyte injury with morphological alteration and detachment from glomerular capillaries leads to severe proteinuria and subsequent renal failure through glomerulosclerosis. Previous RNA sequencing analysis of primary rat podocytes exposed to puromycin aminonucleoside (PAN), a well-known experimental model of injured podocytes, identified several transcripts as being aberrantly expressed. However, how the expression of these transcripts is regulated remains unclear. MicroRNAs (miRNAs) are small noncoding RNAs that posttranscriptionally inhibit the expression of their target transcripts. In this study, using small RNA sequencing analysis, miR-217-5p was identified as the most upregulated transcript in PAN-treated rat podocytes. MiR-217-5p overexpression in E11 podocyte cells led to shrunken cells with abnormal actin cytoskeletons. Consistent with these changes in cell morphology, gene ontology (GO) enrichment analysis showed that interactive GO terms related to cell morphogenesis were enriched with the predicted targets of miR-217-5p. Of the predicted targets highly downregulated by PAN, Myosin 1d (Myo1d) is a nonmuscle myosin predicted to be involved in actin filament organization and thought to play a role in podocyte morphogenesis and injury. We demonstrated that miR-217-5p targets Myo1d by luciferase assays, qRT–PCR, and Western blotting. Furthermore, we showed that miR-217-5p was present in urine from PAN- but not saline-administrated rats. Taken together, our data suggest that miR-217-5p may serve as a therapeutic target and a biomarker for podocyte injury. [ABSTRACT FROM AUTHOR]

The five plasma membrane Na+/H+ exchanger (NHE) isoforms in the gastrointestinal tract are characterized by distinct cellular localization, tissue distribution, inhibitor sensitivities, and physiological regulation. NHE1 (Slc9a1) is ubiquitously expressed along the gastrointestinal tract in the basolateral membrane of enterocytes, but so far, an exclusive role for NHE1 in enterocyte physiology has remained elusive. NHE2 (Slc9a2) and NHE8 (Slc9a8) are apically expressed isoforms with ubiquitous distribution along the colonic crypt axis. They are involved in pHi regulation of intestinal epithelial cells. Combined use of a knockout mouse model, intestinal organoid technology, and specific inhibitors revealed previously unrecognized actions of NHE2 and NHE8 in enterocyte proliferation and differentiation. NHE3 (Slc9a3), expressed in the apical membrane of differentiated intestinal epithelial cells, functions as the predominant nutrient-independent Na+ absorptive mechanism in the gut. The new selective NHE3 inhibitor (Tenapanor) allowed discovery of novel pathophysiological and drug-targetable NHE3 functions in cystic-fibrosis associated intestinal obstructions. NHE4, expressed in the basolateral membrane of parietal cells, is essential for parietal cell integrity and acid secretory function, through its role in cell volume regulation. This review focuses on the expression, regulation and activity of the five plasma membrane Na+/H+ exchangers in the gastrointestinal tract, emphasizing their role in maintaining intestinal homeostasis, or their impact on disease pathogenesis. We point to major open questions in identifying NHE interacting partners in central cellular pathways and processes and the necessity of determining their physiological role in a system where their endogenous expression/activity is maintained, such as organoids derived from different parts of the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Gastric electrical stimulation (GES) is currently used as an alternative treatment for medically refractory gastroparesis. GES has been initially developed to accelerate gastric motility, in order to relieve the symptoms of the patients. Subsequent studies, unfortunately, failed to demonstrate the acceleration of gastric emptying using high-frequency stimulation – low energy stimulation although the technique has shown a clinical impact with a reduction of nausea and vomiting for patients with gastroparesis. The present review details the clinical efficacy of GES in gastroparesis as well as its putative mechanisms of action. [ABSTRACT FROM AUTHOR]

