Increasing evidence reveals a large dependency of epithelial cancer cells on oxidative phosphorylation (OXPHOS) for energy production. In this study we tested the potential of ...epigallocatechin-3-gallate (EGCG), a natural polyphenol known to target mitochondria, in inducing OXPHOS impairment and cell energy deficit in human epitheliod (REN cells) and biphasic (MSTO-211H cells) malignant pleural mesothelioma (MMe), a rare but highly aggressive tumor with high unmet need for treatment. Due to EGCG instability that causes H2O2 formation in culture medium, the drug was added to MMe cells in the presence of exogenous superoxide dismutase and catalase, already proved to stabilize the EGCG molecule and prevent EGCG-dependent reactive oxygen species formation. We show that under these experimental conditions, EGCG causes the selective arrest of MMe cell growth with respect to normal mesothelial cells and the induction of mitochondria-mediated apoptosis, as revealed by early mitochondrial ultrastructure modification, swelling and cytochrome c release. We disclose a novel mechanism by which EGCG induces apoptosis through the impairment of mitochondrial respiratory chain complexes, particularly of complex I, II and ATP synthase. This induces a strong reduction in ATP production by OXPHOS, that is not adequately counterbalanced by glycolytic shift, resulting in cell energy deficit, cell cycle arrest and apoptosis. The EGCG-dependent negative modulation of mitochondrial energy metabolism, selective for cancer cells, gives an important input for the development of novel pharmacological strategies for MMe.
•Stabilized EGCG induces a selective growth arrest in human malignant mesothelioma cells.•EGCG induces a strong reduction in ATP production by OXPHOS impairment in MMe cells.•EGCG induces cell cycle arrest and mitochondrial-mediated apoptosis in MMe cells.•The negative modulation of OXPHOS could give an input for novel therapeutic strategies for MMe.
Under physiological conditions, the complex planarian neoblast system is a composite of hierarchically organized stem cell sub-populations with sigma-class neoblasts, including clonogenic neoblasts, ...endowed with larger self-renewal and differentiation capabilities, thus generating all the other sub-populations and dominating the regenerative process. This complex system responds to differentiated tissue demands, ensuring a continuous cell turnover in a way to replace aged specialized cells and maintain tissue functionality. Potency of the neoblast system can be appreciated under challenging conditions in which these stem cells are massively depleted and the few remaining repopulate the entire body, ensuring animal resilience. These challenging conditions offer the possibility to deepen the relationships among different neoblast sub-populations, allowing to expose uncanonical properties that are negligible under physiological conditions. In this paper, we employ short, sub-lethal 5-fluorouracil treatment to specifically affect proliferating cells passing through the S phase and demonstrate that S-phase slowdown triggers a shift in the transcriptional profile of sigma neoblasts, which reduces the expression of their hallmark sox-P1. Later, some cells reactivate sox-P1 expression, suggesting that some neoblasts in the earlier steps of commitment could modulate their expression profile, reacquiring a wider differentiative potential.
The scopes related to the interplay between stem cells and the immune system are broad and range from the basic understanding of organism’s physiology and ecology to translational studies, further ...contributing to (eco)toxicology, biotechnology, and medicine as well as regulatory and ethical aspects. Stem cells originate immune cells through hematopoiesis, and the interplay between the two cell types is required in processes like regeneration. In addition, stem and immune cell anomalies directly affect the organism’s functions, its ability to cope with environmental changes and, indirectly, its role in ecosystem services. However, stem cells and immune cells continue to be considered parts of two branches of biological research with few interconnections between them. This review aims to bridge these two seemingly disparate disciplines towards much more integrative and transformative approaches with examples deriving mainly from aquatic invertebrates. We discuss the current understanding of cross-disciplinary collaborative and emerging issues, raising novel hypotheses and comments. We also discuss the problems and perspectives of the two disciplines and how to integrate their conceptual frameworks to address basic equations in biology in a new, innovative way.
A new pump-seeded, short-cavity Brillouin ring laser source layout intended for Brillouin sensing applications is showcased, showing increased high maximum output (1.5 mW), a strong linewidth ...narrowing effect (producing light with a linewidth of 10 kHz) and limited RIN (~-145 dB/Hz), providing an ultranarrow, highly stable BRL source that can also be employed as a pump-probe source for BOTDA applications.
In this paper we describe the current status of sentinel node mapping (SNM) in thyroid tumors and its potential perspectives. SNM in thyroid cancer has been tested since the end of the twentieth ...century, mainly in papillary thyroid cancer (PTC) and in medullary thyroid cancer (MTC). In PTC, it has been employed to find occult lymph node metastases in the central compartment of the neck as an alternative or indication for prophylactic dissection, by several methods. All of them have proven effective in spotting sentinel nodes, but the results have been somewhat diminished by uncertainty about the clinical significance of occult metastases in differentiated thyroid cancer. SNM in MTC has also been used to find occult lymph node metastases in the lateral compartments of the neck, also with excellent results hindered by a similar doubt about the real clinical significance of MTC micrometastases. Well designed, adequately sized randomized controlled trials are lacking, so SNM in thyroid tumors remains an interesting yet experimental methodology. New technology is emerging that could facilitate such studies, which could add solid information about the clinical significance of occult neck metastases in thyroid cancer.
