Evidence for Cytoprotective Effect of Carbon Monoxide Donor in the Development of Acute Esophagitis Leading to Acute Esophageal Epithelium Lesions

Magierowska, Katarzyna; Bakalarz, Dominik; Wójcik, Dagmara; Korbut, Edyta; Danielak, Aleksandra; Głowacka, Urszula; Pajdo, Robert; Buszewicz, Grzegorz; Ginter, Grzegorz; Surmiak, Marcin; Kwiecień, Sławomir; Chmura, Anna; Magierowski, Marcin; Brzozowski, Tomasz

doi:10.3390/cells9051203

Cited by 18 publications

(16 citation statements)

References 64 publications

(117 reference statements)

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“…Interestingly, BW-CO-111 applied at a dose of 5 mg/kg was not observed to prevent gastric mucosa against ethanol-induced damage. This is in pair with previously published data showing that CO-releasing CORM-2 was also not effective or even cytotoxic when applied at higher doses 78 , 99 , 100 , 101 . Such results are consistent with the biphasic nature of the dose–response curves for compounds with pleotropic effects, especially gasotransmitters such as hydrogen sulfide.…”

Section: Discussionsupporting

confidence: 92%

Organic carbon monoxide prodrug, BW-CO-111, in protection against chemically-induced gastric mucosal damage

Bakalarz

Surmiak

Yang

et al. 2021

Acta Pharmaceutica Sinica B

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Metal-based carbon monoxide (CO)-releasing molecules have been shown to exert anti-inflammatory and anti-oxidative properties maintaining gastric mucosal integrity. We are interested in further development of metal-free CO-based therapeutics for oral administration. Thus, we examine the protective effect of representative CO prodrug, BW-CO-111, in rat models of gastric damage induced by necrotic ethanol or aspirin, a representative non-steroidal anti-inflammatory drug. Treatment effectiveness was assessed by measuring the microscopic/macroscopic gastric damage area and gastric blood flow by laser flowmetry. Gastric mucosal mRNA and/or protein expressions of HMOX1, HMOX2, nuclear factor erythroid 2-related factor 2, COX1, COX2, iNos , Anxa1 and serum contents of TGFB1, TGFB2, IL1B, IL2, IL4, IL5, IL6, IL10, IL12, tumor necrosis factor α , interferon γ , and GM-CSF were determined. CO content in gastric mucosa was assessed by gas chromatography. Pretreatment with BW-CO-111 (0.1 mg/kg, i.g.) increased gastric mucosal content of CO and reduced gastric lesions area in both models followed by increased GBF. These protective effects of the CO prodrug were supported by changes in expressions of molecular biomarkers. However, because the pathomechanisms of gastric damage differ between topical administration of ethanol and aspirin, the possible protective and anti-inflammatory mechanisms of BW-CO-111 may be somewhat different in these models.

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Section: Discussionsupporting

confidence: 92%

Organic carbon monoxide prodrug, BW-CO-111, in protection against chemically-induced gastric mucosal damage

Bakalarz

Surmiak

Yang

et al. 2021

Acta Pharmaceutica Sinica B

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“…Our bioinformatic analysis of possible molecular targets of BW-HS-101 did not reveal any protein target that BW-HS-101 could interact with (calculated scores 0–0.11). Thus, we focused on oxidative- and inflammatory-response markers specific for gastric mucosal barrier maintenance, selected based on our previously published data [ 51 ]. BW-HS-101 exerted anti-inflammatory effects on the systemic level observed as decreased serum contents of IL-1β, TNF-α, IL-10, or VEGFA and locally as expressed by decreased gastric mucosal mRNA fold changes for IL-1R2 and COX-2.…”