In most mammals, leptin plays central and peripheral roles in a wide range of metabolic activities including feed consumption and digestion, energy expenditure and the regulation of carbohydrate‐fat accumulation. Ghrelin is a strong appetite‐stimulating hormone, while obestatin has the opposite effect of ghrelin. The latter is released during feeding, causing a sense of satiety. This study aimed to reveal if the metabolic hormones, as well as OB‐R and GHS‐R, were present in bull and ram abomasums. Streptavidin‐biotin peroxidase method was implemented to determine the expressions and localizations of metabolic hormones and their receptors, and obestatin. Immunoreactivity for leptin and obestatin was present in the cytoplasms of luminal and glandular cells, while smooth muscle cells were immunoreactant for ghrelin, in both bull and ram abomasums. Immunoreactivity for OB‐R was present in luminal and glandular cell, parietal cell cytoplasms, and blood vessels. Immunoreactivity for GHS‐R, on the other hand, was found in glandular epithelial cell cytoplasms and parietal cell cytoplasms, in both bull and ram abomasums. Leptin immunoreactivity was detected in the glandular epithelial cells and stroma, and particularly in the parietal cells. Ghrelin immunoreactivity was not observed in glandular epithelial cells. Obestatin immunoreactivity was found intensely in the bull abomasum, while moderate immunoreactivity was observed in the ram abomasums. As such, leptin, ghrelin and obestatin hormones were expressed in bull and ram abomasums, similar to the abomasums of other species. It is believed that these hormones play important roles in the digestive system activities and the regulation of energy in bulls and rams. [ABSTRACT FROM AUTHOR]

Angiostrongylus cantonensis is a worldwide zoonotic parasite that causes eosinophilic meningoencephalitis in many species of animals including humans. This report describes neuro-angiostrongylosis in a white-eared opossum that showed nervous clinical signs such as circling and depression. At necropsy, no relevant macroscopic lesions were observed. Histologically, eosinophilic meningoencephalitis was associated with multiple sections of nematodes and many intracytoplasmic eosinophilic inclusion bodies within gastric parietal cells. Immunohistochemistry was strongly positive for canine distemper virus in the stomach but there was no immunolabeling in the brain. This study describes a fatal case of eosinophilic meningoencephalitis by A. cantonensis with canine distemper virus concurrent infection in a white-eared opossum in southern Brazil, with histological characterization and molecular confirmation of the parasitism. [ABSTRACT FROM AUTHOR]

Autoimmune gastritis (AIG) is a special type of chronic gastritis characterized by autoimmune disorders caused by cellular immunity, resulting in the destruction of parietal cells and production of antiparietal cell antibodies. Endoscopic findings of AIG are mainly characterized by corpus‐dominant advanced atrophy. The antral area is generally considered to have no or mild atrophy; however, there are cases wherein the gastric mucosa is red or faded due to past infection with Helicobacter pylori or bile reflux. Currently, there are no diagnostic criteria for AIG in Japan, and it is important to make a diagnosis based on the presence of gastric autoantibodies and characteristic endoscopic and histological findings. AIG is associated with gastric cancer, neuroendocrine tumors (NETs), and other autoimmune diseases, such as thyroid diseases, anemia, and neurological symptoms due to impaired absorption of iron and vitamin B12, and thus requires systemic treatment. The significance of diagnosing AIG is to include patients as a high‐risk group for the development of gastric cancer and gastric NETs, provide an opportunity to detect autoimmune endocrine diseases, and initiate therapeutic intervention before anemia and neurological symptoms develop. It is important to pay close attention to the occurrence of AIG comorbidities not only at the time of AIG diagnosis but also during follow‐up after detection. [ABSTRACT FROM AUTHOR]

Background The sodium–glucose cotransporter-2 (SGLT2) inhibitor empagliflozin lowers blood glucose via reduced tubular reabsorption of filtered glucose and is an important new therapy for diabetic nephropathy (DN). This study tested whether treatment with empagliflozin would ameliorate proteinuria and the pathologic alterations of DN including podocyte number and integrity in the leptin-deficient BTBR ob/ob mouse model of DN. Methods Study cohorts included wild-type (WT) BTBR mice, untreated diabetic BTBR ob/ob mice and mice treated with empagliflozin for 6 weeks after development of established DN at 18 weeks of age. Results Hyperglycemia, proteinuria, serum creatinine, accumulation of mesangial matrix and the extent of mesangiolysis were reversed with empagliflozin treatment. Treatment with empagliflozin resulted in an increased podocyte number and podocyte density, improvement in the degree of podocyte foot process effacement and parietal epithelial cell activation. SGLT2 inhibition reduced renal oxidative stress, measured by urinary excretion of markers of RNA/DNA damage and in situ demonstration of decreased carbonyl oxidation. There was no discernable difference in accumulations of advanced glycation end-products by immunohistochemistry. Conclusion The structural improvements seen in BTBR ob/ob mice treated with empagliflozin provide insights into potential long-term benefits for humans with DN, for whom there is no comparable biopsy information to identify structural changes effected by SGLT2 inhibition. The findings suggest SGLT2 inhibition may ameliorate DN through glucose lowering–dependent and –independent mechanisms that lead to podocyte restoration and delay or reversal of disease progress. [ABSTRACT FROM AUTHOR]

