Effects of hemin on heme oxygenase‐1, gastric emptying, and symptoms in diabetic gastroparesis

Bharucha, Adil E.; Daley, S. L.; Low, Phillip A.; Gibbons, Simon J.; Choi, Kyoung Moo; Camilleri, Michael; Saw, Jessica J.; Farrugia, Gianrico; Zinsmeister, Alan R.

doi:10.1111/nmo.12874

Cited by 34 publications

(23 citation statements)

References 51 publications

(114 reference statements)

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“…All of the changes could be reversed simultaneously by the induction of HO-1 expression in these diabetic animal models [ 5 , 13 ]. Unfortunately, in diabetic patients with gastroparesis, the inducer of HO-1 could not sustain the increased HO-1 levels for a long time and failed to improve gastroparesis [ 14 ]. These reports may hint that HO-1 is very important to sustain ICC survival and protect gastric function in diabetes.…”

Section: Discussionmentioning

confidence: 99%

Electroacupuncture at ST‐36 Protects Interstitial Cells of Cajal via Sustaining Heme Oxygenase‐1 Positive M2 Macrophages in the Stomach of Diabetic Mice

Tian

Song

Zhu

et al. 2018

Oxidative Medicine and Cellular Longevity

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Background Electroacupuncture (EA) at ST-36 has been reported to improve delayed gastric emptying and protect the networks of ICC in diabetic models. However, the mechanisms of the effects of EA are still unclear. The purpose of this study was to investigate whether the HO-1 positive M2 macrophages participate in the protective effects of EA for the ICC networks. Methods Male C57BL/6 mice were randomized into five groups: the normal control group, diabetic group (DM), diabetic mice with sham EA group (SEA), diabetic mice with low frequency EA group (LEA), and diabetic mice with high frequency EA group (HEA). ICC network changes were detected by Ano1 immunostaining. F4/80 and HO-1 costaining was used to measure HO-1 positive macrophage expression. Western blot and PCR methods were applied to monitor HO-1, IL-10, and macrophage markers, respectively. The serum MDA levels were detected by a commercial kit. Results This study presents the following results: (1) Compared with the control group, ICC networks were severely disrupted in the DM group, but no obvious changes were found in the LEA and HEA groups. (2) Many HO-1 positive macrophages could be observed in the LEA and HEA groups, and the expression of HO-1 was also markedly upregulated. (3) The IL-10 expression was obviously upregulated in the LEA and HEA groups. (4) The serum MDA levels were decreased in the real EA group. (5) When compared to the DM group, the expression of CD163 and Arg-1 was increased in the LEA and HEA groups, but the iNOS expression was decreased. Conclusion The protective effects of EA on the networks of ICC may rely on the HO-1 positive macrophages to mediate anti-inflammatory and antioxidative stress effects.

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Section: Discussionmentioning

confidence: 99%

Electroacupuncture at ST‐36 Protects Interstitial Cells of Cajal via Sustaining Heme Oxygenase‐1 Positive M2 Macrophages in the Stomach of Diabetic Mice

Tian

Song

Zhu

et al. 2018

Oxidative Medicine and Cellular Longevity

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“…After completing objective assessments, patients recorded their daily GI symptoms in the Gastroparesis Cardinal Symptom Index‐Daily Diary (GCSI‐DD) for 2 weeks (Figure ) . The nausea, vomiting, fullness, and pain (NVFP) scores were computed by averaging these 4 symptoms …”

Section: Methodsmentioning

confidence: 99%

“…An analysis of covariance compared symptoms during duodenal lipid infusion and exendin's effects between controls and patients. Multiple linear regression models assessed the extent to which GE and symptoms during the GE scintigraphy predicted (a) daily symptoms summarized by the NVFP score and (b) overall quality of life calculated from the Nepean Dyspepsia Index questionnaire.…”

Section: Methodsmentioning

confidence: 99%

Relationship between symptoms during a gastric emptying study and intestinal chemosensitivity with daily symptoms

