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The location of the primary tumor or lymph node metastases dictates the inclusion of the oral cavity, salivary glands, and jaws in the radiation treatment portals for patients who have head and neck cancer. The clinical sequelae of the radiation treatment include mucositis, hyposalivation, loss of taste, osteoradionecrosis, radiation caries, and trismus. These sequelae may be dose-limiting and have a tremendous effect on the patient's quality of life. Most treatment protocols to prevent these sequelae are still based on clinical experience, but alternatives based on fundamental basic and clinical research are becoming more and more available. Many of these alternatives either need further study before they can be incorporated into the protocols commonly used to prevent and treat the radiation-related oral sequelae or await implementation of these protocols. In this review, the various possibilities for prevention and/or treatment of radiation-induced changes in healthy oral tissues and their consequences are discussed. [ABSTRACT FROM AUTHOR]

In addition to anti-tumor effects, ionizing radiation causes damage in normal tissues located in the radiation portals. Oral complications of radiotherapy in the head and neck region are the result of the deleterious effects of radiation on, e.g., salivary glands, oral mucosa, bone, dentition, masticatory musculature, and temporomandibular joints. The clinical consequences of radiotherapy include mucositis, hyposalivation, taste loss, osteoradionecrosis, radiation caries, and trismus. Mucositis and taste loss are reversible consequences that usually subside early post-irradiation, while hyposalivation is normally irreversible. Furthermore, the risk of developing radiation caries and osteoradionecrosis is a life-long threat. All these consequences form a heavy burden for the patients and have a tremendous impact on their quality of life during and after radiotherapy. In this review, the radiation-induced changes in healthy oral tissues and the resulting clinical consequences are discussed. [ABSTRACT FROM AUTHOR]

Without the protective shielding of Earth's atmosphere, astronauts face higher doses of ionizing radiation in space, causing serious health concerns. Highly charged and high energy (HZE) particles are particularly effective in causing complex and difficult-to-repair DNA double-strand breaks compared to low linear energy transfer. Additionally, chronic cortisol exposure during spaceflight raises further concerns, although its specific impact on DNA damage and repair remains unknown. This study explorers the effect of different radiation qualities (photons, protons, carbon, and iron ions) on the DNA damage and repair of cortisol-conditioned primary human dermal fibroblasts. Besides, we introduce a new measure, the Foci-Integrated Damage Complexity Score (FIDCS), to assess DNA damage complexity by analyzing focus area and fluorescent intensity. Our results show that the FIDCS captured the DNA damage induced by different radiation qualities better than counting the number of foci, as traditionally done. Besides, using this measure, we were able to identify differences in DNA damage between cortisol-exposed cells and controls. This suggests that, besides measuring the total number of foci, considering the complexity of the DNA damage by means of the FIDCS can provide additional and, in our case, improved information when comparing different radiation qualities., (© 2024. The Author(s).)

Relatively quiescent tissues like salivary glands (SGs) respond to stimuli such as injury to expand, replace and regenerate. Resident stem/progenitor cells are key in this process because, upon activation, they possess the ability to self-renew. Macroautophagy/autophagy contributes to and regulates differentiation in adult tissues, but an important question is whether this pathway promotes stem cell self-renewal in tissues. We took advantage of a 3D organoid system that allows assessing the self-renewal of mouse SGs stem cells (SGSCs). We found that autophagy in dormant SGSCs has slower flux than self-renewing SGSCs. Importantly, autophagy enhancement upon SGSCs activation is a self-renewal feature in 3D organoid cultures and SGs regenerating in vivo . Accordingly, autophagy ablation in SGSCs inhibits self-renewal whereas pharmacological stimulation promotes self-renewal of mouse and human SGSCs. Thus, autophagy is a key pathway for self-renewal activation in low proliferative adult tissues, and its pharmacological manipulation has the potential to promote tissue regeneration.

β-Adrenergic signaling blockade is a mainstay of hypertension management. One percent of patients taking β-blockers develop reduced salivary gland (SG) function. Here we investigate the role of SG progenitor cells in β-blocker-induced hyposalivation, using human SG organoid cultures (SGOs). Compared with control SGs, initial low SG progenitor cell yield from patients taking β-blockers was observed. When passaged, these SGOs recovered self-renewal and upregulated Notch pathway expression. Notch signaling was downregulated in situ in β-adrenergic receptor-expressing luminal intercalated duct (ID) cells of patients taking β-blockers. Control SGOs treated with β-adrenergic agonist isoproterenol demonstrated increased proportion of luminal ID SGO cells with active Notch signaling. Control SGOs exposed to isoproterenol differentiated into more mature SGOs (mSGOs) expressing markers of acinar cells. We propose that β-blocker-induced Notch signaling reduction in luminal ID cells hampers their ability to proliferate and differentiate into acinar cells, inducing a persistent hyposalivation in some patients taking β-blocking medication., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Although the salivary glands have a low rate of cell turnover, they are relatively radiosensitive. To study the possible mechanism behind this inherent radiosensitivity, a rat model was developed in which saliva can be collected after local irradiation of the parotid gland without the use of anesthetics or stressful handling. Saliva secretion was induced by the partial muscarinic receptor agonist pilocarpine (0.03-3 mg/kg) with or without pretreatment with the beta-adrenoceptor antagonist propranolol (2.5 mg/kg), or the full muscarinic receptor agonist methacholine (0.16-16 mg/min), and measured during 5 min per drug dose before and 1, 3, 6 and 10 days after irradiation. The maximal secretory response induced by pilocarpine plus propranolol was increased compared to that with pilocarpine alone but did not reach the level of methacholine-induced secretion, which was about five times higher. One day after irradiation a decrease in maximal pilocarpine-induced secretion was observed (-22%) using the same dose of pilocarpine that induces 50% of the maximal response (ED(50)), in both the absence and presence of propranolol, indicating that the receptor-drug interaction was not affected by the radiation at this time. The secretory response to methacholine 1 day after irradiation, however, was normal. At day 3 after irradiation, the maximal methacholine-induced secretion was also affected, whereas pilocarpine (+/-propranolol)-induced maximal secretion decreased further. At day 6 after irradiation, maximal secretory responses had declined to approximately 50% regardless of the agonist used, whereas ED(50) values were still unaffected. No net acinar cell loss was observed within the first 10 days after irradiation, and this therefore could not account for the loss in function. The results indicate that radiation does not affect cell number or receptor-drug interaction, but rather signal transduction, which eventually leads to the impaired response. We hypothesize that the early radiation effect, within 3 days, may be membrane damage affecting the receptor-G-protein signaltransfer. Later critical damage, however, is probably of a different nature and may be located in the second-messenger signal transduction pathway downstream from the G protein, not necessarily involving cellular membranes.