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Pernicious anemia (PA) is a megaloblastic anemia consisting of hematological, gastric and immunological alterations. The immunopathogenesis of PA is sustained by both autoantibodies (e.g. intrinsic factor (IFA) antibodies and anti parietal cell (PCA) antibodies and autoreactive T cells specific for IFA and the parietal cell proton pump ATPase. Iron deficient anemia (IDA) is a microcytic anemia and represents the most common cause of anemia worldwide. Our work aimed to investigate serum levels of several interleukins (IL) of the IL-20 cytokine subfamily in patients with PA, with IDA and in healthy subjects (HC). We compared serum levels of IL-19, IL-20, IL-26, IL-28A and IL-29 in 43 patients with PA and autoimmune gastritis, in 20 patients with IDA and no autoimmune gastritis, and in 47 HC. Furthermore, we analyzed the IL-19 cytokine production by gastric lamina propria mononuclear cells (LPMC) in eight patients with PA and four HC. We found that patients with PA have significantly higher serum levels of IL-19 (163.68 ± 75.96 pg/ml) than patients with IDA (35.49 ± 40.97 pg/ml; p<0.001) and healthy subjects (55.68 ± 36.75 pg/ml; p<0.001). Gastric LPMC from all PA patients were able to produce significantly higher levels of IL-19 (420.67 ± 68.14 pg/ml) than HC (53.69 ± 10.92 pg/ml) (p <0.01). Altogether, our results indicate that IL-19 serum levels are significantly increased in patients with PA but not with IDA and that IL-19 is produced in vivo in the stomach of PA patients. These data open a new perspective on PA pathogenesis and suggest that IL-19 may represent a novel important tool for the management of patients with PA. [ABSTRACT FROM AUTHOR]

Background and Aim: In the gastric mucosa, pepsinogen II (PgII) is produced/secreted by glands in the mucus‐secreting antral and cardia compartments, but also by the chief cells and the oxyntic glands. Increasing PgII serum levels are associated with the whole spectrum of gastric inflammatory diseases, including gastritis induced by Helicobacter pylori (H. pylori). This review critically addresses the clinical value of PgII serology for assessing gastric mucosal inflammation, and as a marker of H. pylori status, in both H. pylori‐positive patients and after eradication therapy. Results: A search in PubMed/Scopus records yielded 39 out of 1190 published scientific studies meeting the selection criteria for this study. In the studies considered, PgII levels were significantly associated with non‐atrophic gastric inflammatory lesions (p‐values: 0.025–0.0001). H. pylori‐positive patients had significantly higher PgII levels than H. pylori‐negative individuals (p‐values: 0.o5–0.0001). While a significant drop in serum PgII levels is consistently reported in H. pylori‐eradicated patients (p‐values: from 0.05 to 0.0001), inconsistencies in the related negative and positive predictive values significantly lower the clinical reliability of PgII testing by comparison with other available non‐invasive tests. Conclusions: PgII serology may provide clinically useful information on gastric inflammatory diseases, particularly if they are non‐atrophic. PgII serology is inconsistent, however, for the purposes of distinguishing patients whose H. pylori eradication therapy is successful from those who remain infected. [ABSTRACT FROM AUTHOR]

The adult gastric mucosa is characterised by deep invaginations of the epithelium called glands. These tissue architectural elements are maintained with the contribution of morphogen signals. Morphogens are expressed in specific areas of the tissue, and their diffusion generates gradients in the microenvironment. Cells at different positions in the gland sense a specific combination of signals that instruct them to differentiate, proliferate, regenerate, or migrate. Differentiated cells perform specific functions involved in digestion, such as the production of protective mucus and the secretion of digestive enzymes or gastric acid. Biopsies from gastric precancerous conditions usually display tissue aberrations and change the shape of the glands. Alteration of the morphogen signalling microenvironment is likely to underlie those conditions. Furthermore, genes involved in morphogen signalling pathways are found to be frequently mutated in gastric cancer. We summarise the most recent findings regarding alterations of morphogen signalling during gastric carcinogenesis, and we highlight the new stem cell technologies that are improving our understanding of the regulation of human tissue shape. [ABSTRACT FROM AUTHOR]