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Background: Low-intensity pulsed ultrasound (LIPUS) combined with acupoint can promote gastric motility of diabetic rats. The switch of gastric smooth muscle cell (GSMCs) phenotype was related to the diabetes-induced gastric dysfunction, but the mechanism is not clearly elucidated. This study was aimed at exploring the underlying mechanism of LIPUS stimulation application in diabetic gastroparesis rats., Methods: In this study, Sprague-Dawley male rats were divided into three groups: control group (CON), diabetic gastroparesis group (DGP), and LIPUS-treated group (LIPUS). LIPUS irradiation was performed bilaterally at ST36 for 20 min per day for 4 weeks. The gastric emptying rate was measured by ultrasound examination. Contraction ability of GSMCs was assessed by muscle strip experiment. The expression of related proteins or mRNAs including α-SMA, SM22α, MHC, RhoA, Rock2, p-MYPT1, MYPT1, p-MLC, MLC, MALAT1, miR-449a, and DLL1 was detected by different methods such as western blotting, RT-qPCR, immunohistochemistry, and immunofluorescence staining, as appropriate., Key Results: (a) LIPUS stimulation at ST36 could improve the gastric motility dysfunction of diabetic rats. (b) LIPUS increased RhoA, Rock2, p-MYPT1, and p-MLC expression level. (c) MALAT1 and DLL1 contents were decreased, but the level of miR-449a was increased in the LIPUS group., Conclusions & Inferences: LIPUS may affect the contractile marker expression of gastric smooth muscle through the RhoA/Rock and MALAT1/miR-449a/DLL1 pathway to ameliorate DGP., (© 2024 John Wiley & Sons Ltd.)

This study aimed to investigate the changes in oxidative stress, adenosine monophosphate-activated protein kinase (AMPK), connexin43 (Cx43), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression, and extracellular matrix (ECM) in the gastric smooth muscle tissues of rats with diabetic gastroparesis (DGP) and high glucose-cultured gastric smooth muscle cells, determine the existence of oxidative stress-AMPK-Cx43-NLRP3 pathway under high glucose condition, and the involvement of this pathway in ECM remodeling in DGP rats. The results showed that with increasing duration of diabetes, oxidation stress levels gradually increased, the AMPK activity decreased first and then increased, NLRP3, CX43 expression, and membrane/cytoplasm ratio of Cx43 expression were increased in the gastric smooth muscle tissues of diabetic rats. Changes in ECM of gastric smooth muscle cells were observed in DGP rats. The DGP group showed higher collagen type I content, increased expression of Caspase-1, transforming growth factor-beta 3 (TGF-β 3 ), and matrix metalloproteinase-2 (MMP-2), decreased tissue inhibitor of metalloproteinase-1 (TIMP-1) expression, and higher interleukin-1 beta content when compared with the control group. For gastric smooth muscle cells cultured under higher glucose, the MMP-2 and TGF-β3 expression was decreased, TGF-β1 and TIMP-1 expression was increased, the interleukin-1 beta content was decreased in cells after inhibition of NLRP3 expression; the NLRP3 and Caspase-1 expression was decreased, and adenosine triphosphate content was lower after inhibition of Cx43; the expression of NLRP3, Caspase-1, P2X7, and the membrane/cytoplasm ratio of CX43 expression was decreased in cells after inhibition of AMPK and oxidative stress, the phospho-AMPK expression was also decreased after suppressing oxidative stress. Our findings suggest that high glucose induced the activation of the AMPK-Cx43-NLRP3 pathway through oxidative stress, and this pathway was involved in the ECM remodeling of gastric smooth muscles in DGP rats by regulating the biological functions of TGF-β3, TGF-β1, MMP-2, and TIMP-1., Competing Interests: Declarations of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Diabetic gastroparesis (DGP) is a common complication of type 2 diabetes mellitus (T2DM). Alpinia officinarum Hance (AOH) is one of the most commonly used both as a food and folk medicines, which is rich in diarylheptanoids and flavonoids. The gastroprotection and hypoglycemic effect make AOH has great potential in developing of anti-DGP complementary medicine. However, the molecular mechanisms of AOH that act against DGP are yet to be elucidated. In this study, we evaluated the therapeutic effects, the potential molecular mechanism, and the changes of gut microbiota of AOH in DGP. The 5 components of the AOH were analyzed, and the potential signaling pathway of AOH improving DGP was predicted by molecular docking. Subsequently, DGP rat model was constructed using high-fat-irregular-diet, AOH intervention significantly reduced blood glucose levels, increased gastrointestinal propulsion rate, and improved gastric histological morphology in DGP rats. Meanwhile, AOH has been shown to regulate the SCF/c-kit signaling pathway and rebalance the gut microbiota, which may be closely related to its role in improving DGP. Taken together, AOH may play a protective role on DGP through multiple mechanisms, which might pave the road for development and utilization of AOH., Competing Interests: Declaration of Competing Interest The research was conducted in the absence of any commercial or financial relationships. All authors have no competing interests to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Diabetic gastroparesis (DGP) is characterized by delayed gastric emptying of solid food. Nitrergic neuron-mediated fundus relaxation and intragastric peristalsis are pivotal for gastric emptying and are impaired in DGP. Transient receptor potential vanilloid 1 (TRPV1) ion channels are expressed in gastrointestinal vagal afferent nerves and have a potential role in relevant gastrointestinal disorders. In this study, mice with high-fat diet (HFD)-induced type 2 diabetes mellitus (T2DM), associated with gastroparesis, were used to determine the role of TRPV1 in DGP. After feeding with HFD, mice exhibited obesity, hyperglycemia, insulin resistance, and delayed gastric emptying. Cholinergic- and nitrergic neuron-mediated neuromuscular contractions and relaxation were impaired. The antral tone of the DGP mice was attenuated. Interestingly, activating or suppressing TRPV1 facilitated or inhibited gastric fundus relaxation in normal mice. These effects were neutralized by using a nitric oxide synthase (NOS) inhibitor. Activation or suppression of TRPV1 also increased or reduced NO release. TRPV1 was specifically localized with neuronal NOS in the gastric fundus. These data suggest that TRPV1 activation facilitates gastric fundus relaxation by regulating neuronal NOS and promoting NO release. However, these effects and mechanisms disappeared in mice with DGP induced by HFD diet. TRPV1 expression was only marginally decreased in the fundus of DGP mice. TRPV1 dysfunction may be a potential mechanism underlying the dysfunction of DGP gastric nitrergic neuromuscular relaxation., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To observe the effect of electroacupuncture (EA) of "Zusanli" (ST36), "Sanyinjiao" (SP6) and "Liangmen" (ST21) on gastrointestinal motility, blood glucose content and expression of autophagy-related proteins 1 light chain 3 (LC3), p62, phosphatidyli-nositol-3 kinase (PI3K), protein kinase B (Akt), p-Akt and mammalian target protein of rapamycin (mTOR) of interstitial cells of Cajal (ICCs) in the cultured gastric antrum cells in diabetic gastroparesis (DGP) rats, so as to reveal its mechanisms underlying improvement of DGP., Methods: A total of 45 Sprague Dawley (SD) rats were randomly divided into blank control, model, EA, medication (3-methyladenine, 3-MA) and EA+3-MA groups, with 9 rats in each group. The DGP model was established by intraperitoneal injection of 2% streptozotocin (STZ) combined with high-fat and high sugar diet for 8 weeks. The gastric emptying rate was measured by using gavage of phenol red (to measure the propelling length of the phenol red/total length of small intestine ×100%). The symptom score (mental state, coat color and luster, behavior and activity, stool traits) of rats was observed every week and the blood glucose content was measured by using a glucometer. EA (20 Hz/100 Hz, 2 mA) was applied to unilateral ST36, SP6 and ST21 alternatively for 15 min, once daily, 5 days a week for 3 weeks. Rats of the 3-MA and 3-MA+EA groups received intraperitoneal injection of 3-MA (30 mg·kg -1 ·d -1 , 10 mg/mL), once daily, 5 days a week for 3 weeks. After 15 days' intervention, the rats were operated for gastric emptying rate test, specimen collection, isolation, and culture of primary ICCs. The expression levels of microtubule associated protein LC3, p62, PI3K, Akt, p-Akt and mTOR of ICCs of cultured gastric antrum cells were detected using Western blot, and the number of autophagosomes in ICC of gastric antrum was observed under transmission electron microscope., Results: Compared with the blank control group, the symptom score, blood glucose, and the expression levels of p62, class Ⅰ PI3K, Akt, p-Akt and mTOR proteins were increased significantly ( P <0.01), while the gastric emptying rate and ratio of LC3Ⅱ/LC3Ⅰ and the expression level of class Ⅲ PI3K protein were significantly decreased ( P <0.05, P <0.01) in the model group. In comparison with the model group, the increase of symptom score, blood glucose, and expression levels of p62, class Ⅰ PI3K, Akt, p-Akt and mTOR proteins and the decrease of gastric empty rate and LC3Ⅱ/LC3Ⅰ ratio and the expression level of class Ⅲ PI3K protein were all reversed in both EA and EA+3-MA groups ( P <0.05, P <0.01), rather than in the 3-MA group. In addition, 3-MA also reversed modeling-induced increase of class Ⅰ PI3K, Akt, p-Akt and mTOR proteins expression ( P <0.01). No significant differences were found between the EA and EA+3-MA in downregulating the levels of symptom score and blood glucose content, and in upregulating gastric empty rate( P >0.05). The effect of EA was notably superior to that of EA+3-MA in upregulating the ratio of LC3Ⅱ/LC3Ⅰ and the expression level of class Ⅲ PI3K protein, and in downregulating the expression of p62, class Ⅰ PI3K, Akt, p-Akt and mTOR proteins ( P <0.05, P <0.01). The findings of transmission electron microscopy showed obvious swelling, breakage of some mitochondrial cristae in the ICC cells of antrum and no autophagosomes in the model group and 3-MA group, which was milder in the damage of mitochondrial cristae and marked increase in the autophagosomes in both EA and EA+3-MA groups., Conclusion: EA can improve the gastrointestinal motility and symptoms in DGP rats, which may be related to its functions in downregulating PI3K/Akt/mTOR signaling to promote autophagy level of ICC.

