Reversing the PAI-1-induced fibrotic immune exclusion of solid tumor by multivalent CXCR4 antagonistic nano-permeator

Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8+ T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.

Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR

Programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) cascade is an effective therapeutic target for immune checkpoint blockade (ICB) therapy. Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity. Using flow cytometry-based assay, we identify tubeimoside-1 (TBM-1) as a promising antitumor immune modulator that negatively regulates PD-L1 level. TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1. Furthermore, TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma (LLC) and B16 melanoma tumor xenograft

Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.

Evaluation of the sedative and hypnotic effects of H057 / 中国药理学通报

Aim To investigate the sedative and hyp-notic effects of a novel compound H057 . Methods The sedative activity of H057 was investigated by re-cording the spontaneous locomotor activity in mice. The hypnotic property was evaluated by the latency and duration of loss of righting reflex( LORR) in mice and effect of H057 on the sleep onset in subthreshold dos-age of sodium pentobarbital treated mice. The extracel-lular levels of GABA and monoamine neurotransmitters in in cerebral cortex were measured by microdialysis in vivo. Results The spontaneous locomotor activity was decreased by 25% and 66% in H057 ( 5 , 25 mg · kg-1 ,i. p. ) treated mice, respectively. H057 ( 3, 5 mg·kg-1 ,i. p. ) increased the sleep onset to 62. 5%and 87. 5% in subthreshold dosage of sodium pentobar-bital(25 mg·kg-1,i. p. ) treated mice. H057(≥60 mg· kg-1 , i. p. ) could completely induce LORR in mice. The latency of LORR at dose of 60 mg · kg-1 was (24 ± 11) min and the duration of LORR was (96 ± 15 ) min. In vivo mircodialysis revealed that H057 (25 mg·kg-1 , i. p. ) could significantly increase the GABA level by 26% and decrease the 5-HT and NE levels by 50% and 38% in cerebral cortex in mice. Conclusion H057 has potent sedative and hypnotic effects, which may be closely related to the increased content of GABA and the decreased contents of 5-HT and NE in the extracellular fluid in cerebral cortex.

Design, synthesis and pharmacological investigation of isoindoline derivatives as 5-HT/NE double reuptake inhibitors / 药学学报

A series of isoindoline derivatives were designed, synthesized, and evaluated for their double inhibitory activities. All of them were new compounds, and their structures were confirmed by 1H NMR and HR-MS. Preliminary in vitro pharmacological tests showed that all compounds exhibited 5-HT or NE reuptake inhibition activity. Among the tested compounds, compound I-3 exhibited potent inhibitory activity against 5-HT and NE reuptake in vitro, and exhibited potent antidepressant activity in vivo. These compounds designed can be further optimized for finding more potent 5-HT/NE dual reuptake inhibitors and antidepressant candidates as well.

Research progress on the relationship between sleep disorders and Alzheimer's disease / 中国药理学通报

Sleep disorders are common diseases with various dys-function during sleep-wake process, including difficulty falling or staying asleep, falling asleep at inappropriate times, excessive total sleep time, or abnormal behaviors associated with sleep. Sleep disorders can lead to the deposition of amyloid beta protein ( Aβ) by affecting the normal metabolism of amyloid beta protein in the brain. Patients with Alzheimer’s disease ( AD) often suffer from sleep disorders, and its pathology always results in more se-vere sleep disorders, which leads to a risk of cognitive impair-ment and hypofunction. Sleep disorders could interact closely with AD, forming a positive feedback loop, which causes serious damage to the body health. This review summarized the current research about sleep disorder in the onset of AD and the current status of medication.

Evaluation of the sedative and hypnotic effects of H1208 / 药学学报

This study is to investigate the sedative and hypnotic effects of a novel compound H1208. The sedative activity of H1208 was investigated by recording the spontaneous locomotor activity of mice. The hypnotic property was evaluated by the latency and duration of sleep (loss of righting reflex) in mice and the effect of hypnotics on sleep pattern of electroencephalogram were studied in conscious, freely moving mice with chronically implanted electrodes. The brain monoamine neurotransmitters levels in mice were measured by high performance liquid chromatography-electrochemical detection. The spontaneous locomotor activity was decreased by 56.7% and 80.2% in H1208 (5 and 25 mg x kg(-1), ip) treated mice, respectively. The loss of righting reflex was directly induced in mice after H1208 (60 mg x kg(-1), ip) administration. The non-rapid eye movement sleep increased significantly by 131% and 259%, respectively, within 3 hours after H1208 (30 and 60 mg x kg(-1), ip) administration. However, the rapid eye movement sleep decreased significantly. The contents of DA in the striatum and cortex and 5-HT in the cortex decreased significantly. These results demonstrated that H1208 has potent sedative and hypnotic effects, which may be closely related to the decreased contents of DA and 5-HT in mouse brain.