Capsaicin inhibits intestinal Cl- secretion and promotes Na+ absorption by blocking TRPV4 channels in healthy and colitic mice

Wan, Hanxing; Chen, Xiong Ying; Zhang, Fenglian; Chu, Fenglan; Sellers, Zachary M.; Xu, Feng; Dong, Hui

doi:10.1016/j.jbc.2022.101847

Cited by 11 publications

(18 citation statements)

References 62 publications

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“…DNA methylation is a classical epigenetic mechanism and participates in the pathogenesis of chronic pain [ 32 , 33 , 34 ]. There are three members of the TET protein family of hydroxymethylase: TET1, TET2, and TET3.…”

Section: Discussionmentioning

confidence: 99%

“…Even though both TET1 and TRPV4 were expressed in L4–6 DRG CGRP and IB4 neurons, and the inhibition of TET1 decreased the expression of TRPV4, it does not necessarily mean that the TET1 works through TRPV4 channels in the BCP rats. Although knockouts are the best way to confirm this, because TRPV4-KO rats have developmental disorders [ 34 ] and a long reproductive cycle, we used a TRPV4 inhibitor (HC067047) to investigate whether TET1 works through TRPV4 channels in the BCP rats. We found that the TRPV4 inhibitor (HC067047) significantly relieved bone cancer pain, which causes overexpression of TET1 and TRPV4, and that inhibition of TET1 reduces TRPV4 expression ( Figure 6 and Figure 7 ).…”

Section: Discussionmentioning

confidence: 99%

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TET1-TRPV4 Signaling Contributes to Bone Cancer Pain in Rats

Niu

Liu

et al. 2023

Brain Sciences

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Bone cancer pain (BCP) is excruciating for cancer patients, with limited clinical treatment options and significant side effects, due to the complex and unclear pathogenesis of bone cancer pain. Peripheral sensitization in dorsal root ganglion (DRG) neurons is a recognized cellular mechanism for bone cancer pain. The pathological mechanism of chronic pain is increasingly being affected by epigenetic mechanisms. In this study, we unbiasedly showed that the DNA hydroxymethylase ten-eleven translocation 1 (TET1) expression was significantly increased in the L4–6 DRG of BCP rats and ten-eleven translocation 2 (TET2) expression did not change significantly. Notably, TET1 inhibition by intrathecal injection of Bobcat339 (a TET1 inhibitor) effectively relieved mechanical hyperalgesia in BCP rats. Peripheral sensitization in chronic pain relies on the activation and overexpression of ion channels on neurons. Here, we demonstrated that TRPV4, one of the transient receptor potential ion channel family members, was significantly elevated in the L4–6 DRG of BCP rats. In addition, TRPV4 inhibition by intrathecal injection of HC067047 (a TRPV4 inhibitor) also significantly attenuated mechanical hyperalgesia in BCP rats. Interestingly, we found that TET1 inhibition downregulated TRPV4 expression in the L4–6 DRG of BCP rats. As a result, these findings suggested that TET1 may contribute to bone cancer pain by upregulating TRPV4 expression in the L4–6 DRG of BCP rats and that TET1 or TRPV4 may become therapeutic targets for bone cancer pain.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TET1-TRPV4 Signaling Contributes to Bone Cancer Pain in Rats

Niu

Liu

et al. 2023

Brain Sciences

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“…In addition to classic nociceptor Trpv1, our GO analysis revealed pain mediator Trpv4 from 55 of the 279 up-regulated DEGs associated with ion homeostasis ( 24 , 71 ). As both Trpv1 and Trpv4 were expressed by MNTs, and responsive to pain inducer capsaicin ( 41 , 72 , 73 ), their roles in the MNT-mediated cancer pain are worth further elucidation for developing novel analgesics. We have taken the advantages of OGB-1 calcium imaging to examine the neuronal activities of MNTs in this study compared to the patch clamp–based electrophysiological experiments, including simultaneously monitoring signals of multiple cells, mapping calcium activity in subcellular compartments of neuron (cell body, axon, and dendrites), and intrinsic signal amplification by calcium-induced calcium release from intracellular store ( 74 , 75 ).…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing uncovers a neuron-like macrophage subset associated with cancer pain

et al. 2022

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Tumor innervation is a common phenomenon with unknown mechanism. Here, we discovered a direct mechanism of tumor-associated macrophage (TAM) for promoting de novo neurogenesis via a subset showing neuronal phenotypes and pain receptor expression associated with cancer-driven nocifensive behaviors. This subset is rich in lung adenocarcinoma associated with poorer prognosis. By elucidating the transcriptome dynamics of TAM with single-cell resolution, we discovered a phenomenon “macrophage to neuron-like cell transition” (MNT) for directly promoting tumoral neurogenesis, evidenced by macrophage depletion and fate-mapping study in lung carcinoma models. Encouragingly, we detected neuronal phenotypes and activities of the bone marrow–derived MNT cells (MNTs) in vitro. Adoptive transfer of MNTs into NOD/SCID mice markedly enhanced their cancer-associated nocifensive behaviors. We identified macrophage-specific Smad3 as a pivotal regulator for promoting MNT at the genomic level; its disruption effectively blocked the tumor innervation and cancer-dependent nocifensive behaviors in vivo. Thus, MNT may represent a precision therapeutic target for cancer pain.

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“…Therefore, it is suggested that capsaicin can promote Na + -glucose absorption by inhibiting TRPV4 channel. 54 Studies in Caco-2 cells showed that reducing Ca 2+ levels stimulated Na(+)/H(+) exchanger 3 (NHE3) activity, thereby maintaining the high electrochemical driving force of PEPT1 to drive peptide transport. 55 Similarly, Yukiko et al found that capsaicin interacts with TRPV1 to reduce PEPT1-mediated transport in rat intestines; the inhibitory effect was attenuated by intravenous administration of ruthenium red, a nonselective inhibitor of TRP channels.…”

Section: The Ca 2+ -Channels In the Intestinal Nutrient Uptakementioning

confidence: 99%

Ion channels and transporters regulate nutrient absorption in health and disease

Lu,

Luo,

et al. 2023

J Cellular Molecular Medi

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Ion channels and transporters are ubiquitously expressed on cell membrane, which involve in a plethora of physiological process such as contraction, neurotransmission, secretion and so on. Ion channels and transporters is of great importance to maintaining membrane potential homeostasis, which is essential to absorption of nutrients in gastrointestinal tract. Most of nutrients are electrogenic and require ion channels and transporters to absorb. This review summarizes the latest research on the role of ion channels and transporters in regulating nutrient uptake such as K+ channels, Ca2+ channels and ion exchangers. Revealing the mechanism of ion channels and transporters associated with nutrient uptake will be helpful to provide new methods to diagnosis and find potential targets for diseases like diabetes, inflammatory bowel diseases, etc. Even though some of study still remain ambiguous and in early stage, we believe that ion channels and transporters will be novel therapeutic targets in the future.

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Capsaicin inhibits intestinal Cl- secretion and promotes Na+ absorption by blocking TRPV4 channels in healthy and colitic mice

Cited by 11 publications

References 62 publications

TET1-TRPV4 Signaling Contributes to Bone Cancer Pain in Rats

TET1-TRPV4 Signaling Contributes to Bone Cancer Pain in Rats

Single-cell RNA sequencing uncovers a neuron-like macrophage subset associated with cancer pain

Ion channels and transporters regulate nutrient absorption in health and disease

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