Objective: To observe the effect of electroacupuncture (EA) combined with Zhuang-medicine-thread moxibustion on expression of apoptosis-related factors in gastric antrum of diabetic gastroparesis (DGP) rats, so as to explore its mechanism underlying improvement of DGP., Methods: Male SD rats were randomly divided into normal, model, medication, EA, Zhuang-medicine-thread moxibustion (moxibustion) and EA+moxibustion (combination) groups (12 rats in each group). The DGP model was established by intraperitoneal injection of streptozotocin (STZ). Rats of the medication group were treated by gavage of 0.15 mg/mL mosapride citrate suspension （10 mL/kg）. EA (10 Hz/50 Hz, 2 mA, 20 min) or Zhuang-medicine-thread moxibustion (3 cones) was applied to "Zhongwan" (CV12), bilateral "Neiguan" (PC6) and bilateral "Sanyinjiao" (SP6) of the related groups, once a day for 3 weeks. The blood glucose, gastric emptying rate and intestinal propulsion rate of rats were measured. The apoptosis index of gastric antrum cells were observed by TUNEL staining. The protein and mRNA expressions of Caspase-3, B-cell lymphoma/leukemia-2 (Bcl-2) and Bcl-2 associated X protein (Bax) in gastric antrum were detected by Wes-tern blot and real-time quantitative PCR, respectively., Results: Compared with the normal group, the blood glucose, the apoptosis index, the protein and gene expressions of Caspase-3 and Bax were significantly increased ( P <0.01), and the gastric emptying rate, intestinal propulsive rate, the protein and gene expressions of Bcl-2 were considerably decreased ( P <0.01) in the model group. In contrast to the model group, the blood glucose in the EA, moxibustion and combination groups, the apoptosis index in the 4 treatment groups, as well as Caspase-3 protein, Bax protein and mRNA expressions in the medication, EA and combination groups, Caspase-3 protein and mRNA, Bax mRNA expressions in the moxibustion group were significantly decreased ( P <0.01, P <0.05); while the gastric emptying rate and intestinal propulsive rate in the 4 treatment groups, and Bcl-2 protein and mRNA expressions in the medication and combination groups, Bcl-2 mRNA expressions in the EA and moxibustion groups were obviously increased ( P <0.01). The effects of EA+moxibustion were significantly superior to those of simple EA, moxibustion or medication in increasing gastric emptying rate and intestinal propulsive rate, and in lowering blood glucose ( P <0.05, P <0.01). And the effects of the combination treatment were better than those of EA in lowering Caspase-3 protein and Bax mRNA expressions ( P <0.01), and in increasing Bcl-2 protein and mRNA expressions ( P <0.05, P <0.01). Also the effects of the combination treatment were better than those of moxibustion in lowering the apoptosis index, Caspase-3 protein, and Bax protein and mRNA expressions ( P <0.01, P <0.05), and in increasing Bcl-2 protein expression ( P <0.05)., Conclusion: EA combined with Zhuang-medicine-thread moxibustion can reduce blood glucose and improve gastrointestinal motility in DGP rats, which may be related to its effect in regulating of Caspase-3, Bax and Bcl-2 expression.

Motilin is a 22-amino-acid gastrointestinal (GI) hormone and is involved in the regulation of GI motility through binding to GPR38, the motilin receptor which is expressed on smooth muscle cells in the GI tract. Therefore, GPR38 agonists are expected to be novel gastrointestinal prokinetic agents for the treatment of functional gastrointestinal disorders such as gastroparesis and chronic constipation. We identified a series of N-methylanilide derivatives as novel non-macrolide GPR38 agonists. Among them, 12 di-l-tartrate (DS-3801b) was selected as a clinical candidate for further evaluation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Gastric peristalsis is critically dependent on an underlying electrical conduction system. Recent years have witnessed substantial progress in clarifying the operations of this system, including its pacemaking units, its cellular architecture, and slow-wave propagation patterns. Advanced techniques have been developed for assessing its functions at high spatiotemporal resolutions. This review synthesizes and evaluates this progress, with a focus on human and translational physiology. A current conception of the initiation and conduction of slow-wave activity in the human stomach is provided first, followed by a detailed discussion of its organization at the cellular and tissue level. Particular emphasis is then given to how gastric electrical disorders may contribute to disease states. Gastric dysfunction continues to grow in their prevalence and impact, and while gastric dysrhythmia is established as a clear and pervasive feature in several major gastric disorders, its role in explaining pathophysiology and informing therapy is still emerging. New insights from high-resolution gastric mapping are evaluated, together with historical data from electrogastrography, and the physiological relevance of emerging biomarkers from body surface mapping such as retrograde propagating slow waves. Knowledge gaps requiring further physiological research are highlighted.

