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Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of Gch1, the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell-specific Gch1 or Tph1 showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P-driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.
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Mastócitos , Dor Pós-Operatória , Serotonina , Mastócitos/imunologia , Serotonina/metabolismo , Animais , Dor Pós-Operatória/imunologia , Camundongos , Humanos , Camundongos Endogâmicos C57BL , Substância P/metabolismo , Masculino , Camundongos Knockout , Triptofano Hidroxilase/metabolismoRESUMO
Oogenesis is a complex process regulated by precise coordination of multiple factors, including maternal genes. Zygote arrest 1 (zar1) has been identified as an ovary-specific maternal gene that is vital for oocyte-to-embryo transition and oogenesis in mouse and zebrafish. However, its function in other species remains to be elucidated. In the present study, zar1 was identified with conserved C-terminal zinc finger domains in Nile tilapia. zar1 was highly expressed in the ovary and specifically expressed in phase I and II oocytes. Disruption of zar1 led to the failed transition from oogonia to phase I oocytes, with somatic cell apoptosis. Down-regulation and failed polyadenylation of figla, gdf9, bmp15 and wee2 mRNAs were observed in the ovaries of zar1-/- fish. Cpeb1, a gene essential for polyadenylation that interacts with Zar1, was down-regulated in zar1-/- fish. Moreover, decreased levels of serum estrogen and increased levels of androgen were observed in zar1-/- fish. Taken together, zar1 seems to be essential for tilapia oogenesis by regulating polyadenylation and estrogen synthesis. Our study shows that Zar1 has different molecular functions during gonadal development by the similar signaling pathway in different species.
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Proteínas do Ovo , Proteínas de Peixes , Tilápia , Animais , Feminino , Camundongos , Ciclídeos/genética , Ciclídeos/metabolismo , Proteínas do Ovo/metabolismo , Estrogênios , Fatores de Poliadenilação e Clivagem de mRNA/genética , Oogênese/genética , Poliadenilação , Tilápia/genética , Tilápia/metabolismo , Fatores de Transcrição/genética , Peixe-Zebra/metabolismo , Proteínas de Peixes/metabolismoRESUMO
The BCL-2 inhibitor Venetoclax is a promising agent for the treatment of acute myeloid leukemia (AML). However, many patients are refractory to Venetoclax, and resistance develops quickly. ATP-binding cassette (ABC) transporters mediate chemotherapy resistance but their role in modulating the activity of targeted small-molecule inhibitors is unclear. Using CRISPR/Cas9 screening, we find that loss of ABCC1 strongly increases the sensitivity of AML cells to Venetoclax. Genetic and pharmacologic ABCC1 inactivation potentiates the anti-leukemic effects of BCL-2 inhibitors and efficiently re-sensitizes Venetoclax-resistant leukemia cells. Conversely, ABCC1 overexpression induces resistance to BCL-2 inhibitors by reducing intracellular drug levels, and high ABCC1 levels predicts poor response to Venetoclax therapy in patients. Consistent with ABCC1-specific export of glutathionylated substrates, inhibition of glutathione metabolism increases the potency of BCL-2 inhibitors. These results identify ABCC1 and glutathione metabolism as mechanisms limiting efficacy of BCL-2 inhibitors, which may pave the way to development of more effective therapies.
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Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Transportadores de Cassetes de Ligação de ATP , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Glutationa , Proteínas Proto-Oncogênicas c-bcl-2/genéticaRESUMO
BACKGROUND: The human genome is the complete set of genetic instructions encoded in an individual's DNA. Genetics plays an important role in the development and progression of muscle injuries. Many genes are involved in muscle development, growth, and repair, and variations in these genes can affect an athlete's susceptibility to muscle injury. SPECIFIC GENES: Several genes have been linked to muscle injury, such as myostatin (MSTN), insulin-like growth factor 1 (IGF-1), and several collagen genes (COL). In addition to genes involved in muscle development, growth, and repair, genes involved in inflammation and pain signaling, such as tumor necrosis factor alpha (TNF-α), mu opioid receptor (OPRM1), and interleukin (IL) genes, may also play a role in the development and progression of muscle injury. GENETIC TESTS: Genetic testing can be a helpful tool in the prevention of muscle injuries in athletes. Testing for variations in genes associated with muscle development, repair, and growth, as well as collagen formation, can provide valuable information about an athlete's susceptibility to muscle injury. It is important to note that while genetic testing can provide valuable information for injury prevention, it is only one piece of the puzzle. Other factors such as an individual's training history, general health, and lifestyle habits also play a role in injury risk. Therefore, all injury prevention strategies should be individualized and based on a comprehensive assessment of all relevant factors.
