Kaempferol-3-O-rutinoside (K3R) has been proven to have biological activities for the prevention and treatment of central nervous system (CNS) diseases. However, the details of its absorption from the gastrointestinal tract and transport across the blood–brain barrier (BBB) are not clear. Therefore, to provide a basis for its efficacy, we explored its intestinal absorption with Caco-2 monolayer cells, rat orthotopic intestinal perfusion, its transport across a BBB model based on bEnd.3 monolayer cells and its pharmacological effects on PC12 cells in terms of neuropathy. The results indicated that the transport of K3R is concentration dependent; moreover, the apparent permeability coefficient (P_app) of K3R lacked directionality, and the efflux rate after adding P-glycoprotein inhibitor did not show a significant change. K3R was found to be completely absorbed in the intestines of rats, and the absorption process follows the first-order kinetics. K3R can pass through the BBB with passive diffusion. The neuroprotective effects of K3R were related to stabilization of the mitochondrial membrane and a decrease in reactive oxygen species. These results demonstrated that K3R can be absorbed in a relatively moderate ratio in the gastrointestinal tract and transported to the brain. Thus, K3R may be a potent drug for the prevention and treatment of neurodegenerative diseases such as Parkinson's disease.

Cellular senescence is a stable state of cell cycle arrest caused by telomere shortening or various stresses. After senescence, cells cease dividing and exhibit many age-related characteristics. Unlike the halted proliferation of senescence cells, cancer cells are considered to have unlimited growth potential. When cells display senescence-related features, such as telomere loss or stem cell failure, they can inhibit tumor development. Therefore, inducing cells to enter a senescence state can serve as a barrier to tumor cell development. However, many recent studies have found that sustained senescence of tumor cells or normal cells under certain circumstances can exert environment-dependent effects of tumor promotion and inhibition by producing various cytokines. In this review, we first introduce the causes and characteristics of induced cellular senescence, analyze the senescence process of immune cells and cancer cells, and then discuss the dual regulatory role of cell senescence on tumor growth and senescence-induced therapies targeting cancer cells. Finally, we discuss the role of senescence in tumor progression and treatment opportunities, and propose further studies on cellular senescence and cancer therapy.

Protein lysine succinylation is a crucial post-translational modification that regulates nearly all aspects of eukaryotic and prokaryotic cell, including gene transcription, cell metabolism and redox homeostasis. Among them, metabolic disorders caused by dysfunctional post-translational modifications induce aging and aged-related diseases, including cancer. This study quantified the dynamic changes in protein succinylation in response to DNA damage stress induced by etoposide (ETOP) in tumor cells. A total of 4354 lysine succinylation sites on 1259 proteins were identified, many of which have not been previously reported. Bioinformatics analysis revealed that many proteins are involved in the metabolism of nicotinamide adenine dinucleotide phosphate (NADPH) in mitochondria (including MTHFD2). We further found that low activity or depletion of MTHFD2 enhances the degree of TIS in breast cancer cells and decreases their resistance to chemotherapeutic agents. Interestingly, we also found that SIRT5-mediated desuccinylation of MTHFD2 was able to reduce the senescence of breast cancer cells, thereby enhancing their resistance to chemotherapeutic drugs. This effect may explain the poorer prognosis observed in breast cancer patients with high expression levels of SIRT5 or MTHFD2. These systematic analyses provide new insights into targeting succinylation-modified metabolic proteins to enhance TIS, and their combination with senolytics for breast cancer therapy.