Bacterial phytopathogens employ a type III secretion system to deliver effector proteins into the plant cell to suppress defense pathways; however, the molecular mechanisms and subcellular localization strategies that drive effector function largely remain a mystery. Here, we demonstrate that the plant plasma membrane is the primary site for subcellular localization of the Pseudomonas syringae effector AvrPphB and five additional cysteine protease family members. AvrPphB and two AvrPphB-like effectors, ORF4 and NopT, autoproteolytically process following delivery into the plant cell to expose embedded sites for fatty acylation. Host-dependent lipidation of these three effectors directs plasma membrane localization and is required for the avirulence activity of AvrPphB. Surprisingly, the AvrPphB-like effectors RipT, HopC1, and HopN1 utilize an acylation-independent mechanism to localize to the cellular plasma membrane. Although some AvrPphB-like effectors employ acylation-independent localization strategies, others hijack the eukaryotic lipidation machinery to ensure plasma membrane localization, illustrating the diverse tactics employed by type III effectors to target specific subcellular compartments.

The comparative quantitative autoradiographic distribution of ionotropic glutamate receptor subtypes were investigated in young adults (six months) and aged (24-25 months) cognitively impaired and unimpaired male Long-Evans rats. Aged rats were behaviorally characterized as either cognitively impaired or unimpaired based upon their performances in the Morris water maze task compared to the young adult controls. The status of the N-methyl-D-aspartate, [125I]dizocilpine maleate, [3H]kainate and amino-3-hydroxy-5-methylisoxasole-4-propionate (AMPA, [3H]AMPA) receptor binding sites were then established in these three subgroups of animals as a function of their cognitive performance in the Morris water maze task. The apparent densities of both N-methyl-D-aspartate/[125I]dizocilpine maleate and kainate binding sites were significantly decreased in various regions of the aged rat brain. Marked losses in [125I]dizocilpine maleate binding sites were observed in outer laminae of the frontal, parietal and temporal cortices, and the stratum radiatum of the CA3 subfield of the hippocampus. Interestingly, losses in [125I]dizocilpine maleate binding sites were generally most evident in the cognitively unimpaired aged subgroup, suggesting a possible inverse relationship between losses of this receptor subtype and cognitive performances in the Morris water maze task. The levels of [3H]kainate binding were most significantly diminished in various cortical and hippocampal areas as well as the striatum and septal nuclei of both groups of aged rats. In contrast, the apparent density of [3H]AMPA binding was increased in most hippocampal subfields and the superficial laminae of the occipital cortex of the cognitively impaired vs young adult rats. Changes in [3H]AMPA labeling failed to reach significance in the unimpaired cohort. Taken together, these results show that while losses in [3H]kainate binding were similar in both subgroups of aged rats, differences were seen with respect to cognitive status for both [125I]dizocilpine maleate/N-methyl-D-aspartate and [3H]AMPA binding sites. Decreases in [125I]dizocilpine maleate binding sites were mostly restricted to cortical areas of cognitively unimpaired rats, while increases in the AMPA binding subtype were seen in the memory-impaired subgroup. It would thus appear that changes in N-methyl-D-aspartate and AMPA receptor subtypes may be more critical than alterations in kainate binding sites for the emergence of the functional deficits seen in the aged cognitively impaired rat.

