Cancer cell employs a microenvironmental neural signal trans-activating nucleus-mitochondria coordination to acquire stemness.

Cancer cell receives extracellular signal inputs to obtain a stem-like status, yet how tumor microenvironmental (TME) neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive. Here, a pan-cancer transcriptomic screening for 10852 samples of 33 TCGA cancer types reveals that cAMP-responsive element (CRE) transcription factors are convergent activators for cancer stemness. Deconvolution of transcriptomic profiles, specification of neural markers and illustration of norepinephrine dynamics uncover a bond between TME neural signals and cancer-cell CRE activity. Specifically, neural signal norepinephrine potentiates the stemness of proximal cancer cells by activating cAMP-CRE axis, where ATF1 serves as a conserved hub. Upon activation by norepinephrine, ATF1 potentiates cancer stemness by coordinated trans-activation of both nuclear pluripotency factors MYC/NANOG and mitochondrial biogenesis regulators NRF1/TFAM, thereby orchestrating nuclear reprograming and mitochondrial rejuvenating. Accordingly, single-cell transcriptomes confirm the coordinated activation of nuclear pluripotency with mitochondrial biogenesis in cancer stem-like cells. These findings elucidate that cancer cell acquires stemness via a norepinephrine-ATF1 driven nucleus-mitochondria collaborated program, suggesting a spatialized stemness acquisition by hijacking microenvironmental neural signals.

Network pharmacology and pharmacological evaluation for deciphering novel indication of Sishen Wan in insomnia treatment.

BACKGROUND: Insomnia is the most frequent sleep disorder worldwide and is a prominent risk factor for mental and physical health deterioration. The clinical application of common pharmacological treatments for insomnia is far from satisfactory due to their various adverse effects. In recent years, drugs developed from natural herbs have become potential alternative therapies for insomnia. Sishen Wan (SSW), a traditional Chinese medicine (TCM) used for centuries to treat diarrheal disease, consists of multiple neurologically active herbs with sleep-regulating potential that may have therapeutic effects on insomnia. However, its hypnotic and sleep-regulating effects have not been evaluated in clinical practice or laboratory experiments. PURPOSE: To investigate the anti-insomnia effects of SSW and explore its possible mechanisms using preclinical models. STUDY DESIGN AND METHODS: The sedative effect of the SSW formula was investigated using network pharmacology analysis that was validated using various pharmacological approaches, including the evaluation of locomotor activity (LMA), pentobarbital-induced sleep time, and electroencephalography/electromyogram (EEG/EMG)-based sleep profiling in normal rats. Several animal models of insomnia, including sleep deprivation, serotonin depletion, and cage-changing models, have been used to further assess the anti-insomnia effects of SSW. Furthermore, the potential underlying mechanisms of action of SSW were predicted using bioinformatics methods and verified using in vivo and in silico experiments. RESULTS: The results showed that SSW reduced LMA and prolonged pentobarbital-induced sleep time in a dose-dependent manner, which was consistent with the increase in non-rapid eye movement (NREM) sleep in normal rats, indicating a solid sedative effect. In animal models of insomnia, SSW alleviated sleep disturbance by increasing NREM sleep time, shortening NREM sleep latency, and inhibiting sleep fragmentation, suggesting a possible curative effect of SSW on insomnia. Finally, through functional enrichment analysis and in vivo and in silico experiments, 5-HT1A was identified as the key target of the anti-insomnia effect of SSW. Moreover, (S)-propranolol, nuciferine, zizyphusine, and N,N-dimethyl-5-methoxytryptamine may be the active compounds of SSW responsible for its anti-insomnia effect. CONCLUSION: This study extended the possible indication scope for SSW, which provides a potential therapeutic TCM that may be used for insomnia treatment, as well as a reference scheme for the discovery of novel indications of TCM.

CAD v1.0: Cancer Antigens Database Platform for Cancer Antigen Algorithm Development and Information Exploration.

Cancer vaccines have gradually attracted attention for their tremendous preclinical and clinical performance. With the development of next-generation sequencing technologies and related algorithms, pipelines based on sequencing and machine learning methods have become mainstream in cancer antigen prediction; of particular focus are neoantigens, mutation peptides that only exist in tumor cells that lack central tolerance and have fewer side effects. The rapid prediction and filtering of neoantigen peptides are crucial to the development of neoantigen-based cancer vaccines. However, due to the lack of verified neoantigen datasets and insufficient research on the properties of neoantigens, neoantigen prediction algorithms still need to be improved. Here, we recruited verified cancer antigen peptides and collected as much relevant peptide information as possible. Then, we discussed the role of each dataset for algorithm improvement in cancer antigen research, especially neoantigen prediction. A platform, Cancer Antigens Database (CAD, http://cad.bio-it.cn/), was designed to facilitate users to perform a complete exploration of cancer antigens online.