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Lactate is an essential component of carbon metabolism in mammals. Recently, lactate was shown to signal through the G protein coupled receptor 81 (GPR81) and to thus modulate inflammatory processes. This study demonstrates that lactate inhibits pro-inflammatory signaling in a GPR81-independent fashion. While lipopolysaccharide (LPS) triggered expression of IL-6 and IL-12 p40, and CD40 in bone marrow-derived macrophages, lactate was able to abrogate these responses in a dose dependent manner in Gpr81-/- cells as well as in wild type cells. Macrophage activation was impaired when glycolysis was blocked by chemical inhibitors. Remarkably, lactate was found to inhibit LPS-induced glycolysis in wild type as well as in Gpr81-/- cells. In conclusion, our study suggests that lactate can induce GPR81-independent metabolic changes that modulate macrophage pro-inflammatory activation.

Metabolic reprogramming is crucial to respond to cancer cell requirements during tumor development. In the last decade, metabolic alterations have been shown to modulate cancer cells’ sensitivity to chemotherapeutic agents including conventional and targeted therapies. Recently, it became apparent that changes in lipid metabolism represent important mediators of resistance to anticancer agents. In this review, we highlight changes in lipid metabolism associated with therapy resistance, their significance and how dysregulated lipid metabolism could be exploited to overcome anticancer drug resistance.

Abstract Cellular senescence is implicated in a great number of diseases including cancer. Although alterations in mitochondrial metabolism were reported as senescence drivers, the underlying mechanisms remain elusive. We report the mechanism altering mitochondrial function and OXPHOS in stress-induced senescent fibroblasts. We demonstrate that TRPC3 protein, acting as a controller of mitochondrial Ca 2+ load via negative regulation of IP 3 receptor-mediated Ca 2+ release, is down regulated in senescence regardless of the type of senescence inducer. This remodelling promotes cytosolic/mitochondrial Ca 2+ oscillations and elevates mitochondrial Ca 2+ load, mitochondrial oxygen consumption rate and oxidative phosphorylation. Re-expression of TRPC3 in senescent cells diminishes mitochondrial Ca 2+ load and promotes escape from OIS-induced senescence. Cellular senescence evoked by TRPC3 downregulation in stromal cells displays a proinflammatory and tumour-promoting secretome that encourages cancer epithelial cell proliferation and tumour growth in vivo. Altogether, our results unravel the mechanism contributing to pro-tumour behaviour of senescent cells.

Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase. To understand the mechanisms responsible for survival of BRAFi-resistant melanoma cells in the context of oxidative stress, we have established a preclinical murine model that accurately recapitulates in vivo the acquisition of resistance to MAPK inhibitors including several BRAF or MEK inhibitors alone and in combination. Using mice model and melanoma cell lines generated from mice tumors, we have confirmed that the acquisition of resistance is associated with an increase in mitochondrial oxidative phosphorylation as well as the importance of glutamine metabolism. Moreover, we have demonstrated that BRAFi-resistant melanoma can adapt mitochondrial metabolism to support glucose-derived glutamate synthesis leading to increase in glutathione content. Besides, BRAFi-resistant melanoma exhibits a strong activation of NRF-2 pathway leading to increase in the pentose phosphate pathway, which is involved in the regeneration of reduced glutathione, and to increase in xCT expression, a component of the xc—amino acid transporter essential for the uptake of cystine required for intracellular glutathione synthesis. All these metabolic modifications sustain glutathione level and contribute to the intracellular redox balance to allow survival of BRAFi-resistant melanoma cells.

Elesclomol is a first-in-class investigational drug currently undergoing clinical evaluation as a novel cancer therapeutic. The potent antitumor activity of the compound results from the elevation of reactive oxygen species (ROS) and oxidative stress to levels incompatible with cellular survival. However, the molecular target(s) and mechanism by which elesclomol generates ROS and subsequent cell death were previously undefined. The cellular cytotoxicity of elesclomol in the yeast S. cerevisiae appears to occur by a mechanism similar, if not identical, to that in cancer cells. Accordingly, here we used a powerful and validated technology only available in yeast that provides critical insights into the mechanism of action, targets and processes that are disrupted by drug treatment. Using this approach we show that elesclomol does not work through a specific cellular protein target. Instead, it targets a biologically coherent set of processes occurring in the mitochondrion. Specifically, the results indicate that elesclomol, driven by its redox chemistry, interacts with the electron transport chain (ETC) to generate high levels of ROS within the organelle and consequently cell death. Additional experiments in melanoma cells involving drug treatments or cells lacking ETC function confirm that the drug works similarly in human cancer cells. This deeper understanding of elesclomol's mode of action has important implications for the therapeutic application of the drug, including providing a rationale for biomarker-based stratification of patients likely to respond in the clinical setting.