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Traumatismos em Atletas , Esportes , Humanos , Traumatismos em Atletas/genética , Músculos , Testes Genéticos , Colágeno/genéticaRESUMO
Postoperative pain affects most patients after major surgery and can transition to chronic pain. Here, we discovered that postoperative pain hypersensitivity correlated with markedly increased local levels of the metabolite BH4. Gene transcription and reporter mouse analyses after skin injury identified neutrophils, macrophages and mast cells as primary postoperative sources of GTP cyclohydrolase-1 (Gch1) expression, the rate-limiting enzyme in BH4 production. While specific Gch1 deficiency in neutrophils or macrophages had no effect, mice deficient in mast cells or mast cell-specific Gch1 showed drastically decreased postoperative pain after surgery. Skin injury induced the nociceptive neuropeptide substance P, which directly triggers the release of BH4-dependent serotonin in mouse and human mast cells. Substance P receptor blockade substantially ameliorated postoperative pain. Our findings underline the unique position of mast cells at the neuro-immune interface and highlight substance P-driven mast cell BH4 production as promising therapeutic targets for the treatment of postoperative pain.
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Aim: Interleukin 6 (IL-6) is considered to play a role in the dysbiotic host response in the development of periodontitis. While the inhibition of the IL-6 receptor using monoclonal antibodies is a well-established therapy for some diseases, so far, its potential benefit in patients with periodontitis has not been examined. We tested the association of genetically proxied downregulation of IL-6 signaling with periodontitis to explore whether downregulation of IL-6 signaling could represent a viable treatment target for periodontitis. Materials and methods: As proxies for IL-6 signaling downregulation, we selected 52 genetic variants in close vicinity of the gene encoding IL-6 receptor that were associated with lower circulating C-reactive protein (CRP) levels in a genome-wide association study (GWAS) of 575 531 participants of European ancestry from the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Associations with periodontitis were tested with inverse-variance weighted Mendelian randomization in a study of 17 353 cases and 28 210 controls of European descent in the Gene-Lifestyle Interactions in Dental Endpoints (GLIDE) consortium. In addition, the effect of CRP reduction independent of the IL-6 pathway was assessed. Results: Genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis (odds ratio (OR) = 0.81 per 1-unit decrement in log-CRP levels; 95% confidence interval (CI): [0.66;0.99]; P = 0.0497). Genetically proxied reduction of CRP independent of the IL-6 pathway had a similar effect (OR = 0.81; 95% CI: [0.68; 0.98]; P = 0.0296). Conclusion: In conclusion, genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis and CRP might be a causal target for the effect of IL-6 on the risk of periodontitis.