To investigate whether secretory granules play a role in the radiosensitivity of the salivary glands of rats, parotid acinar cells, submandibular acinar cells and/or submandibular granular convoluted tubule (GCT) cells were degranulated prior to irradiation. Degranulation of GCT cells was obtained by pretreatment with phenylephrine (5 mg/kg, t = -60 min) and methacholine (3.75 mg/kg, t = -120 min). Degranulation of acinar cells was attained by pretreatment with isoproterenol (5 mg/kg, t = -90 min). Combinations of pretreatments were also tested. Irradiation was performed with a single dose of 15 Gy of X rays. Samples of parotid and submandibular/sublingual saliva were collected 4 days prior to and 1, 3, 6, 10 and 30 days after irradiation. Pretreatment with phenylephrine, isoproterenol and methacholine plus phenylephrine resulted in less radiation damage to parotid gland function as indicated by the lag phase and flow rate. Since the pretreatment with phenylephrine and phenylephrine plus methacholine did not degranulate parotid gland acinar cells, the observed protective effect on this gland cannot be explained by the "degranulation concept." Furthermore, salivary gland function was significantly greater 3 days after irradiation as a result of pretreatment with phenylephrine and phenylephrine plus methacholine compared to rats given only radiation. This may indicate recovery from damage rather than a reduced amount of initial damage. The sparing was most obvious for the later effects (6-30 days). Submandibular/sublingual gland function was improved significantly after pretreatment with methacholine plus phenylephrine, although no increase in degranulation of GCT cells was observed compared to pretreatment with phenylephrine alone, again not favoring the degranulation concept. The results indicate that the secretory granules do not play the often-assumed important role in the radiosensitivity of the salivary gland. The mechanism underlying the observed improvement of salivary gland function may involve second messenger-induced increases in proliferation of salivary gland cells resulting in recovery of tissue after the irradiation.

1. The duration of the facilitatory effect of adrenaline on the electrically evoked overflow of noradrenaline was studied in the portal vein of permanently adreno-demedullated freely moving rats. 2. Rats were infused with adrenaline (20 or 100 ng min-1) for 2 h. After an interval of 1 h, when plasma adrenaline had returned to undetectable levels, electrical stimulation resulted in an enhanced catecholamine overflow amounting to 219% (noradrenaline) and 241% (noradrenaline plus adrenaline) of control (saline infusion), respectively. 3. When stimulation was applied again, in the same animal, at 24, 48 and 72 h after the first stimulation episode, the evoked noradrenaline overflow was 150, 111 and 102% (after 20 ng ml-1 adrenaline) and 158, 134 and 105% (after 100 ng min-1 adrenaline) of control. 4. The beta 2-adrenoceptor antagonist, ICI 118,551 (0.3 mg kg-1), blocked the facilitatory effect obtained after the 100 ng min-1 adrenaline infusion on all days. 5. The results show that adrenaline, after being taken up by and released from sympathetic nerve terminals, is able to facilitate the evoked noradrenaline overflow through activation of prejunctional beta 2-adrenoceptors for at least 48 h after administration.

1. In the portal vein of the freely moving unanaesthetized rat, the existence of presynaptically located inhibitory muscarinic receptors was investigated by use of the muscarinic agonist methacholine (MCh) 2. Infusion of MCh (0.3 micrograms min-1) did not significantly inhibit the endogenous noradrenaline (NA) overflow in portal plasma. However, after inducing high intra-synaptic concentrations of NA by blocking the presynaptic alpha 2-adrenoceptors with yohimbine (1 mg kg-1), MCh (0.3 microgram min-1) was able to reduce the yohimbine-induced enhanced NA overflow by 38%. 3. The MCh-induced inhibition was almost completely abolished after blockade of the presynaptic muscarinic receptors with atropine (0.6 mg kg-1). 4. During electrical stimulation of the portal vein nervous plexus the evoked NA overflow was strongly inhibited (95%) during MCh-infusion (0.3 microgram min-1). Again atropine (0.6 mg kg-1) was able to reverse this inhibition. 5. These results show the existence of presynaptic muscarinic receptors inhibiting endogenous NA overflow from the portal vein nervous plexus under conditions of enhanced sympathetic activity in the freely moving rat.