Alcohol use initiated early in adolescence is a major predictor for the development of alcohol use disorders. This risk may be increased when drinking is initiated around the time of puberty, given evidence of bidirectional relationships between alcohol and gonadal hormones. The current study examined the effects of adolescent intermittent ethanol exposure (AIE) on pubertal timing and expression of novelty-seeking and peer-directed behaviors as well as neural correlates of these behaviors. AIE did not affect pubertal timing or the later expression of novelty-seeking and peer-directed behaviors. AIE increased corticosterone (CORT) levels in females not tested behaviorally in adulthood or tested in the novel-object exploration paradigm, whereas social interaction blunted CORT levels in AIE females. Delays in pubertal timing and decreases in CORT levels were correlated, however, with increased novelty seeking in adult males - a phenotype associated with increased addiction vulnerability. In females, social testing elevated oxytocin receptor (OXTR) mRNA expression in the central amygdala (CeA), with this social testing-associated elevation evident in the lateral septum (LS), regardless of sex. Vasopressin receptor 1a (AVP-1aR) mRNA expression in the CeA was enhanced by social testing in females, but not males, with expression of this gene suppressed by social testing in the LS in males, but not females. Together, these data demonstrate that behavioral and neural alterations that may serve as risk factors in later drug vulnerabilities are likely not the result of a single insult, but may reflect interactions among several variables including sex, pubertal timing, stress reactivity, and test circumstances.

Alcohol consumption can be enhanced or moderated by sensitivity to its aversive and appetitive properties, including positive social outcomes. These differences emerge post-pubertally, suggesting a potential role of gonadal hormones. To determine the role of gonadal hormones in sensitivity to the social impairing and social context-related attenuations in the aversive effects of ethanol, prepubertal male and female rats were gonadectomized (GX) or sham (SH) operated on postnatal day (P) 25, or left non-manipulated (NM). In adulthood (P70), rats were restrained for 90 min prior to challenge with 0.0 or 1.0 g/kg ethanol and social interaction (SI) testing. At P77, groups of 4 same-sex littermates from the same surgical condition were given access to a supersaccharin (SS) solution (3% sucrose, 0.125% saccharin), followed by an intraperitoneal injection of ethanol (0.0, 0.50, 1.0, 1.5 g/kg). Intakes of SS were examined 24h later for expression of conditioned taste aversions. Acute stress prior to SI testing increased frequency of play fighting in both sexes, whereas there were no GX effects on this measure, social investigation nor contact. GX, however, decreased baseline social preference (a social anxiety-like effect) in males, while inducing anxiolytic-like increases in baseline social preference in females. The social drinking test revealed that females developed ethanol conditioned taste aversions at a lower dose relative to males, regardless of surgical condition. These findings suggest a potential role for gonadal hormones in moderating social-anxiety like behaviors but not sensitivity to the social impairing effects of ethanol or ethanol's aversive consequences in a social context.

The immune system is implicated in the pathology of neurodegenerative disorders. The C-C chemokine receptor 2 (CCR2) is one of the key targets involved in the activation of the immune system. A suitable ligand for CCR2 could be a useful tool to study immune activation in central nervous system (CNS) disorders. Herein, we describe the synthesis, tritium radiolabelling, and preliminary in vitro evaluation in post-mortem human brain tissue of a known potent small molecule antagonist for CCR2. The preparation of a tritium-labelled analogue for the autoradiography (ARG) study gave rise to an intriguing and unexpected side reaction profile through a novel amination of ethanol and methanol in the presence of tritium. After successful preparation of the tritiated radioligand, in vitro ARG measurements on human brain sections revealed nonspecific binding properties of the selected antagonist in the CNS.

Treatment of patients with glucocorticoids can result in an increased risk of infection with pathogens such as fungi. Dectin-1 is a member of the C-type lectin receptor superfamily and was shown to be one of the major receptors for fungal beta-glucans. Activation of Dectin-1 increases the production of cytokines and chemokines and T-cell stimulatory capacity of DC and mediates resolution of fungal infections. Here we show that antigen-presenting cells generated in the presence of dexamethasone (Dex-DC) have a reduced capacity to stimulate T-cell proliferation and decreased expression of costimulatory molecules, that can not be enhanced upon stimulation with Dectin-1 ligands. Stimulation of Dex-DC with beta-glucans induced a strong upregulation of Syk phosphorylation and increased secretion of IL-10, while the production of IL-12, IL-23 and TNF-alpha was reduced. Downstream of Syk stimulation of Dectin-1 on Dex-DC resulted in phosphorylation of STAT3 and reduced nuclear localization of transcription factors involved in DC activation and function.

