Interstitial cells of the sip syncytium regulate basal membrane potential in murine gastric corpus.

Smooth muscle cells (SMCs), Interstitial cells of Cajal (ICC) and Platelet-derived growth factor receptor α positive (PDGFRα+) cells form an integrated, electrical syncytium within the gastrointestinal (GI) muscular tissues known as the SIP syncytium. Immunohistochemical analysis of gastric corpus muscles showed that c-KIT+/ANO1+ ICC-IM and PDGFRα+ cells were closely apposed to one another in the same anatomical niches. We used intracellular microelectrode recording from corpus muscle bundles to characterize the roles of intramuscular ICC and PDGFRα+ cells in conditioning membrane potentials of gastric muscles. In muscle bundles, that have a relatively higher input impedance than larger muscle strips or sheets, we recorded an ongoing discharge of stochastic fluctuations in membrane potential, previously called unitary potentials or spontaneous transient depolarizations (STDs) and spontaneous transient hyperpolarizations (STHs). We reasoned that STDs should be blocked by antagonists of ANO1, the signature conductance of ICC. Activation of ANO1 has been shown to generate spontaneous transient inward currents (STICs), which are the basis for STDs. Ani9 reduced membrane noise and caused hyperpolarization, but this agent did not block the fluctuations in membrane potential quantitatively. Apamin, an antagonist of small conductance Ca2+-activated K+ channels (SK3), the signature conductance in PDGFRα+ cells, further reduced membrane noise and caused depolarization. Reversing the order of channel antagonists reversed the sequence of depolarization and hyperpolarization. These experiments show that the ongoing discharge of STDs and STHs by ICC and PDGFRα+ cells, respectively, exerts conditioning effects on membrane potentials in the SIP syncytium that would effectively regulate the excitability of SMCs.

Gastric slow-wave modulation via power-controlled, irrigated radio-frequency ablation.

BACKGROUND: Recently, radio-frequency ablation has been used to modulate slow-wave activity in the porcine stomach. Gastric ablation is, however, still in its infancy compared to its history in the cardiac field, and electrophysiological studies have been restricted to temperature-controlled, non-irrigated ablation. Power-controlled, irrigated ablation may improve lesion formation at lower catheter-tip temperatures that produce the desired localized conduction block. METHODS AND RESULTS: Power-controlled, irrigated radio-frequency ablation was performed on the gastric serosal surface of female weaner pigs (n = 5) in vivo. Three combinations of power (10-15 W) and irrigation settings (2-5 mL min-1) were investigated. A total of 12 linear lesions were created (n = 4 for each combination). Slow waves were recorded before and after ablation using high-resolution electrical mapping. KEY RESULTS: Irrigation maintained catheter-tip temperature below 50°C. Ablation induced a complete conduction block in 8/12 cases (4/4 for 10 W at 2 mL min-1, 1/4 for 10 W at 5 mL min-1, 3/4 for 15 W at 5 mL min-1). Blocks were characterized by a decrease in signal amplitude at the lesion site, along with changes in slow-wave propagation patterns, where slow waves terminated at and/or rotated around the edge of the lesion. CONCLUSIONS AND INFERENCES: Power-controlled, irrigated ablation can successfully modulate gastric slow-wave activity at a reduced catheter-tip temperature compared to temperature-controlled, non-irrigated ablation. Reducing the irrigation rate is more effective than increasing power for blocking slow-wave activity. These benefits suggest that irrigated ablation is a suitable option for further translation into a clinical intervention for gastric electrophysiology disorders.

Randomized, crossover trial: comparing the effects of standardized egg-white meal and Vital® on global gastric emptying parameters and intragastric meal distribution in healthy Asian participants.