Probiotics have been suggested to be effective for functional dyspepsia, but their effect on gastric motility is not clear. We evaluated the effect of Lactobacillus gasseri OLL2716 (LG21 strain) on mild to moderate delayed gastric emptying by a double-blind, parallel-group, placebo-controlled, randomized trial. Participants ( n = 28) were randomly assigned to ingest LG21 strain-containing yogurt (LG21 strain group) or LG21 strain-free yogurt (placebo group) for 12 weeks. The 13 C gastric emptying breath test was performed to measure the gastric emptying rate over time following ingestion of a liquid meal, and the time to reach the peak (Tmax) was used as an indicator of gastric emptying. We also measured the salivary amylase concentration, an indicator of autonomic dysfunction under stress. The per-protocol population ( n = 27, male n = 4, female n = 23) was evaluated for efficacy. When a ≥30% reduction in the difference between participant's Tmax and the Japanese mean Tmax was defined as an improvement, the odds ratio of improvement in delayed gastric emptying compared to placebo after 12 weeks was 4.1 (95% confidence interval, 0.8 to 20.2). Moreover, salivary amylase concentrations were significantly lower than in the placebo group, indicating an improvement in autonomic function. The present data were not enough to support the beneficial effects of the LG21 strain on delayed gastric emptying. However, if we define the odds ratio in further study investigated with a larger number of participants, LG21 strain might be expected to have some impact on delayed gastric emptying.

Background & Aims: Interstitial cells of Cajal (ICCs) and pancreatic β cells require receptor tyrosine kinase (KIT) to develop and function properly. Degeneration of ICCs is linked to diabetic gastroparesis. The mechanisms linking diabetes and gastroparesis are unclear, but may involve microRNA (miRNA)-mediated post-transcriptional gene silencing in KIT + cells., Methods: We performed miRNA-sequencing analysis from isolated ICCs in diabetic mice and plasma from patients with idiopathic and diabetic gastroparesis. miR-10b-5p target genes were identified and validated in mouse and human cell lines. For loss-of-function studies, we used KIT + cell-restricted mir-10b knockout mice and KIT + cell depletion mice. For gain-of-function studies, a synthetic miR-10b-5p mimic was injected in multiple diabetic mouse models. We compared the efficacy of miR-10b-5p mimic treatment vs antidiabetic and prokinetic medicines., Results: miR-10b-5p is highly expressed in ICCs from healthy mice, but drastically depleted in ICCs from diabetic mice. A conditional knockout of mir-10b in KIT + cells or depletion of KIT + cells in mice leads to degeneration of β cells and ICCs, resulting in diabetes and gastroparesis. miR-10b-5p targets the transcription factor Krüppel-like factor 11 (KLF11), which negatively regulates KIT expression. The miR-10b-5p mimic or Klf11 small interfering RNAs injected into mir-10b knockout mice, diet-induced diabetic mice, and TALLYHO polygenic diabetic mice rescue the diabetes and gastroparesis phenotype for an extended period of time. Furthermore, the miR-10b-5p mimic is more effective in improving glucose homoeostasis and gastrointestinal motility compared with common antidiabetic and prokinetic medications., Conclusions: miR-10b-5p is a key regulator in diabetes and gastrointestinal dysmotility via the KLF11-KIT pathway. Restoration of miR-10b-5p may provide therapeutic benefits for these disorders., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Gastric motility is coordinated by underlying bioelectrical "slow wave" activity. Slow wave dysrhythmias are associated with motility disorders, including gastroparesis, offering an underexplored potential therapeutic target. Although ablation is widely used to treat cardiac arrhythmias, this approach has not yet been trialed for gastric electrical abnormalities. We hypothesized that ablation can create localized conduction blocks and modulate slow wave activation. Radiofrequency ablation was performed on the porcine serosa in vivo, encompassing a range of parameters (55-85°C, adjacent points forming a line, 5-10 s/point). High-resolution electrical mapping (16 × 16 electrodes; 6 × 6 cm) was applied to define baseline and acute postablation activation patterns. Tissue damage was evaluated by hematoxylin and eosin and c-Kit stains. Results demonstrated that RF ablation successfully induced complete conduction block and a full thickness lesion in the muscle layer at energy doses of 65-75°C for 5-10 s/point. Gastric ablation may hold therapeutic potential for gastric electrical abnormalities in the future. NEW & NOTEWORTHY This study presents gastric ablation as a new method for modulating slow wave activation and propagation in vivo, by creating localized electrical conduction blocks in the stomach, validated by high-resolution electrical mapping and histological tissue analysis. The results define the effective energy dose range for creating conduction blocks, while maintaining the mucosal and submucosal integrity, and demonstrate the electrophysiological effects of ablation. In future, gastric ablation can now be translated toward disrupting dysrhythmic slow wave activation.

Background: Gastroparesis is a heterogeneous disorder. Patient characteristics and treatment responsiveness may differ based on the extent of delay in gastric emptying., Aims: Characterize gastroparesis patients based on the degree of delay in gastric emptying, and assess the relationship of patient demographics, symptoms and response to therapy based on the extent of delay., Methods: 1333 solid-phase 4-h scintigraphic gastric emptying scans were reviewed. Delayed emptying was categorized on percent retention at 4 h: mild (10-19%), moderate (20-29%), and severe (≥ 30%). Analyses were performed with regard to demographics, symptoms, esophagogastroduodenoscopy findings, medication use, and emergency department (ED) visits/hospitalizations., Results: 284 patients had delayed gastric emptying: mild (42.6%), moderate (19.3%), and severe (37.3%). 79.5% were women, the mean age was 45 years (± 15), and mean symptom duration was 4.6 years (± 6.5). The main categories of gastroparesis were idiopathic and diabetes mellitus. The most commonly prescribed medications were metoclopramide, domperidone and erythromycin. Opiate use (n = 69) was associated with an increased degree of delayed gastric emptying (p = 0.03) with 50% of opiate users having very delayed gastric emptying. One-way analysis revealed that severely delayed gastric emptying correlated with both increased hospitalizations and ED visits., Conclusions: Severe delay in gastric emptying is a risk factor for increased hospitalizations and ED visits. Opiate use correlates with increased severity of gastric emptying. Identifying at-risk patients, stopping opioids, and instituting a programmatic care plan for patients with severely delayed gastric emptying may reduce ED visits, hospitalizations, and healthcare costs.

Oral levothyroxine sodium is absorbed in the small intestine, mainly in the jejunum and the ileum being lower the absorption rate at duodenal level. The time interval between the ingestion of oral thyroxine and its appearance in the plasma renders unlike a gastric absorption of the hormone. However, several evidence confirm the key role of the stomach as a prerequisite for an efficient absorption of oral levothyroxine. In the stomach, in fact, occur key steps leading to the dissolution of thyroxine from the solid form, the process bringing the active ingredient from the pharmaceutical preparation to the aqueous solution. In particular, gastric juice pH, volume, viscosity, as well as gastric emptying time seem to be the most important limiting factors. These hypotheses are confirmed by the detection of an increased need for levothyroxine in patients with Helicobacter pylori infection, chronic atrophic gastritis, gastroparesis, or in simultaneous treatment with drugs interfering with gastric acidic output. The aim of the present article is to focus on the knowledge of pathophysiologic events that determine the absorptive fate of traditional (tablet) and alternative thyroxine preparations (softgel capsule and liquid solution) in patients bearing gastric disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Virili, Brusca, Capriello and Centanni.)