Previously, we have reported that spherical particles (SPs) are formed by the thermal remodeling of rigid helical virions of native tobacco mosaic virus (TMV) at 94°C. SPs have remarkable features: stability, unique adsorption properties and immunostimulation potential. Here we performed a comparative study of the amino acid composition of the SPs and virions surface to characterize their properties and take an important step to understanding the structure of SPs. The results of tritium planigraphy showed that thermal transformation of TMV leads to a significant increase in tritium label incorporation into the following sites of SPs protein: 41-71 а.a. and 93-122 a.a. At the same time, there was a decrease in tritium label incorporation into the N- and C- terminal region (1-15 a.a., 142-158 a.a). The use of complementary physico-chemical methods allowed us to carry out a detailed structural analysis of the surface and to determine the most likely surface areas of SPs. The obtained data make it possible to consider viral protein thermal rearrangements, and to open new opportunities for biologically active complex design using information about SPs surface amino acid composition and methods of non-specific adsorption and bioconjugation.

The purpose of this study was to investigate the effects of Chahuangjing, a novel traditional Chinese medicinal compound, on decorporation and radiation protection against tritiated water (HTO). Sixty male specific-pathogen-free-grade C57BL/6J mice were randomly divided into 12 groups: mice in 4 control groups were intraperitoneally injected with sterile water; mice in 4 HTO groups were intraperitoneally injected with 11.1 × 105 Bq/g of HTO; and mice in the other 4 groups were administered with HTO and a Chahuangjing compound (0.2 mL, once daily). After 1, 7, 14, and 21 days, the mice were killed and samples were collected. A liquid scintillation counting method was used for tritium measurement. A fully automated hematology analyzer was used to assess blood samples. The superoxide dismutase (SOD) and malondialdehyde (MDA) content was analyzed using commercial kits. Chahuangjing significantly increased decorporation and shortened the effective half-life of tritium. To a certain extent, Chahuangjing alleviated the HTO-induced reduction in white blood cells and elevated red blood cells after HTO exposure. Moreover, Chahuangjing alleviated the HTO-induced reduction in SOD activity and reduced MDA. Our study demonstrated that Chahuangjing can enhance the elimination of tritium and reduce free radicals to alleviate HTO-induced radiation injury.

In 2019, 254 samples were collected from five aquifer systems to evaluate perfluoroalkyl and polyfluoroalkyl substance (PFAS) occurrence in groundwater used as a source of drinking water in the eastern United States. The samples were analyzed for 24 PFAS, major ions, nutrients, trace elements, dissolved organic carbon (DOC), volatile organic compounds (VOCs), pharmaceuticals, and tritium. Fourteen of the 24 PFAS were detected in groundwater, with 60 and 20% of public-supply and domestic wells, respectively, containing at least one PFAS detection. Concentrations of tritium, chloride, sulfate, DOC, and manganese + iron; percent urban land use within 500 m of the wells; and VOC and pharmaceutical detection frequencies were significantly higher in samples containing PFAS detections than in samples with no detections. Boosted regression tree models that consider 57 chemical and land-use variables show that tritium concentration, distance to the nearest fire-training area, percentage of urban land use, and DOC and VOC concentrations are the top five predictors of PFAS detections, consistent with the hydrologic position, geochemistry, and land use being important controls on PFAS occurrence in groundwater. Model results indicate that it may be possible to predict PFAS detections in groundwater using existing data sources.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a critical enzyme in the mevalonate pathway that regulates the biosynthesis of cholesterol as well as isoprenoids that mediate the membrane association of certain GTPases. Blockade of this enzyme by atorvastatin (AT) inhibits the destructive proinflammatory T helper cell (Th)1 response during experimental autoimmune encephalomyelitis and may be beneficial in the treatment of multiple sclerosis and other Th1-mediated autoimmune diseases. Here we present evidence linking specific isoprenoid intermediates of the mevalonate pathway to signaling pathways that regulate T cell autoimmunity. We demonstrate that the isoprenoid geranylgeranyl-pyrophosphate (GGPP) mediates proliferation, whereas both GGPP and its precursor, farnesyl-PP, regulate the Th1 differentiation of myelin-reactive T cells. Depletion of these isoprenoid intermediates in vivo via oral AT administration hindered these T cell responses by decreasing geranylgeranylated RhoA and farnesylated Ras at the plasma membrane. This was associated with reduced extracellular signal-regulated kinase (ERK) and p38 phosphorylation and DNA binding of their cotarget c-fos in response to T cell receptor activation. Inhibition of ERK and p38 mimicked the effects of AT and induced a Th2 cytokine shift. Thus, by connecting isoprenoid availability to regulation of Th1/Th2 fate, we have elucidated a mechanism by which AT may suppress Th1-mediated central nervous system autoimmune disease.

