Age-dependent DNA repair and cell cycle distribution of human skin fibroblasts in response to UVA irradiation

International audienc

IL-1beta mediates MMP secretion and IL-1beta neosynthesis via upregulation of p22phox and NOX4 activity in human articular chondrocytes

Objectives: Osteoarthritis (OA) is characterized by a progressive alteration of the biochemical properties of the articular cartilage. Inflammation plays a major role in OA, particularly through the cytokine Interleukine-1β, promoting reactive oxygen species (ROS) generation and matrix metalloproteinases (MMP) synthesis by the chondrocytes, orchestrating matrix proteolysis. NADPH oxidases (NOX) are membrane enzymes dedicated to the production of ROS. Role of oxidative stress is well established in OA; however, contribution of NOX in this process is still poorly documented. In this study, we addressed the role of NOX in primary human articular chondrocytes (HAC) upon inflammatory conditions - namely IL-1β and OA. Design: HAC were collected from patients undergoing hip surgery. Chondrocytes were treated with IL-1β and NOX inhibitors Diphenylene Iodonium, GKT136901, Tiron and Heme oxygenase-1 before MMP expression and NOX activity assessment. Finally, NOX4 expression was compared between OA and non OA parts of hip cartilage (n = 14). Results: This study establishes for the first time in human that NOX4 is the main NOX isoform expressed in chondrocytes. We found a significant upregulation of NOX4 mRNA in OA chondrocytes. Expression of NOX4/p22phox as well as ROS production is enhanced by IL-1β. On the other hand, the use of NOX4 inhibitors decreased IL-1β-induced collagenase synthesis by chondrocytes. Moreover, our study support the existence of a redox dependant loop sustaining pro-catabolic pathways induced by IL-1β. Conclusions: This study points out NOX4 as a new putative target in OA and suggests that NOX-targeted therapies could be of interest for the causal treatment of the pathology. © 2015 Osteoarthritis Research Society International

Whole genome sequencing identifies a homozygous splicing variant in TDRKH segregating with non-obstructive azoospermia in an Iranian family

International audienceNon‐obstructive azoospermia (NOA) resulting from primary spermatogenic failure represents one of the most severe forms of male infertility, largely because therapeutic options are very limited. Beyond their diagnostic value, genetic tests for NOA also hold prognostic potential. Specifically, genetic diagnosis enables the establishment of genotype‐testicular phenotype correlations, which, in some cases, provide a negative predictive value for testicular sperm extraction (TESE), thereby preventing unnecessary surgical procedures. In this study, we employed whole‐genome sequencing (WGS) to investigate two generations of an Iranian family with NOA and identified a homozygous splicing variant in TDRKH (NM_001083965.2: c.562‐2A>T). TDRKH encodes a conserved mitochondrial membrane‐anchored factor essential for piRNA biogenesis in germ cells. In Tdrkh knockout mice, de‐repression of retrotransposons in germ cells leads to spermatogenic arrest and male infertility. Previously, our team reported TDRKH involvement in human NOA cases through the investigation of a North African cohort. This current study marks the second report of TDRKH 's role in NOA and human male infertility, underscoring the significance of the piRNA pathway in spermatogenesis. Furthermore, across both studies, we demonstrated that men carrying TDRKH variants, similar to knockout mice, exhibit complete spermatogenic arrest, correlating with failed testicular sperm retrieval