Background and Aims: Gut microbiota-derived metabolites play a vital role in maintenance of human health and progression of disorders, including obesity and type 2 diabetes (T2D). Indole-3-propionic ...acid (IPA), a gut-derived tryptophan metabolite, has been recently shown to be lower in individuals with obesity and T2D. IPA’s beneficial effect on liver health has been also explored in rodent and cell models. In this study, we investigated the association of IPA with human liver histology and transcriptomics, and the potential of IPA to reduce hepatic stellate cell activation in vitro. Methods: A total of 233 subjects (72% women; age 48.3 ± 9.3 years; BMI 43.1 ± 5.4 kg/m2) undergoing bariatric surgery with detailed liver histology were included. Circulating IPA levels were measured using LC-MS and liver transcriptomics with total RNA-sequencing. LX-2 cells were used to study hepatoprotective effect of IPA in cells activated by TGF-β1. Results: Circulating IPA levels were found to be lower in individuals with liver fibrosis compared to those without fibrosis (p = 0.039 for all participants; p = 0.013 for 153 individuals without T2D). Accordingly, levels of circulating IPA associated with expression of 278 liver transcripts (p < 0.01) that were enriched for the genes regulating hepatic stellate cells (HSCs) activation and hepatic fibrosis signaling. Our results suggest that IPA may have hepatoprotective potential because it is able to reduce cell adhesion, cell migration and mRNA gene expression of classical markers of HSCs activation in LX-2 cells (all p < 0.05). Conclusion: The association of circulating IPA with liver fibrosis and the ability of IPA to reduce activation of LX-2 cells suggests that IPA may have a therapeutic potential. Further molecular studies are needed to investigate the mechanisms how IPA can ameliorate hepatic fibrosis.
Autophagy is a cellular bulk degradation process used as an alternative source of energy and metabolites and implicated in various diseases. Inefficient autophagy in nutrient-deprived cancer cells ...would be beneficial for cancer therapy making its modulation valuable as a therapeutic strategy for cancer treatment, especially in combination with chemotherapy. Dipyridamole (DIP) is a vasodilator and antithrombotic drug. Its major effects involve the block of nucleoside uptake and phosphodiestesase inhibition, leading to increased levels of intracellular cAMP. Here we report that DIP increases autophagic markers due to autophagic flux blockage, resembling autophagosome maturation and/or closure impairment. Treatment with DIP results in an increased number of autophagosomes and autolysosomes and impairs degradation of SQSTM1/p62. As blockage of autophagic flux decreases the recycling of cellular components, DIP reduced the intracellular ATP levels in cancer cells. Autophagic flux blockage was neither through inhibition of lysosome function nor blockage of nucleoside uptake, but could be prevented by treatment with a PKA inhibitor, suggesting that autophagic flux failure mediated by DIP results from increased intracellular levels of cAMP. Treatment with DIP presented antiproliferative effects in vitro alone and in combination with chemotherapy drugs. Collectively, these data demonstrate that DIP can impair autophagic degradation, by preventing the normal autophagosome maturation, and might be useful in combination anticancer therapy.
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•Dipyridamole (DIP) blocks autophagic flux.•DIP leads to the accumulation of double-membrane structures, resembling failure in autophagosome maturation process.•DIP treatment has antiproliferative effects in vitro and sensitizes cancer cells to antineoplastic treatments.
•Liraglutide induces smaller lipid droplets in human adipocytes.•Liraglutide promotes mitochondrial respiration and biogenesis in human adipocytes.•Liraglutide recovers TNF-induced defects in ...mitochondrial respiration and inflammation.•Liraglutide has a therapeutic potential on mitochondrial activity in obesity.
Liraglutide (LG), a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been shown to improve white adipose tissue mitochondrial metabolism in mice but not in human adipocytes. Therefore, we explored whether LG has therapeutic efficacy in mitochondrial dysfunction in human adipocytes in vitro.