BACKGROUND AND AIM: Measurements of gastric emptying and accommodation for alternative test-meal protocol during gastric emptying scintigraphy (GES), such as high-calorie nutrient drinks, are not fully established. We aimed to compare the effects of standardized egg-white meal (EWM) versus high-calorie nutrient drink (Vital®; Abbott Laboratories) on global GES parameters and intragastric meal distribution at immediate scan (IMD0h). METHODS: Of 84 screened participants, 60 asymptomatic healthy Asian population (38 females; 24.0 ± 1.5 years; 23.8 ± 2.6 kg/m2) were recruited in this 2 × 2 (AB/BA) crossover trial. Participants were randomized to a 4-h GES with 99mTc-radiolabeled EWM (~255.8 kcal), followed by a 200 mL Vital® (300 kcal), or vice versa, separated by a 2-week washout period. Global meal retention (GMR), power-exponential model emptying parameters (half-emptying [T1/2], lag phases [Tlag2%, Tlag5%, Tlag10%]), and IMD0h were determined and compared. RESULTS: GMRs for both test meals were within the international standard references for solid GES. Compared to EWM, Vital® exhibited significantly lower GMRs (faster emptying) from 0.5 to 3 h (all P < 0.001) but comparable at 4 h (P = 0.153). Similar observations were found for the model-based T1/2 and the different Tlag thresholds (all P < 0.001). Furthermore, IMD0h was found to be lower with Vital®, indicating lower gastric accommodation (faster antral filling) immediately post-ingestion (P < 0.001). Both test meals showed significant moderate-to-strong positive associations at the late-phase GE (GMR 2-4 h, T1/2) (all P < 0.05). CONCLUSIONS: Overall, Vital® is an acceptable alternative test meal to the EWM for GES; however, exercise caution when interpreting early-phase GE. The normative values for global GES parameters and IMD0h are also established.

Regional differences in stomach stretch during organ filling and their implications on the mechanical stress response.

As part of the digestive system, the stomach plays a crucial role in the health and well-being of an organism. It produces acids and performs contractions that initiate the digestive process and begin the break-up of ingested food. Therefore, its mechanical properties are of interest. This study includes a detailed investigation of strains in the porcine stomach wall during passive organ filling. In addition, the observed strains were applied to tissue samples subjected to biaxial tensile tests. The results show inhomogeneous strains during filling, which tend to be higher in the circumferential direction (antrum: 13.2%, corpus: 22.0%, fundus: 67.8%), compared to the longitudinal direction (antrum: 4.8%, corpus: 24.7%, fundus: 50.0%) at a maximum filling of 3500 ml. Consequently, the fundus region experienced the greatest strain. In the biaxial tensile experiments, the corpus region appeared to be the stiffest, reaching nominal stress values above 400 kPa in the circumferential direction, whereas the other regions only reached stress levels of below 50 kPa in both directions for the investigated stretch range. Our findings gain new insight into stomach mechanics and provide valuable data for the development and validation of computational stomach models.

Stochastic Differential Equation-based Mixed Effects Model of the Fluid Volume in the Fasted Stomach in Healthy Adult Human.

The rate and extent of drug dissolution and absorption from a solid oral dosage form depend largely on the fluid volume along the gastrointestinal tract. Hence, a model built upon the gastric fluid volume profiles can help to predict drug dissolution and subsequent absorption. To capture the great inter- and intra-individual variability (IAV) of the gastric fluid volume in fasted human, a stochastic differential equation (SDE)-based mixed effects model was developed and compared with the ordinary differential equation (ODE)-based model. Twelve fasted healthy adult subjects were enrolled and had their gastric fluid volume measured before and after consumption of 240 mL of water at pre-determined intervals for up to 2 hours post ingestion. The SDE- and ODE-based mixed effects models were implemented and compared using extended Kalman filter algorithm via NONMEM. The SDE approach greatly improved the goodness of fit compared with the ODE counterpart. The proportional and additive measurement error of the final SDE model decreased from 14.4 to 4.10% and from 17.6 to 4.74 mL, respectively. The SDE-based mixed effects model successfully characterized the gastric volume profiles in the fasted healthy subjects, and provided a robust approximation of the physiological parameters in the very dynamic system. The remarkable IAV could be further separated into system dynamics terms and measurement error terms in the SDE model instead of only empirically attributing IAV to measurement errors in the traditional ODE method. The system dynamics were best captured by the random fluctuations of gastric emptying coefficient Kge.