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Interleucina-6 , Periodontite , Humanos , Interleucina-6/genética , Estudo de Associação Genômica Ampla , Regulação para Baixo , Análise da Randomização Mendeliana , Periodontite/genética , Periodontite/complicações , Receptores de Interleucina-6/genéticaRESUMO
Mutations in the COL7A1 gene lead to malfunction, reduction or complete absence of type VII collagen (C7) in the skin's basement membrane zone (BMZ), impairing skin integrity. In epidermolysis bullosa (EB), more than 800 mutations in COL7A1 have been reported, leading to the dystrophic form of EB (DEB), a severe and rare skin blistering disease associated with a high risk of developing an aggressive form of squamous cell carcinoma. Here, we leveraged a previously described 3'-RTMS6m repair molecule to develop a non-viral, non-invasive and efficient RNA therapy to correct mutations within COL7A1 via spliceosome-mediated RNA trans-splicing (SMaRT). RTM-S6m, cloned into a non-viral minicircle-GFP vector, is capable of correcting all mutations occurring between exon 65 and exon 118 of COL7A1 via SMaRT. Transfection of the RTM into recessive dystrophic EB (RDEB) keratinocytes resulted in a trans-splicing efficiency of ~1.5% in keratinocytes and ~0.6% in fibroblasts, as confirmed on mRNA level via next-generation sequencing (NGS). Full-length C7 protein expression was primarily confirmed in vitro via immunofluorescence (IF) staining and Western blot analysis of transfected cells. Additionally, we complexed 3'-RTMS6m with a DDC642 liposomal carrier to deliver the RTM topically onto RDEB skin equivalents and were subsequently able to detect an accumulation of restored C7 within the basement membrane zone (BMZ). In summary, we transiently corrected COL7A1 mutations in vitro in RDEB keratinocytes and skin equivalents derived from RDEB keratinocytes and fibroblasts using a non-viral 3'-RTMS6m repair molecule.
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Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Humanos , Trans-Splicing , Pele/metabolismo , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa/genética , Queratinócitos/metabolismo , Colágeno Tipo VII/genética , MutaçãoRESUMO
OBJECTIVES: Oral mucositis caused by intensive cancer chemotherapy or radiotherapy frequently results in pronounced damage of the oral mucosa leading to painful oral hygiene. To support oral care, antimicrobial effective mouth rinses may be used. Thus, the efficacy of a hypochlorite-based mouth rinse (Granudacyn®), assumed to be highly biocompatible because of the compounds being part of the natural pathogen defense, as possible antiseptic agent in case of oral mucositis was compared to that of an octenidine based antiseptic mouth rinse (Octenidol® md). MATERIALS AND METHODS: The study was conducted as monocentric, controlled, randomized, blind cross over comparative study on 20 volunteers. As a proof of principle, we performed the study on orally healthy subjects and not cancer patients. The efficacy was determined as reduction of colony forming units (cfu) on buccal mucosa as well as in saliva. After mouth rinsing for 30 s, samples were taken after 1 min, 15 min, 30 and 60 min. The lg-reduction was calculated as difference between lg-values of cfu pre- and post-treatment. RESULTS: Both antiseptic mouth rinses induced a significant reduction of cfu on buccal mucosa and in saliva 1 min after mouth rinsing. The effect persisted up to 60 min. The octenidine based rinse was significantly superior to the hypochlorite-based rinse up to the last sample 60 min after rinsing. However, the known cytotoxicity of octenidine argues against its application. CONCLUSION: Within the limits of this study, due to its antiseptic efficacy, the hypochlorite-based rinse Granudacyn® can be regarded appropriate to support the oral hygiene in patients with a sensitive oral mucosa during an aggressive cancer chemotherapy and radiation treatment in case of oral mucositis.
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Anti-Infecciosos Locais , Antineoplásicos , Mucosite , Estomatite , Humanos , Antissépticos Bucais/uso terapêutico , Antissépticos Bucais/farmacologia , Anti-Infecciosos Locais/farmacologia , Ácido Hipocloroso/efeitos adversos , Estomatite/prevenção & controle , Estomatite/induzido quimicamente , Antineoplásicos/efeitos adversosRESUMO
Aim: To investigate the effect of genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) on the risk of periodontitis. Materials and methods: Genetic instruments were selected from the vicinity of TNFR superfamily member 1A (TNFRSF1A) gene (chromosome 12; base pairs 6,437,923-6,451,280 as per GRCh37 assembly) based on their association with C-reactive protein (N= 575,531). Summary statistics of these variants were obtained from a genome-wide association study (GWAS) of 17,353 periodontitis cases and 28,210 controls to estimate the effect of TNFR1 inhibition on periodontitis using a fixed-effects inverse method. Results: Considering rs1800693 as an instrument, we found no effect of TNFR1 inhibition on periodontitis risk (Odds ratio (OR) scaled per standard deviation increment in CRP: 1.57, 95% confidence interval (CI): 0.38;6.46). Similar results were derived from a secondary analysis that used three variants (rs767455, rs4149570, and rs4149577) to index TNFR1 inhibition. Conclusions: We found no evidence of a potential efficacy of TNFR1 inhibition on periodontitis risk.
