Doxercalciferol alleviates UVB-induced HaCaT cell senescence and skin photoaging.

Prolonged or excessive ultraviolet (UV) exposure can lead to premature skin aging. Doxercalciferol (Dox), an analog of vitamin D2, is chiefly used to treat endocrine diseases, cardiovascular diseases, kidney diseases, etc. To date, research on Dox in alleviating photoaging and UV-induced inflammation is scarce. In this research, we evaluated the function of Dox in ultraviolet radiation B (UVB)-induced photoaging and explored the potential mechanism in human keratinocytes (Hacat) and BALB/c mice. First, we established a stable UVB-induced photoaging cell model. Then, we found that the senescence ß-galactosidase (SA-ß-Gal) positive rate, senescence-related protein (p16), aging-related genes (p21 and p53), senescence-associated secretory phenotype (SASP), inflammatory driving factors (IL-1ß and IL-6) and matrix metalloproteinases (MMPs) (MMP1 and MMP9) were upregulated in HaCaT cells after UVB irradiation. At the same time, the effect of UVB on the back skin of BALB/c mice showed a consistent trend. Dox effectively alleviated the aforementioned changes caused by UVB radiation. Mechanistically, we found that UVB activated mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways, and Dox inhibited UVB-activated NF-κB and MAPK. Furthermore, Dox inhibited UVB-induced skin photoaging and damage in mice. In summary, Dox has been improved to inhibit photoaging, which may help to develop therapies to delay skin photoaging.

Peficitinib ameliorates doxorubicin-induced cardiotoxicity by suppressing cellular senescence and enhances its antitumor activity.

Irreversible cardiotoxicity limits the clinical applications of doxorubicin (DOX). Cardiotoxicity can be detected early using clinical assessment; however, effective preventive measures are still lacking. Peficitinib (ASP015K), a JAK (Janus kinase) inhibitor, is a potent anti-inflammatory agent in autoimmune diseases. Nevertheless, little research has been conducted on anti-ageing and anti-tumour therapies. In this study, we investigated whether ASP015K could attenuate DOX-induced cardiotoxicity through its anti-ageing effects and whether it would affect the tumour treatment effect of DOX by establishing senescence, acute heart injury, and xenograft models. We observed that ASP015K could antagonise the senescence induced by various factors, including hydrogen peroxide and DOX. In addition, ASP015K treatment significantly alleviated cardiac function damage, histopathological deterioration, myocardial fibrosis, and oxidative damage in acute injury mouse models. ASP015K enhanced the sensitivity of tumour cells to DOX therapy and significantly slowed down the tumour growth rate and tumour volume in the xenograft mouse model. Therefore, ASP015K is expected to be developed as a potential cardioprotective agent to prevent or reduce the cardiotoxic side effects of anthracyclines in chemotherapy.

Trifluridine induces HUVECs senescence by inhibiting mTOR-dependent autophagy.

Trifluridine, a key component of trifluridine/tipiracil, is a potential anti-cancer drug that can act effectively on refractory metastatic colorectal cancer. Chemotherapy is important for cancer treatment, but its adverse effects limit its use. Long-term side-effects caused by the drug used during chemotherapy are closely related to the accumulation of cellular senescence. However, the relationship between trifluridine and normal cell aging remains unclear. The purpose of this study is to evaluate whether trifluridine can induce the senescence of human umbilical vein endothelial cells and to explore the possible mechanism. Human umbilical vein endothelial cells were treated with trifluridine, senescence levels were measured via senescence-related acidic ß-galactosidase staining and senescence-associated secretory phenotype levels respectively. Autophagy was assessed by the protein levels of LC3II/LC3I and p62, and LC3 fusion was detected by fluorescence microscopy. Chloroquine diphosphate salt and rapamycin were used to detect the effect of trifluridine on autophagy flux and mTOR signaling pathway. Trifluridine increased the expression of senescence-associated acidic ß-galactosidase and senescence-related secretory phenotype mRNA levels in cells. In addition, also trifluridine induced cellular senescence by inhibiting autophagy and was closely related to the activation of the mTOR signaling pathway, therefore, we believe that trifluridine may be an effective mTOR activator. The findings also provide a new strategy for establishing autophagy or aging models, as well as a new theoretical basis for the use of trifluridine in clinical treatment.