In the precedent research conducted by the same team, it concluded that the activities in C-type natriuretic peptide (CNP)/cyclic guanosine monophosphate (cGMP)/cyclic adenosine monophosphate (cAMP)/β-type phospholipase C (PLCβ) pathways of rat antral smooth muscle were changed due to diabetes, which was the key pathogenetic mechanism for diabetic gastric dysmotility. As the follow-on step, this study was designed to probe into the downstream signaling pathway of CNP/PLCβ. The results showed that level of α-type protein kinase C (PKCα),cell membrane to cytoplasm ratio of PKCα, cell membrane to cytoplasmic ratio of βI-type protein kinase C (PKCβI) and level of Phosphor-PKCα (P-PKCα) were significantly reduced in diabetes rat antral smooth muscle samples. The content of tetraphosphate inositol (IP4) in gastric antral smooth muscle of diabetic rats reduced, and the content of diacyl-glycerol (DG) was unchanged. CNP significantly decreased the content of IP4 and DG, this effect was more obvious in diabetic rats. Subsequent to the addition of protein kinase A (PKA) blocker N-[2- (p-Bromocin-namylamino)ethyl]-5 -isoquinolinesulfonamide dihydrochloride (H-89) before CNP treatment, the inhibitory effect of CNP was reduced; subsequent to the addition of protein kinase G (PKG) blocker KT5823 before CNP treatment, the inhibitory effect of CNP was also reduced. With the addition of the combination of H-89 and KT5823 before CNP treatment, the inhibition by CNP could be offset. These results were concluded that CNP inhibited the activity of PKC family in rat smooth muscle and reduced the levels of IP4 and DG through the PKG/PKA-PLCβ pathways, causing inhibited muscular contractions, which may be a key pathogenetic factor for diabetic gastroparesis.

Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in diabetic mice. Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages has been reported in full-thickness gastric biopsies from gastroparesis patients. We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients. Additionally, we determined correlations between protein expressions, gastric emptying, and symptoms. Full-thickness gastric antrum biopsies were obtained from nine DG patients, seven IG patients, and five nondiabetic controls. Aptamer-based SomaLogic tissue scan that quantitatively identifies 1,305 human proteins was used. Protein fold changes were computed, and differential expressions were calculated using Limma. Ingenuity pathway analysis and correlations were carried out. Multiple-testing corrected P < 0.05 was considered statistically significant. Seventy-three proteins were differentially expressed in DG, 132 proteins were differentially expressed in IG, and 40 proteins were common to DG and IG. In both DG and IG, "Role of Macrophages, Fibroblasts and Endothelial Cells" was the most statistically significant altered pathway [DG false discovery rate (FDR) = 7.9 × 10 -9 ; IG FDR = 6.3 × 10 -12 ]. In DG, properdin expression correlated with GCSI bloating ( r = -0.99, FDR = 0.02) and expressions of prostaglandin G/H synthase 2, protein kinase C-ζ type, and complement C2 correlated with 4 h gastric retention ( r = -0.97, FDR = 0.03 for all). No correlations were found between proteins and symptoms or gastric emptying in IG. Protein expression changes suggest a central role of macrophage-driven immune dysregulation in gastroparesis, specifically, complement activation in diabetic gastroparesis. NEW & NOTEWORTHY This study uses SOMAscan, a novel proteomics assay for determination of altered proteins and associated molecular pathways in human gastroparesis. Seventy-three proteins were changed in diabetic gastroparesis, 132 in idiopathic gastroparesis compared with controls. Forty proteins were common in both. Macrophage-based immune dysregulation pathway was most significantly affected in both diabetic and idiopathic gastroparesis. Proteins involved in the complement and prostaglandin synthesis pathway were associated with symptoms and gastric emptying delay in diabetic gastroparesis.

Background: Gastric emptying is impaired in patients with gastroparesis whereas it is either unchanged or accelerated in obese individuals. The goal of the current study was to identify changes in gene expression in the stomach muscularis that may be contributing to altered gastric motility in idiopathic gastroparesis and obesity., Methods: Quantitative real time RT-PCR and whole transcriptome sequencing were used to compare the transcriptomes of lean individuals, obese individuals and either lean or obese individuals with idiopathic gastroparesis., Results: Obesity leads to an increase in mRNAs associated with muscle contractility whereas idiopathic gastroparesis leads to a decrease in mRNAs associated with PDGF BB signaling. Both obesity and idiopathic gastroparesis were also associated with similar alterations in pathways associated with inflammation., Conclusions: Our findings show that obesity and idiopathic gastroparesis result in overlapping but distinct changes in the gastric muscularis transcriptome. Increased expression of mRNAs encoding smooth muscle contractile proteins may be contributing to the increased gastric motility observed in obese subjects, whereas decreased PDGF BB signaling may be contributing to the impaired motility seen in subjects with idiopathic gastroparesis.

This study aimed to investigate the effect of AMPK on apoptosis and energy metabolism of gastric smooth muscle cells in diabetic rats and to explore the role of AMPK in the pathogenesis of diabetic gastroparesis (DGP). After establishment of a diabetic rat model, rats were divided into normal control (NC), 4-week (DM4W), 6-week (DM6W), and 8-week (DM8W) diabetic model groups. The gastric residual pigment ratio, intestinal transit rate, and intestinal propulsion rate in each group were detected to confirm the successful establishment of the DGP model. The spontaneous contraction in isolated gastric smooth muscle strips of the NC and DM8W groups was experimentally observed. The expression of phospho-AMPK, AMPK, phospho-LKB1, LKB1, phospho-TAK1, TAK1, and CaMMKβ in rat gastric smooth muscle tissues was detected by western blot analysis; ADP, AMP, ATP contents, and the energy charge were detected using Elisa; and apoptosis of gastric smooth muscle cells was detected by flow cytometry. The rat gastric smooth muscle cells were cultured in vitro, and treated with an AMPK inhibitor and an agonist. At 24 and 48 h, the effects of AMPK on apoptosis and energy metabolism of gastric smooth muscle cells were observed. Reduced spontaneous contractions, AMPK activation, cell apoptosis, and energy metabolism disorders were observed in gastric smooth muscle tissues of a diabetic rat, and AMPK activation was associated with an increased ratio of ADP/ATP, AMP/ATP, LKB1 activity, and CaMMKβ expression. From in vitro cell culture experiments, we found that AMPK activation of high-glucose conditions promoted cell apoptosis. Inhibition of AMPK had no obvious effect on apoptosis at the early stage with high glucose, but the inhibitory effect was significant at the late stage with high glucose. AMPK can regulate both mitochondrial metabolism and glycolysis pathways under high-glucose conditions. During the early stage with high glucose, AMPK was the main promotion factor of the mitochondrial metabolism pathway, but did not increase the ATP production, AMPK also promoted the glycolysis pathway. During the late stage with high glucose, AMPK was a major inhibitor of the mitochondrial pathway, and still played a role in promoting the glycolytic pathway, which acted as the main regulator. Apoptosis and energy metabolism disorders were present in gastric smooth muscle cells during the occurrence of DGP. Under high-glucose condition, AMPK was activated, which can promote apoptosis, change the energetic metabolism pathway of cells, inhibit mitochondrial energy metabolism, and promote glycolysis.