Prox2 and Runx3 vagal sensory neurons regulate esophageal motility.

Vagal sensory neurons monitor mechanical and chemical stimuli in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many distinct subtypes of vagal sensory neurons. Here, we use genetically guided anatomical tracing, optogenetics, and electrophysiology to identify and characterize vagal sensory neuron subtypes expressing Prox2 and Runx3 in mice. We show that three of these neuronal subtypes innervate the esophagus and stomach in regionalized patterns, where they form intraganglionic laminar endings. Electrophysiological analysis revealed that they are low-threshold mechanoreceptors but possess different adaptation properties. Lastly, genetic ablation of Prox2 and Runx3 neurons demonstrated their essential roles for esophageal peristalsis in freely behaving mice. Our work defines the identity and function of the vagal neurons that provide mechanosensory feedback from the esophagus to the brain and could lead to better understanding and treatment of esophageal motility disorders.

Localized bioelectrical conduction block from radiofrequency gastric ablation persists after healing: safety and feasibility in a recovery model.

Gastric ablation has demonstrated potential to induce conduction blocks and correct abnormal electrical activity (i.e., ectopic slow-wave propagation) in acute, intraoperative in vivo studies. This study aimed to evaluate the safety and feasibility of gastric ablation to modulate slow-wave conduction after 2 wk of healing. Chronic in vivo experiments were performed in weaner pigs (n = 6). Animals were randomly divided into two groups: sham-ablation (n = 3, control group; no power delivery, room temperature, 5 s/point) and radiofrequency (RF) ablation (n = 3; temperature-control mode, 65°C, 5 s/point). In the initial surgery, high-resolution serosal electrical mapping (16 × 16 electrodes; 6 × 6 cm) was performed to define the baseline slow-wave activation profile. Ablation (sham/RF) was then performed in the mid-corpus, in a line around the circumferential axis of the stomach, followed by acute postablation mapping. All animals recovered from the procedure, with no sign of perforation or other complications. Two weeks later, intraoperative high-resolution mapping was repeated. High-resolution mapping showed that ablation successfully induced sustained conduction blocks in all cases in the RF-ablation group at both the acute and 2 wk time points, whereas all sham-controls had no conduction block. Histological and immunohistochemical evaluation showed that after 2 wk of healing, the lesions were in the inflammation and early proliferation phase, and interstitial cells of Cajal (ICC) were depleted and/or deformed within the ablation lesions. This safety and feasibility study demonstrates that gastric ablation can safely and effectively induce a sustained localized conduction block in the stomach without disrupting the surrounding slow-wave conduction capability.NEW & NOTEWORTHY Ablation has recently emerged as a tool for modulating gastric electrical activation and may hold interventional potential for disorders of gastric function. However, previous studies have been limited to the acute intraoperative setting. This study now presents the safety of gastric ablation after postsurgical recovery and healing. Localized electrical conduction blocks created by ablation remained after 2 wk of healing, and no perforation or other complications were observed over the postsurgical period.

Effect of Kvass on Improving Functional Dyspepsia in Rats.

Functional dyspepsia (FD) is a common digestive system disease, and probiotics in the treatment of FD have a good curative effect. Patients with gastrointestinal diseases often show a poor response to traditional drug treatments and suffer from adverse reactions. Kvass can be used as a functional drink without side effects to improve the symptoms of FD patients. The results showed that compared with those of the model group, the body weight and food intake of the treatment group were significantly increased (P < 0.05), and the gastric residual rate of the treatment group was significantly decreased (P < 0.05); the amount of pepsin in the treatment group was significantly higher than that in the model group (P < 0.05); a high dose of Kvass could increase the contents of ghrelin, motilin (MTL), and gastrin (GAS) in the plasma and decrease the contents of vasoactive intestinal peptide (VIP) in the plasma; the contents of ghrelin, MTL, and GAS in the gastric antrum were also increased in the high-dose group. Kvass beverage can significantly improve the gastrointestinal function of rats, which may be because it can improve the contents of ghrelin, MTL, GAS, and VIP in both the serum and gastric antrum by regulating the expression of short-chain fatty acids in the colon.