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Periodontite , Receptores Tipo I de Fatores de Necrose Tumoral , Humanos , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Polimorfismo de Nucleotídeo Único , Estudo de Associação Genômica Ampla , Periodontite/genéticaRESUMO
STATEMENT OF PROBLEM: Dental restorations and removable dental prostheses have been considered as risk factors for potentially malignant disorders of the oral mucosa. It remains unclear whether amalgam, composite resins, and prosthesis materials can induce potentially malignant disorders. PURPOSE: The purpose of this clinical study was to determine the relationship between the presence of amalgam and composite resin restorations, crowns and fixed partial dentures, and removable prostheses in potentially malignant disorders. MATERIAL AND METHODS: The data of 6041 participants in the population-based Studies of Health in Pomerania (SHIP) were accessed. Potentially malignant disorders had been clinically diagnosed by calibrated dentists and documented with photographs. Dental treatment was subdivided into restored and replaced teeth. Dental restorations were subclassified as buccal composite resin or amalgam restorations. Prosthetic treatment was subclassified into removable partial or complete prostheses and definitive restorations with crowns and fixed partial dentures. RESULTS: In the maxilla, participants with removable prostheses had a higher incidence of potentially malignant disorders than participants not undergoing treatment with removable prostheses (OR 2.12; 95% CI: 1.08-4.18), but not in the mandible (OR 1.30; 95% CI: 0.67-2.53). The surfaces with composite resin restorations were associated with a slightly higher risk of mucosal lesions than those without the restorations (OR 1.04; 95% CI: 1.01-1.07). No significant association was found between amalgam restorations and mucosal lesions. CONCLUSIONS: Participants with removable prostheses have a higher risk of potentially malignant disorders. Composite resin restorations are associated with a higher risk of mucosal lesions, whereas no significant association was found between amalgam restorations and mucosal lesions.
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Restauração Dentária Permanente , Mucosa Bucal , Humanos , Restauração Dentária Permanente/efeitos adversos , Resinas Compostas/uso terapêutico , Prótese Parcial Fixa , Coroas , Amálgama Dentário/efeitos adversos , Falha de Restauração DentáriaRESUMO
Cardiac surgery is frequently associated with significant postoperative bleeding. Platelet-dysfunction is the main cardiopulmonary bypass (CPB)-induced hemostatic defect. Not only the number of platelets decreases, but also the remaining are functionally impaired. Although lipid metabolism is crucial for platelet function, little is known regarding platelet metabolic changes associated with CPB-dysfunction. Our aim is to explore possible contribution of metabolic perturbations for platelet dysfunction after cardiac surgery. DESIGN: Prospective cohort study. SETTING: Tertiary academic cardiothoracic-surgery ICU. PATIENTS: Thirty-three patients submitted to elective surgical aortic valve replacement. INTERVENTIONS: Samples from patients were collected at three time points (preoperative, 6- and 24-hr postoperative). Untargeted metabolic analysis using high-performance liquid chromatography-tandem mass spectrometry was performed to compare patients with significant postoperative bleeding with patients without hemorrhage. Principal component analyses, Wilcoxon matched-pairs signed-rank tests, adjusted to FDR, and pairwise comparison were used to identify pathways of interest. Enrichment and pathway metabolomic complemented the analyses. MEASUREMENTS AND MAIN RESULTS: We identified a platelet-related signature based on an overrepresentation of changes in known fatty acid metabolism pathways involved in platelet function. We observed that arachidonic acid (AA) levels and other metabolites from the pathway were reduced at 6 and 24 hours, independently from antiagreggation therapy and platelet count. Concentrations of preoperative AA were inversely correlated with postoperative chest tube blood loss but were not correlated with platelet count in the preoperative, at 6 or at 24 hours. Patients with significant postoperative blood-loss had considerably lower values of AA and higher transfusion rates. Values of postoperative interleukin-6 were strongly correlated with AA variability. CONCLUSIONS AND RELEVANCE: Our observations suggest that an inflammatory-related perturbation of AA metabolism is a signature of cardiac surgery with CPB and that preoperative levels of AA may be more relevant than platelet count to anticipate and prevent postoperative blood loss in patients submitted to cardiac surgery with CPB.