To evaluate the impact of corneas from donors over 80 years of age on the activity of the North of France Tissue Bank and to determine the potential cost implications for banks using corneas from older donors. We analyzed data from a single-center retrospective cohort study of 6,023 corneas preserved at the Lille Tissue Bank between 2012 and 2023. Donors, unrestricted by age, were divided into two groups: younger (≤ 80 years) and older (> 80 years). Corneas were categorized based on endothelial cell density (ECD). Data were collected from patients who underwent corneal transplantation. A financial impact model was created to assess the effects of using corneas from different age groups on the overall benefits of corneal transplant procedures. The average donor age was 67.5 ± 14.5 years. The median age of donors gradually increased from 66 to 73 years over the 12-year study period, with donors over 80 years old representing more than 24% since 2021. Corneas from older donors had a higher discard rate (62.53% vs. 39.66%) due to poor endothelial quality and serological concerns (both  < 0.0001). Additionally, these corneas had lower ECD, with a larger proportion deemed unsuitable for grafting due to low ECD (30% vs. 8.2%). Corneas from younger donors were more often used for endothelial transplants, which require higher ECD. The mean economic benefit per cornea showed a moderate negative correlation with donor age. The net benefit of corneal transplants decreased as the proportion of donors aged over 80 years increased. It is predicted that a net benefit of zero would be attained when the proportion of donors over 80 years is 44.4%. Using corneas from donors over 80 years of age can help alleviate the shortage of donor tissue and be effective if certain quality standards are met. However, additional costs incurred by eye banks must be factored into this equation.

Background Sepsis survivors often experience sustained muscle weakness, leading to physical disability, with no pharmacological treatments available. Despite these well‐documented long‐term clinical consequences, research exploring the cellular and molecular mechanisms is sorely lacking. Methods Bioinformatic analysis was performed in the vastus lateralis transcriptome of human ICU survivors 7 days after ICU discharge (D7), 6 months (M6) and age‐ and sex‐matched controls. Enrichment analysis using Gene Ontology (GO) terms and Mitocarta3.0 was performed at D7 and M6 on differentially expressed genes (DEGs) and modules identified by weighted gene co‐expression network analysis (WGCNA). Using a murine model of resuscitated sepsis induced by caecal slurry injection, pathways identified by the bioinformatics analysis were explored in 18‐ to 24‐week‐old sepsis‐surviving (SS) mice at Day 10. Autophagy flux was investigated both in vivo and in vitro with chloroquine, a lysosomal inhibitor and urolithin A (UA), an autophagy inducer. Systemic metabolism was evaluated with indirect calorimetry, muscle phenotype with in situ and ex vivo contractility, muscle mass, myofibre cross‐sectional area and typing and mitochondrial population with transmission electron microscopy (TEM), as well as mitochondrial function with high‐resolution respirometry. Autophagic vacuole (AV) level was monitored using LC3B‐II and P62 protein expression and TEM. Results Pathways related to ‘mitochondrion’ were the only ones whose deregulation persisted between D7 and M6 (p < 0.05) and characterized WGCNA modules correlated with muscle mass, strength and physical function. Shared mitochondrial DEGs between D7 and M6 encoded matrix mitochondrial proteins related to ‘metabolism’ and ‘mitochondrial dynamics’. SS mice exhibited reduced complex I‐driven oxygen consumption (CI‐JO2) (−45%), increased S‐nitrosylation of complex I, damaged (+35%) and oxidized (+51%) mitochondria and AV accumulation (5 vs. 50 AVs/mm2) compared with sham pair‐fed mice (p < 0.05) despite no differences in mitochondrial size or number. Autophagy flux was reduced in SS mice due to decreased AV degradation ratio (p < 0.05). UA restored a balanced autophagy flux (turnover ratio 0.96 vs. −0.17) by increasing AVs formation and degradation ratio (p < 0.05). UA also improved CI‐JO2 (81 vs. 106 pmol/s/mg), tetanic force (215 vs. 244 mN/mm2) and hindlimb muscle weight in SS mice (p < 0.05). Conclusion Mitochondrial and autophagy disruption contributes to long‐term muscle dysfunction in human and mouse sepsis survivors. We demonstrate for the first time that sepsis induces an autophagy flux blockade. Urolithin A prevents mitochondrial and muscle impairments both in vivo and in vitro by improving autophagy flux.