Effects of Anatomical Variations of the Stomach on Body-Surface Gastric Mapping Investigated Using a Large Population-Based Multiscale Simulation Approach.

Body-surface gastric mapping (BSGM) measures the resultant body-surface potentials of gastric slow waves using an array of cutaneous electrodes. However, there is no established protocol to guide the placement of the mapping array and to account for the effects of biodiversity on the interpretation of BSGM data. This study aims to quantify the effect of anatomical variation of the stomach on body surface potentials. To this end, 93 subject specific models of the stomach and torso were developed, based on data obtained from the Cancer Imaging Archive. For each subject a set of points were created to model general anatomy the stomach and the torso, using a finite element mesh. A bidomain model was used to simulate the gastric slow waves in the antegrade wave (AW) direction and formation of colliding waves (CW). A forward modeling approach was employed to simulate body-surface potentials from the equivaelent dipoles. Simulated data were sampled from a 5 × 5 array of electrodes from the body-surface and compared between AW and CW cases. Anatomical parameters such as the Euclidean distance from the xiphoid process (8.6 ± 2.2 cm), orientation relative to the axial plane (195 ± 20.0°) were quantified. Electrophysiological simulations of AW and CW were both correlated to specific metrics derived from BSGM signals. In general, the maximum amplitude ( ∆ ϕ) and orientation ( θ) of the signals provided consistent separation of AW and CW. The findings of this study will aid gastric BSGM electrode array design and placement protocol in clinical practices.

Cellular Plasticity, Reprogramming, and Regeneration: Metaplasia in the Stomach and Beyond.

The mucosa of the body of the stomach (ie, the gastric corpus) uses 2 overlapping, depth-dependent mechanisms to respond to injury. Superficial injury heals via surface cells with histopathologic changes like foveolar hyperplasia. Deeper, usually chronic, injury/inflammation, most frequently induced by the carcinogenic bacteria Helicobacter pylori, elicits glandular histopathologic alterations, initially manifesting as pyloric (also known as pseudopyloric) metaplasia. In this pyloric metaplasia, corpus glands become antrum (pylorus)-like with loss of acid-secreting parietal cells (atrophic gastritis), expansion of foveolar cells, and reprogramming of digestive enzyme-secreting chief cells into deep antral gland-like mucous cells. After acute parietal cell loss, chief cells can reprogram through an orderly stepwise progression (paligenosis) initiated by interleukin-13-secreting innate lymphoid cells (ILC2s). First, massive lysosomal activation helps mitigate reactive oxygen species and remove damaged organelles. Second, mucus and wound-healing proteins (eg, TFF2) and other transcriptional alterations are induced, at which point the reprogrammed chief cells are recognized as mucus-secreting spasmolytic polypeptide-expressing metaplasia cells. In chronic severe injury, glands with pyloric metaplasia can harbor both actively proliferating spasmolytic polypeptide-expressing metaplasia cells and eventually intestine-like cells. Gastric glands with such lineage confusion (mixed incomplete intestinal metaplasia and proliferative spasmolytic polypeptide-expressing metaplasia) may be at particular risk for progression to dysplasia and cancer. A pyloric-like pattern of metaplasia after injury also occurs in other gastrointestinal organs including esophagus, pancreas, and intestines, and the paligenosis program itself seems broadly conserved across tissues and species. Here we discuss aspects of metaplasia in stomach, incorporating data derived from animal models and work on human cells and tissues in correlation with diagnostic and clinical implications.

Functional characterization of cathepsin B and its role in the antimicrobial immune responses in golden pompano (Trachinotus ovatus).

