The Endogenous Hydrogen Sulfide Producing Enzyme Cystathionine-β Synthase Contributes to Visceral Hypersensitivity in a Rat Model of Irritable Bowel Syndrome

Xu, Guiyun; Winston, John H.; Shenoy, Mohan; Zhou, Shufang; Chen, Jiande D.Z.; Pasricha, P. J.

doi:10.1186/1744-8069-5-44

Cited by 76 publications

(95 citation statements)

References 39 publications

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“…STZ has been widely used to induce type 1 diabetes in rodents for the study of diabetic neuropathic pain (Grabauskas et al, 2011;Xu et al, 2011). In the present study, after a single intraperitoneal injection of STZ (65 mg/kg body weight), we monitored rat blood glucose level and body weight once every week for 5 weeks.…”

Section: Stz Injection Induces Gastric Hypersensitivitymentioning

confidence: 99%

“…We have recently reported that the endogenous H 2 S-producing enzyme cystathionine-␤-synthetase (CBS) played an important role in chronic visceral hypersensitivity (Xu et al, 2008;Xu et al, 2009;Li et al, 2012; and that peripheral inflammation led to cbs gene DNA demethylation (Qi et al, 2013), indicating a crucial role for CBS and an epigenetic mechanism in chronic pain Qi et al, 2013). However, roles for NF-B and CBS/H 2 S signaling in diabetic gastric hypersensitivity remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Promoted Interaction of Nuclear Factor-κB with Demethylated Cystathionine-β-Synthetase Gene Contributes to Gastric Hypersensitivity in Diabetic Rats

Zhang

Zhou

et al. 2013

J. Neurosci.

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Patients with long-standing diabetes frequently demonstrate gastric hypersensitivity with an unknown mechanism. The present study was designed to investigate roles for nuclear factor-B (NF-B) and the endogenous H 2 S-producing enzyme cystathionine-␤-synthetase (CBS) signaling pathways by examining cbs gene methylation status in adult rats with diabetes. Intraperitoneal injection of streptozotocin (STZ) produced gastric hypersensitivity in female rats in response to gastric balloon distention. Treatment with the CBS inhibitor aminooxyacetic acid significantly attenuated STZ-induced gastric hypersensitivity in a dose-dependent fashion. Aminooxyacetic acid treatment also reversed hyperexcitability of gastric-specific dorsal root ganglion (DRG) neurons labeled by the dye DiI in diabetic rats. Conversely, the H 2 S donor NaHS enhanced neuronal excitability of gastric DRG neurons. Expression of CBS and p65 were markedly enhanced in gastric DRGs in diabetic rats. Blockade of NF-B signaling using pyrrolidine dithiocarbamate reversed the upregulation of CBS expression. Interestingly, STZ treatment led to a significant demethylation of CpG islands in the cbs gene promoter region, as determined by methylation-specific PCR and bisulfite sequencing. STZ treatment also remarkably downregulated the expression of DNA methyltransferase 3a and 3b. More importantly, STZ treatment significantly enhanced the ability of cbs to bind DNA at the p65 consensus site, as shown by chromatin immunoprecipitation assays. Our findings suggest that upregulation of cbs expression is attributed to cbs promoter DNA demethylation and p65 activation and that the enhanced interaction of the cbs gene and p65 contributes to gastric hypersensitivity in diabetes. This finding may guide the development and evaluation of new treatment modalities for patients with diabetic gastric hypersensitivity.

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Section: Stz Injection Induces Gastric Hypersensitivitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Promoted Interaction of Nuclear Factor-κB with Demethylated Cystathionine-β-Synthetase Gene Contributes to Gastric Hypersensitivity in Diabetic Rats

Zhang

Zhou

et al. 2013

J. Neurosci.

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“…As described previously, 20,22 DRG neurons innervating the colon were labeled by injection of fluorescent dye DiI (Invitrogen, New York, NY, USA) into the colon wall. Rats were anesthetized with chloral hydrate (0.36 g/kg i.p.…”

Section: Cell Retrograde Labelingmentioning

confidence: 99%

Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes

Song

Zhang

et al. 2015

J Neurogastroenterol Motil

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Background/AimsPatients with long-standing diabetes often demonstrate intestinal dysfunction and abdominal pain. However, the pathophysiology of abdominal pain in diabetic patients remains elusive. The purpose of study was to determine roles of voltage-gated sodium channels in dorsal root ganglion (DRG) in colonic hypersensitivity of rats with diabetes. MethodsDiabetic models were induced by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg) in adult female rats, while the control rats received citrate buffer only. Behavioral responses to colorectal distention were used to determine colonic sensitivity in rats. Colon projection DRG neurons labeled with DiI were acutely dissociated for measuring excitability and sodium channel currents by whole-cell patch clamp recordings. Western blot analysis was employed to measure the expression of Na V 1.7 and Na V 1.8 of colon DRGs. ResultsSTZ injection produced a significantly lower distention threshold than control rats in responding to colorectal distention. STZ injection also depolarized the resting membrane potentials, hyperpolarized action potential threshold, decreased rheobase and increased frequency of action potentials evoked by 2 and 3 times rheobase and ramp current stimulation. Furthermore, STZ injection enhanced neuronal sodium current densities of DRG neurons innervating the colon. STZ injection also led to a significant upregulation of Na V 1.7 and Na V 1.8 expression in colon DRGs compared with age and sex-matched control rats. ConclusionsOur results suggest that enhanced neuronal excitability following STZ injection, which may be mediated by upregulation of Na V 1.7 and Na V 1.8 expression in DRGs, may play an important role in colonic hypersensitivity in rats with diabetes.

