Targeting the Homologous Recombination Pathway in Cancer With a Novel Class of RAD51 Inhibitors.

Targeting DNA damage response (DDR) pathway has been proposed as an approach for amplifying tumor-specific replicative lesions. RAD51 plays a central role in the DDR process, and thus represents a promising anti-tumor target. We here report the discovery of a series of next generation RAD51 inhibitors that can prevent RAD51 foci formation. The lead compounds dramatically impaired human cancer cell growth, induced cell cycle arrest in S-phase, and resulted in elevated γH2AX. Furthermore, cancer cells became sensitized to chemotherapy and other DDR inhibitors. Dosed either as a single agent or in combination with cisplatin, the compounds significantly inhibited tumor growth in vivo. By upregulating ATR-CHK1 signaling, the RAD51 inhibitors increased surface PD-L1 levels in various tumor cells, suggesting a potential combination of RAD51 inhibitors with PD-1/PD-L1 blockade. Overall, our findings provide the preclinical rationale to explore RAD51 inhibitors as monotherapy or in combination with chemotherapy, immunotherapy or DDR-targeting therapy in cancer treatment.

The effect of Tai Chi on the quality of life in the elderly patients recovering from coronavirus disease 2019: A protocol for systematic review and meta-analysis.

BACKGROUND: coronavirus disease 2019 (COVID-19) is spreading fast starting late 2019. As their cardiopulmonary and immune functions gradually decline, elderly people are prone to COVID-19. Tai Chi has a positive impact on heart function, blood pressure, lung function, blood circulation, and so on, and it's suitable for the elderly. Quality of life (QoL)can reflect of individuals' physical and mental health, it can also reflects their ability to participate in society. This systematic review and meta-analysis will summarize the current evidence that Tai Chi improve the QoL in the elderly patients recovering from COVID-19. METHODS: We will search PubMed, EMBASE, MEDLINE, the Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Chinese Science and Technology Periodical Database, Wanfang Database, Clinical Trials and Chinese Clinical Trial Registry. The complete process will include study selection, data extraction, risk of bias assessment and meta-analyses. Endnote X9.3 will be used to manage data screening. The statistical analysis will be completed by Stata/SE 15.1 software. RESULTS: This proposed study will evaluate the effectiveness and safety of Tai Chi for the improvement of QoL in elderly COVID-19 patients during the recovery period. CONCLUSION: The conclusion of this study will provide evidence to prove the safety and effectiveness of Tai Chi on elderly COVID-19 patients during the recovery period. ETHICS AND DISSEMINATION: This protocol will not evaluate individual patient information or infringe patient rights and therefore does not require ethical approval. REGISTRATION: PEROSPERO CRD42020206875.

Kai-Xin-San series formulae alleviate depressive-like behaviors on chronic mild stressed mice via regulating neurotrophic factor system on hippocampus.

Kai-xin-san (KXS) is a famous Chinese medicinal formula applied for treating stress-related psychiatric diseases with the symptoms such as depression, forgetfulness and dizziness. In clinic, the composition ratio of KXS is always varied and KXS series formulae are created. Here, we aim to compare the anti-depressive effect of different ratios of KXS and reveal its action mechanism on regulation of neurotrophic factor system. Firstly, daily intra-gastric administration of chemically standardized extracts of KXS series formulae for seven days significantly alleviated the depressive symptoms of chronic unpredictable mild stressed mice displayed by enhanced sucrose consumptions and decreased immobile time of forced swimming coupled with increased locomotor activities. KXS might fulfill this effect by up-regulating the expressions of NGF, BDNF and Trk receptors in hippocampus, which were confirmed by the treatment of corresponding blockers tPA-stop and K252a. The ratio with higher amounts of Ginseng Radix et Rhizoma and Polygalae Radix exerted most profound effect on anti-depression and regulation enzymes in metabolic pathway of neurotrophic factors. These findings suggested that KXS was beneficial for enhancing supplies, up-regulating receptors, and restoring the dysfunction of metabolic pathway of neurotrophic factors, which might account for its anti-depression effect.

Kai-Xin-San, a standardized traditional Chinese medicine formula, up-regulates the expressions of synaptic proteins on hippocampus of chronic mild stress induced depressive rats and primary cultured rat hippocampal neuron.

BACKGROUND: Kai-xin-san (KXS), composed of Ginseng Radix et Rhizoma, Polygalae Radix, Acori Tatarinowii Rhizoma and Poria, is a famous Chinese medicinal formula applied for treating stress-related psychiatric disease with the symptoms such as depression, forgetfulness and dizziness. Dependent on the symptom differentiation of patients, the composition ratio of KXS was varied and one ratio of 3:2:2:3 was widely applied. However, its molecular mechanism has seldom been investigated. PURPOSE: We aimed to reveal the action mechanism of KXS on anti-depression on synaptic protein regulation in both in vivo and in vitro models. STUDY DESIGN/METHODS: Firstly, the anti-depression effect of KXS was evaluated on a chronic mild stress induced depressive animal model and the mRNA expressions of various synaptic proteins in hippocampus of the depressive rat brains were determined. Then, KXS with different ratios as well as single herb were further evaluated on rat primary cultured hippocampus neurons and the possible signaling pathway was explored. RESULTS: Intra-gastric administration of a chemically standardized KXS for only 6h significantly alleviated the CUMS-induced depressive symptoms displayed by enhanced sucrose consumption and this effect was maintained after daily treatment for seven days. Simultaneously, the mRNA expressions of various synaptic proteins in hippocampus were regulated. Among these synaptic proteins, synaptotagmin (pre-synaptic marker) and post synaptic density protein (post-synaptic marker), with the higher altered magnitude on animal model, were further evaluated on rat primary cultured hippocampus neurons. After neuronal cultures treated with three ratios of KXS at the early and late stages of its life episode, the expression levels of synaptotagmin and PSD95 were both enhanced dramatically via stimulating cAMP dependent pathway. However, different ratio exerted different efficacy. The ratio with higher amounts of Ginseng Radix et Rhizoma and Polygalae Radix showed better effect in early life episode while higher amounts of Acori Tatarinowii Rhizoma and Poria behaved better in late life episode. The contribution of single herb on expressions of synaptic proteins was also evaluated. CONCLUSIONS: KXS was beneficial for synaptogenesis by inducing synaptic protein expressions, which might account for its anti-depression effect.