We tested the effects of short-term (ST-LG: 24 h) and long-term (LT-LG: D0-15 days) treatments in human SGBS adipocytes on mitochondrial respiration, mRNA and protein expression. GLP-1R inhibition was investigated by the co-treatment of GLP-1R inhibitor, exendin 9–39 (Ex9-39) and ST-LG treatment. We also explored the ability of ST-LG to alleviate mitochondrial dysfunction induced by tumor necrosis factor-alpha (TNFα).
LT-LG treatment induced the formation of smaller lipid droplets and increased the expression of genes related to lipolysis. Both ST-LG and LT-LG treatments promoted mitochondrial respiration. Additionally, LT-LG treatment increased the expression of a brown adipocyte marker, uncoupling protein 1 (UCP-1), and the markers of mitochondrial biogenesis. Interestingly, ST-LG rescued TNFα-induced defects in mitochondrial energy metabolism and inflammation in SGBS adipocytes.
LG stimulates mitochondrial respiration and biogenesis in human adipocytes, potentially via UCP-1-mediated adipocyte browning. Importantly, our study demonstrates for the first time that LG has a therapeutic potential on mitochondrial activity in human adipocytes.
Background
Evidence regarding the feelings evoked, distress caused, and the best way to conduct protective stabilization for the management of young children is lacking.
Aim
Describe the perceptions ...of mothers, psychologists, and pediatric dentists regarding the use of protective stabilization during the dental care of children up to three years of age attending a University Dental Clinic in southern Brazil.
Design
After watching a video of dental care involving the protective stabilization technique, individualized qualitative interviews were held with three groups mothers (n = 5), psychologists (n = 7), and pediatric dentists (n = 4) to investigate four categories of interest: importance of the technique, affective attitude, distress caused to the child, and participation of parents. After the transcription of the recorded comments, qualitative content analysis was performed.
Results
Protective stabilization generated emotional discomfort but was well accepted by all groups. All expressed the need to create a bond between the dentist and caregiver; and the active participation of the caregiver was considered fundamental. The mothers and psychologists rejected other options, such as passive restraint, general anesthesia, and sedation.
Conclusion
The three groups admitted having negative feelings, recognized the importance of protective stabilization, and suggested conditions for its use.
Background and Aim
Subjective pulp tests are not trustworthy, particularly in traumatized teeth, and may lead to inaccurate diagnosis. The use of an objective test such as pulse oximetry (PO) could ...be a more reliable method to properly evaluate pulp status in this condition. The aim of this study was to analyze the effectiveness of PO in determining pulp vitality in traumatized teeth based on oxygen saturation measurements (%SpO2).
Subjects and methods
Fifty‐nine permanent teeth that had undergone lateral luxation, and which were unresponsive to a cold spray test and were free from signs of necrosis, were selected and tested with PO at 7, 30 and 60 days after trauma.
Results
Fifty‐nine teeth were tested. At 7 days after trauma, 8 teeth had low rates of oxygenation, compared to 10 at 30 and 60 days. Low rates were defined as a saturation reading ≤77%SpO2. These teeth were assigned to the pulp necrosis (PN) group. The other 49 teeth were either considered to have healthy pulps (HP) (saturation ≥90%SpO2) or were assigned to a pulpitis (PP) group (saturation ≥78 to ≤89%SpO2). The 10 non‐responsive teeth were followed up for 1 year and all exhibited indications for endodontic treatment. The other 49 teeth (HP or PP) began to show positive responses to the cold spray (after 3–9 months of follow up). No significant differences (P < 0.05) were detected between the three periods analyzed, but %SpO2 rates were significantly different (P < 0.01) between the groups (HP vs PP, HP vs PN and PP vs PN).
Conclusions
PO can be extremely useful for the assessment of dental pulp status in traumatized teeth, particularly when these teeth do not show signs of PN and do not respond to cold tests.
