In a recent issue in Nature Cell Biology, Sung Min Son et al. unveil a novel layer in the regulation of the mTORC1/autophagy axis by EP300 which can undergo nucleocytoplasmic shuttling in response to alterations in nutrient availability. The study highlights that, in Hutchinson-Gilford progeria syndrome, overabundant cytoplasmic EP300 results in mTORC1 hyperactivation and impaired autophagy, potentially contributing to premature and accelerated aging.

The eight biological hallmarks of health that we initially postulated (Cell. 2021 Jan 7;184(1):33-63) include features of spatial compartmentalization (integrity of barriers, containment of local perturbations), maintenance of homeostasis over time (recycling & turnover, integration of circuitries, rhythmic oscillations) and an array of adequate responses to stress (homeostatic resilience, hormetic regulation, repair & regeneration). These hallmarks affect all eight somatic strata of the human body (molecules, organelles, cells, supracellular units, organs, organ systems, systemic circuitries and meta-organism). Here we postulate that mental and socioeconomic factors must be added to this 8×8 matrix as an additional hallmark of health (“psychosocial adaptation”) and as an additional stratum (“psychosocial interactions”), hence building a 9×9 matrix. Potentially, perturbation of each of the somatic hallmarks and strata affects psychosocial factors and vice versa. Finally, we discuss the (patho)physiological bases of these interactions and their implications for mental health improvement.

For many diseases, and cancer in particular, early diagnosis allows a wider range of therapies and a better disease management. This has led to improvements in diagnostic procedures, most often based on tissue biopsies or blood samples. Other biological fluids have been used to diagnose disease, and among them saliva offers a number of advantages because it can be collected non-invasively from large populations at relatively low cost. To what extent might saliva content reveal the presence of a tumour located at a distance from the oral cavity and the molecular information obtained from saliva be used to establish a diagnosis are current questions. This review focuses primarily on the content of saliva and shows how it potentially offers a source of diagnosis, possibly at an early stage, for pathologies such as cancers or endometriosis.

Cold exposure has been historically used for medicinal purposes, but its benefits and associated mechanisms in mammalian organisms still remain unclear. Here, we explore the chemoprotective properties of cold temperature using a mouse model of hepatocellular carcinoma (HCC) that recapitulates several human features. Chronic cold exposure is shown to prolong lifespan in diseased mice, enhance liver health, and suppress the development of aggressive HCC, preventing hepatocellular hypertrophy, high-grade oval cell hyperplasia, liver steatosis, and aberrant hepatocyte hyperproliferation. Mechanistically, exposure to cold temperatures reinstates NAD⁺ levels in the HCC mouse models that originally exhibited low NAD⁺ levels, a contributing process to the development of liver tumors. These findings uncover the role of cold therapy to attenuate HCC development and potentially other existing malignancies involving NAD⁺ modulation.

Exceeding physiological limits of the cell membrane potential compromises structural integrity, enabling the passage of normally impermeant solutes and disrupting cell function. Electropermeabilization has been studied extensively at the cellular scale, but not at the individual membrane lesion level. We employed fast total internal reflection fluorescence (TIRF) imaging of Ca²⁺ entry transients to discern individual lesions in a hyperpolarized cell membrane and characterize their focality, thresholds, electrical conductance, and the lifecycle. A diffuse and momentary membrane permeabilization without a distinct pore formation was observed already at a -100 mV threshold. Polarizing down to -200 mV created focal pores with a low 50- to 300-pS conductance, which disappeared instantly once the hyperpolarization was removed. Charging to – 240 mV created high-conductance (> 1 nS) pores which persisted for seconds even at zero membrane potential. With incremental hyperpolarization steps, persistent pores often emerged at locations different from those where the  short-lived, low-conductance pores or diffuse permeabilization were previously observed. Attempts to polarize membrane beyond the threshold for the formation of persistent pores increased their conductance adaptively, preventing further potential build-up and ”clamping” it at a certain limit (-270 ± 6 mV in HEK cells, -284 ± 5 mV in CHO cells, and -243 ± 9 mV in neurons). The data suggest a previously unknown role of electroporative lesions as a protective mechanism against a potentially fatal membrane overcharging and cell disintegration.

Human peripheral blood mononuclear cells (PBMCs) are used to examine biological processes and disease, when basal variability in cellular activation and splicing is described and unexplained. Using isolation systems that maintained buffy coat cells (PBMCs, platelets) in their own plasma, poly-A enriched RNA-sequencing (RNASeq) detected 42,720 Ensembl gene IDs, including >95% of the top 100 Genotype Tissue Expression Project (GTEx)-expressed genes in lung, colon, heart, skeletal muscle and liver, and 10/17 clinically-actionable genes listed by the Pharmacogenomics Knowledgebase. Transcriptome changes were defined after 1h treatment with 32^◦C hypothermia (hsp70 family member change), 10 µmol/L ferric citrate that had no discernible effect, and 100 µg/mL cycloheximide leading to induction of primary response (immediate early) genes including IL1B and TNF. Same-donor PBMCs prepared conventionally using washes then resuspension in serum-supplemented media demonstrated basal upregulation of stress signalling pathway genes that masked and overlapped differential gene  expression profiles after 100 µg/L cycloheximide. Plasma-resuspended PBMCs demonstrated minor transcriptome changes after 40 µmol/L ferric citrate, whereas consistent and greater magnitude changes were observed for washed/media- resuspended PBMCs. We conclude that endogenous plasma-maintained PBMCs provide a more robust platform to interrogate acute cellular perturbations trig- gering innate immunity, and that varying susceptibility of PBMCs to preparative stresses is an important component of experimental variability.