Diabetic gastroparesis (GP) is a clinical syndrome characterized by delayed gastric emptying (DGE). Loss of Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) led to reduced nNOSα mediated gastric motility and DGE. The molecular signaling of cinnamaldehyde (CNM) mediated Nrf2 activation and its mechanistic role on DGE were further investigated in obese/T2D female mice. Adult female homozygous Nfe2l2 -/- (C57BL/6J) and their wild-type (WT) littermates (Nfe2l2 +/+ ) mice were fed with high fat diet (HFD; Obese/T2D model), or normal diet (ND) with or without CNM (50 mg/kg b.w; i.p). Supplementation of CNM attenuated (p < 0.05) DGE in WT female but not in Nrf2 KO Obese/T2D mice. CNM (1) normalized serum estradiol-17β levels, (2) induced gastric Nrf2 and phase II antioxidant enzymes through extracellular signal-regulated kinase, (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK), (3) reduced glucose synthase kinase 3 beta (GSK3β) and aryl hydrocarbon receptor (AhR) and this was associated with (4) increased estrogen receptor expression, BH 4 (Cofactor of nNOS) biosynthesis enzyme GCH-1 and nNOSα dimerization in WT Obese/T2 diabetic female mice. In addition, CNM restored impaired nitrergic relaxation in hyperglycemic conditions. These findings emphasize the importance of Nrf2 in maintaining nNOSα mediated GE and may have a translational relevance to treat obese/diabetic gastroparesis in women., (Copyright © 2019. Published by Elsevier Inc.)

Actually, arterial hypertension is a major public health concern, which involves the renin angiotensin aldosterone system (RAS), via activation of the angiotensin receptors AT 1 and AT 2 of the cardiovascular system. Although angiotensin is an important stimulant of the gut permeability to sodium and water, little is known about the effects of arterial hypertension on gut motor behavior. Thus, we evaluated in rats the effect of hypertension induced by two-kidney one-clip (2K1C) model on the gastric motility, as well as the influence of exercise and RAS blockers treatment in such phenomenon. One week after surgery the rats were treated with Aliskiren (50 mg·kg -1 , p.o.), Captopril (50 mg·kg -1 , p.o.) or Losartan (10 mg·kg -1 , p.o). Other group of rats was submitted to swimming with 5% body weight overload. After 4 weeks of physical training or pharmacological treatment, we assessed the gastric retention in all groups (GR) of a liquid test meal, the mean arterial pressure (MAP), the heart rate (HR) and the HR variation (HRV) as well as the in vitro contractility of gastric fundus. Renovascular hypertension increased (p < 0.05) the GR, MAP and HR, a phenomenon prevented by pretreatment with RAS blockers or exercise. The two kidney one-clip Hypertension (2K1C) decreased (p < 0.05) the gastric fundus responsiveness, a phenomenon also prevented by exercise. It conclusion, renovascular hypertension delays the gastric emptying of liquids, a phenomenon involving the activation of RAS, where exercise or blockade with aliskiren, captopril and losartan prevent gastric dysmotility., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Anorexia nervosa, a restrictive eating disorder, is often associated with gastrointestinal disorders, particularly a delayed gastric emptying. However, the mechanisms remained poorly documented. Thus, we aimed to evaluate gastric emptying and antrum protein metabolism in the Activity-Based Anorexia model (ABA)., Methods: Females C57Bl/6 mice were randomized into 3 groups: Control, ABA, and Limited Food Access (LFA). Food access has been progressively limited from 6 h/day at day 6 to 3 h/day at day 9 and until day 17. ABA mice had free access to an activity wheel. Gastric emptying was assessed. On gastric extracts, a proteomic analysis was performed, as well as an evaluation of protein synthesis and protein oxidation., Key Results: Both LFA and ABA mice exhibited a delayed gastric emptying compared with Controls (P < .05). Proteomic approach revealed 15 proteins that were differentially expressed. Among these proteins, we identified 2 clusters of interest contributing to (i) the organization of muscle fiber with ACTA2, VCL, KRT19, KRT8, and DES proteins and (ii) "heat shock proteins" with STIP1, HSPD1, and HSPA8 proteins. ABA mice specifically exhibited an increased rate of gastric oxidized proteins., Conclusions and Inferences: Delayed gastric emptying observed in anorectic conditions appears to be secondary to malnutrition. However, an oxidative stress is specifically present in the stomach of ABA mice. Its role remains to be further studied., (© 2018 John Wiley & Sons Ltd.)

Interstitial cells of Cajal (ICC), especially myenteric interstitial cells of Cajal (ICC-MY), are key to gastrointestinal motility. However, their role in the pathogenesis of functional dyspepsia (FD) is unclear. Therefore, autophagy and differentiation of ICC-MY were investigated to elucidate the pathogenesis of gastric motility disorder in FD. FD model was induced by chronic stress via tail clamping in rats, which was assessed by the vital signs of rats, gastric emptying rate result, and histology. The ultrastructure of ICC-MY was examined using transmission electron microscope. In ICC-MY, changes in autophagic biomarkers (Beclin1 and LC3B) and differentiation biomarkers (c-kit and SCF) were evaluated with in situ hybridization, quantitative real time PCR, immunofluorescence, and Western blot, respectively. The FD model was successfully induced in rats, as evidenced by the abnormal vital signs (such as loss of appetite, liquid excreta, less activity, and slower weight gain), the decrease in gastric emptying rates, and little pathological change in gastric antrum tissue. Compared with the control group, FD caused increased organelle denaturation or reduction and increase in vacuolization. FD also promoted generation of autophagosomes in ICC-MY. Moreover, increased the expression of Beclin1 and LC3B, but decreased expression of c-kit and SCF. Excessive autophagy and abnormal differentiation of ICC-MY may contribute to the pathogenesis of gastric motility disorder in FD., (© 2017 International Union of Biochemistry and Molecular Biology, Inc.)

Joint hypermobility is a common, primarily benign finding in the general population. However, in a subset of individuals joint hypermobility causes a range of clinical problems mainly affecting the musculoskeletal system and, to a lesser extent, extra-articular disorders. Joint hypermobility often appears as a familial trait and is shared by several inherited connective tissue disorders, including the hypermobility subtype of Ehlers-Danlos syndrome (hEDS) and benign joint hypermobility syndrome (BJHS/JHS). Although joint hypermobility has primarily been thought of as a rheumatological disorder, increasing evidence shows significant associations between both hEDS and BJHS with specific extra-articular disorders. To date, the strongest associations of these 2 conditions are with anxiety disorders, orthostatic tachycardia, various functional gastrointestinal (GI) disorders and pelvic and bladder dysfunction. This review article focuses on GI disorders associated with both hEDS and BJHS. The aim of this review is to evaluate existing research and literature regarding associations between JHS (hEDS/BJHS) and GI disorders. Our goal is to raise awareness of BJHS/JHS and hEDS as an explanation for chronic unexplained symptoms and functional GI disorders as well as to review the current standard tests available for proper evaluation of GI symptoms in these patients., (Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: The molecular changes that occur in the stomach that are associated with idiopathic gastroparesis are poorly described. The aim of this study was to use quantitative analysis of mRNA expression to identify changes in mRNAs encoding proteins required for the normal motility functions of the stomach., Methods: Full-thickness stomach biopsy samples were collected from non-diabetic control subjects who exhibited no symptoms of gastroparesis and from patients with idiopathic gastroparesis. mRNA was isolated from the muscularis externa and mRNA expression levels were determined by quantitative reverse transcriptase (RT)-PCR., Key Results: Smooth muscle tissue from idiopathic gastroparesis patients had decreased expression of mRNAs encoding several contractile proteins, such as MYH11 and MYLK1. Conversely, there was no significant change in mRNAs characteristic of interstitial cells of Cajal (ICCs) such as KIT or ANO1. There was also a significant decrease in mRNA-encoding platelet-derived growth factor receptor α (PDGFRα) and its ligand PDGFB and in Heme oxygenase 1 in idiopathic gastroparesis subjects. In contrast, there was a small increase in mRNA characteristic of neurons. Although there was not an overall change in KIT expression in gastroparesis patients, KIT expression showed a significant correlation with gastric emptying whereas changes in MYLK1, ANO1 and PDGFRα showed weak correlations to the fullness/satiety subscore of patient assessment of upper gastrointestinal disorder-symptom severity index scores., Conclusions and Inferences: Our findings suggest that idiopathic gastroparesis is associated with altered smooth muscle cell contractile protein expression and loss of PDGFRα + cells without a significant change in ICCs., (© 2017 John Wiley & Sons Ltd.)