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AIM: To examine the associations between bone turnover markers and periodontitis in two cross-sectional population-based studies. MATERIALS AND METHODS: We used data from two independent adult samples (N = 4993), collected within the Study of Health in Pomerania project, to analyse cross-sectional associations of N-procollagen type 1 amino-terminal propeptide (P1NP), C-terminal cross-linking telopeptide, osteocalcin, bone-specific alkaline phosphatase (BAP), fibroblast growth factor 23, wingless-type mouse mammary tumour virus integration site family member 5a (WNT5A), and sclerostin values with periodontitis. Confounder-adjusted gamma and fractional response regression models were applied. RESULTS: Positive associations were found for P1NP with mean pocket probing depth (PPD; eß=1.008 ; 95% confidence interval [CI]: 1.001-1.015), mean clinical attachment loss (mean CAL; eß=1.027 ; 95% CI: 1.011-1.044), and proportion of sites with bleeding on probing (%BOP; eß=1.055 ; 95% CI: 1.005-1.109). Similar associations were seen for BAP with %BOP ( eß=1.121 ; 95% CI: 1.042-1.205), proportion of sites with PPD ≥4 mm (%PPD4) ( eß=1.080 ; 95% CI: 1.005-1.161), and sclerostin with %BOP ( eß=1.308 ; 95% CI: 1.005-1.704). WNT5A was inversely associated with mean PPD ( eß=0.956 ; 95% CI: 0.920-0.993) and %PPD4 ( eß=0.794 ; 95% CI: 0.642-0.982). CONCLUSIONS: This study revealed scattered associations of P1NP, BAP, WNT5A, and sclerostin with periodontitis, but the results are contradictory in the overall context. Associations reported in previous studies could not be confirmed.
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Remodelação Óssea , Periodontite , Fosfatase Alcalina , Animais , Biomarcadores , Remodelação Óssea/fisiologia , Colágeno Tipo I , Estudos Transversais , CamundongosRESUMO
Cellular metabolism must adapt to changing demands to enable homeostasis. During immune responses or cancer metastasis, cells leading migration into challenging environments require an energy boost, but what controls this capacity is unclear. Here, we study a previously uncharacterized nuclear protein, Atossa (encoded by CG9005), which supports macrophage invasion into the germband of Drosophila by controlling cellular metabolism. First, nuclear Atossa increases mRNA levels of Porthos, a DEAD-box protein, and of two metabolic enzymes, lysine-α-ketoglutarate reductase (LKR/SDH) and NADPH glyoxylate reductase (GR/HPR), thus enhancing mitochondrial bioenergetics. Then Porthos supports ribosome assembly and thereby raises the translational efficiency of a subset of mRNAs, including those affecting mitochondrial functions, the electron transport chain, and metabolism. Mitochondrial respiration measurements, metabolomics, and live imaging indicate that Atossa and Porthos power up OxPhos and energy production to promote the forging of a path into tissues by leading macrophages. Since many crucial physiological responses require increases in mitochondrial energy output, this previously undescribed genetic program may modulate a wide range of cellular behaviors.
