P2X7 receptor deletion suppresses γ-radiation-induced hyposalivation

Head and neck cancer treatments typically involve a combination of surgery and radiotherapy, often leading to collateral damage to nearby tissues causing unwanted side effects. Radiation damage to salivary glands frequently leads to irreversible dysfunction by poorly understood mechanisms. The P2X7 receptor (P2X7R) is a ligand-gated ion channel activated by extracellular ATP released from damaged cells as “danger signals.” P2X7R activation initiates apoptosis and is involved in numerous inflammatory disorders. In this study, we utilized P2X7R knockout (P2X7R−/−) mice to determine the role of the receptor in radiation-induced salivary gland damage. Results indicate a dose-dependent increase in γ-radiation-induced ATP release from primary parotid gland cells of wild-type but not P2X7R−/− mice. Despite these differences, apoptosis levels are similar in parotid glands of wild-type and P2X7R−/− mice 24–72 h after radiation. However, γ-radiation caused elevated prostaglandin E2 (PGE2) release from primary parotid cells of wild-type but not P2X7R−/− mice. To attempt to uncover the mechanism underlying differential PGE2 release, we evaluated the expression and activities of cyclooxygenase and PGE synthase isoforms. There were no consistent trends in these mediators following radiation that could explain the reduction in PGE2 release in P2X7R−/− mice. Irradiated P2X7R−/− mice have stimulated salivary flow rates similar to unirradiated controls, whereas irradiated wild-type mice have significantly decreased salivary flow rates compared with unirradiated controls. Notably, treatment with the P2X7R antagonist A438079 preserves stimulated salivary flow rates in wild-type mice following γ-radiation. These data suggest that P2X7R antagonism is a promising approach for preventing γ-radiation-induced hyposalivation.

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The effects of 5-hydroxydopamine on salivary flow rates and protein secretion by the submandibular and parotid glands of rats

Experimental Physiology ◽

10.1113/expphysiol.1996.sp003965 ◽

1996 ◽

Vol 81 (4) ◽

pp. 645-653 ◽

Cited By ~ 1

Author(s):

K Abe ◽

T Itoh ◽

M Tashiro ◽

A Okina ◽

C Gao ◽

...

Keyword(s):

Protein Secretion ◽

Salivary Flow ◽

Parotid Glands ◽

Flow Rates

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Relationship of salivary flow and pressure in dog submaxillary and parotid glands

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1961.201.2.285 ◽

1961 ◽

Vol 201 (2) ◽

pp. 285-286 ◽

Cited By ~ 7

Author(s):

L. L. Langley ◽

R. S. Brown

Keyword(s):

Blood Pressure ◽

Parotid Gland ◽

Submaxillary Gland ◽

Salivary Flow ◽

Capillary Blood ◽

Parotid Glands ◽

Flow Rates ◽

Relationship Of

The maximal secretion pressure in both the submaxillary and parotid gland varies directly with the rate of flow. At high rates (1 ml/min) of flow the pressure in the submaxillary gland is significantly higher than that in the parotid. At these flow rates the secretion pressure in both glands is higher than the capillary blood pressure.

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Radiation-induced gastric epithelial apoptosis occurs in the proliferative zone and is regulated by p53, bak, bax, and bcl-2

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00391.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. G620-G627 ◽

Cited By ~ 18

Author(s):

S. M. C. Przemeck ◽

C. A. Duckworth ◽

D. M. Pritchard

Keyword(s):

Small Intestine ◽

Epithelial Cells ◽

Gastric Epithelium ◽

Apoptotic Cells ◽

Gastric Epithelial Cells ◽

Wild Type ◽

Γ Radiation ◽

Proliferative Zone ◽

Radiation Induced ◽

Hematoxylin And Eosin

Unlike the small intestine and colon where γ-radiation-induced apoptosis has previously been well characterized, the response of murine gastric epithelium to γ-radiation has not been investigated in detail. Apoptosis was therefore assessed on a cell positional basis in gastric antral and corpus glands from adult male mice following γ-radiation. Maximum numbers of apoptotic cells were observed in both antrum and corpus at 48 h and at radiation doses greater than 12 Gy. However, the number of apoptotic cells observed in the gastric epithelium was much lower than observed in the small intestine or colon after similar doses of radiation. Hematoxylin and eosin, caspase 3 immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling detected similar numbers and cell positional distributions of apoptotic cells, hence hematoxylin and eosin was used for subsequent studies. The highest numbers of apoptotic cells were observed at cell positions 5–6 in the antrum and cell positions 15–18 in the corpus. These distributions coincided with the distributions of PCNA-labeled proliferating cells, but not with the distributions of H+-K+-ATPase-labeled parietal cells or TFF2-labeled mucous neck cells. Decreased numbers of apoptotic gastric epithelial cells were observed in p53-null, bak-null, and bax-null mice compared with wild-type counterparts 6 and 48 h after 12 Gy γ-radiation. Significantly increased numbers of apoptotic gastric epithelial cells were observed in bcl-2-null mice compared with wild-type littermates 6 h after 12 Gy γ-radiation. Radiation therefore induces apoptosis in the proliferative zone of mouse gastric epithelium. This response is regulated by the expression of p53, bak, bax, and bcl-2.