Background Soft-tissue reconstruction is crucial in fields such as plastic surgery and oncology to address the repair of damaged tissues. Knitted scaffolds from bioresorbable copolymers, specifically poly(D,L-lactide) (PLA) and polycaprolactone (PCL), offer mechanical and biological properties that are essential for tissue engineering. This study assessed three-dimensional knitted scaffolds fabricated from melt-spun PLA and PCL multifilaments for soft tissue engineering applications. It examined the impact of the PLA/PCL ratio on the knitted scaffold structure, mechanical properties, and biological responses to determine the optimal composition for adipose tissue reconstruction. Results Knitted scaffolds fabricated with the PLA/PCL blends (PLA 70 /PCL 30 and PLA 90 /PCL 10 ) exhibited distinct mechanical and biological profiles. PLA 70 /PCL 30 scaffolds with a higher PCL content showed enhanced elasticity and porosity, whereas PLA 90 /PCL 10 scaffolds maintained better structural integrity and stiffness. Biological assays confirmed the biocompatibility of all scaffolds in vitro, with no cytotoxic effects. The scaffolds supported adipogenic differentiation in vitro, although PLA 70 /PCL 30 exhibited slightly reduced efficacy. Vascularization was evident using chorioallantoic membrane assays, in which blood vessel formation and penetration were observed, regardless of the scaffold composition. In vivo implantation in rat models revealed effective adipocyte integration, structural stability, and minimal inflammatory response, with PLA 90 /PCL 10 scaffolds outperforming PLA 70 /PCL 30 in terms of vascularization and less macrophage infiltration of connective tissue. Conclusion PLA/PCL knitted scaffolds offer a promising solution for enhancing graft volume maintenance and improving long-term outcomes, with tunable mechanical properties and biodegradability. The PLA 90 /PCL 10 scaffold is a superior candidate for adipose tissue reconstruction, balancing the structural stability with biological compatibility. These findings underscore the potential of PLA/PCL scaffolds for reconstructive surgery. Future studies should focus on scalability and long-term biocompatibility to facilitate clinical translation.

Due to its intrinsic properties, there has been growing interest in human amniotic membrane (hAM) in recent years particularly for the treatment of ocular surface disorders and for wound healing. Herein, we investigate the potential use of hAM and amnion-chorion membrane (ACM) in oral surgery. Based on our analysis of the literature, it appears that their applications are very poorly defined. There are two options: implantation or use as a cover material graft. The oral cavity is submitted to various mechanical and biological stimulations that impair membrane stability and maintenance. Thus, some devices have been combined with the graft to secure its positioning and protect it in this location. This current opinion paper addresses in detail suitable procedures for hAM and ACM utilization in soft and hard tissue reconstruction in the oral cavity. We address their implantation and/or use as a covering, storage format, application side, size and number, multilayer use or folding, suture or use of additional protective covers, re-application and resorption/fate. We gathered evidence on pre- and post-surgical care and evaluation tools. Finally, we integrated ophthalmological and wound healing practices into the collected information. This review aims to help practitioners and researchers better understand the application of hAM and ACM in the oral cavity, a place less easily accessible than ocular or cutaneous surfaces. Additionally, it could be a useful reference in the generation of new ideas for the development of innovative protective covering, suturing or handling devices in this specific indication. Finally, this overview could be considered as a position paper to guide investigators to fulfill all the identified criteria in the future.

Lamellarin D (Lam D), a marine alkaloid, exhibits a potent cytotoxicity against many different tumors. The pro-apoptotic function of Lam D has been attributed to its direct induction of mitochondrial permeability transition (MPT). This study was undertaken to explore the mechanisms through which Lam D promotes changes in mitochondrial function and as a result apoptosis. The use of eight Lam derivatives provides useful structure-apoptosis relationships. We demonstrate that Lam D and structural analogues induce apoptosis of cancer cells by acting directly on mitochondria inducing reduction of mitochondrial membrane potential, swelling and cytochrome c release. Cyclosporin A, a well-known inhibitor of MPT, completely prevents mitochondrial signs of apoptosis. The drug decreases calcium uptake by mitochondria but not by microsomes indicating that Lam D-dependent permeability is specific to mitochondrial membranes. In addition, upon Lam D exposure, a rapid decline of mitochondrial respiration and ATP synthesis occurs in isolated mitochondria as well as in intact cells. Evaluation of the site of action of Lam D on the electron-transport chain revealed that the activity of respiratory chain complex III is reduced by a half. To determine whether Lam D could induce MPT-dependent apoptosis by inhibiting mitochondrial respiration, we generated respiration-deficient cells (ρ0) derived from human melanoma cells. In comparison to parental cells, ρ0 cells are totally resistant to the induction of MPT-dependent apoptosis by Lam D. Our results indicate that functional mitochondria are required for Lam D-induced apoptosis. Inhibition of mitochondrial respiration is responsible for MPT-dependent apoptosis of cancer cells induced by Lam-D.