Human milk is widely acknowledged as the best food for infants, and that is not just because of nutritional features. Human milk also contains a plethora of bioactive molecules, including a large set of human milk oligosaccharides (hMOs). Especially fucosylated hMOs have received attention for their anti-adhesive effects on pathogens, preventing attachment to the intestine and infection. Because hMOs are generally challenging to produce in sufficient quantities to study and ultimately apply in (medical) infant formula, novel compounds that are inspired by hMO structures (so-called "mimics") are interesting compounds to produce and evaluate for their biological effects. Here we present our thorough study into the digestion, fermentation and anti-adhesive capacity of the novel compound di-fucosyl-β-cyclodextrin (DFβCD), which was inspired by the molecular structures of hMOs. We establish that DFβCD is not digested by α-amylase and also resistant to fermentation by microbial enzymes from a 9 month-old infant inoculum. In addition, we reveal that DFβCD blocks adhesion of enterotoxigenic E. coli (ETEC) to Caco-2 cells, especially when DFβCD is pre-incubated with ETEC prior to addition to the Caco-2 cells. This suggests that DFβCD functions through a decoy effect. We expect that our results inspire the generation and biological evaluation of other fucosylated hMOs and mimics, to obtain a comprehensive overview of the anti-adhesive power of fucosylated glycans.

Up-regulation of the membrane-bound efflux pump P-glycoprotein (P-gp) is associated with the phenomenon of multidrug-resistance in pathogenic organisms, including protozoan parasites. In addition, P-gp plays a role in normal physiological processes, however our understanding of these P-gp functions remains limited. In this study we investigated the effects of the P-gp inhibitor GF120918 in Toxoplasma gondii, a model apicomplexan parasite and an important human pathogen. We found that GF120918 treatment severely inhibited parasite invasion and replication. Further analyses of the molecular mechanisms involved revealed that the P-gp inhibitor modulated parasite motility, microneme secretion and egress from the host cell, all cellular processes known to depend on Ca2+ signaling in the parasite. In support of a potential role of P-gp in Ca2+-mediated processes, immunoelectron and fluorescence microscopy showed that T. gondii P-gp was localized in acidocalcisomes, the major Ca2+ storage in the parasite, at the plasma membrane, and in the intravacuolar tubular network. In addition, metabolic labeling of extracellular parasites revealed that inhibition or down-regulation of T. gondii P-gp resulted in aberrant lipid synthesis. These results suggest a crucial role of T. gondii P-gp in essential processes of the parasite biology and further validate the potential of P-gp activity as a target for drug development.