Background: Diabetic gastroparesis in human and animal models suggest different developmental causes in females vs males. Previously, we demonstrated that although male and female diabetic gastroparetic rats exhibited similarity in disease pathology, molecular mechanisms were different: slow gastric emptying in male diabetic gastroparetic rats was not associated with the level of expression and dimerization of neuronal nitric oxide synthase α in gastric tissues, as was demonstrated in females. Male gastroparesis may involve other mechanisms, such as oxidative stress. We hypothesize that sustained increased reactive oxygen species (ROS) and degradation of MAP kinase phosphatase-1 with subsequent unregulated activation of c-Jun N-terminal kinase and p38MAP kinase pathways are associated with gastroparesis in a male diabetic rat model., Methods: Using a male rat model of diabetic gastroparesis, we analyzed serum and pyloric tissue for ROS and antioxidant enzyme levels using ELISA; MAP kinase phosphatase-1, c-Jun N-terminal kinases, and p38MAP kinase levels utilized western blotting techniques and phospho-specific antibodies., Key Results: Both diabetic and diabetic gastroparetic rats demonstrated overproduction of ROS. However, loss of MAP kinase phosphatase-1, a MAP kinase pathway negative regulator, with subsequent activation of c-Jun N-terminal kinase 2 and p38MAP kinase pathways, were observed only in diabetic gastroparetic rats. Diabetic rats without gastroparesis had no significant pathway activation., Conclusions & Inferences: These results suggest that sustained, increased ROS and degradation of MAP kinase phosphatase-1, with subsequent unregulated activation of c-Jun N-terminal kinase and p38MAP kinase pathways, are likely to be factors in diabetic gastroparesis phenotype in a male diabetic rat model., (© 2017 John Wiley & Sons Ltd.)

Recent years, widespread long non-coding RNAs (lncRNAs) were identified and known as regulator of gene expression. Diabetic gastroparesis (DGP) is one of the most common chronic complications of diabetes mellitus. There was no research reported the role of lncRNAs in DGP. In this study, we firstly established a rat model of DGP by STZ injection. Then, we detected the expression of MALAT1 and found that expression of MALAT1 was up-regulated in rat model of DGP, comparing to the control group (P < .01). Furthermore, we revealed that MALAT1 expression was increased in the samples from diabetic patients with DGP symptoms, in comparison with the control. In addition, we demonstrated that the inhibition of MALAT1 increased the expression of α-SMA and SM myosin heavy chains, reduced the cell viability, inhibited the potential of cell migration and induced cell apoptosis in human gastric smooth muscle cells (SMCs). Ultimately, we found that the regulation of MALAT1 expression modulated the function of high-glucose stimulation in human gastric SMCs. Therefore, our study firstly indicated that MALAT1 was up-regulated in DGP and played an important role in the pathogenesis of DGP., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Diabetic gastroparesis is a common complication of diabetes mellitus (DM) that is characterized by decreased serum insulin and insulin-like growth factor-1 (IGF-1). Despite the fact that insulin treatment not glycemic control potently accelerated gastric emptying in type 1 DM patients, the role of insulin/InsR and IGF-1/IGF-1R signaling in diabetic gastroparesis remains incompletely elucidated. In the present study, type 1 DM mice were established and treated with insulin or Voglibose for 8 weeks. The gastric emptying was delayed from DM week 4 when the gastric InsR and IGF-1R were declined. Meanwhile, the gastric choline acetyltransferase (ChAT) was significantly reduced and the myenteric cholinergic neurones and their fibers were significantly diminished. The production of stem cell factor (SCF) was dramatically repressed in the gastric smooth muscles in DM week 6. TWereafter, interstitial cells of Cajal (ICC) were clearly lost and their networks were impaired in DM week 8. Significantly, compared with Voglibose, an 8-week treatment with insulin more efficiently delayed diabetic gastroparesis development by protecting the myenteric cholinergic neurones and ICC. In conclusion, diabetic gastroparesis was an aggressive process due to the successive damages of myenteric cholinergic neurones and ICC by impairing the insulin/InsR and IGF-1/IGF-1R signaling. Insulin therapy in the early stage may delay diabetic gastroparesis., (© 2017 The Author(s).)

Background: Diabetic gastroparesis is a common complication of diabetes mellitus, which mainly affects women. Previous studies have demonstrated that oxidative stress is involved in its onset and development., Aims: This study evaluated the role of vitamin C on diabetes-associated gastric dysmotility., Methods: Female rats with streptozotocin-induced diabetes were treated with vehicle (water, 1 mL/kg, p.o.), vitamin C (300 mg/kg/day, p.o.), or insulin (6 IU/day, s.c.). Gastric emptying, in vitro gastric contractility, and biochemistry parameters were analyzed at the end of the treatment (i.e. 8 weeks after the diabetes induction)., Results: Vitamin C reversed the delayed gastric emptying of diabetic rats to normal levels, and avoided the changes in the contractile responses to acetylcholine (0.1 nM-1 µM), but not to 5-hydroxytryptamine (0.1 nM-1 µM), in the pylorus and fundus from diabetic rats. Moreover, the contraction evoked by KCl (40 mM) in the fundus, but not in the pylorus, was intensely increased in diabetic rats treated with vitamin C. Notably, the vitamin C reestablished the reduced glutathione levels by 77% and decreased the reactive oxygen species content by 60% in the gastric tissue from diabetic rats. Despite the effects on gastric motility, vitamin C treatment did not change the fasting glycaemia or the glycated hemoglobin of diabetic rats. Unsurprisingly, insulin treatment normalized all parameters evaluated., Conclusions: Vitamin C exhibited a remarkable beneficial effect on gastric emptying dysfunction in diabetic rats, which was mediated by attenuation of oxidative stress and maintenance of the cholinergic contractile responses in fundus and pylorus.

The aim of the present study was to investigate the significance of cell apoptosis, the phosphoinositide-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway, and the 5' adenosine monophosphate-activated protein kinase (AMPK)‑mTOR pathways in the process of diabetic gastroparesis. Changes in gastric smooth muscle cells of diabetic rats with induced gastroparesis were examined. The diabetic rat model was established by dividing animals into a normal control group and diabetic model groups examined at 2, 4 and 6 weeks. Diabetic gastroparesis was evaluated by examining the rates of gastric residual pigment, whereas flow cytometry was used to detect the apoptosis of gastric smooth muscle cells. The expression levels of PI3K and phosphorylated (p‑) AKT, AMPK, mTOR, tuberous sclerosis complex 2, p70 ribosomal S6 kinase, and eukaryotic translation initiation factor 4‑binding protein 1 were determined in gastric muscles using western blot analysis. Diabetic gastroparesis was confirmed in models at 6 weeks. The apoptosis of gastric smooth muscle cells gradually increased in all diabetic groups, and significant changes were observed in key proteins involved in PI3K‑AKT‑mTOR and AMPK‑mTOR signaling. The results indicated that apoptosis was important in the occurrence of diabetic gastroparesis, and the PI3K‑AKT‑mTOR and AMPK‑mTOR pathways were activated during the apoptotic processes, but were incapable of regulating apoptosis.

