Mitochondrial translocation of TFEB regulates complex I and inflammation.

TFEB is a master regulator of autophagy, lysosome biogenesis, mitochondrial metabolism, and immunity that works primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomics analysis reveals extensive TFEB co-immunoprecipitation with several mitochondrial proteins, whose interactions are disrupted upon infection with S. Typhimurium. High resolution confocal microscopy and biochemistry confirms TFEB localization in the mitochondrial matrix. TFEB translocation depends on a conserved N-terminal TOMM20-binding motif and is enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.

Performance and Safety of Amino-Acid- and Hydroxyapatite Enriched-Hyaluronic Acid Intradermal Gel in Facial Skin Defects.

Background and Objectives: The facial skin defects associated with aging are common concerns in the aging population. Hyaluronic-acid-based intradermal gels have established themselves as safe and effective treatments for addressing these concerns. Recently developed enriched products aim to enhance the efficacy of these gels, yet their effectiveness lacks thorough validation in the existing literature. Materials and Methods: In this retrospective analysis, we investigated the outcomes of intradermal gel treatments in 103 patients with soft tissue defects. This study included three groups: 35 patients received amino-acid-enriched hyaluronic acid gel, another 35 were treated with hydroxyapatite-enriched hyaluronic acid gel, and the remaining 33 underwent hyaluronic acid treatment only. The efficacy of the treatments was assessed using the Global Aesthetic Improvement Scale (GAIS) score, while patient satisfaction was gauged through a detailed questionnaire. Any adverse event was monitored. Results: The treatments demonstrated remarkable efficacy, as evidenced by mean GAIS scores of 1.714 points for those treated with amino acid-enriched hyaluronic acid gel, 1.886 points for individuals receiving hydroxyapatite-enriched hyaluronic acid gel, and 1.697 for those treated with hyaluronic acid alone, all showing statistical significance (p < 0.0001). Patient satisfaction was very high. Significantly, there were no recorded instances of major adverse events. Conclusions: Hyaluronic gels, particularly those enriched with amino acids and hydroxyapatite, are effective and safe interventions for addressing facial skin aging defects. They serve as valuable tools in mitigating age-related blemishes and contribute to the overall improvement of skin aesthetics.

Mitochondrial transfer from Adipose stem cells to breast cancer cells drives multi-drug resistance.

BACKGROUND: Breast cancer (BC) is a complex disease, showing heterogeneity in the genetic background, molecular subtype, and treatment algorithm. Historically, treatment strategies have been directed towards cancer cells, but these are not the unique components of the tumor bulk, where a key role is played by the tumor microenvironment (TME), whose better understanding could be crucial to obtain better outcomes. METHODS: We evaluated mitochondrial transfer (MT) by co-culturing Adipose stem cells with different Breast cancer cells (BCCs), through MitoTracker assay, Mitoception, confocal and immunofluorescence analyses. MT inhibitors were used to confirm the MT by Tunneling Nano Tubes (TNTs). MT effect on multi-drug resistance (MDR) was assessed using Doxorubicin assay and ABC transporter evaluation. In addition, ATP production was measured by Oxygen Consumption rates (OCR) and Immunoblot analysis. RESULTS: We found that MT occurs via Tunneling Nano Tubes (TNTs) and can be blocked by actin polymerization inhibitors. Furthermore, in hybrid co-cultures between ASCs and patient-derived organoids we found a massive MT. Breast Cancer cells (BCCs) with ASCs derived mitochondria (ADM) showed a reduced HIF-1α expression in hypoxic conditions, with an increased ATP production driving ABC transporters-mediated multi-drug resistance (MDR), linked to oxidative phosphorylation metabolism rewiring. CONCLUSIONS: We provide a proof-of-concept of the occurrence of Mitochondrial Transfer (MT) from Adipose Stem Cells (ASCs) to BC models. Blocking MT from ASCs to BCCs could be a new effective therapeutic strategy for BC treatment.

ß2-AR inhibition enhances EGFR antibody efficacy hampering the oxidative stress response machinery.

The ß2-Adrenergic receptor (ß2-ARs) is a cell membrane-spanning G protein-coupled receptors (GPCRs) physiologically involved in stress-related response. In many cancers, the ß2-ARs signaling drives the tumor development and transformation, also promoting the resistance to the treatments. In HNSCC cell lines, the ß2-AR selective inhibition synergistically amplifies the cytotoxic effect of the MEK 1/2 by affecting the p38/NF-kB oncogenic pathway and contemporary reducing the NRF-2 mediated antioxidant cell response. In this study, we aimed to validate the anti-tumor effect of ß2-AR blockade and the synergism with MEK/ERK and EGFR pathway inhibition in a pre-clinical orthotopic mouse model of HNSCC. Interestingly, we found a strong ß2-ARs expression in the tumors that were significantly reduced after prolonged treatment with ß2-Ars inhibitor (ICI) and EGFR mAb Cetuximab (CTX) in combination. The ß2-ARs down-regulation correlated in mice with a significant tumor growth delay, together with the MAPK signaling switch-off caused by the blockade of the MEK/ERK phosphorylation. We also demonstrated that the administration of ICI and CTX in combination unbalanced the cell ROS homeostasis by blocking the NRF-2 nuclear translocation with the relative down-regulation of the antioxidant enzyme expression. Our findings highlighted for the first time, in a pre-clinical in vivo model, the efficacy of the ß2-ARs inhibition in the treatment of the HNSCC, remarkably in combination with CTX, which is the standard of care for unresectable HNSCC.