The structural and functional interaction between D₂ dopamine receptor (DR) and A(2A) adenosine receptor (AR) has suggested these two receptors as a pharmacological target in pathologies associated with dopamine dysfunction, such as Parkinson's disease. In transfected cell lines it has been demonstrated the activation of D₂DR induces a significant negative regulation of A(2A)AR-mediated responses, whereas few data are at now available about the regulation of A(2A)AR by D₂DR agonists at receptor recognition site. In this work we confirmed that in A(2A)AR/D₂DR co-transfected cells, these receptors exist as homo- and hetero-dimers. The classical D₂DR agonists were able to negatively modulate both A(2A)AR affinity and functionality. These effects occurred even if any significant changes in A(2A)AR/D₂DR energy transfer interaction could be detected in BRET experiments. Since the development of new molecules able to target A(2A)/D₂ dimers may represent an attractive tool for innovative pharmacological therapy, we also identified a new small molecule, 3-(3,4-dimethylphenyl)-1-(2-piperidin-1-yl)ethyl)piperidine (compound 1), full agonist of D₂DR and modulator of A(2A)-D₂ receptor dimer. This compound was able to negatively modulate A(2A)AR binding properties and functional responsiveness in a manner comparable to classical D₂R agonists. In contrast to classical agonists, compound 1 led to conformational changes in the quaternary structure in D₂DR homomers and heteromers and induced A(2A)AR/D₂DR co-internalization. These results suggest that compound 1 exerts a high control of the function of heteromers and could represent a starting point for the development of new drugs targeting A(2A)AR/D₂ DR heteromers.

Hypertension is of unknown aetiology, with sympathetic nervous system hyperactivation being one of the possible contributors. Hypertension may have a developmental origin, owing to the exposure to adverse factors during the intrauterine period. Our hypothesis is that sympathetic hyperinnervation may be implicated in hypertension of developmental origins, being this is a common feature with essential hypertension. Two-animal models were used: spontaneously hypertensive rats (SHR-model of essential hypertension) and offspring from dams exposed to undernutrition (MUN-model of developmental hypertension), with their respective controls. In adult males, we assessed systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), sympathetic nerve function (3H-tritium release), sympathetic innervation (immunohistochemistry) and vascular remodelling (histology). MUN showed higher SBP/DBP, but not HR, while SHR exhibited higher SBP/DBP/HR. Regarding the mesenteric arteries, MUN and SHR showed reduced lumen, increased media and adventitial thickness and increased wall/lumen and connective tissue compared to respective controls. Regarding sympathetic nerve activation, MUN and SHR showed higher tritium release compared to controls. Total tritium tissue/tyrosine hydroxylase detection was higher in SHR and MUN adventitia arteries compared to respective controls. In conclusion, sympathetic hyperinnervation may be one of the contributors to vascular remodelling and hypertension in rats exposed to undernutrition during intrauterine life, which is a common feature with spontaneous hypertension.

Salmonella in pigs is a concern for human foodborne salmonellosis. Dietary fungal fermented products, coated butyrate, and organic acids (OAs) may be promising control strategies. The objectives of this study were (i) to evaluate in vitro binding affinity of Salmonella enterica serovar Typhimurium (S. Typh) and Enteritidis (S. Ent), and enterotoxigenic Escherichia coli (ETEC) F4 or F18 to mannan-rich hydrolyzed copra meal (MCM) and fermented rye (FR) with Agaricus subrufescens; and (ii) to assess MCM and FR efficacy to control in vivo S. Typh shedding when combined with OAs and compared with coated butyrate strategy. A 31-d study included 32 pigs [6.29 ± 0.76 kg BW] individually housed and distributed into four dietary treatments: control diet; OA.BU, 4 kg/t OA plus 6 kg/t coated butyrate; OA.MCM, 4 kg/t OA plus 1 kg/t MCM; and OA.FR, 4 kg/t OA plus 2 kg/t FR. All pigs were challenged for 7 d with 1 mL S. Typh (109 colony forming units daily) at 10 d postweaning. Temperature and fecal samples were collected before and after challenge, and fecal Salmonella shedding quantified. Diarrhea scores were monitored daily and growth performance was evaluated weekly. In vitro, culture with MCM and FR showed significant (P < 0.01) binding affinity for both S. Typh and S. Ent, but not for ETEC F4 and F18. In vivo, pigs fed OA.MCM and OA.FR had lower (P < 0.05) shedding and day 3 peak shedding of S. Typh after infections than pigs fed control and OA.BU diets. Pigs fed OA.FR diet tended to have an 18% increase (P = 0.068) in BW on day 14 post first inoculation compared with control and OA.BU, and 19% increased (P = 0.093) final BW at day 21 compared with control. Diarrhea frequency post infection was overall lower (P = 0.006) for OA.FR (18.9%) than OA.BU (44.8%) and OA.MCM (41.7%) while control (28.7%) was not different. In conclusion, FR and MCM show in vitro-binding affinity to Salmonella enterica serovars Typh and Ent. Feeding FR or MCM combined with OA to nursery pigs reduces the peak and averages S. Typh shedding compared with control. Fermented rye with OA tends to improve pig performance after S. Typh challenge.

