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Although cellular senescence acts primarily as a tumour suppression mechanism, the accumulation of senescent cells in vivo eventually exerts deleterious side effects through inflammatory/tumour-promoting factor secretion. Thus, the development of new drugs that cause the specific elimination of senescent cells, termed senolysis, is anticipated. Here, by an unbiased high-throughput screening of chemical compounds and a bio-functional analysis, we identify BET family protein degrader (BETd) as a promising senolytic drug. BETd provokes senolysis through two independent but integrated pathways; the attenuation of non-homologous end joining (NHEJ), and the up-regulation of autophagic gene expression. BETd treatment eliminates senescent hepatic stellate cells in obese mouse livers, accompanied by the reduction of liver cancer development. Furthermore, the elimination of chemotherapy-induced senescent cells by BETd increases the efficacy of chemotherapy against xenograft tumours in immunocompromised mice. These results reveal the vulnerability of senescent cells and open up possibilities for its control., Senescent cells can influence the tumour microenvironment by secreting immunomodulatory factors and are thus a therapeutic target. Here, the authors identify a compound that degrades BET leading to DNA damage and activation of autophagy and a reduction in tumour growth.

Reports on the long-term survival effect of edaravone, which was approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2015 in Japan, are rare. Herein, we report our retrospective analysis of 45 consecutive patients with ALS who initially visited our hospital between 2013 and 2018. Of these, 22 patients were treated with edaravone for an average duration of 26.6 (range, 2–64) months, whereas the remaining patients were not treated with edaravone and comprised the control group. There were no differences in baseline demographics between the two groups. The primary endpoint was tracheostomy positive-pressure ventilation (TPPV) or death, and the follow-up period ended in December 2020. The survival rate was significantly better in the edaravone group than in the control group based on the Kaplan–Meier analysis, which revealed that the median survival durations were 49 (9–88) and 25 (8–41) months in the edaravone and control groups, respectively (p = 0.001, log-rank test). There were no serious edaravone-associated adverse effects during the study period. Overall, the findings of this single-center retrospective study suggest that edaravone might prolong survival in patients with ALS.

Accumulating evidence indicates that the senescence-associated secretory phenotype (SASP) contributes to many aspects of physiology and disease. Thus, controlling the SASP will have tremendous impacts on our health. However, our understanding of SASP regulation is far from complete. Here, we show that cytoplasmic accumulation of nuclear DNA plays key roles in the onset of SASP. Although both DNase2 and TREX1 rapidly remove the cytoplasmic DNA fragments emanating from the nucleus in pre-senescent cells, the expression of these DNases is downregulated in senescent cells, resulting in the cytoplasmic accumulation of nuclear DNA. This causes the aberrant activation of cGAS-STING cytoplasmic DNA sensors, provoking SASP through induction of interferon-β. Notably, the blockage of this pathway prevents SASP in senescent hepatic stellate cells, accompanied by a decline of obesity-associated hepatocellular carcinoma development in mice. These findings provide valuable new insights into the roles and mechanisms of SASP and possibilities for their control., Activation of DNA damage response induces the acquisition of senescence-associated secretory phenotype (SASP) in senescent cells, but precise mechanisms remain unclear. Here, the authors show that the cytoplasmic accumulation of nuclear DNA activated cytoplasmic DNA sensors to provoke SASP.

Two peroxiredoxins, classified as Type II and PrxQ, were characterized in the purple non-sulfur photosynthetic bacterium Rhodobacter sphaeroides. Both recombinant proteins showed remarkable thioredoxin-dependent peroxidase activity with broad substrate specificity in vitro. Nevertheless, PrxQ of R. sphaeroides, unlike typical PrxQs studied to date, does not contain one of the two conserved catalytic Cys residues. We found that R. sphaeroides PrxQ and other PrxQ-like proteins from several organisms conserve a different second Cys residue, indicating that these proteins should be categorized into a novel PrxQ subfamily. Disruption of either the Type II or PrxQ gene in R. sphaeroides had a dramatic effect on cell viability when the cells were grown under aerobic light or oxidative stress conditions created by exogenous addition of reactive oxygen species to the medium. Growth rates of the mutants were significantly decreased compared with that of wild type under aerobic but not anaerobic conditions. These results indicate that the peroxiredoxins are crucial for antioxidative stress response in this bacterium. The gene disruptants also demonstrated reduced levels of photopigment synthesis, suggesting that the peroxiredoxins are directly or indirectly involved in regulated synthesis of the photosynthetic apparatus.

In a batchwise variable-pressure/variable-rate expression process, the expression pressure is increased to a predetermined maximum pressure and then held constant until final equilibrium compression is obtained. For analyzing the variable-pressure/variable-rate expression process, the following assumption is made: the internal condition of compressed cake under the instantaneous pressure p in a variable-pressure/variable-rate operation is close to that in a constant-pressure operation under such a pressure p when the same volume of liquid is removed from the same amount of original materials in both operations. Using this assumption, the changes of sample thickness with expression time can be calculated from the analytical equation for the constant-pressure process based on the Terzaghi-Voigt combined model. The match between experiment and theory was satisfactory for the expression of semisolid Korean kaolin.