pH-Activatable Ruthenium(II) Fluorescein Salphen Schiff Base Photosensitizers for Theranostic Applications.

Ruthenium(II) polypyridyl complexes exhibit a lack of selectivity toward cancer tissues despite extensive studies as photosensitizers for photodynamic therapy (PDT). Here, we report pH-activatable Ru photosensitizers for molecularly targeted PDT by exploiting the higher acidity of tumoral tissue. The fluorescein moiety, well known for its high pH sensitivity, was connected to a Ru center to yield novel photosensitizers for pH-sensitive O photogeneration.

Mitochondria and telomeres: hand in glove.

Born as an endosymbiont, the bacteria engulfed by the proto-eukaryotic cell more than 1.45 billion years ago progressively evolved as an important organelle with multiple interactions with the host cell. In particular, strong connections between mitochondria and the chromosome ends, the telomeres, led to propose a new theory of ageing in which dysfunctional telomeres and mitochondria are the main actors of a vicious circle reducing cell fitness and promoting cellular ageing.

Senescence and senotherapies in biliary atresia and biliary cirrhosis.

Background: Premature senescence occurs in adult hepatobiliary diseases and worsens the prognosis through deleterious liver remodeling and hepatic dysfunction. Senescence might also arises in biliary atresia (BA), the first cause of pediatric liver transplantation. Since alternatives to transplantation are needed, our aim was to investigate premature senescence in BA and to assess senotherapies in a preclinical model of biliary cirrhosis.

Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology.

Aging is the main risk factor for Alzheimer's disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes underlying pathological aging of the nervous system are poorly understood. AD pathology seems to correlate with the appearance of cells that become senescent due to the progressive accumulation of cellular insults causing DNA damage. Senescence has also been shown to reduce the autophagic flux, a mechanism involved in clearing damaged proteins from the cell, and such impairment has been linked to AD pathogenesis.

Photo-induced telomeric DNA damage in human cancer cells.

Herein we report on the study of novel dinuclear ruthenium(ii) complexes designed to target and to photo-react with G-quadruplex telomeric DNA. Upon irradiation, complexes efficiently generate guanine radical cation sites as photo-oxidation products. The compounds also display efficient cell penetration with localization to the nucleus and show strong photocytotoxicity toward osteosarcoma cells.

TERRA and RAD51AP1 at the R&D-loop department of ALT telomeres.

In this issue of Molecular Cell, Kaminski et al. and Yadav et al. demonstrate that RAD51AP1 and TERRA non-coding RNA positively regulate the alternative mechanism of telomere maintenance by promoting D-loop formation and chromatin-directed mechanisms to suppress transcription-collision events during ALT telomere synthesis.

Detection of alternative lengthening of telomeres mechanism on tumor sections.

The vast majority of adult cancer cells achieve cellular immortality by activating a telomere maintenance mechanism (TMM). While this is mostly achieved by the de-silencing of hTERT telomerase gene expression, an alternative homologous recombination-based and telomerase-independent mechanism, known as ALT (Alternative Lengthening of Telomeres), is frequently activated in a subset of tumors, including paediatric cancers. Being absent from normal cells, the ALT mechanism offers interesting perspectives for new targeted cancer therapies.

Lung Microenvironments and Disease Progression in Fibrotic Hypersensitivity Pneumonitis.

Fibrotic hypersensitivity pneumonitis (fHP) is an interstitial lung disease caused by sensitization to an inhaled allergen. To identify the molecular determinants associated with progression of fibrosis. Nine fHP explant lungs and six unused donor lungs (as controls) were systematically sampled (4 samples/lung).

Child to adulthood clinical description of MDPL syndrome due to a novel variant in POLD1.

Mandibular hypoplasia, Deafness, Progeroid features, and Lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder caused by mutations in POLD1 gene and characterized by mandibular hypoplasia, deafness, progeroid features and lipodystrophy. One recurrent mutation p.(Ser605del) was reported in almost all affected patients.

Endurance training alleviates MCP-1 and TERRA accumulation at old age in human skeletal muscle.

Both oxidative stress and telomere transcription are up-regulated by acute endurance exercise in human skeletal muscle. Whether and how life-long exercise training influences the antioxidant system response at transcriptional level and TERRA expression is unknown, especially during aging. Response to acute endurance exercise was investigated in muscle biopsies of 3 male subjects after 45 min of cycling.

The multifaceted hTR telomerase RNA from a structural perspective: Distinct domains of hTR differentially interact with protein partners to orchestrate its telomerase-independent functions.

Human telomerase progressively emerged as a multifaceted ribonucleoprotein complex with additional functions beyond telomeric repeat synthesis. Both the hTERT catalytic subunit and the hTR long non-coding RNA (lncRNA) subunit are engaged in highly regulated cellular pathways that, together, contribute to cell fitness and protection against apoptosis. We recently described a new role for hTR in regulating the abundance of replication protein A at telomeres, adding to the growing repertoire of hTR's functions.

NHP2 downregulation counteracts hTR-mediated activation of the DNA damage response at ALT telomeres.

About 10% of cancer cells employ the "alternative lengthening of telomeres" (ALT) pathway instead of re-activating the hTERT subunit of human telomerase. The hTR RNA subunit is also abnormally silenced in some ALT cells not expressing hTERT, suggesting a possible negative non-canonical impact of hTR on ALT. Indeed, we show that ectopically expressed hTR reduces phosphorylation of ssDNA-binding protein RPA (p-RPA ) at ALT telomeres by promoting the hnRNPA1- and DNA-PK-dependent depletion of RPA.

PAR-TERRA is the main contributor to telomeric repeat-containing RNA transcripts in normal and cancer mouse cells.

