Pathophysiological Role of Purinergic P2X Receptors in Digestive System Diseases

P2X receptors (P2XRs) are trimeric, non-selective cation channels activated by extracellular ATP and widely distributed in the digestive system. P2XRs have an important role in the physiological function of the digestive system, such as neurotransmission, ion transports, proliferation and apoptosis, muscle contraction, and relaxation. P2XRs can be involved in pain mechanisms both centrally and in the periphery and confirmed the association of P2XRs with visceral pain. In the periphery, ATP can be released as a result of tissue injury, visceral distension, or sympathetic activation and can excite nociceptive primary afferents by acting at homomeric P2X(3)R or heteromeric P2X(2/3)R. Thus, peripheral P2XRs, and homomeric P2X(3) and/or heteromeric P2X(2/3)R in particular, constitute attractive targets for analgesic drugs. Recently studies have shown that P2XRs have made significant advances in inflammation and cancer. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. It is believed that with the further study of P2XRs and its subtypes, P2XRs and its specific antagonists will be expected to be widely used in the treatment of human digestive diseases in the future.

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Isoorientin Alleviates Inflammatory Bowel Disease by Inhibiting NLRP3 Inflammasome Activation through Nrf2/NQO1 Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.18:392-397 ◽

2020 ◽

Vol 18 (4) ◽

pp. 392-397

Author(s):

Qirun Cheng ◽

Xianjin Yu ◽

Rong Zhang ◽

Lipeng Chen

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Sulfonic Acid ◽

Tissue Injury ◽

Biological Activities ◽

Trinitrobenzene Sulfonic Acid ◽

Inflammasome Activation ◽

Nucleotide Binding Domain ◽

Nlrp3 Inflammasome Activation ◽

Inflammatory Bowel

Inflammatory bowel disease comprises a series of related conditions characterized by idiopathic inflammation of the gastrointestinal tract. To develop therapeutic agents to combat these conditions, a better understanding of the inflammatory mechanisms is of paramount importance. Isoorientin is a c-glycosylflavone common to plants such as Phyllostachys japonicus and buckwheat. While it has been documented to exhibit multiple biological activities, its effects on inflammatory bowel disease, and the potential regulatory mechanism remain to be explored. We have shown here that isoorientin relieves the intestinal tissue injury and decreases the activity and expression of myeloperoxidase in trinitrobenzene sulfonic acid-exposed rats. Furthermore, isoorientin alleviated cytokine secretion in rats after trinitrobenzene sulfonic acid exposure. Also, isoorientin suppressed the levels of the nucleotide-binding domain and leucine-rich repeat-containing protein family and enhanced the Nrf2/NQO1 pathway in trinitrobenzene sulfonic acid-induced bowel disease. In conclusion, isoorientin could serve as a promising drug for the treatment of chronic enteritis.

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Triptolide Inhibits the Activation of NLRP3 Inflammasome by Inhibiting NF-κB Pathway and Improves Myocardial Fibrosis

10.21203/rs.3.rs-590702/v1 ◽

2021 ◽

Author(s):

Jianyao Shen ◽

Hailiang Ma ◽

Chaoquan Wang

Keyword(s):

Myocardial Fibrosis ◽

Nlrp3 Inflammasome ◽

Subcutaneous Injection ◽

Tissue Injury ◽

Myocardial Cell ◽

Inflammatory Factors ◽

Inflammasome Activation ◽

Related Factors ◽

Nlrp3 Inflammasome Activation ◽

Tnf Α

Abstract ObjectiveTriptolide (TPL) is identified to be involved in the treatment for myocardial fibrosis (MF). This study investigated the mechanism of TPL in MF in rats and observed its effect on NLRP3 inflammasome signaling pathway.Materials and MethodsThe MF rat model was established by subcutaneous injection of isoproterenol (ISO), and treated by subcutaneous injection of TPL. After modeling for 1 week, the cardiac function of rats was evaluated, including LVEF, LVFS, LVES, LVED LVIDs and LVPWs. The HMI and LVMI were measured. The expressions of ANP, BNP, inflammatory related factors (IL-1β, IL-18, TNF-α, MCP-1, VCAM-1), and NLRP3 inflammasome factors (NLRP3, ASC, caspase-1) in rats were detected. HE staining and Masson staining were used to observe myocardial cell inflammation and fibrosis of rats.ResultsLVED, LVES, LVIDs and LVPWs of MF group were significantly upregulated, LVEF and LVFS were significantly downregulated, HMI and LVMI were upregulated, while TPL treatment reversed these trends; TPL treatment downregulated the tissue injury and improved the pathological damage of MF rats. TPL treatment downregulated the levels of inflammatory factors and fibrosis factors, and inhibited the activation of NLRP3 inflammasome. Activation of NLRP3 inflammasome or NF-κB pathway reversed the effect of TPL on MF.ConclusionsTPL inhibited the activation of NLRP3 inflammasome by inhibiting NF-κB pathway, and improved the degree of MF in MF rats.

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Intracolonic Mustard Oil Induces Visceral Pain in Mice by TRPA1-Dependent and -Independent Mechanisms: Role of Tissue Injury and P2X Receptors

Frontiers in Pharmacology ◽

10.3389/fphar.2020.613068 ◽

2021 ◽

Vol 11 ◽

Author(s):

Rafael Gonzalez-Cano ◽

Ángeles Montilla-García ◽

Gloria Perazzoli ◽

Jesús M. Torres ◽

Francisco J. Cañizares ◽

...

Keyword(s):

Low Dose ◽

Visceral Pain ◽

Tissue Injury ◽

P2x Receptors ◽

Mechanical Hyperalgesia ◽

Mustard Oil ◽

Colonic Epithelium ◽

High Dose ◽

Nociceptive Responses

Both TRPA1 and purinergic P2X receptors have been proposed as potential targets for the treatment of visceral pain. We found that the intracolonic administration of a low dose mustard oil (0.5%), a well-known TRPA1 agonist, produced nociceptive responses and abdominal wall referred mechanical hyperalgesia, without inducing apparent tissue damage. Both nociceptive responses and referred hyperalgesia were abolished by the ablation of TRPV1-expressing neurons (and the consequent ablation of TRPA1+ nociceptors) by resiniferatoxin (RTX) treatment, and by the TRPA1 antagonist AP18. However, a higher dose of mustard oil (2.5%) damaged the colonic epithelium and induced pERK activation in the spinal cord, and these processes were clearly independent of TRPV1-expressing neurons ablated by RTX. This higher dose of mustard oil induced nociceptive responses and referred mechanical hyperalgesia which were insensitive or only slightly sensitive to resiniferatoxin or AP18, but were markedly reduced by the P2X antagonist TNP-ATP, which is known to inhibit nociceptive actions induced by ATP released from injured tissues. In conclusion, whereas a low dose of intracolonic mustard oil induces visceral pain in a manner fully dependent on TRPA1 actions, when a high dose of this chemical irritant is used, visceral pain becomes mostly independent of TRPA1 activation but clearly enhanced by ATP purportedly released by the damaged colonic epithelium. Therefore, TRPA1 inhibition is not sufficient to substantially decrease visceral pain during tissue injury, whereas purinergic antagonism appears to be a more effective strategy.

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