Cathepsin B (CTSB) is one of the typical representatives of cysteine protease family. It has the activity of both exopeptidase and endopeptidase. It plays an important role in antigen presentation, degradation, apoptosis, inflammatory response and physiological process of many diseases. In this study, CTSB of Trachinotus ovatus (TroCTSB) was cloned, and its structure and function were analyzed. The results showed that the coding region of TroCTSB was 993 bp, encoding 330 amino acid residues. The homology analysis showed that the amino acid sequence of TroCTSB was similar to that in other teleosts and mammals (68.69%-88.48%). Under normal physiological conditions, TroCTSB was widely distributed in various tissues with the highest expression level in stomach, followed by liver, and the lowest expression level in blood. The optimal pH and temperature of purified recombinant protein rTroCTSB were 5.5 and 40 °C, respectively. The toxicity test of metal ions showed that Fe2+, Cu2+, Ca2+ and Zn2+ could all inhibit the activity of TroCTSB, with Zn2+ ranking the first. In addition, after Edwardsiella tarda infection, the expression of TroCTSB was significantly up-regulated in liver, spleen and head kidney. The overexpression of TroCTSB significantly inhibited the infection of E. tarda in golden pompano tissues, and the knockdown of TroCTSB remarkably promoted the reproduction of E. tarda in golden pompano tissues in vivo. This study suggests that TroCTSB was involved in the antibacterial immune response of T. ovatus, and provided a reference for further research in elucidating the resistance mechanism of TroCTSB.

Gastric Sensory and Motor Functions and Energy Intake in Health and Obesity-Therapeutic Implications.

Sensory and motor functions of the stomach, including gastric emptying and accommodation, have significant effects on energy consumption and appetite. Obesity is characterized by energy imbalance; altered gastric functions, such as rapid gastric emptying and large fasting gastric volume in obesity, may result in increased food intake prior to reaching usual fullness and increased appetite. Thus, many different interventions for obesity, including different diets, anti-obesity medications, bariatric endoscopy, and surgery, alter gastric functions and gastrointestinal motility. In this review, we focus on the role of the gastric and intestinal functions in food intake, pathophysiology of obesity, and obesity management.

Whole genome transcriptome analysis of the stomach resected in human vertical sleeve gastrectomy: cutting more than calories.

Vertical sleeve gastrectomy (VSG) is a surgical weight loss procedure that resects 80% of the stomach, creating a tube linking the esophagus to the duodenum. Because of the efficacy and relative simplicity of VSG, it is preferred in the United States, with VSG currently at >61% of bariatric surgeries performed. Surprisingly, there has never been a complete molecular characterization of the human stomach greater curvature's fundus and corpus. Here we compare and contrast the molecular makeup of these regions. We performed a prospective cohort study to obtain gastric tissue samples from patients undergoing elective VSG. Paired fundus and corpus samples were obtained. Whole genome transcriptome analysis was performed by RNA sequencing (N = 10), with key findings validated by qPCR (N = 24). Participants were primarily female (95.8%) and White (79.15%). Mean body mass index, body weight, and age were 46.1 kg/m2, 121.6 kg, and 43.29 yr, respectively. Overall, 432 gene transcripts were significantly different between the fundus and the corpus (P < 0.05). A significant correlation was found between the RNA sequencing dataset and qPCR validation, demonstrating robust gene expression differences between the fundus and the corpus. Significant genes included progastricsin, acidic chitinase, and gastokine 1 and 2 in both the fundus and the corpus. Of the very highly expressed genes in both regions, 87% were present in both the stomach's fundus and corpus, indicating substantial overlap. Despite significant overlap in the greater curvature gene signature, regional differences exist within the fundus and the corpus. Given that the mechanism of VSG is partly unresolved, the potential that the resected tissue may express genes that influence long-term body weight regulation is unknown and could influence VSG outcomes.

Ephrin receptor A2, the epithelial receptor for Epstein-Barr virus entry, is not available for efficient infection in human gastric organoids.