Telomeric repeat-containing RNA (TERRA) molecules play important roles at telomeres, from heterochromatin regulation to telomerase activity control. In human cells, TERRA is transcribed from subtelomeric promoters located on most chromosome ends and associates with telomeres. The origin of mouse TERRA molecules is, however, unclear, as transcription from the pseudoautosomal PAR locus was recently suggested to account for the vast majority of TERRA in embryonic stem cells (ESC).

Short telomeres increase the risk of severe COVID-19.

Telomeres are non-coding DNA sequences that protect chromosome ends and shorten with age. Short telomere length (TL) is associated with chronic diseases and immunosenescence. The main risk factor for mortality of coronavirus disease 2019 (COVID-19) is older age, but outcome is very heterogeneous among individuals of the same age group.

No effect of the endurance training status on senescence despite reduced inflammation in skeletal muscle of older individuals.

The aim of the present study was to determine if the training status decreases inflammation, slows down senescence, and preserves telomere health in skeletal muscle in older compared with younger subjects, with a specific focus on satellite cells. Analyses were conducted on skeletal muscle and cultured satellite cells from vastus lateralis biopsies ( = 34) of male volunteers divided into four groups: young sedentary (YS), young trained cyclists (YT), old sedentary (OS), and old trained cyclists (OT). The senescence state and inflammatory profile were evaluated by telomere dysfunction-induced foci (TIF) quantification, senescence-associated β-galactosidase (SA-β-Gal) staining, and quantitative (q)RT-PCR.

Flexible Ru Schiff Base Complexes: G-Quadruplex DNA Binding and Photo-Induced Cancer Cell Death.

A series of new Ru Schiff base complexes built on the salphen moiety has been prepared. This includes four flexible monometallic Ru compounds and six rigid bimetallic analogues that contain Ni , Pd or Pt cations into the salphen complexation site. Steady state luminescence titrations illustrated the capacity of the compounds to photoprobe G-quadruplex (G4) DNA.

An Optimized Protocol for Histochemical Detection of Senescence-associated Beta-galactosidase Activity in Cryopreserved Liver Tissue.

Senescence-associated beta-galactosidase (SA-β-gal) activity assay is commonly used to evaluate the increased beta-galactosidase (β-gal) activity in senescent cells related to enhanced lysosomal activity. Although the optimal pH for β-gal is 4.0, this enzymatic activity has been most commonly investigated at a suboptimal pH by using histochemical reaction on fresh tissue material.

Telomere maintenance mechanisms in cancer: telomerase, ALT or lack thereof.

Cancer cells acquire replicative immortality by activating a telomere maintenance mechanism (TMM), either the telomerase or the Alternative Lengthening of Telomeres (ALT) mechanism. ALT is frequently activated in tumors derived from mesenchymal cells, which are more frequent in childhood cancers. Recent studies showed that, occasionally, cancer cells can arise without any TMM activation.

Specific death of ALT cells through TSPYL5 depletion.

Some tumors acquire replicative immortality by activating an ALTernative telomerase-independent telomere maintenance mechanism. ALT offers interesting therapeutic perspectives but lacks any known specific targets. We discovered a crucial role for TSPYL5 (Testis-Specific Y-encoded-Like Protein 5) in keeping ALT cell viability by protecting POT1 (Protection Of Telomeres 1) from proteasomal degradation.

Exploring the Phototoxicity of Hypoxic Active Iridium(III)-Based Sensitizers in 3D Tumor Spheroids.

Among all molecules developed for anticancer therapies, photodynamic therapeutic agents have a unique profile. Their maximal activity is specifically triggered in tumors by light, and toxicity of even systemically delivered drug is prevented in nonilluminated parts of the body. Photosensitizers exert their therapeutic effect by producing reactive oxygen species via a light-activated reaction with molecular oxygen.

TSPYL5 Depletion Induces Specific Death of ALT Cells through USP7-Dependent Proteasomal Degradation of POT1.

A significant fraction (∼10%) of cancer cells maintain their telomere length via a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT). There are no known molecular, ALT-specific, therapeutic targets. We have identified TSPYL5 (testis-specific Y-encoded-like protein 5) as a PML body component, co-localizing with ALT telomeres and critical for ALT cell viability.

Physical Activity and Nutrition: Two Promising Strategies for Telomere Maintenance?

As the world demographic structure is getting older, highlighting strategies to counteract age-related diseases is a major public health concern. Telomeres are nucleoprotein structures that serve as guardians of genome stability by ensuring protection against both cell death and senescence. A hallmark of biological aging, telomere health is determined throughout the lifespan by a combination of both genetic and non-genetic influences.

Towards the Development of Photo-Reactive Ruthenium(II) Complexes Targeting Telomeric G-Quadruplex DNA.

The design and characterization of new ruthenium(II) complexes aimed at targeting G-quadruplex DNA is reported. Importantly, these complexes are based on oxidizing 1,4,5,8-tetraazaphenanthrene (TAP) ancillary ligands known to favour photo-induced electron transfer (PET) with DNA. The photochemistry of complexes 1-4 has been studied by classical methods, which revealed two of them to be capable of photo-abstracting an electron from guanine.

Environmental hypoxia favors myoblast differentiation and fast phenotype but blunts activation of protein synthesis after resistance exercise in human skeletal muscle.

We hypothesized that a single session of resistance exercise performed in moderate hypoxic (FiO: 14%) environmental conditions would potentiate the anabolic response during the recovery period spent in normoxia. Twenty subjects performed a 1-leg knee extension session in normoxic or hypoxic conditions. Muscle biopsies were taken 15 min and 4 h after exercise in the vastus lateralis of the exercised and the nonexercised legs.