Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor ß type II receptor.

BACKGROUND: The transforming growth factor ß (TGFß) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFß type II receptor (TGFßR2), followed by the recruitment of TGFßR1 finally triggering downstream signaling pathway. AIM: To find drugs targeting TGFßR2 that inhibit TGFßR1/TGFßR2 complex formation, theoretically inhibit TGFß signaling pathway, and thereby ameliorate liver fibrosis. METHODS: Food and Drug Administration-approved drugs were screened for binding affinity with TGFßR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8 (CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect. RESULTS: We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine (DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFß induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFßR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFßR2 disrupted the binding of TGFßR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson's trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver. CONCLUSION: DHE alleviates liver fibrosis by binding to TGFßR2 thereby suppressing TGFß signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.

Magnesium valproate adjuvant therapy on patients with dementia: A protocol for systematic review and meta-analysis.

BACKGROUND: With the aging population, the prevalence and incidence of dementia disease will continue to rise, and the associated economic burden is increasing as well. However, the available anti-dementia therapeutic arsenal is limited. Meanwhile, magnesium valproate (VPM) as an adjuvant therapy had a general positive effect on the cognitive function and psychiatric symptoms of patient with dementia (PwD). At present, there is lack of meta-analysis focusing on cognitive improvement and disease-modifying about VPM-assisted therapy in the present peer-reviewed literature. Thus, we aimed to likely analyze the efficacy and safety of VPM adjuvant therapy of PwD. METHODS: We will research MEDLINE via PubMed, Cochrane Library, EBSCO, Embase, China National Knowledge (CNKI) and Wan fang databases to gather relevant data on VPM assistant therapy on the PwD. Meta-analysis will be performed using Stata16.0 software. RESULTS: We aim to evaluate the efficacy and safety of VPM in the adjuvant treatment of PwD. CONCLUSION: VPM maybe plays an active role in the treatment of dementia patients and this research will provide reliable evidence for clinicians in therapy of PwD. INPLASY REGISTRATION NUMBER: INPLASY2021110038 (DOI: 10.37766/inplasy2021.11.0038).