Objective: To observe the effect of point-moxibustion and electroacupuncture(EA) on gastrointestinal motility, and expression of endothelial nitric oxide synthase(eNOS) mRNA and angiotensin 2(AT Ⅱ) mRNA in gastric antrum in diabetic gastroparesis(DGP) rats, so as to reveal the different effect between point-moxibustion and EA, and explore the mechanism underlying improvement of DGP., Methods: Forty SD rats were randomly divided into normal, model, point-moxibustion and EA groups, 10 rats in each group. The DGP model was established by intraperitoneal injection of streptozotocin (STZ, 2%, 55 mmol/kg) and fed with high-sugar and high-fat fodder. "Zusanli" (ST 36), "Sanyinjiao" (SP 6) and "Liangmen" (ST 21) were chosen to be stimulated with moxibustion at 0, 10 and 20 min in the point-moxibustion group or with EA for 20 min in the EA group. The treatment was conducted once daily for 15 days. After treatment, blood glucose, gastric emptying rate and small intestinal propulsive rate were measured. The plasma endothelin 1(ET-1) content was detected by ELISA. The mRNA expression of eNOS and AT Ⅱ in gastric antrum were detected by Real-time PCR., Results: Compared with the normal group, the blood glucose in the model group was significantly higher ( P <0.01). Compared with the model group, the blood glucose decreased significantly in the point-moxibustion group and EA group ( P <0.05). In comparison with the normal group, gastric emptying rate and small intestinal propulsive rate were decreased, the content of plasma ET-1 was increased, the expression of eNOS mRNA in gastric antrum was significantly reduced and the expression of ATⅡ mRNA was significantly increased in the model group( P <0.01). In comparison with the model group, gastric emptying rate and small intestinal propulsive rate were increased, the content of plasma ET-1 was decreased, the expression of eNOS mRNA in gastric antrum was higher and the expression of AT Ⅱ mRNA was significantly lower in both point-moxibustion group and EA group ( P <0.05), and there were no significant differences between the two treatment groups in above mentioned indexes ( P >0.05)., Conclusions: Both point-moxibustion and EA can effectively promote gastrointestinal motility in DGP rats and improve the symptoms of delayed gastric emptying. The two therapies are effective, and their mechanism may be related to the increase of eNOS mRNA expression and the decrease of AT Ⅱ mRNA expression in gastric antrum.

Background: Animal studies have increasingly highlighted the role of macrophages in the development of delayed gastric emptying. However, their role in the pathophysiology of human gastroparesis is unclear. Our aim was to determine changes in macrophages and other cell types in the gastric antrum muscularis propria of patients with diabetic and idiopathic gastroparesis., Methods: Full thickness gastric antrum biopsies were obtained from patients enrolled in the Gastroparesis Clinical Research Consortium (11 diabetic, 6 idiopathic) and 5 controls. Immunolabeling and quantitative assessment was done for interstitial cells of Cajal (ICC) (Kit), enteric nerves protein gene product 9.5, neuronal nitric oxide synthase, vasoactive intestinal peptide, substance P, tyrosine hydroxylase), overall immune cells (CD45) and anti-inflammatory macrophages (CD206). Gastric emptying was assessed using nuclear medicine scintigraphy and symptom severity using the Gastroparesis Cardinal Symptom Index., Results: Both diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls (Mean [standard error of mean]/hpf: diabetic, 2.28 [0.16]; idiopathic, 2.53 [0.47]; controls, 6.05 [0.62]; P=.004). Overall immune cell population (CD45) was unchanged but there was a loss of anti-inflammatory macrophages (CD206) in circular muscle (diabetic, 3.87 [0.32]; idiopathic, 4.16 [0.52]; controls, 6.59 [1.09]; P=.04) and myenteric plexus (diabetic, 3.83 [0.27]; idiopathic, 3.59 [0.68]; controls, 7.46 [0.51]; P=.004). There was correlation between the number of ICC and CD206-positive cells (r=.55, P=.008). Enteric nerves (PGP9.5) were unchanged: diabetic, 33.64 (3.45); idiopathic, 41.26 (6.40); controls, 46.80 (6.04)., Conclusion: Loss of antral CD206-positive anti-inflammatory macrophages is a key feature in human gastroparesis and it is associates with ICC loss., (© 2017 John Wiley & Sons Ltd.)

Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems' metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome.

Background: This study aimed to evaluate the role of H 2 S on gastric emptying rate (GER) and also to determine the effect of gastric distention on mRNA and protein expression of cystathionine β-lyase (CBS) and cystathionine γ-synthase (CSE) in diabetic-gastroparetic and normal rats., Methods: Adult normal rats intraperitoneally received either propargylglycine (PAG), L-cysteine or NaHS 30 min prior to GER marker (acetaminophen) to investigate H 2 S involvement in GER and the same protocols were performed in diabetes-induced gastroparesis rats. The role of calcitonin gene related peptide (CGRP) neurons in the prokinetic effect of endogenous H 2 S on GER was determined. The level of CBS and CSE expressions in response to gastric distention were also determined. The effect of H 2 S on frequency and tension of spontaneous contractions of gastric smooth muscle strips was investigated., Key Results: Our results showed that: (i) H 2 S and L-cysteine increased GER in gastroparetic and normal rats. (ii) The increased levels of CSE expression in response to gastric distention in diabetic rats were lower than in normal rats. (iii) PAG inhibited the excitatory effect of capsaicin on GER and on tension of spontaneous contractions of strips. (iv) Hydrogen sulphide increased the frequency and tension of spontaneous contractions of gastric strip muscles in normal and diabetic rats., Conclusions & Inferences: The results showed that delayed GER in diabetic rats can be due to down-regulation of H 2 S biosynthesis enzyme, CSE and suggested that a potential prokinetic role for H 2 S to treat the delayed gastric emptying in diabetic patients., (© 2016 John Wiley & Sons Ltd.)