Chakraborty

Desai

Halland

et al. 2019

Neurogastroenterology Motil

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Background Non‐ulcer dyspepsia (NUD) is a heterogeneous disorder, which is characterized by upper gastrointestinal symptoms and sensorimotor disturbances, including abnormal gastric emptying (GE) and increased intestinal chemosensitivity, and associated with greater plasma glucagon‐like peptide‐1 (GLP‐1) levels during duodenal lipid infusion. However, the relationship(s) between these disturbances and daily symptoms in NUD is variable. We hypothesize that abnormal GE and symptoms during a GE study and during duodenal lipid infusion are associated with the severity of daily symptoms and that GLP‐1 mediates symptoms during duodenal lipid infusion in NUD. Methods Gastric emptying of solids, symptoms during the GE study and duodenal lipid infusion, and daily gastrointestinal symptoms (2 week diary) were measured in 24 healthy controls and 40 NUD patients. During duodenal lipid infusion, participants received the GLP‐1 antagonist exendin 9‐39 or placebo. Key Results In controls and patients, GE of solids was normal in 75% and 75%, delayed in 8% and 12.5%, or rapid in 17% and 12.5%, respectively. No controls but 26 patients (65%) had severe symptoms during the GE study. During lipid infusion, gastrointestinal symptoms were greater (P = .001) in patients and not affected by exendin. Symptoms during GE study and lipid infusion accounted for respectively 62% and 37% of variance in daily symptom severity. Conclusions In NUD, symptoms during a GE study and to a lesser extent during lipid infusion explain the variance in daily symptoms. Intestinal chemosensitivity is not reduced by GLP‐1 antagonist. Assessment of symptoms during a GE study may provide a useful biomarker for NUD in research and clinical practice.

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“…Bharucha and colleagues recently explored this question by trying to induce heme oxygenase-1, which is expressed in M2 macrophages and plays an important anti-inflammatory role 8 . Their pilot data show a potent induction of the enzyme but no influence on symptoms or emptying 28 . Even if macrophages or specific enzymes have not yet found their way into successful treatment strategies, these findings illustrate how preclinical data are translated into novel treatment strategies.…”

Section: Will Novel Concepts Bring Novel Treatments?mentioning

confidence: 99%

Glass half empty? Lessons learned about gastroparesis

McKenzie

Bielefeldt

2018

F1000Res

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Gastroparesis is defined as a combination of chronic dyspeptic symptoms and delayed emptying of a solid test meal. It remains a difficult-to-treat disorder with a significant impact on quality of life. Although gastroparesis is defined by delayed emptying, several important studies did not find a correlation between this biomarker and symptom severity or treatment success. Thus, some of the more recent trials explored strategies that ranged from antiemetics to antidepressants. Although dietary management showed benefit, most of the other interventions were barely superior to placebo or were not superior at all. Placebo responses were often quite high and this complicates the assessment of active agents. While it complicates the design and interpretation of clinical trials, high response rates for active and sham interventions indicate that we can achieve symptom relief in many patients and thus give them some reassurance. If indeed most therapies are only marginally better than placebo, the differences in adverse effects should be weighed more strongly, a point that is especially important in view of the controversy surrounding metoclopramide. Mechanistic studies introduced the network of macrophages as another potentially important player in the development of gastroparesis. Results are too preliminary and are largely based on preclinical data but show up- and downregulation of cellular elements controlling gastric function. Thus, future developments may teach us how they interfere with some of these mechanisms in clinical settings, potentially making gastroparesis a reversible process.

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Effects of hemin on heme oxygenase‐1, gastric emptying, and symptoms in diabetic gastroparesis

Cited by 34 publications

References 51 publications

Electroacupuncture at ST‐36 Protects Interstitial Cells of Cajal via Sustaining Heme Oxygenase‐1 Positive M2 Macrophages in the Stomach of Diabetic Mice

Electroacupuncture at ST‐36 Protects Interstitial Cells of Cajal via Sustaining Heme Oxygenase‐1 Positive M2 Macrophages in the Stomach of Diabetic Mice

Relationship between symptoms during a gastric emptying study and intestinal chemosensitivity with daily symptoms

Glass half empty? Lessons learned about gastroparesis

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