Two innovative optical fiber cable layouts designed to improve strain measurement accuracy for Brillouin Optical Time Domain Analysis (BOTDA) sensors through improved strain transfer efficiency are ...presented and discussed. Swept Wavelength Interferometry (SWI) is used to experimentally evaluate their performance alongside analytical models and numerical simulation through Finite Element Method (FEM). The results show good agreement between the different methods and show that the second sensing cable design presents good features to minimize the mismatch between measured and actual strain. Finally, the strain response of both strain and temperature sensing cables of this design are evaluated, showing that their difference in response is reliable enough to allow temperature compensation.
Obesity's role in thyroid cancer development is still debated, as well as its association with aggressive histopathological subtypes (AHSs). To clarify the link between Body Mass Index (BMI) and AHS ...of differentiated thyroid carcinoma (DTC), we evaluated patients who underwent thyroidectomy for DTC from 2020 to 2022 at four European referral centres for endocrine surgery. Based on BMI, patients were classified as normal-underweight, overweight, or obese. AHSs were defined according to 2022 WHO guidelines. Among 3868 patients included, 34.5% were overweight and 19.6% obese. Histological diagnoses were: 93.6% papillary (PTC), 4.8% follicular (FTC), and 1.6% Hürthle cell (HCC) thyroid carcinoma. Obese and overweight patients with PTC had a higher rate of AHSs (
= 0.03), bilateral, multifocal tumours (
= 0.014, 0.049), and larger nodal metastases (
= 0.017). In a multivariate analysis, BMI was an independent predictor of AHS of PTC, irrespective of gender (
= 0.028). In younger patients (<55 years old) with PTC > 1 cm, BMI predicted a higher ATA risk class (
= 0.036). Overweight and obese patients with FTC had larger tumours (
= 0.036). No difference was found in terms of AHS of FTC and HCC based on BMI category. Overweight and obese patients with PTC appear to be at an increased risk for AHS and aggressive clinico-pathological characteristics.
3-Iodothyronamine (T1AM) is an endogenous high-affinity ligand of the trace amine-associated receptor 1 (TAAR1), detected in mammals in many organs, including the brain. Recent evidence indicates ...that pharmacological TAAR1 activation may offer a novel therapeutic option for the treatment of a wide range of neuropsychiatric and metabolic disorders. To assess potential neuroprotection by TAAR1 agonists, in the present work, we initially investigated whether T1AM and its corresponding 3-methylbiaryl-methane analog SG-2 can improve learning and memory when systemically administered to mice at submicromolar doses, and whether these effects are modified under conditions of MAO inhibition by clorgyline. Our results revealed that when i.p. injected to mice, both T1AM and SG-2 produced memory-enhancing and hyperalgesic effects, while increasing ERK1/2 phosphorylation and expression of transcription factor
-fos. Notably, both compounds appeared to rely on the action of ubiquitous enzymes MAO to produce the corresponding oxidative metabolites that were then able to activate the histaminergic system. Since autophagy is key for neuronal plasticity, in a second line of experiments we explored whether T1AM and synthetic TAAR1 agonists SG1 and SG2 were able to induce autophagy in human glioblastoma cell lines (U-87MG). After treatment of U-87MG cells with 1 μM T1AM, SG-1, SG-2 transmission electron microscopy (TEM) and immunofluorescence (IF) showed a significant time-dependent increase of autophagy vacuoles and microtubule-associated protein 1 light chain 3 (LC3). Consistently, Western blot analysis revealed a significant increase of the LC3II/LC3I ratio, with T1AM and SG-1 being the most effective agents. A decreased level of the p62 protein was also observed after treatment with T1AM and SG-1, which confirms the efficacy of these compounds as autophagy inducers in U-87MG cells. In the process to dissect which pathway induces ATG, the effects of these compounds were evaluated on the PI3K-AKT-mTOR pathway. We found that 1 μM T1AM, SG-1 and SG-2 decreased pAKT/AKT ratio at 0.5 and 4 h after treatment, suggesting that autophagy is induced by inhibiting mTOR phosphorylation by PI3K-AKT-mTOR pathway. In conclusion, our study shows that T1AM and thyronamine-like derivatives SG-1 and SG-2 might represent valuable tools to therapeutically intervene with neurological disorders.
Chlorophyll derivatives are known to enhance vision in vertebrates. They are thought to bind visual pigments (i.e., opsins apoproteins bound to retinal chromophores) directly within the retina. ...Consistent with previous findings in vertebrates, here we show that chlorin e
- a chlorophyll derivative - enhances photophobicity in a flatworm (Dugesia japonica), specifically when exposed to UV radiation (λ = 405 nm) or red light (λ = 660 nm). This is the first report of chlorophyll derivatives acting as modulators of invertebrate phototaxis, and in general the first account demonstrating that they can artificially alter animal response to light at a behavioral level. Our findings show that the interaction between chlorophyll derivatives and opsins virtually concerns the vast majority of bilaterian animals, and also occurs in visual systems based on rhabdomeric (rather than ciliary) opsins.
PDF