Mesenchymal-epithelial plasticity driving cancer progression in cancer-associated fibroblasts (CAFs) is undetermined. This work identifies a subgroup of CAFs in human breast cancer exhibiting mesenchymal-to-epithelial transition (MET) or epithelial-like profile with high miR-200c expression. MiR-200c overexpression in fibroblasts is sufficient to drive breast cancer aggressiveness. Oxidative stress in the tumor microenvironment induces miR-200c by DNA demethylation. Proteomics, RNA-seq and functional analyses reveal that miR-200c is a novel positive regulator of NFκB-HIF signaling via COMMD1 downregulation and stimulates pro-tumorigenic inflammation and glycolysis. Reprogramming fibroblasts toward MET via miR-200c reduces stemness and induces a senescent phenotype. This pro-tumorigenic profile in CAFs fosters carcinoma cell resistance to apoptosis, proliferation and immunosuppression, leading to primary tumor growth, metastases, and resistance to immuno-chemotherapy. Conversely, miR-200c inhibition in fibroblasts restrains tumor growth with abated oxidative stress and an anti-tumorigenic immune environment. This work determines the mechanisms by which MET in CAFs via miR-200c transcriptional enrichment with DNA demethylation triggered by oxidative stress promotes cancer progression. CAFs undergoing MET trans-differentiation and senescence coordinate heterotypic signaling that may be targeted as an anti-cancer strategy.

Aberrant response to physiological cell stress is part of the mechanisms underlying the development of diverse human diseases, including neuropatholo- gies. Neuroglobin (NGB), an intracellular monomeric globin, has gained attention for its role in endogenous stress response pathways in neuroprotection. To date, evidence supports the concept of NGB as an inducible protein, triggered by phys- iological and pathological stimuli via transcriptional and/or post-transcriptional mechanisms, offering cell-autonomous neuroprotective functions under various cellular stresses. Notably, recent evidence suggests the extracellular occurrence of NGB. We aimed to explore whether NGB redistribution in the cell microenvi- ronment may serve in transmitting resilience capability in a model with neuronal characteristics. Results obtained in SH-SY5Y demonstrated that intracellular NGB upregulation is associated with the promotion of the extracellular release of the globin. Additionally, cell secretome from NGB-overexpressing cells, characterized by globin accumulation, exhibits protective effects against oxidative stress and mitochondrial toxicity, as evidenced by reduced apoptosis and preserved mito- chondrial structure. These findings shed light on the potential significance of extracellular NGB as part of a common cell response to physiological and stress conditions and as a factor promoting cell resilience. Furthermore,  the potential  for neuroprotection of extracellular NGB paves the way for future therapeutic opportunities.

Stress granules (SGs) are highly dynamic micromolecular membraneless condensates that generate in cells subjected to stress. Formed from pools of untranslating messenger ribonucleoproteins (RNP), SGs dynamics constitute vital processes essential for cell survival. Here, we investigate whether established cytotoxic agents, such as the platinum-based chemotherapeutic agent cisplatin and the aminoglycoside antibiotic gentamicin, elicit SG formation in the House Ear Institute-Organ of Corti-1 (HEI-OC1) auditory cell line, H4 human neuroglioma cells and HEK-293T human embryonic kidney cells. Cells were treated with cisplatin or gentamicin for specific durations at designated concentrations. SG formation was assessed using immunocytochemistry and live cell imaging. Levels of essential proteins involved in SG assembly were evaluated using immunoblotting. We observed cisplatin-associated SG assembly in HEI-OC1 and H4 cells via confocal microscopy through antibody colabeling of G3BP1 with PABP or Caprin1. While maintaining an unchanged pattern of expression of main constituent SG proteins, cisplatin-related SGs in H4 cells persisted for at least 12 h after drug removal. Cells subjected to gentamicin exposure did not exhibit SGs. Our findings offer insights into subcellular mechanisms related to cisplatin-associated cytotoxicity, highlighting the need for future studies to further investigate this stress-response mechanism.

Anoikis is a common programmed death for most of detached cells, but cancer cells can obtain anoikis resistance to facilitate their distant metastasis through the circulation system. Researches have indicated that enhanced autophagic flux accounts for the survival of many cancer cells under detached conditions. Targeting ATG4B, the key factor of autophagy progress, can inhibit cancer metastasis in vitro, but ATG4B-deficient mice are susceptible to many serious diseases, which indicates the potential uncontrolled side effects of direct targeting of ATG4B. In our recent research, we confirmed that ATG4B is a novel RNA binding protein in the gastric cancer (GC) cell. It interacts with circSPECC1 which consequently facilitates the liquid-liquid phase separation and ubiquitination of ATG4B. Additionally, the m⁶A reader ELAVL1 inhibits the expression of circSPECC1 to enhance the expression of ATG4B and anoikis resistance of GC cells. Further, we screened out an FDA-approved compound, lopinavir, to restore circSPECC1 abundance and suppress GC metastasis. In conclusion, our research identified a novel signal pathway (ELAVL1-circSPECC1-ATG4B-autophagy) to facilitate anoikis resistance and metastasis of GC cells and screened out a compound with clinical application potential to block this pathway, providing a novel strategy for the prevention of GC metastasis.