Decommissioning fission and fusion facilities can result in the production of airborne particles containing tritium that could inadvertently be inhaled by workers directly involved in the operations, and potentially others, resulting in internal exposures to tritium. Of particular interest in this context, given the potentially large masses of material involved, is tritiated steel. The International Commission on Radiological Protection (ICRP) has recommended committed effective dose coefficients for inhalation of some tritiated materials, but not specifically for tritiated steel. The lack of a dose coefficient for tritiated steel is a concern given the potential importance of the material. To address this knowledge gap, a "dissolution" study, in vivo biokinetic study in a rodent model (1 MBq intratracheal instillation, 3-month follow-up) and associated state-of-the-art modelling were undertaken to derive dose coefficients for model tritiated steel particles. A committed effective dose coefficient for the inhalation of 3.3 × 10-12 Sv Bq-1 was evaluated for the particles, reflecting an activity median aerodynamic diameter (AMAD) of 13.3 µm, with the value for a reference AMAD for workers (5 µm) of 5.6 × 10-12 Sv Bq-1 that may be applied to occupational inhalation exposure to tritiated steel particles.

Tritium is a potentially significant source of internal radiation exposure which, at high levels, can be carcinogenic. We evaluated whether single intraperitoneal injection of BALB/c and C57BL/6 mice with tritiated water (HTO) leading to exposure to low (0.01 or 0.1 Gy) and intermediate (1.0 Gy) cumulative whole-body doses of β radiation is immunosuppressive, as judged by enhancement of artificial tumour metastases, functioning of NK lymphocytes and macrophages, circulating cytokine's levels, and numbers of bone marrow, spleen, and peripheral blood cells. We demonstrate that internal contamination of radiosensitive BALB/c and radioresistant C57BL/6 mice with HTO at all the absorbed doses tested did not affect the development of neoplastic colonies in the lungs caused by intravenous injection of syngeneic cancer cells. However, internal exposure of BALB/c and C57BL/6 mice to 0.1 and 0.01 Gy of β radiation, respectively, up-regulated cytotoxic activity of and IFN-γ synthesis in NK lymphocytes and boosted macrophage secretion of nitric oxide. Internal contamination with HTO did not affect the serum levels of pro- (IL-1β, IL-2, IL-6, TNF-α,) and anti-inflammatory (IL-1Ra, IL-4, IL-10) cytokines. In addition, exposure of mice of both strains to low and intermediate doses from the tritium-emitted β-particles did not result in any significant changes in the numbers of bone marrow, spleen, and peripheral blood cells. Overall, our data indicate that internal tritium contamination of both radiosensitive and radioresistant mice leading to low and intermediate absorbed β-radiation doses is not immunosuppressive but may enhance some but not all components of anticancer immunity.