This article reviews the sex differences in upper gastrointestinal (GI) motility for both healthy and common dysmotility conditions. It focuses on gastroesophageal reflux disease and other esophageal motor disorders for the esophagus and on gastroparesis and accelerated gastric emptying for the stomach. It also describes differences in upper GI motility signs and symptoms during each female hormonal stage (ie, menstrual cycle, pregnancy, perimenopause, menopause) for both healthy participants and those suffering from one of the aforementioned upper GI dysmotility conditions. More research still needs to be conducted to better understand sex differences in upper GI motility., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To observe the effect of electroacupuncture (EA) stimulation of "Zusanli" (ST 36), "Liangmen" (ST 21) and "Sanyinjiao" (SP 6) on gastrointestinal motility and expression of ghrelin and growth hormone secretagogue receptor (GHSR) mRNA in diabetic gastroparesis (diabetic gastroparesis, DGP) rats, so as to explore its mechanism underlying improvement of diabetic gastroparesis., Methods: Sixty SD rats were randomly and equally divided into normal control, model, EA acupoint, EA non-acupoint, medication (metoclopramide) groups (n = 12 rat/group). The DGP model was established by intraperitoneal injection of streptozotocin (STZ, 55 mg/kg, 2%) and raised by high-sugar and high-fat fodder irregularly for 8 weeks. EA was applied to "Zusanli" (ST 36), "Liangmen" (ST 21) and "Sanyinjiao" (SP 6), and non-acupoints (about 5 mm lateral to the 3 acupoints, respectively). Those rats of the medication group were given with metoclopramide (1 mL/100 g). The blood sugar level was measured by glucometer, and the urine sugar level measured by Tes-Tape [urine glucose test paper]. The intestinal propulsion rate (IPR) was identified as ratio of the phenolsulfonphthalein promoting distance and the total length of the small intestine, and the gastric emptying rate (GER) was assessed by gavage of a liquid test meal (1.5 mL) containing a nonabsorbable marker (0. 5 mg/mL of phenol red in 5% glucose solution) and identification after being sacrificed 72 h after modeling. The expression levels of ghrelin mRNA and GHSR mRNA of gastric antrum tissue were examined by Quantitative real-time PCR., Results: In comparison with the normal control group, the blood sugar and urine sugar levels of the model group was significantly increased in the model group (P < 0.01), while the GER and IPR and the expression level of ghrelin mRNA and GHSR mRNA in the gastric antrum were significantly decreased in the model group (P < 0.01, P < 0.05). Following EA stimulation of acupoint, the blood sugar and urine sugar levels were obviously down-regulated (P < 0.05), both GER and IPR, and ghrelin mRNA and GHSR mRNA expression levels in the EA-acupoint group were significantly up-regulated (P < 0.05, P < 0.01). No significant changes were found in both blood sugar and urine sugar levels, in both GER and IPR, and ghrelin mRNA and GHSR mRNA expression levels of both EA non-acupoint and medication groups after the intervention (P > 0.05). The GER and IPR were significantly higher in the EA acupoint group than in the EA non-acupoint group (P < 0.05, P < 0.01)., Conclusion: EA stimulation of ST 36, ST 21 and SP 6 can promote the gastrointestinal motility of DGP rats, which may be closely associated with its effects in up-regulating the expression level of ghrelin mRNA and GHSR mRNA in gastric antrum.

Background: Acupuncture may improve gastrointestinal symptoms in patients with various disorders, but its efficacy in diabetic gastroparesis is unclear., Objective: To evaluate the short-term effects of acupuncture on gastric emptying and gastroparesis symptoms in patients with diabetic gastroparesis., Methods: In a single-blind controlled crossover trial, 25 patients with diabetic gastroparesis were randomly assigned to undergo 1 week of real acupuncture (RA) treatment followed by 1 week of sham acupuncture (SA) treatment, or vice versa, with a washout of 1 month in between. Before and after each intervention, gastric retention, the Gastroparesis Cardinal Symptom Index (GCSI), fasting blood glucose (FBG) and HbA1c levels were measured., Results: 21 patients completed the study. Compared with SA treatment, RA treatment was associated with significantly greater reductions in gastric retention at 2 h (-11.1±7.0%; 95% CI -13.6% to -6.2%; p<0.01) and at 4 h (-5.0±2.8%; 95% CI -6.0% to -0.2%; p=0.04) and in GCSI score (-8.0±3.4; 95% CI -8.4 to -2.8; p<0.01). There were no significant differences in FBG and HbA1c levels between RA and SA treatments., Conclusions: In patients with diabetic gastroparesis, 1 week of short-term manual acupuncture reduces gastric retention and improves gastroparesis symptoms., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To observe the effect of Zhuang-medicine medicated-thread moxibustion therapy on interstitial cells of Cajal (ICC) in the gastric antrum of diabetic gastroparesis (DGP) rats, so as to investigate its mechanism underlying improving DGP., Methods: Sprague-Dawley (SD) male rats were randomly divided into 3 groups: control (n = 30) , model (n = 30) and moxibustion (n = 30). The DGP model was established by intraperitoneal injection of streptozotocin (STZ) and by feeding the rats with high fat-sugar forage. Zhuang-medicine medicated-thread moxibustion was applied to "Zhongwan" (CV 12), bilateral "Pishu" (BL 20), "Weishu" (BL 21), "Neiguan" (PC 6) and "Zusanli" (ST 36) once per day, for 3 weeks except weekends. The gastrointestinal propulsion rate and weight of stool in 24 h were determined, and c-kit (a marker for ICC) expression of the gastric antrum tissue was measured by immunohistochemistry., Results: The stool weight was significantly higher in the model group than in the control group (P < 0.01), but the rate of gastrointestinal propulsion and the rate of c-kit immunoreaction (IR) positive cells in the gastric antrum tissue were significantly lower in the model group than in the control group (P < 0.01). After moxibustion, the increased stool weight and the decreased gastrointestinal propulsion rate and decreased c-kit IR-positive cell rate were reversed (P < 0.01)., Conclusion: Zhuang-medicine medicated-thread moxibustion therapy can improve gastrointestinal function in DGP rats, which may be associated with its effect in up-regulating the expression of c-kit IR-positive ICC.

Objectives: The aim of the present study was to develop an ultrasonographic approach to comparatively assess gastric emptying in newborn wild-type and guanosine triphosphate cyclohydrolase knockout hph-1 mice, because we previously reported gastroparesis early in life in this strain., Methods: Stomach transverse, anteroposterior, and longitudinal ultrasonographic measurements were obtained with a 40-MHz transducer in pups immediately after maternal separation and 4 hours later. A conventional equation was used and the predicted values validated by obtaining postmortem gastric content volume measurements. Wild-type and hph-1 mice gastric emptying rates were comparatively evaluated at 1 to 3 and 5 to 8 days of age, respectively., Results: The ultrasound equation closely predicted the newborn stomach content volumes with a correlation coefficient (R) of 0.93 and 0.81 (P < 0.01) for measurements obtained on full stomach and after 4 hours of fasting, respectively. In wild-type mice, gastric emptying was age dependent and associated with a greater residual volume at 1 to 3 days (65% ± 7%), as compared with 5- to 8-day-old pups (33% ± 4%; P  < 0.01), after fasting. In contrast, an equal duration of fasting resulted in a significantly greater residual gastric content volume in 5- to 8-day-old hph-1 mice (68%  ± 7%; P < 0.01), as compared with same-age wild-type mice., Conclusions: Ultrasonography offers a sensitive and accurate estimate of gastric content volume in newborn mice. In wild-type newborn mice, gastric emptying rate is age dependent and significantly reduced in the immediate postnatal period. The newborn hph-1 mice have a significantly higher gastric residual volume, as compared with wild-type same-age animals.

There remains an unmet need for effective pharmacologic treatments for gastroparesis. Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor and has been shown to regulate energy homeostasis and exert prokinetic effects on gastrointestinal motility. In recent years, several ghrelin receptor agonists have been studied in clinical trials of patients with diabetic gastroparesis. The intravenous macrocyclic peptidomimetic, TZP-101, initially suggested improvement in gastroparesis symptoms with intravenous administration when compared to placebo. However, in subsequent studies of oral preparations, TZP-102 failed to confirm these results. Another ghrelin receptor agonist, RM-131, was recently shown to significantly accelerate gastric emptying (GE) in patients with type 1 and type 2 diabetes and delayed GE. RM-131 reduced total Gastroparesis Cardinal Symptom Index-Daily Diary (GCSI-DD) and composite scores among type 1 diabetics. Continued development of ghrelin agonists should be explored in attempts to expand therapeutic options for the treatment of gastroparesis.