Section: Discussionmentioning

confidence: 99%

“…Samples from healthy (intact) gastric mucosa were further used as reference control during calculations. Expression of mRNA for iNOS, HMOX-1, SOCS3, IL1-R1, IL1-R2, TNF-R2, COX-1, COX-2 and succinate dehydrogenase complex, subunit A (SDHA) and β-actin (ACTB) as reference genes was determined using specific primers as described previously [ 50 , 51 , 57 ]. PCR reaction was run using thermal cycler Quant Studio 3 (Thermo Fisher Scientific, Waltham, MA, USA) and SYBR Green I dye including kit (SG qPCR Master Mix (2×), EURx, Gdansk, Poland).…”

Section: Methodsmentioning

confidence: 99%

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Novel Hydrogen Sulfide (H2S)-Releasing BW-HS-101 and Its Non-H2S Releasing Derivative in Modulation of Microscopic and Molecular Parameters of Gastric Mucosal Barrier

Bakalarz

Korbut

Yuan

et al. 2021

IJMS

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Hydrogen sulfide (H2S) is an endogenously produced molecule with anti-inflammatory and cytoprotective properties. We aimed to investigate for the first time if a novel, esterase-sensitive H2S-prodrug, BW-HS-101 with the ability to release H2S in a controllable manner, prevents gastric mucosa against acetylsalicylic acid-induced gastropathy on microscopic and molecular levels. Wistar rats were pretreated intragastrically with vehicle, BW-HS-101 (0.5–50 μmol/kg) or its analogue without the ability to release H2S, BW-iHS-101 prior to ASA administration (125 mg/kg, intragastrically). BW-HS-101 was administered alone or in combination with nitroarginine (L-NNA, 20 mg/kg, intraperitoneally) or zinc protoporphyrin IX (10 mg/kg, intraperitoneally). Gastroprotective effects of BW-HS-101 were additionally evaluated against necrotic damage induced by intragastrical administration of 75% ethanol. Gastric mucosal damage was assessed microscopically, and gastric blood flow was determined by laser flowmetry. Gastric mucosal DNA oxidation and PGE2 concentration were assessed by ELISA. Serum and/or gastric protein concentrations of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-13, VEGF, GM-CSF, IFN-γ, TNF-α, and EGF were determined by a microbeads/fluorescent-based multiplex assay. Changes in gastric mucosal iNOS, HMOX-1, SOCS3, IL1-R1, IL1-R2, TNF-R2, COX-1, and COX-2 mRNA were assessed by real-time PCR. BW-HS-101 or BW-iHS-101 applied at a dose of 50 μmol/kg protected gastric mucosa against ASA-induced gastric damage and prevented a decrease in the gastric blood flow level. H2S prodrug decreased DNA oxidation, systemic and gastric mucosal inflammation with accompanied upregulation of SOCS3, and EGF and HMOX-1 expression. Pharmacological inhibition of nitric oxide (NO) synthase but not carbon monoxide (CO)/heme oxygenase (HMOX) activity by L-NNA or ZnPP, respectively, reversed the gastroprotective effect of BW-HS-101. BW-HS-101 also protected against ethanol-induced gastric injury formation. We conclude that BW-HS-101, due to its ability to release H2S in a controllable manner, prevents gastric mucosa against drugs-induced gastropathy, inflammation and DNA oxidation, and upregulate gastric microcirculation. Gastroprotective effects of this H2S prodrug involves endogenous NO but not CO activity and could be mediated by cytoprotective and anti-inflammatory SOCS3 and EGF pathways.