Epstein-Barr virus (EBV) is best known for infection of B cells, in which it usually establishes an asymptomatic lifelong infection, but is also associated with the development of multiple B cell lymphomas. EBV also infects epithelial cells and is associated with all cases of undifferentiated nasopharyngeal carcinoma (NPC). EBV is etiologically linked with at least 8% of gastric cancer (EBVaGC) that comprises a genetically and epigenetically distinct subset of GC. Although we have a very good understanding of B cell entry and lymphomagenesis, the sequence of events leading to EBVaGC remains poorly understood. Recently, ephrin receptor A2 (EPHA2) was proposed as the epithelial cell receptor on human cancer cell lines. Although we confirm some of these results, we demonstrate that EBV does not infect healthy adult stem cell-derived gastric organoids. In matched pairs of normal and cancer-derived organoids from the same patient, EBV only reproducibly infected the cancer organoids. While there was no clear pattern of differential expression between normal and cancer organoids for EPHA2 at the RNA and protein level, the subcellular location of the protein differed markedly. Confocal microscopy showed EPHA2 localization at the cell-cell junctions in primary cells, but not in cancer cell lines. Furthermore, histologic analysis of patient tissue revealed the absence of EBV in healthy epithelium and presence of EBV in epithelial cells from inflamed tissue. These data suggest that the EPHA2 receptor is not accessible to EBV on healthy gastric epithelial cells with intact cell-cell contacts, but either this or another, yet to be identified receptor may become accessible following cellular changes induced by inflammation or transformation, rendering changes in the cellular architecture an essential prerequisite to EBV infection.

Histological characterization of the gastrointestinal tract of the adult horseshoe crab (Limulus polyphemus) with special reference to the stomach.

The American horseshoe crab (Limulus polyphemus) is one of four extant species in the Order Xiphosura, subphylum Chelicerata, and are evolutionarily more closely related to scorpions and spiders, than crabs. The basic structure, function, and physiology of these invertebrates and their internal organs are not well documented in the literature. In this study, the gastrointestinal system, with a focus on the stomach, of adult L. polyphemus were assessed by gross and histologic methods to further characterize the pyloric valve, the lining of the ventricular lumen, and the muscular tunics of the stomach. Determination of normal anatomical structure of this organ system, along with characterization of the esophagus and intestinal tract, will set a standard against which tissue abnormalities, such as those seen with disease or pathology were to arise, would allow for better interpretation.

Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During Aging.

BACKGROUND & AIMS: Gastric dysfunction in the elderly may cause reduced food intake, frailty, and increased mortality. The pacemaker and neuromodulator cells interstitial cells of Cajal (ICC) decline with age in humans, and their loss contributes to gastric dysfunction in progeric klotho mice hypomorphic for the anti-aging Klotho protein. The mechanisms of ICC depletion remain unclear. Klotho attenuates Wnt (wingless-type MMTV integration site) signaling. Here, we examined whether unopposed Wnt signaling could underlie aging-associated ICC loss by up-regulating transformation related protein TRP53 in ICC stem cells (ICC-SC). METHODS: Mice aged 1-107 weeks, klotho mice, APCΔ468 mice with overactive Wnt signaling, mouse ICC-SC, and human gastric smooth muscles were studied by RNA sequencing, reverse transcription-polymerase chain reaction, immunoblots, immunofluorescence, histochemistry, flow cytometry, and methyltetrazolium, ethynyl/bromodeoxyuridine incorporation, and ex-vivo gastric compliance assays. Cells were manipulated pharmacologically and by gene overexpression and RNA interference. RESULTS: The klotho and aged mice showed similar ICC loss and impaired gastric compliance. ICC-SC decline preceded ICC depletion. Canonical Wnt signaling and TRP53 increased in gastric muscles of klotho and aged mice and middle-aged humans. Overstimulated canonical Wnt signaling increased DNA damage response and TRP53 and reduced ICC-SC self-renewal and gastric ICC. TRP53 induction persistently inhibited G1/S and G2/M cell cycle phase transitions without activating apoptosis, autophagy, cellular quiescence, or canonical markers/mediators of senescence. G1/S block reflected increased cyclin-dependent kinase inhibitor 1B and reduced cyclin D1 from reduced extracellular signal-regulated kinase activity. CONCLUSIONS: Increased Wnt signaling causes age-related ICC loss by up-regulating TRP53, which induces persistent ICC-SC cell cycle arrest without up-regulating canonical senescence markers.

