Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

With the acceleration of aging process and the increase of average life in China, the number of disabled elderly in China is also growing rapidly, which undoubtedly brings a heavy care burden and pressure to families and society.Facing the great challenges brought by aging, the increasing evidences show that only by reducing the incidence of disease and disability from the source, improving the health level of the elderly, prolonging their healthy life and realizing healthy aging, we can fundamentally alleviate the great pressure brought by the aging society.The concept of motor function maintenance and health promotion of the elderly has become an important link and breakthrough to realize healthy aging and active health.Facing the requirements of active health medicine and the development trend of science and technology in the future, it is imperative to deeply study the motion characteristics and function maintenance of the elderly, and promote the development of sports medicine with innovative technologies such as internet, big data and artificial intelligence.In the future, we will continue to improve the assessment and maintenance system for motor function of the elderly, develop and optimize functional maintenance products that meet the exercise needs of the elderly, and actively build an elderly-friendly sports environment support system, thereby promoting the healthy China strategy and realize healthy aging to the greatest extent.

Objective:To explore the in vitro antiviral activity of Mizoribine (Miz) against BK polyomavirus (BKV) and analyze preliminarily the replication stage during inhibition.Methods:The solvent of Miz, was employed as a negative control, while Sirolimus (Sir) with in vitro anti-BKV activity was applied as a positive control. Firstly, the half maximal inhibitory concentrations (IC50) of Miz and Sir were analyzed in different cell lines. Then, prior to BKV infection, cells were treated with a gradient of drug concentrations according to the IC50 results. At different timepoints post-infection, BKV replication curves were measured by quantitative detection of its DNA in supernatant while the cells were subjected to immunofluorescence for detecting the infection rate. Finally 293FT cells treated with drugs was infected by BKV single-round pseudovirus for determining the effects of Miz on the early stage of BKV infection.Results:As compared with control group, immunofluorescence showed a lowered infection rate of BKV in a Miz dose-dependent manner, viral replication curve was significantly inhibited according to the quantitative detection of viral DNA in cell supernatant. The inhibitory effect of Sir on the level of BKV infection and replication was similar to that of Miz. However, neither Miz nor Sir exhibited a significant effect on the early stage of BKV infection.Conclusions:Miz has anti-BKV activity at cellular level and the inhibitory effect does not appear in the early stage of viral infection.