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“…However, whether H 2 S acts on CSLV afferents is unknown; if it does, then the H 2 S-induced effect and its underlying mechanism remain to be explored. The application of NaHS has been reported to induce somatic hyperalgesia and the depolarization of dorsal root ganglion neurons, which are dependent on transient receptor potential ankyrin 1 (TRPA1) receptors (2,28,48). The TRPA1 receptor, a Ca 2ϩ -permeable, nonselective cation channel, is predominantly expressed on nociceptive sensory neurons that include CSLV neurons (31,40).…”

mentioning

confidence: 99%

“…The application of sodium hydrosulfide (NaHS, a donor of H 2 S) has been demonstrated to induce the sensitization of colon nociceptive neurons (44,48), a counterpart of CSLV neurons in visceral tissues. Moreover, one study showed that the intratracheal instillation of NaHS triggered airway neurogenic inflammation that was nearly abolished by the desensitization of CSLV afferents (41), which implied the effects of H 2 S on the afferents.…”

mentioning

confidence: 99%

Hydrogen sulfide induces hypersensitivity of rat capsaicin-sensitive lung vagal neurons: role of TRPA1 receptors

Hsu

Lin

Lee

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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-The sensitization of capsaicin-sensitive lung vagal (CSLV) afferents by inflammatory mediators is important in the development of airway hypersensitivity. Hydrogen sulfide (H 2 S) is an endogenous mediator inducing hyperalgesia through transient receptor potential ankyrin 1 (TRPA1) receptors located on nociceptors. We conducted this study to determine whether H 2S elevates the sensitivity of rat CSLV afferents. In anesthetized, artificially ventilated rats, the inhalation of aerosolized sodium hydrosulfide (NaHS, a H2S donor) caused no significant changes in the baseline activity of CSLV afferents. However, the afferent responses to right atrial injection of capsaicin or phenylbiguanide and to lung inflation were all markedly potentiated after NaHS inhalation. By contrast, the inhalation of its vehicle or NaOH (with a similar pH to NaHS) failed to enhance the afferent responses. Additionally, the potentiating effect on the afferent responses was found in rats inhaling L-cysteine (a substrate of H2S synthase) that slowly releases H2S. The potentiating effect of NaHS on the sensitivity of CSLV afferents was completely blocked by pretreatment of HC-030031 (a TRPA1 receptor antagonist) but was unaffected by its vehicle. In isolated rat CSLV neurons, the perfusion of NaHS alone did not influence the intracellular Ca 2ϩ concentration but markedly potentiated the Ca 2ϩ transients evoked by capsaicin. The NaHScaused effect was totally abolished by HC-030031 pretreatment. These results suggest that H2S induces a nonspecific sensitizing effect on CSLV fibers to both chemical and mechanical stimulation in rat lungs, which appears mediated through an action on the TRPA1 receptors expressed on the nerve endings of CSLV afferents. lung; lung vagal C fibers; afferent sensitization; H2S; TRPA1 receptors CAPSAICIN-SENSITIVE LUNG VAGAL (CSLV) afferents are nociceptive-like free nerve endings innervating all levels of the respiratory tract. CSLV afferents can detect several inhaled irritants (22, 25) and inflammatory mediators (16,25,26,39) that might in turn trigger various respiratory reflexes such as cough, mucus secretion, and bronchoconstriction (7,22). The afferents are sensitized by several mediators released because of lung inflammation (2,7,15,27), which might then exaggerate these respiratory reflexes. Therefore, the sensitization of CSLV afferents is probably involved in the pathogenesis of airway hypersensitivity in diseases such as chronic cough and asthma (7, 26, 47).Hydrogen sulfide (H 2 S), an irritant gas with the smell of rotten eggs, is emitted principally from volcanoes, hot springs, and numerous industrial sites. Lung exposure to H 2 S might lead to adverse respiratory effects, such as cough, airway irritation, airway hypersensitivity, and lung inflammation (16, 37, 41). Therefore, for the past decades, H 2 S was generally considered only an exogenous irritant. However, beginning with a report in 1996, H 2 S was suggested to act as an endogenous neuromodulator facilitating the hippocampal long-term potentiati...

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The Endogenous Hydrogen Sulfide Producing Enzyme Cystathionine-β Synthase Contributes to Visceral Hypersensitivity in a Rat Model of Irritable Bowel Syndrome

Cited by 76 publications

References 39 publications

Promoted Interaction of Nuclear Factor-κB with Demethylated Cystathionine-β-Synthetase Gene Contributes to Gastric Hypersensitivity in Diabetic Rats

Promoted Interaction of Nuclear Factor-κB with Demethylated Cystathionine-β-Synthetase Gene Contributes to Gastric Hypersensitivity in Diabetic Rats

Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes

Hydrogen sulfide induces hypersensitivity of rat capsaicin-sensitive lung vagal neurons: role of TRPA1 receptors

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