Identifying potential treatments of COVID-19 from Traditional Chinese Medicine (TCM) by using a data-driven approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicine (TCM) has been widely used as an approach worldwide. Chinese Medicines (CMs) had been used to treat and prevent viral infection pneumonia diseases for thousands of years and had accumulated a large number of clinical experiences and effective prescriptions. AIM OF THE STUDY: This research aimed to systematically excavate the classical prescriptions of Chinese Medicine (CM), which have been used to prevent and treat Pestilence (Wenbing, Wenyi, Shiyi or Yibing) for long history in China, to obtain the potential prescriptions and ingredients to alternatively treat COVID-19. MATERIALS AND METHODS: We developed the screening system based on data mining, molecular docking and network pharmacology. Data mining and association network were used to mine the high-frequency herbs and formulas from ancient prescriptions. Virtual screening for the effective components of high frequency CMs and compatibility Chinese Medicine was explored by a molecular docking approach. Furthermore, network pharmacology method was used to preliminarily uncover the molecule mechanism. RESULTS: 574 prescriptions were obtained from 96,606 classical prescriptions with the key words to treat "Warm diseases (Wenbing)", "Pestilence (Wenyi or Yibing)" or "Epidemic diseases (Shiyi)". Meanwhile, 40 kinds of CMs, 36 CMs-pairs, 6 triple-CMs-groups existed with high frequency among the 574 prescriptions. Additionally, the key targets of SARS-COV-2, namely 3CL hydrolase (Mpro) and angiotensin-converting enzyme 2(ACE2), were used to dock the main ingredients from the 40 kinds by the LigandFitDock method. A total of 66 compounds components with higher frequency were docked with the COVID-19 targets, which were distributed in 26 kinds of CMs, among which Gancao (Glycyrrhizae Radix Et Rhizoma), HuangQin (Scutellariae Radix), Dahuang (Rhei Radix Et Rhizome) and Chaihu (Bupleuri Radix) contain more potential compounds. Network pharmacology results showed that Gancao (Glycyrrhizae Radix Et Rhizoma) and HuangQin (Scutellariae Radix) CMs-pairs could also interact with the targets involving in immune and inflammation diseases. CONCLUSIONS: These results we obtained probably provided potential candidate CMs formulas or active ingredients to overcome COVID-19. Prospectively, animal experiment and rigorous clinic studies are needed to confirm the potential preventive and treat effect of these CMs and compounds.

GPR30-mediated estrogenic regulation of actin polymerization and spatial memory involves SRC-1 and PI3K-mTORC2 in the hippocampus of female mice.

AIMS: The G-protein-coupled estrogen receptor GPR30 (also referred to as GPER) has been implicated in the estrogenic regulation of hippocampal plasticity and spatial memory; however, the molecular mechanisms are largely unclear. METHODS: In this study, we initially examined the levels of GPR30 in the hippocampus of postnatal, ovariectomy (OVX)- and letrozole (LET)-treated female mice. Under G1, G15, and/or OVX treatment, the spatial memory, spine density, levels of ERα, ERß, and SRC-1, selected synaptic proteins, mTORC2 signals (Rictor and p-AKT Ser473), and actin polymerization dynamics were subsequently evaluated. Furthermore, G1, G15, and/or E2 combined with SRC-1 and/or PI3K inhibitors, actin cytoskeleton polymerization modulator JPK, and CytoD treatments were used to address the mechanisms that underlie GPR30 regulation in vitro. Finally, mTORC2 activator A-443654 (A4) was used to explore the role of mTORC2 in GPR30 regulation of spatial memory. RESULTS: The results showed that high levels of GPR30 were detected in the adult hippocampus and the levels were downregulated by OVX and LET. OVX induced an impairment of spatial memory, and changes in other parameters previously described were reversed by G1 and mimicked by G15. Furthermore, the E2 effects on SRC-1 and mTORC2 signals, synaptic proteins, and actin polymerization were inhibited by G15, whereas G1 effects on these parameters were inhibited by the blockade of SRC-1 or PI3K; the levels of synaptic proteins were regulated by JPK and CytoD. Importantly, G15-induced actin depolymerization and spatial memory impairment were rescued by mTORC2 activation with A4. CONCLUSIONS: Taking together, these results demonstrated that decreased GPR30 induces actin depolymerization through SRC-1 and PI3K/mTORC2 pathways and ultimately impairs learning and memory, indicating its potential role as a therapeutic target against hippocampus-based, E2-related memory impairments.

Nuclear and membrane estrogen receptor antagonists induce similar mTORC2 activation-reversible changes in synaptic protein expression and actin polymerization in the mouse hippocampus.

AIMS: Estrogens play pivotal roles in hippocampal synaptic plasticity through nuclear receptors (nERs; including ERα and ERß) and the membrane receptor (mER; also called GPR30), but the underlying mechanism and the contributions of nERs and mER remain unclear. Mammalian target of rapamycin complex 2 (mTORC2) is involved in actin cytoskeleton polymerization and long-term memory, but whether mTORC2 is involved in the regulation of hippocampal synaptic plasticity by ERs is unclear. METHODS: We treated animals with nER antagonists (MPP/PHTPP) or the mER antagonist (G15) alone or in combination with A-443654, an activator of mTORC2. Then, we examined the changes in hippocampal SRC-1 expression, mTORC2 signaling (rictor and phospho-AKTSer473), actin polymerization (phospho-cofilin and profilin-1), synaptic protein expression (GluR1, PSD95, spinophilin, and synaptophysin), CA1 spine density, and synapse density. RESULTS: All of the examined parameters except synaptophysin expression were significantly decreased by MPP/PHTPP and G15 treatment. MPP/PHTPP and G15 induced a similar decrease in most parameters except p-cofilin, GluR1, and spinophilin expression. The ER antagonist-induced decreases in these parameters were significantly reversed by mTORC2 activation, except for the change in SRC-1, rictor, and synaptophysin expression. CONCLUSIONS: nERs and mER contribute similarly to the changes in proteins and structures associated with synaptic plasticity, and mTORC2 may be a novel target of hippocampal-dependent dementia such as Alzheimer's disease as proposed by previous studies.

Press-fit cementless acetabular fixation with and without screws.

PURPOSE: Cementless acetabular fixation for total hip arthroplasty (THA) is widely used. The question of using screws for a better primary and secondary acetabular fixation has been discussed in the literature in recent years. The aim of this meta-analysis was to compare fixation of acetabular cups with and without screws in total hip arthroplasty. METHODS: Electronic databases Embase, PubMed and Cochrane Library were used to search for randomised controlled trials reported through May 2013 of cementless acetabular fixation for THA with and without screws. Two independent reviewers assessed the trials for eligibility and quality. All related data matching our standards were abstracted for meta-analysis by RevMan 5.0. Evaluation criteria included revisions, migration and osteolysis. RESULTS: A total of 1,130 THAs enrolled into five trials were included in this meta-analysis. All studies compared fixation of acetabular cups with and without screws, and our pooled data showed no statistical significance between the two surgical methods in revision, migration and osteolysis. CONCLUSION: There is no significant difference between cementless acetabular fixation for THA with and without screws in revisions, migration or osteolysis.