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.
Introduction: In Brazil, the right to health has a constitutional and universal provision. However, the judicial route has been widely used to access health goods and services. Objective: To analyze ...the lawsuits of medicines filed by citizens of a Brazilian municipality. Methods: Quantitative and retrospective study evaluating 652 lawsuits filed in 2016 conducted in Uruguaiana, state of Rio Grande do Sul. The information was made available by the State Department of Health. Results: 55.5% of lawsuits filed were related to drugs provided by the public health system Sistema Único de Saúde (SUS). 44.5% did not fit into the guidelines of the Brazilian Policy for Pharmaceutical Services. Most of the lawsuits were filed by women over 60 years old. Regarding the therapeutic classification, the most requested drugs were for the nervous system. The most described pathological condition according to the ICD-10 (International Classification of Diseases) was Diabetes Mellitus. Conclusion: These data corroborate the situation found in other parts of the country, demonstrating the need to reorganize the Pharmaceutical Service Policy to ensure universal and equitable access to medicines, as described in the Federal Constitution.
•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.
Na fase crônica da hepatite C pode ocorrer manifestações extra-hepáticas, como doenças cardiometabólicas, que estão entre as principais causas de morte por doenças crônicas não transmissíveis no ...mundo. Objetivo: Avaliar a prevalência de Síndrome Metabólica (SM) e as características de uma coorte de pacientes com hepatite C de Uruguaiana/RS e prever o efeito dos Antivirais de Ação Direta nos parâmetros bioquímicos da SM. Métodos: Trata-se de um estudo de Coorte Retrospectiva, em que as variáveis sociodemográficas, antropométricas, pressóricas e bioquímicas foram coletadas a partir de prontuários. Foi utilizado os critérios da International Diabetes Federation para a classificação da SM. A análise estatística envolveu os testes de Kolmogorov-Smirnov, teste t de Student e qui-quadrado de Pearson, regressão logística binária. Resultados: Foi possível verificar alta prevalência de SM na maioria dos pacientes e traçar um perfil dos indivíduos. O tratamento composto por Sofosbuvir e Daclatasvir não influenciou na glicemia e HDL-c, mas apresentou menores chances de hipertrigliceridemia após o tratamento. Considerações finais: Os resultados demonstram relevância e permitem criar metas eficazes de cuidado aos pacientes com hepatite C e comorbidades. O desenvolvimento de ações de prevenção, planejamento e estratégias econômicas influenciam positivamente no bem-estar dos pacientes e na alocação de recursos públicos, reduzindo os custos com essas doenças.
Caveolin‐1 (Cav‐1) expression is increased in hepatic stellate cells (HSC) upon liver cirrhosis and it functions as an integral membrane protein of lipid rafts and caveolae that regulates and ...integrates multiple signals as a platform. This study aimed to evaluate the role of Cav‐1 in HSC. Thus, the effects of exogenous expression of Cav‐1 in GRX cells, a model of activated HSC, were determined. Here, we demonstrated through evaluating well‐known HSC activation markers – such as α‐smooth muscle actin, collagen I, and glial fibrillary acidic protein – that up regulation of Cav‐1 induced GRX to a more activated phenotype. GRXEGFP‐Cav1 presented an increased migration, an altered adhesion pattern, a reorganization f‐actin cytoskeleton, an arrested cell cycle, a modified cellular ultrastructure, and a raised endocytic flux. Based on this, GRX
EGFP‐Cav1 represents a new cellular model that can be an important tool for understanding of events related to HSC activation. Furthermore, our results reinforce the role of Cav‐1 as a molecular marker of HSC activation.
1‐ Exogenous expression of caveolin‐1 (Cav‐1) leads hepatic stellate cells (HSC) to more activated phenotype 2‐ GRXEGFP‐Cav1 cell line is a first‐rate tool for liver fibrosis studying 3‐ Cav‐1 is a potential molecular marker for HSC activation.
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.
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