1. This investigation was undertaken to compare pre- and postjunctional receptors involved in the responses of the canine mesenteric and pulmonary arteries to angiotensin II. 2. In the mesenteric artery, angiotensin II caused an enhancement of tritium overflow evoked by electrical stimulation (EC30% = 5 nM), the maximal effect representing an increase by about 45%. Postjunctionally, angiotensin II caused concentration-dependent contractions (pD2 = 8.57). Saralasin antagonized both pre- and postjunctional effects of angiotensin II, but it was more potent at post- than at prejunctional level (pA2 of 9.51 and 8.15, respectively), while losartan antagonized exclusively the postjunctional effects of angiotensin II (pA = 8.15). PD123319 had no antagonist effect either pre- or postjunctionally. 3. In the pulmonary artery, angiotensin II also caused an enhancement of the electrically-evoked tritium overflow (EC30% = 1.54 nM), its maximal effect increasing tritium overflow by about 80%. Postjunctionally, angiotensin II caused contractile responses (pD2 = 8.52). As in the mesenteric artery, saralasin antagonized angiotensin II effects at both pre- and postjunctional level and it was more potent postjunctionally (pA2 of 9.58 and 8.10, respectively). Losartan antagonized only the postjunctional effects of angiotensin II (pA2 = 7.96) and PD123319 was ineffective. 4. It is concluded that in both vessels: (1) pre- and postjunctional receptors belong to a different subtype, since they are differently antagonized by the same antagonists; (2) postjunctional receptors belong to AT1 subtype, since they are blocked by losartan but not by AT2 antagonists; (3) prejunctional receptors apparently belong to neither AT1 or AT2 subtype since they are blocked by neither AT1 nor AT2 antagonists.

During the decommissioning of nuclear facilities, the tritiated materials must be removed. These operations generate tritiated steel and cement particles that could be accidentally inhaled by workers. Thus, the consequences of human exposure by inhalation to these particles in terms of radiotoxicology were investigated. Their cyto-genotoxicity was studied using two human lung models: the BEAS-2B cell line and the 3D MucilAirTM model. Exposures of the BEAS-2B cell line to particles (2 and 24 h) did not induce significant cytotoxicity. Nevertheless, DNA damage occurred upon exposure to tritiated and non-tritiated particles, as observed by alkaline comet assay. Tritiated particles only induced cytostasis; however, both induced a significant increase in centromere negative micronuclei. Particles were also assessed for their effects on epithelial integrity and metabolic activity using the MucilAirTM model in a 14-day kinetic mode. No effect was noted. Tritium transfer through the epithelium was observed without intracellular accumulation. Overall, tritiated and non-tritiated stainless steel and cement particles were associated with moderate toxicity. However, these particles induce DNA lesions and chromosome breakage to which tritium seems to contribute. These data should help in a better management of the risk related to the inhalation of these types of particles.

Upregulation of the ATP-binding cassette (ABC) transporter is one of the most important factors leading to multidrug resistance (MDR) in several types of cancer. In the present study, we investigated the ability of rucaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor which is currently in clinical development, on overcoming ABC transporters-mediated MDR in cervical cancer cell lines. Rucaparib significantly enhanced the cytotoxic effects of a series of conventional chemotherapeutic drugs in drug resistance cervical cancer cell lines. Moreover, rucaparib significantly increased the accumulation of rhodamine 123 in doxorubicin- and paclitaxel-resistance cervical cancer cell lines. In addition, rucaparib significantly increased the accumulation of tritium-labeled chemotherapeutic drugs in drug resistance cervical cancer cells, and decrease the efflux of tritium-labeled chemotherapeutic drugs. Molecular docking study indicated that rucaparib could bind to the active site of the ABC transporters. The present study indicated that rucaparib could antagonize MDR in cervical cancer cells by blocking the function of ABC transporters. The results obtained in the present study provide the potential possibilities that the combination of rucaparib with other chemotherapeutic agents may benefit patients with cervical cancer.