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Developing a Genetic System in Deinococcus radiodurans for Analyzing Mutations

Genetics ◽

10.1093/genetics/166.2.661 ◽

2004 ◽

Vol 166 (2) ◽

pp. 661-668

Author(s):

Mandy Kim ◽

Erika Wolff ◽

Tiffany Huang ◽

Lilit Garibyan ◽

Ashlee M Earl ◽

...

Keyword(s):

Dna Sequences ◽

Deinococcus Radiodurans ◽

Genetic System ◽

Base Change ◽

Base Substitution ◽

Wild Type ◽

Base Pairs ◽

E Coli ◽

Radiation Induced ◽

Induced Mutagenesis

Abstract We have applied a genetic system for analyzing mutations in Escherichia coli to Deinococcus radiodurans, an extremeophile with an astonishingly high resistance to UV- and ionizing-radiation-induced mutagenesis. Taking advantage of the conservation of the β-subunit of RNA polymerase among most prokaryotes, we derived again in D. radiodurans the rpoB/Rif r system that we developed in E. coli to monitor base substitutions, defining 33 base change substitutions at 22 different base pairs. We sequenced >250 mutations leading to Rif r in D. radiodurans derived spontaneously in wild-type and uvrD (mismatch-repair-deficient) backgrounds and after treatment with N-methyl-N′-nitro-N-nitrosoguanidine (NTG) and 5-azacytidine (5AZ). The specificities of NTG and 5AZ in D. radiodurans are the same as those found for E. coli and other organisms. There are prominent base substitution hotspots in rpoB in both D. radiodurans and E. coli. In several cases these are at different points in each organism, even though the DNA sequences surrounding the hotspots and their corresponding sites are very similar in both D. radiodurans and E. coli. In one case the hotspots occur at the same site in both organisms.

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Melatonin exerts a neuroprotective effect against γ-radiation-induced brain injury in the rat through the modulation of neurotransmitters, inflammatory cytokines, oxidative stress, and apoptosis

Environmental Science and Pollution Research ◽

10.1007/s11356-021-12951-5 ◽

2021 ◽

Author(s):

Mohamed Amr El-Missiry ◽

Sameh Shabana ◽

Sara J. Ghazala ◽

Azza I. Othman ◽

Maggie E. Amer

Keyword(s):

Oxidative Stress ◽

Brain Injury ◽

Inflammatory Cytokines ◽

Neuroprotective Effect ◽

Γ Radiation ◽

Radiation Induced

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Reduced High-Dose Radiation-Induced Residual Genotoxic Damage by Induction of Radioadaptive Response and Prophylactic Mild Dietary Restriction in Mice

Dose-Response ◽

10.1177/1559325820982166 ◽

2021 ◽

Vol 19 (1) ◽

pp. 155932582098216

Author(s):

Bing Wang ◽

Kaoru Tanaka ◽

Takanori Katsube ◽

Kouichi Maruyama ◽

Yasuharu Ninomiya ◽

...

Keyword(s):

Dietary Restriction ◽

High Dose ◽

Cancer Treatments ◽

Hematopoietic Stem ◽

Beneficial Effects ◽

Radiation Induced ◽

Potential Strategy ◽

Higher Doses

Radioadaptive response (RAR) describes a phenomenon in a variety of in vitro and in vivo systems that a low-dose of priming ionizing radiation (IR) reduces detrimental effects of a subsequent challenge IR at higher doses. Among in vivo investigations, studies using the mouse RAR model (Yonezawa Effect) showed that RAR could significantly extenuate high-dose IR-induced detrimental effects such as decrease of hematopoietic stem cells and progenitor cells, acute radiation hematopoietic syndrome, genotoxicity and genomic instability. Meanwhile, it has been demonstrated that diet intervention has a great impact on health, and dietary restriction shows beneficial effects on numerous diseases in animal models. In this work, by using the mouse RAR model and mild dietary restriction (MDR), we confirmed that combination of RAR and MDR could more efficiently reduce radiogenotoxic damage without significant change of the RAR phenotype. These findings suggested that MDR may share some common pathways with RAR to activate mechanisms consequently resulting in suppression of genotoxicity. As MDR could also increase resistance to chemotherapy and radiotherapy in normal cells, we propose that combination of MDR, RAR, and other cancer treatments (i.e., chemotherapy and radiotherapy) represent a potential strategy to increase the treatment efficacy and prevent IR risk in humans.

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