Resveratrol has been the focus of numerous studies reporting opposite effects that depend on its concentration. The GRX is an activated hepatic stellate cells model used to study liver fibrosis ...development and resolution. We recently showed that GRX treatment with RSV (0.1–50 µM) for 24 h triggered dose-dependent pro-oxidant effects, resulting in cytotoxicity and cell damage only at the highest concentration. Here, we evaluated whether the pro-oxidant effect of resveratrol treatment is accompanied by alterations on the GRX mitochondrial metabolism, and whether the concomitantly autophagy/mitophagy induction can influence on cell death or survival. We demonstrated that all concentrations of resveratrol promoted an increase of GRX cell death signals, altering the mitochondrial dynamics and function. Cells treated with all resveratrol concentrations presented higher autophagy/mitophagy features, but only treatments with 1 and 10 µM of resveratrol-induced mitochondrial biogenesis. Since cell damage was higher and there was no mitochondrial biogenesis in GRX treated with 50 µM of resveratrol, we suggest that these cells failed to remove and replace all damaged mitochondria. In conclusion, the cytotoxic effect of resveratrol that effectively promotes cell death could be related to the interrelation between the concomitant induction of apoptosis, autophagy/mitophagy and mitochondrial biogenesis in GRX.
Caveolin‐1 (Cav‐1) is an integral membrane protein present in all organelles, responsible for regulating and integrating multiple signals as a platform. Mitochondria are extremely adaptable to ...external cues in chronic liver diseases, and expression of Cav‐1 may affect mitochondrial flexibility in hepatic stellate cells (HSCs) activation. We previously demonstrated that exogenous expression of Cav‐1 was sufficient to increase some classical markers of activation in HSCs. Here, we aimed to evaluate the influence of exogenous expression and knockdown of Cav‐1 on regulating the mitochondrial plasticity, metabolism, endoplasmic reticulum (ER)‐mitochondria distance, and lysosomal activity in HSCs. To characterize the mitochondrial, lysosomal morphology, and ER‐mitochondria distance, we perform transmission electron microscope analysis. We accessed mitochondria and lysosomal networks and functions through a confocal microscope and flow cytometry. The expression of mitochondrial machinery fusion/fission genes was examined by real‐time polymerase chain reaction. Total and mitochondrial cholesterol content was measured using Amplex Red. To define energy metabolism, we used the Oroboros system in the cells. We report that GRX cells with exogenous expression or knockdown of Cav‐1 changed mitochondrial morphometric parameters, OXPHOS metabolism, ER‐mitochondria distance, lysosomal activity, and may change the activation state of HSC. This study highlights that Cav‐1 may modulate mitochondrial function and structural reorganization in HSC activation, being a potential candidate marker for chronic liver diseases and a molecular target for therapeutic intervention.
To investigate the association between malocclusion/dentofacial anomalies and traumatic dental injuries (TDI) in adolescents.
The sample of this cross-sectional study comprised 509 adolescents aged ...11 to 14 years enrolled at public schools in the city of Osório, southern Brazil. Parents answered a structured questionnaire addressing demographic and socioeconomic characteristics. An examiner who had undergone a training and calibration exercise recorded malocclusion/dentofacial anomalies (Dental Aesthetic Index, DAI), TDI (Andreasen), and dental caries (World Health Organisation). Statistical analyses (SPSS software) involved Poisson regression with robust variance.
The prevalence of TDI was 11.6%, and the prevalence of defined, severe, and handicapping malocclusion was 24.0%, 21.6%, and 22.0%, respectively. The multivariate analysis demonstrated that the probability of TDI was approximately twofold higher among adolescents with severe malocclusion (prevalence ratio PR 2.22; 95% confidence interval CI 1.14-4.31) and handicapping malocclusion (PR 1.95; 95% CI 1.01-3.85) in comparison to those with normal occlusion or minor malocclusion. Defined malocclusion was not significantly associated with the outcome. Among the dentofacial anomalies evaluated, the probability of TDI was nearly twofold higher among adolescents with overjet greater than 3 mm (PR 1.96; 95% CI 1.14-3.37) and 2.2-fold higher among those with an abnormal molar relationship (PR 2.24; 95% CI 1.17-4.32), after controlling for confounding variables.
Severe and handicapping malocclusion, accentuated overjet, and abnormal molar relationship were strongly associated with the occurrence of TDI. Future studies should investigate whether the treatment of these conditions can help reduce the occurrence of TDI in adolescents.
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