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“…For the control and CCl 4 groups, the mice received an intraperitoneal injection of saline. iCORM-2 was generated as previously described by incubation overnight (18 h) at 37°C and bubbling with air (N 2 ) to remove the residual CO [ 24 ]. The WT C57BL/6 mice were randomized into six groups: control ( n = 6), CCl 4 ( n = 10), CCl 4 +CoPP ( n = 12), CCl 4 +ZnPP ( n = 12), CCl 4 +CORM-2 ( n = 13), and CCl 4 +iCORM-2 ( n = 10).…”

Section: Methodsmentioning

confidence: 99%

HO‐1/CO Maintains Intestinal Barrier Integrity through NF‐κB/MLCK Pathway in Intestinal HO‐1^-/- Mice

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Background. Intestinal barrier injury is an important contributor to many diseases. We previously found that heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal barrier. This study is aimed at elucidating the molecular mechanisms of HO-1/CO in barrier loss. Materials and Methods. We induced gut leakiness by injecting carbon tetrachloride (CCl4) to wildtype or intestinal HO-1-deficient mice. In addition, we administrated tumor necrosis factor-α (TNF-α) to cells with gain- or loss-of-HO-1 function. The effects of HO-1/CO maintaining intestinal barrier integrity were investigated in vivo and in vitro. Results. Cobalt protoporphyrin and CO-releasing molecule-2 alleviated colonic mucosal injury and TNF-α levels; upregulated tight junction (TJ) expression; and inhibited epithelial IκB-α degradation and phosphorylation, NF-κB p65 phosphorylation, long MLCK expression, and MLC-2 phosphorylation after administration of CCl4. Zinc protoporphyrin completely reversed these effects. These findings were further confirmed in vitro, using Caco-2 cells with gain- or loss-of-HO-1-function after TNF-α. Pretreated with JSH-23 (NF-κB inhibitor) or ML-7 (long MLCK inhibitor), HO-1 overexpression prevented TNF-α-induced TJ disruption, while HO-1 shRNA promoted TJ damage even in the presence of JSH-23 or ML-7, thus suggesting that HO-1 dependently protected intestinal barrier via the NF-κB p65/MLCK/p-MLC-2 pathway. Intestinal HO-1-deficient mice further demonstrated the effects of HO-1 in maintaining intestinal barrier integrity and its relative mechanisms. Alleviated hepatic fibrogenesis and serum ALT levels finally confirmed the clinical significance of HO-1/CO repairing barrier loss in liver injury. Conclusion. HO-1/CO maintains intestinal barrier integrity through the NF-κB/MLCK pathway. Therefore, the intestinal HO-1/CO-NF-κB/MLCK system is a potential therapeutic target for diseases with a leaky gut.

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Evidence for Cytoprotective Effect of Carbon Monoxide Donor in the Development of Acute Esophagitis Leading to Acute Esophageal Epithelium Lesions

Cited by 18 publications

References 64 publications

Organic carbon monoxide prodrug, BW-CO-111, in protection against chemically-induced gastric mucosal damage

Organic carbon monoxide prodrug, BW-CO-111, in protection against chemically-induced gastric mucosal damage

Novel Hydrogen Sulfide (H2S)-Releasing BW-HS-101 and Its Non-H2S Releasing Derivative in Modulation of Microscopic and Molecular Parameters of Gastric Mucosal Barrier

HO‐1/CO Maintains Intestinal Barrier Integrity through NF‐κB/MLCK Pathway in Intestinal HO‐1^-/- Mice

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Evidence for Cytoprotective Effect of Carbon Monoxide Donor in the Development of Acute Esophagitis Leading to Acute Esophageal Epithelium Lesions

Cited by 18 publications

References 64 publications

Organic carbon monoxide prodrug, BW-CO-111, in protection against chemically-induced gastric mucosal damage

Organic carbon monoxide prodrug, BW-CO-111, in protection against chemically-induced gastric mucosal damage

Novel Hydrogen Sulfide (H2S)-Releasing BW-HS-101 and Its Non-H2S Releasing Derivative in Modulation of Microscopic and Molecular Parameters of Gastric Mucosal Barrier

HO‐1/CO Maintains Intestinal Barrier Integrity through NF‐κB/MLCK Pathway in Intestinal HO‐1-/- Mice

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Product

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HO‐1/CO Maintains Intestinal Barrier Integrity through NF‐κB/MLCK Pathway in Intestinal HO‐1^-/- Mice