Author: Tao, W Andy ; Chen, Lan ; Zhang, Zhong-Yin ; Zhang, Sheng ; Jassim, Brenson A ; Tiganis, Tony ; Lin, Jianping ; Zhu, Peipei ; Qu, Zihan ; Miao, Jinmin ; Wiede, Florian ; Dong, Jiajun ; Nguyen, Quyen ; Bai, Yunpeng ; Miao, Yiming

AbstractProtein tyrosine phosphatase 1B (PTP1B) and T‐cell protein tyrosine phosphatase (TC‐PTP) play non‐redundant negative regulatory roles in T‐cell activation, tumor antigen presentation, insulin and leptin signaling, and are potential targets for several therapeutic applications. Here, we report the development of a highly potent and selective small molecule degrader DU‐14 for both PTP1B and TC‐PTP. DU‐14 mediated PTP1B and TC‐PTP degradation requires both target protein(s) and VHL E3 ligase engagement and is also ubiquitination‐ and proteasome‐dependent. DU‐14 enhances IFN‐γ induced JAK1/2‐STAT1 pathway activation and promotes MHC‐I expression in tumor cells. DU‐14 also activates CD8+ T‐cells and augments STAT1 and STAT5 phosphorylation. Importantly, DU‐14 induces PTP1B and TC‐PTP degradation in vivo and suppresses MC38 syngeneic tumor growth. The results indicate that DU‐14, as the first PTP1B and TC‐PTP dual degrader, merits further development for treating cancer and other indications.

01 Dec 2020·TrialsQ4 · MEDICINE

Efficacy of acupuncture at three nasal acupoints plus acupoint application for perennial allergic rhinitis: A multicenter, randomized controlled trial protocol

Q4 · MEDICINE

ArticleOA

Author: Shou, Yin ; Xu, Shifen ; Yuan, Long ; Zhang, Kaiyong ; Jiang, Huiru ; Zhang, Bimeng ; Xu, Siwei ; Zhang, Cuihong ; Li, Bingrong ; Huang, Li ; Hu, Li ; Jin, Qi

AbstractBackgroundMany studies have shown the potential therapeutic effect of acupuncture on allergic rhinitis. Most of these studies were limited by low-quality evidence. Preliminary experiments showed that the use of acupuncture at three nasal acupoints plus acupoint application (AAP) achieves a more persistent effect in the treatment of perennial allergic rhinitis than acupuncture alone. In this study, a multicenter, single-blind, randomized controlled trial will be performed, in which acupuncture at nonmeridian acupoints and sham AAP will be used as the control group to evaluate the effect of AAP through long-term observation.MethodsThe trial is designed on the basis of the Consolidated Standards of Reporting Trials 2010 guidelines and Standards for Reporting Interventions in Controlled Trials of Acupuncture. A total of 120 participants with perennial allergic rhinitis will be randomly assigned to a treatment or control group. A specially appointed investigator will be in charge of randomization. The participants in the treatment group will be treated with acupuncture at EX-HN3, LI20, and EX-HN8 thrice per week for a total of 12 sessions. In addition, they will undergo AAP at DU14, BL13, EX-BI, and RN22. The participants in the control group will be treated with sham AAP. The primary outcome will be the change in the Total Nasal Symptom Score from baseline to the completion of 4-week treatment. Secondary outcomes include changes in visual analog scale and total non-nasal symptom scores from baseline to the second and fourth weeks of treatment, as well as 1, 3, and 6 months after the completion of treatment. Peripheral blood IL-4, IL-5, IL-6, IL-8, and IL-10 levels will be measured, and any side effects related to treatment will be observed and recorded.DiscussionIt is expected that this randomized clinical trial will provide evidence to determine the effects of AAP compared with acupuncture at nonmeridian acupoints and sham AAP, particularly the long-term effect. These findings will help improve the clinical application of this technique.Trial registrationAcupuncture-Moxibustion Clinical Trial Registry AMCTR-ICR-18000179. Registered on 12 April 2018.

01 Jul 2016·Hormones and BehaviorQ3 · MEDICINE

Steroid sulfatase inhibitor DU-14 protects spatial memory and synaptic plasticity from disruption by amyloid β protein in male rats

Q3 · MEDICINE

Article

Author: Wang, Zhao-Jun ; Cai, Hong-Yan ; Qi, Jin-Shun ; Tong, Jia-Qing ; Liu, Xiao-Jie ; Liu, Xu ; Yue, Xing-Hua ; Zhang, Jun

Alzheimer's disease (AD) is an age-related mental disorder characterized by progressive loss of memory and multiple cognitive impairments. The overproduction and aggregation of Amyloid β protein (Aβ) in the brain, especially in the hippocampus, are closely involved in the memory loss in the patients with AD. Accumulating evidence indicates that the Aβ-induced imbalance of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) in the brain plays an important role in the AD pathogenesis and progression. The level of DHEA is elevated, while DHEAS is dramatically decreased in the AD brain. The present study tried to restore the balance between DHEA and DHEAS by using a non-steroidal sulfatase inhibitor DU-14, which increases endogenous DHEAS through preventing DHEAS converted back into DHEA. We found that: (1) DU-14 effectively attenuated the Aβ1-42-induced cognitive deficits in spatial learning and memory of rats in Morris water maze test; (2) DU-14 prevented Aβ1-42-induced decrease in the cholinergic theta rhythm of hippocampal local field potential (LFP) in the CA1 region; (3) DU-14 protected hippocampal synaptic plasticity against Aβ1-42-induced suppression of long term potentiation (LTP). These results provide evidence for the neuroprotective action of DU-14 against neurotoxic Aβ, suggesting that up-regulation of endogenous DHEAS by DU-14 could be beneficial to the alleviation of Aβ-induced impairments in spatial memory and synaptic plasticity.

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Indication	Highest Phase	Country/Location	Organization	Date
Cognition Disorders	Discovery	US	Duquesne University of The Holy Spirit	-

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