A new method using a vessel-sealing system provides coagulation effects to various types of bleeding with less thermal damage.

BACKGROUND: Hemostasis is very important for a safe surgery, particularly in endoscopic surgery. Accordingly, in the last decade, vessel-sealing systems became popular as hemostatic devices. However, their use is limited due to thermal damage to organs, such as intestines and nerves. We developed a new method for safe coagulation using a vessel-sealing system, termed flat coagulation (FC). This study aimed to evaluate the efficacy of this new FC method compared to conventional coagulation methods. METHODS: We evaluated the thermal damage caused by various energy devices, such as the vessel-sealing system (FC method using LigaSure™), ultrasonic scissors (Sonicision™), and monopolar electrosurgery (cut/coagulation/spray/soft coagulation (SC) mode), on porcine organs, including the small intestine and liver. Furthermore, we compared the hemostasis time between the FC method and conventional methods in the superficial bleeding model using porcine mesentery. RESULTS: FC caused less thermal damage than monopolar electrosurgery's SC mode in the porcine liver and small intestine (liver: mean depth of thermal damage, 1.91 ± 0.35 vs 3.37 ± 0.28 mm; p = 0.0015). In the superficial bleeding model, the hemostasis time of FC was significantly shorter than that of electrosurgery's SC mode (mean, 19.54 ± 22.51 s vs 44.99 ± 21.18 s; p = 0.0046). CONCLUSION: This study showed that the FC method caused less thermal damage to porcine small intestine and liver than conventional methods. This FC method could provide easier and faster coagulation of superficial bleeds compared to that achieved by electrosurgery's SC mode. Therefore, this study motivates for the use of this new method to achieve hemostasis with various types of bleeds involving internal organs during endoscopic surgeries.

Ghrelin ameliorates nonalcoholic steatohepatitis induced by chronic low-grade inflammation via blockade of Kupffer cell M1 polarization.

Whether the stomach influences the progression of nonalcoholic steatohepatitis (NASH) remains largely unknown. Ghrelin, a 28-amino acid gastric hormone, is critical for the regulation of energy metabolism and inflammation. We investigated whether ghrelin affects the progression of NASH. NASH was induced with lipopolysaccharide (LPS; 240 µg/kg/day) in male C57BL/6J mice with high-fat diet (HFD). Ghrelin (11 nmol/kg/day) was administrated by a subcutaneous mini-pump. Liver steatosis, inflammation, and fibrosis were assessed. Kupffer cells and hepatocytes isolated from wild type, GHSR1a-/- or PPARγ+/- mice were cocultured to determine the cellular and molecular mechanism by which ghrelin ameliorates NASH. A low concentration of LPS activates the Kupffer cells, leading to the development of NASH in mice fed HFD. Ghrelin blocked the progression of NASH induced by LPS via GHSR1a-mediated attenuation of Kupffer cells M1 polarization. GHSR1a was detected in Kupffer cells isolated from wild-type mice but not in GHSR1a deficient animals. Upon binding with ghrelin, internalization of GHSR1a occurred. Ghrelin reduced levels of tumor necrosis factor-α and inducible nitricoxide synthase while increasing Arg1 in Kupffer cells treated with LPS. Ghrelin markedly attenuated the upregulation of lipid accumulation induced by the supernatant of Kupffer cells under both basal and LPS-treated conditions. Deficiency of PPARγ significantly reduced the effect of LPS on the hepatic steatosis in mice and in cultured hepatocytes. Our studies indicate that the stomach may improve the development of NASH via ghrelin. Ghrelin may serve as a marker and therapeutic target for NASH.

From 3D Back to 2D Monolayer Stomach Organoids-on-a-Chip.

2D monolayer gastric organoids (2DMGOs)-on-a-chip have consistent structures and can live for more than a year in culture. This state-of-the-art cell physiological system in a microfluidic device provides a way to investigate biomedically relevant, stimuli-dependent cellular responses in a variety of differentiated 2DMGOs.