Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction

Liu, Xibao; Cotrim, Ana P.; Teos, Leyla; Zheng, Changyu; Swaim, William D.; Mitchell, James B.; Mori, Yasuo; Ambudkar, Indu S.

doi:10.1038/ncomms2526

Cited by 61 publications

(106 citation statements)

References 50 publications

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“…As a popular cancer therapeutic approach, radiotherapy kills both cancer cells and bystander normal cells, thereby remarkably affecting the integrity and function of healthy tissues [27]. Recently, wealth of clinical studies support the notion that radiotherapy-mediated side effects remain a conundrum, intertwined with impaired life quality of survivors.…”

Section: Discussionmentioning

confidence: 99%

Total abdominal irradiation exposure impairs cognitive function involving miR-34a-5p/BDNF axis

Cui¹,

Xiao²,

Li³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Radiotherapy is often employed to treat abdominal and pelvic malignancies, but is frequently accompanied by diverse acute and chronic local injuries. It was previously unknown whether abdominal and pelvic radiotherapy impairs distant cognitive dysfunction. In the present study, we demonstrated that total abdominal irradiation (TAI) exposure caused cognitive deficits in mouse models. Mechanically, microarray assay analysis revealed that TAI elevated the expression level of miR-34a-5p in small intestine tissues and peripheral blood (PD), which targeted the 3′UTR of Brain-derived neurotrophic factor (Bdnf) mRNA in hippocampus to mediate cognitive dysfunction. Tail intravenous injection of miR-34a-5p antagomir immediately after TAI exposure rescued TAI-mediated cognitive impairment via blocking the up-regulation of miR-34a-5p in PD, resulting in restoring the Bdnf expression in the hippocampus. More importantly, high throughput sequencing validated that the gut bacterial composition of mice was shifted after TAI exposure, which was retained by miR-34a-5p antagomir injection. Thus, 27(7):916-932our findings provide new insights into pathogenic mechanism underlying abdominal and pelvic radiotherapy-mediated distant cognitive impairment.

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Section: Discussionmentioning

confidence: 99%

Total abdominal irradiation exposure impairs cognitive function involving miR-34a-5p/BDNF axis

Cui¹,

Xiao²,

Li³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Although the data presented above demonstrates activation of a nonselective cation current across the plasma membrane and a rise in [Ca 2+ ] cyt in hepatocytes in response to acetaminophen treatment, the identity of the channels responsible for this Ca 2+ entry is not known. One possible candidate that is activated in response to oxidative stress is the TRPM2 (24)(25)(26). Evidence that acetaminophen-induced nonselective cation current is mediated by TRPM2 is as follows: (i) the current shows a linear I-V relationship; (ii) it is blocked by clotrimazole and ACA; and (iii) it is activated by H 2 O 2 (19,27).…”

Section: Acetaminophen-induced Nonselective Cation Current In Hepatocmentioning

confidence: 99%

TRPM2 channels mediate acetaminophen-induced liver damage

Kheradpezhouh

Morphett

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Acetaminophen (paracetamol) is the most frequently used analgesic and antipyretic drug available over the counter. At the same time, acetaminophen overdose is the most common cause of acute liver failure and the leading cause of chronic liver damage requiring liver transplantation in developed countries. Acetaminophen overdose causes a multitude of interrelated biochemical reactions in hepatocytes including the formation of reactive oxygen species, deregulation of Ca 2+ homeostasis, covalent modification and oxidation of proteins, lipid peroxidation, and DNA fragmentation. Although an increase in intracellular Ca 2+ concentration in hepatocytes is a known consequence of acetaminophen overdose, its importance in acetaminophen-induced liver toxicity is not well understood, primarily due to lack of knowledge about the source of the Ca 2+ rise. Here we report that the channel responsible for Ca 2+ entry in hepatocytes in acetaminophen overdose is the Transient Receptor Potential Melanostatine 2 (TRPM2) cation channel. We show by whole-cell patch clamping that treatment of hepatocytes with acetaminophen results in activation of a cation current similar to that activated by H 2 O 2 or the intracellular application of ADP ribose. siRNA-mediated knockdown of TRPM2 in hepatocytes inhibits activation of the current by either acetaminophen or H 2 O 2 . In TRPM2 knockout mice, acetaminophen-induced liver damage, assessed by the blood concentration of liver enzymes and liver histology, is significantly diminished compared with wildtype mice. The presented data strongly suggest that TRPM2 channels are essential in the mechanism of acetaminophen-induced hepatocellular death.

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“…A major drawback in developing a successful treatment strategy for this condition has been the lack of clear understanding of the mechanism by which irradiation (IR) induces a decrease in salivary gland function. The studies in several animal models, including mini-pig, rats and mice, 6–11 have reported that following a single dose of IR there is a slow loss of salivary gland tissue 3 due to likely damage of progenitor cell population within the gland. 12 In addition, the effects of IR on neuronal cells as well as vasculature have also been suggested to contribute to the loss of salivary gland function and regenerative capacity.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-mediated hAQP1 expression in irradiated mouse salivary glands causes recovery of saliva secretion by enhancing acinar cell volume decrease

et al. 2016

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Head and neck irradiation (IR) during cancer treatment causes by-stander effects on the salivary glands leading to irreversible loss of saliva secretion. The mechanism underlying loss of fluid secretion is not understood and no adequate therapy is currently available. Delivery of an adenoviral vector encoding human aquaporin-1 (hAQP1) into the salivary glands of human subjects and animal models with radiation-induced salivary hypofunction leads to significant recovery of saliva secretion and symptomatic relief in subjects. To elucidate the mechanism underlying loss of salivary secretion and the basis for AdhAQP1-dependent recovery of salivary gland function we assessed submandibular gland function in control mice and mice 2 and 8 months after treatment with a single 15-Gy dose of IR (delivered to the salivary gland region). Salivary secretion and neurotransmitter-stimulated changes in acinar cell volume, an in vitro read-out for fluid secretion, were monitored. Consistent with the sustained 60% loss of fluid secretion following IR, a carbachol (CCh)-induced decrease in acinar cell volume from the glands of mice post IR was transient and attenuated as compared with that in cells from non-IR age-matched mice. The hAQP1 expression in non-IR mice induced no significant effect on salivary fluid secretion or CCh-stimulated cell volume changes, except in acinar cells from 8-month group where the initial rate of cell shrinkage was increased. Importantly, the expression of hAQP1 in the glands of mice post IR induced recovery of salivary fluid secretion and a volume decrease in acinar cells to levels similar to those in cells from non-IR mice. The initial rates of CCh-stimulated cell volume reduction in acinar cells from hAQP1-expressing glands post IR were similar to those from control cells. Altogether, the data suggest that expression of hAQP1 increases the water permeability of acinar cells, which underlies the recovery of fluid secretion in the salivary glands functionally compromised post IR.

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Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction

Cited by 61 publications

References 50 publications

Total abdominal irradiation exposure impairs cognitive function involving miR-34a-5p/BDNF axis

Total abdominal irradiation exposure impairs cognitive function involving miR-34a-5p/BDNF axis

TRPM2 channels mediate acetaminophen-induced liver damage

Adenovirus-mediated hAQP1 expression in irradiated mouse salivary glands causes recovery of saliva secretion by enhancing acinar cell volume decrease

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