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Drosophila , Sacaropina Desidrogenases , Animais , Drosophila/metabolismo , Metabolismo Energético , Macrófagos/metabolismo , Mitocôndrias/metabolismo , RNA Mensageiro/metabolismo , Sacaropina Desidrogenases/genética , Sacaropina Desidrogenases/metabolismoRESUMO
IDO1 oxidizes tryptophan (TRP) to generate kynurenine (KYN), the substrate for 1-carbon and NAD metabolism, and is implicated in pro-cancer pathophysiology and infection biology. However, the mechanistic relationships between IDO1 in amino acid depletion versus product generation have remained a longstanding mystery. We found an unrecognized link between IDO1 and cell survival mediated by KYN that serves as the source for molecules that inhibit ferroptotic cell death. We show that this effect requires KYN export from IDO1-expressing cells, which is then available for non-IDO1-expressing cells via SLC7A11, the central transporter involved in ferroptosis suppression. Whether inside the "producer" IDO1+ cell or the "receiver" cell, KYN is converted into downstream metabolites, suppressing ferroptosis by ROS scavenging and activating an NRF2-dependent, AHR-independent cell-protective pathway, including SLC7A11, propagating anti-ferroptotic signaling. IDO1, therefore, controls a multi-pronged protection pathway from ferroptotic cell death, underscoring the need to re-evaluate the use of IDO1 inhibitors in cancer treatment.
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Sistema y+ de Transporte de Aminoácidos , Ferroptose , Cinurenina , Neoplasias , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Cinurenina/metabolismo , Cinurenina/farmacologia , Neoplasias/metabolismo , Transdução de Sinais , Triptofano/metabolismoRESUMO
Conventional anti-cancer therapies based on chemo- and/or radiotherapy represent highly effective means to kill cancer cells but lack tumor specificity and, therefore, result in a wide range of iatrogenic effects. A promising approach to overcome this obstacle is spliceosome-mediated RNA trans-splicing (SMaRT), which can be leveraged to target tumor cells while leaving normal cells unharmed. Notably, a previously established RNA trans-splicing molecule (RTM44) showed efficacy and specificity in exchanging the coding sequence of a cancer target gene (Ct-SLCO1B3) with the suicide gene HSV1-thymidine kinase in a colorectal cancer model, thereby rendering tumor cells sensitive to the prodrug ganciclovir (GCV). In the present work, we expand the application of this approach, using the same RTM44 in aggressive skin cancer arising in the rare genetic skin disease recessive dystrophic epidermolysis bullosa (RDEB). Stable expression of RTM44, but not a splicing-deficient control (NC), in RDEB-SCC cells resulted in expression of the expected fusion product at the mRNA and protein level. Importantly, systemic GCV treatment of mice bearing RTM44-expressing cancer cells resulted in a significant reduction in tumor volume and weight compared with controls. Thus, our results demonstrate the applicability of RTM44-mediated targeting of the cancer gene Ct-SLCO1B3 in a different malignancy.
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Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa/complicações , Terapia Genética/métodos , Splicing de RNA , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/terapia , Trans-Splicing , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Epidermólise Bolhosa/genética , Epidermólise Bolhosa Distrófica/genética , Ganciclovir/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Loci Gênicos , Terapia Genética/efeitos adversos , Humanos , Camundongos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVES: Associations between saliva volumes or salivary flow rates and potentially xerogenic medication are rarely evaluated in cohorts with a wide age range. This cross-sectional cohort study investigated possible relationships between the regular consumption of potentially xerogenic medication and stimulated saliva volumes. METHODS: Data from the German Studies of Health in Pomerania (SHIP-2 and SHIP-Trend-0) were pooled. Potentially xerogenic medications were identified using the Workshop on Oral Medicine VI criteria. Stimulated saliva was sampled using Salivette®, and saliva volumes expressed as µl/min were determined. Applying linear mixed models with adjustment for time point of saliva collection, associations of (a) age and sex with regularly consumed medication, (b) age and sex with saliva volumes, and (c) the number of regularly consumed xerogenic medications with saliva volumes were evaluated. RESULTS: Six thousand seven hundred and fifty-three participants aged 20-83 years (mean 53.4 ± 14.9) were included. The average number of medications did not differ markedly between females (2.21 ± 2.46) and males (2.24 ± 2.83). Males took more potentially xerogenic medication (1.0 ± 1.3) than did females (0.9 ± 1.3). Also, males took more potentially xerogenic cardiovascular medications than did females (0.9 ± 1.2 versus 0.7 ± 1.1), while females were prescribed a higher number of potentially xerogenic medications affecting the nervous system (0.2 ± 0.5 versus 0.1 ± 0.4). The average stimulated saliva volume was 967.0 ± 433.3 µL/min. Regularly consumed and potentially xerogenic medications were associated with lower saliva volumes. Older age correlated not only with a higher number of total medications and a higher number of xerogenic medications affecting either the cardiovascular (in males) or the nervous system (in females), but also with lower saliva volumes. CONCLUSIONS: Ageing was associated with polypharmacy, especially with the intake of potentially xerogenic medication, and lower average saliva volumes. With regard to complications of dry mouth, anamnesis of medication consumption is of high importance.
