Dopamine signaling is a crucial part of the brain reward system and can affect feeding behavior. Dopamine receptors are also expressed in the hypothalamus, which is known to control energy metabolism in peripheral tissues. Here we show that pharmacological or chemogenetic stimulation of dopamine receptor 2 (D2R) expressing cells in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in rodents in a feedingindependent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system and orexin system to exert its action and involves inhibition of PI3K in the LHA/ZI. We further demonstrate that, as early as 3 months after onset of treatment, patients treated with the D2R agonist cabergoline experience an increase in energy expenditure that persists for one year, leading to total body weight and fat loss through a prolactin-independent mechanism. Our results may provide a mechanistic explanation for how clinically used D2R agonists act in the CNS to regulate energy balance.
Fused deposition modelling (FDM) 3D printing (3DP) is a revolutionary technology with the potential to transform drug product design in both the pre-clinical and clinical arena. The objective of this pilot study was to explore the intestinal behaviour of four different polymer-based devices fabricated using FDM 3DP technology in rats. Small capsular devices of 8.6 mm in length and 2.65 mm in diameter were printed from polyvinyl alcohol-polyethylene glycol graft-copolymer (PVA-PEG copolymer, Kollicoat IR), hydroxypropylcellulose (HPC, Klucel), ethylcellulose (EC, Aqualon N7) and hypromellose acetate succinate (HPMCAS, Aquasolve-LG). A smaller sized device, 3.2 mm in length and 2.65 mm in diameter, was also prepared with HPMCAS to evaluate the cut off size of gastric emptying of solid formulations in rats. The devices were radiolabelled with Fluorodeoxyglucose (F-FDG) and small animal positron emission tomography/computed tomography (microPET/CT) was used to track the movement and disintegration of the fabricated devices in the rats. The PVA-PEG copolymer and HPC devices disintegrated after 60min following oral administration. The EC structures did not disintegrate in the gastrointestinal tracts of the rats, whereas the HPMCAS-based systems disintegrated after 420 min. Interestingly, it was noted that the devices which remained intact over the course of the study had not emptied from the stomach of the rats. This was also the case with the smaller sized device. In summary, we report for the first time, the use of a microPET/CT imaging technique to evaluate the in vivo behaviour of 3D printed formulations. The manipulation of the 3D printed device design could be used to fabricate dosage forms of varying sizes and geometries with better gastric emptying characteristics suitable for rodent administration. The increased understanding of the capabilities of 3DP in dosage form design could, henceforth, accelerate pre-clinical testing of new drug candidates in animal models.
The aim of this investigation was to determine the circulating levels of amyloid beta (Aβ) peptides using the Porphyromonas gingivalis (Pg) lipopolysaccharide (LPS) model to induce periodontitis. Methods: Experimental periodontitis was induced in 6 male Sprague-Dawley rats. Alveolar bone loss was measure by micro computed tomography. Serum concentrations of Aβ 1-40 and Aβ 1-42 prior to periodontal induction, at 24 h, 7, 14, and 21 days the last injection of Pg-LPS. Results: The distance between the cemento-enamel junction and the bone crest (i.e., alveolar bone loss) was significantly higher at the end of periodontal induction compared to baseline (2.92 ± 0.29 mm vs. 3.8 ± 0.28 mm, P < 0.001). Periodontitis evoked a slight acute elevation of Aβ 1-40 serum levels that were maintained during the whole experiment. Aβ 1-42 peptide levels peak at the end of the study. A positive strong correlation was observed between alveolar bone loss and Aβ 1-40 serum levels at 7 days (r = 0.695, P = 0.012) and as well as with serum Aβ 1-42 concentrations at 21 days (r = 0.968, P = 0.002). Conclusions: Periodontitis induced Pg-LPS produced increased serum levels of Aβ peptides. Further studies are needed to confirm our results and to investigate the mechanisms by which periodontitis could be associated with an overexpression of Aβ.
Magnetic resonance imaging (MRI) volumetric measures have become a standard tool for the detection of incipient Alzheimer's Disease (AD) dementia in mild cognitive impairment (MCI). Focused on providing an earlier and more accurate diagnosis, sophisticated MRI machine learning algorithms have been developed over the recent years, most of them learning their non-disease patterns from MCI that remained stable over 2–3 years. In this work, we analyzed whether these stable MCI over short-term periods are actually appropriate training examples of non-disease patterns. To this aim, we compared the diagnosis of MCI patients at 2 and 5 years of follow-up and investigated its impact on the predictive performance of baseline volumetric MRI measures primarily involved in AD, i.e., hippocampal and entorhinal cortex volumes. Predictive power was evaluated in terms of the area under the ROC curve (AUC), sensitivity, and specificity in a trial sample of 248 MCI patients followed-up over 5 years. We further compared the sensitivity in those MCI that converted before 2 years and those that converted after 2 years. Our results indicate that 23% of the stable MCI at 2 years progressed in the next three years and that MRI volumetric measures are good predictors of conversion to AD dementia even at the mid-term, showing a better specificity and AUC as follow-up time increases. The combination of hippocampus and entorhinal cortex yielded an AUC that was significantly higher for the 5-year follow-up (AUC = 73% at 2 years vs. AUC = 84% at 5 years), as well as for specificity (56% vs. 71%). Sensitivity showed a non-significant slight decrease (81% vs. 78%). Remarkably, the performance of this model was comparable to machine learning models at the same follow-up times. MRI correctly identified most of the patients that converted after 2 years (with sensitivity >60%), and these patients showed a similar degree of abnormalities to those that converted before 2 years. This implies that most of the MCI patients that remained stable over short periods and subsequently progressed to AD dementia had evident atrophies at baseline. Therefore, machine learning models that use these patients to learn non-disease patterns are including an important fraction of patients with evident pathological changes related to the disease, something that might result in reduced performance and lack of biological interpretability.
Metabolic reprogramming is considered hallmarks of cancer. Aerobic glycolysis in tumors cells has been well-known for almost a century, but specific factors that regulate lactate generation and the effects of lactate in both cancer cells and stroma are not yet well understood. In the present study using breast cancer cell lines, human primary cultures of breast tumors, and immune deficient murine models, we demonstrate that the POU1F1 transcription factor is functionally and clinically related to both metabolic reprogramming in breast cancer cells and fibroblasts activation. Mechanistically, we demonstrate that POU1F1 transcriptionally regulates the lactate dehydrogenase A (LDHA) gene. LDHA catalyzes pyruvate into lactate instead of leading into the tricarboxylic acid cycle. Lactate increases breast cancer cell proliferation, migration, and invasion. In addition, it activates normal-associated fibroblasts (NAFs) into cancer-associated fibroblasts (CAFs). Conversely, LDHA knockdown in breast cancer cells that overexpress POU1F1 decreases tumor volume and [18F]FDG uptake in tumor xenografts of mice. Clinically, POU1F1 and LDHA expression correlate with relapse- and metastasis-free survival. Our data indicate that POU1F1 induces a metabolic reprogramming through LDHA regulation in human breast tumor cells, modifying the phenotype of both cancer cells and fibroblasts to promote cancer progression.
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