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Saliva , Xerostomia , Estudos Transversais , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Polimedicação , Xerostomia/etiologiaRESUMO
AIM: To investigate the associations of tobacco smoking and alcohol consumption with periodontitis using Mendelian randomization (MR) analysis. MATERIALS AND METHODS: We used 17 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for the number of cigarettes per day from a genome-wide association study (GWAS) of 337,334 individuals, 109 SNPs for a lifetime smoking index from GWAS of 462,690 participants, and 33 SNPs for the number of drinks per week from GWAS of 941,280 individuals. The periodontitis GWAS included 12,289 cases and 22,326 controls. Wald ratios were obtained by dividing the SNP-periodontitis effects by SNP-exposure effects and pooled using an inverse-variance weighted model. RESULTS: Genetic liabilities for higher number of cigarettes per day (odds ratio [OR] per one standard deviation (1SD) increment = 1.56; 95% CI: 1.18-2.07, p-value = .0018, Q-value = .0054), lifetime smoking index (OR per 1SD = 1.26; 95% CI: 1.04-1.53, p-value = .0161, Q-value = .0242), and drinks per week (OR per 1SD = 1.41; 95% CI: 1.04-1.90, p-value = .0265, Q-value = .0265) were associated with increased odds of periodontitis. Estimates were consistent across robust and multivariable MR analyses. CONCLUSIONS: The findings of this MR analysis suggest an association between tobacco smoking and alcohol consumption with periodontitis.
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Análise da Randomização Mendeliana , Periodontite , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Estudo de Associação Genômica Ampla , Humanos , Periodontite/etiologia , Periodontite/genética , Polimorfismo de Nucleotídeo Único/genética , Fumar TabacoRESUMO
PURPOSE: Periodontitis is an inflammatory disease of the oral cavity with an alarmingly high prevalence within the adult population. The signaling lipid sphingosine-1-phosphate (S1P) plays a crucial role in inflammatory and immunomodulatory responses. In addition to cardiovascular disease, sepsis and tumor entities, S1P has been recently identified as both mediator and biomarker in osteoporosis. We hypothesized that S1P may play a role in periodontitis as an inflammation-prone bone destructive disorder. The goal of our study was to evaluate associations between periodontitis and S1P serum concentrations in the Study of Health in Pomerania (SHIP)-Trend cohort. In addition, we investigated the expression of S1P metabolizing enzymes in inflamed gingival tissue. PATIENTS AND METHODS: We analyzed data from 3371 participants (51.6% women) of the SHIP-Trend cohort. Periodontal parameters and baseline characteristics were assessed. Serum S1P was measured by liquid chromatography tandem mass spectrometry. The expression of S1P metabolizing enzymes was determined by immunofluorescence staining of human gingival tissue. RESULTS: S1P serum concentrations were significantly increased in subjects with both moderate and severe periodontitis, assessed as probing depth and clinical attachment loss. In contrast, no significant association of S1P was seen with caries variables (number and percentage of decayed or filled surfaces). S1P concentrations significantly increased with increasing high-sensitivity C-reactive protein (hs-CRP) levels. Interestingly, inflamed compared to normal human gingival tissue exhibited elevated expression levels of the S1P-generating enzyme sphingosine kinase 1 (SphK1). CONCLUSION: We report an intriguingly significant association of various periodontal parameters with serum levels of the inflammatory lipid mediator S1P. Our data point towards a key role of S1P during periodontitis pathology. Modulation of local S1P levels or its signaling properties may represent a potential future therapeutic strategy to prevent or to retard periodontitis progression and possibly reduce periodontitis-related tooth loss.
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BACKGROUND & AIMS: Irritable bowel syndrome (IBS) and inflammatory bowel diseases result in a substantial reduction in quality of life and a considerable socioeconomic impact. In IBS, diagnosis and treatment options are limited, but evidence for involvement of the gut microbiome in disease pathophysiology is emerging. Here we analyzed the prevalence of endoscopically visible mucosal biofilms in gastrointestinal disease and associated changes in microbiome composition and metabolism. METHODS: The presence of mucosal biofilms was assessed in 1426 patients at 2 European university-based endoscopy centers. One-hundred and seventeen patients were selected for in-depth molecular and microscopic analysis using 16S ribosomal RNA gene amplicon-sequencing of colonic biopsies and fecal samples, confocal microscopy with deep learning-based image analysis, scanning electron microscopy, metabolomics, and in vitro biofilm formation assays. RESULTS: Biofilms were present in 57% of patients with IBS and 34% of patients with ulcerative colitis compared with 6% of controls (P < .001). These yellow-green adherent layers of the ileum and right-sided colon were microscopically confirmed to be dense bacterial biofilms. 16S-sequencing links the presence of biofilms to a dysbiotic gut microbiome, including overgrowth of Escherichia coli and Ruminococcus gnavus. R. gnavus isolates cultivated from patient biofilms also formed biofilms in vitro. Metabolomic analysis found an accumulation of bile acids within biofilms that correlated with fecal bile acid excretion, linking this phenotype with a mechanism of diarrhea. CONCLUSIONS: The presence of mucosal biofilms is an endoscopic feature in a subgroup of IBS and ulcerative colitis with disrupted bile acid metabolism and bacterial dysbiosis. They provide novel insight into the pathophysiology of IBS and ulcerative colitis, illustrating that biofilm can be seen as a tipping point in the development of dysbiosis and disease.
Assuntos
Bactérias/crescimento & desenvolvimento , Biofilmes/crescimento & desenvolvimento , Colite Ulcerativa/microbiologia , Colo/microbiologia , Colonoscopia , Microbioma Gastrointestinal , Mucosa Intestinal/microbiologia , Síndrome do Intestino Irritável/microbiologia , Áustria , Bactérias/metabolismo , Bactérias/ultraestrutura , Estudos de Casos e Controles , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/metabolismo , Colo/patologia , Aprendizado Profundo , Alemanha , Humanos , Interpretação de Imagem Assistida por Computador , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Síndrome do Intestino Irritável/metabolismo , Síndrome do Intestino Irritável/patologia , Metabolômica , Microscopia Confocal , Microscopia Eletrônica de Varredura , Valor Preditivo dos Testes , RibotipagemRESUMO
The tRNA ligase complex (tRNA-LC) splices precursor tRNAs (pre-tRNA), and Xbp1-mRNA during the unfolded protein response (UPR). In aerobic conditions, a cysteine residue bound to two metal ions in its ancient, catalytic subunit RTCB could make the tRNA-LC susceptible to oxidative inactivation. Here, we confirm this hypothesis and reveal a co-evolutionary association between the tRNA-LC and PYROXD1, a conserved and essential oxidoreductase. We reveal that PYROXD1 preserves the activity of the mammalian tRNA-LC in pre-tRNA splicing and UPR. PYROXD1 binds the tRNA-LC in the presence of NAD(P)H and converts RTCB-bound NAD(P)H into NAD(P)+, a typical oxidative co-enzyme. However, NAD(P)+ here acts as an antioxidant and protects the tRNA-LC from oxidative inactivation, which is dependent on copper ions. Genetic variants of PYROXD1 that cause human myopathies only partially support tRNA-LC activity. Thus, we establish the tRNA-LC as an oxidation-sensitive metalloenzyme, safeguarded by the flavoprotein PYROXD1 through an unexpected redox mechanism.