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BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is deemed as an emerging global epidemic, whereas the underlying pathogenic mechanism remains to be clarified. We aimed to systemically analyze all the NAFLD-related gene expression datasets from published human-based studies, by which exploring potential key factors and mechanisms accounting for the pathogenesis of NAFLD. APPROACH & RESULTS: By using Robust rank aggregation method to integrate all public datasets of human NAFLD transcriptome, the present study identified IGFBP2 (Insulin-like growth factor binding protein 2) being the most significantly down-regulated gene in all NAFLD subjects. The decreased IGFBP2 expression was further confirmed in the liver tissues from patients and animal models of NAFLD. IGFBP2 deficiency aggravated hepatic steatosis and NASH phenotypes and promoted lipogenic gene expression both in vivo and in vitro. Mechanistically, IGFBP2 directly binds to and regulates EGFR, whereas blockage of the IGFBP2-EGFR complex by knockdown of IGFBP2 resulted in the EGFR-STAT3 pathway activation, which in turn promoted the promoter activity of Srebf1. By using molecular docking simulation and protein-protein interaction analysis, the sequence of 233-257 amino acids in IGFBP2 was characterized as a key motif responding for its specific binding to EGFR and the protective effect against hepatic steatosis. CONCLUSIONS: The current study has, for the first time, identified IGFBP2 as a novel protector against hepatosteatosis. The protective effect is mediated by its specific interaction with EGFR and thereby suppressing the EGFR-STAT3 pathway. Therefore, pharmaceutically targeting the IGFBP2-EGFR-STAT3 axis may provide a theoretical basis for for the treatment of NAFLD/NASH and the associated diseases.

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Coronavirus disease 2019 (COVID-19), resulting from infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause severe and fatal pneumonia along with other life-threatening complications. The COVID-19 pandemic has taken a heavy toll on the healthcare system globally and has hit the economy hard in all affected countries. As a result, there is an unmet medical need for both the prevention and treatment of COVID-19 infection. Several herbal remedies have claimed to show promising clinical results, but the mechanisms of action are not clear. We set out to identify the anti-viral natural products of these herbal remedies that presumably inhibit the life cycle of SARS-CoV-2. Particularly we chose four key SARS-CoV-2 viral enzymes as targets: Papain-like protease, Main protease, RNA dependent RNA polymerase, and 2'-O-ribose methyltransferase, which were subjected to an unbiased in silico screening against a small molecule library of 33,765 compounds originating from herbs and medicinal plants. The small molecules were then ranked based on their free energy of fitting into the "druggable" pockets on the surface of each target protein. We have analyzed the best "fit" molecules and annotated them according to their plant sources and pharmacokinetic properties. Here we present a list of potential anti-viral ingredients of herbal remedies targeting SARS-CoV-2 and explore the potential mechanisms of action of these compounds as a framework for further development of chemoprophylaxis agents against COVID-19.

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Alpha-momorcharin (α-MMC), trichosanthin (TCS), and momordica anti-HIV protein of 30 kD (MAP30) are potential anti-tumor drug candidates but have cytotoxicity to normal cells. The binding of these proteins to LRP1 receptor and the subsequent endocytosis are essential to their cytotoxicity, but this binding process remains largely unknown. This study, in-silico analysis of the binding patterns, was conducted via the protein-protein docking software, ZDOCK 3.0.2 package, to better understand the binding process. Specifically, α-MMC, TCS and MAP30 were selected and bound to binding subunits CR56 and CR17 of LRP1. After docking, the 10 best docking solutions are retained based on the default ZDOCK scores and used for structural assessment. Our results showed that, α-MMC bound to LRP1 stably at the amino acid residues 1-20, at which 8 residues formed 21 hydrogen bonds with 15 residues of CR56 and 10 residues formed 15 hydrogen bonds with 12 residues of CR17. In contrast, TCS and MAP30 bound mainly to LRP1 at the residues 1-57/79-150 and residues 58-102, respectively, which were functional domains of TCS and MAP30. Since residues 1-20 are outside the functional domain of α-MMC, α-MMC is considered more suitable to attenuate by mutating the receptor binding site. Thus, our analysis lays the foundation for future genetic engineering work on α-MMC, and makes important contributions to its potential clinical use in cancer treatment.

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In recent years, hypersensitivity reactions to the Shuanghuanglian injection have attracted broad attention. However, the componential chief culprits inducing the reactions and the underlying mechanisms involved have not been completely defined. In this study, we used a combination of approaches based on the mouse model, human umbilical vein endothelial cell monolayer, real-time cellular monitoring, immunoblot analysis, pharmacological inhibition, and molecular docking. We demonstrated that forsythoside A and forsythoside B contributed to Shuanghuanglian injection-induced pseudoallergic reactions through activation of the RhoA/ROCK signaling pathway. Forsythoside A and forsythoside B could trigger dose-dependent vascular leakage in mice. Moreover, forsythoside A and forsythoside B slightly elicited mast cell degranulation. Correspondingly, treatment with forsythoside A and forsythoside B disrupted the endothelial barrier and augmented the expression of GTP-RhoA, p-MYPT1, and p-MLC2 in a concentration-dependent manner. Additionally, the ROCK inhibitor effectively alleviated forsythoside A/forsythoside B-induced hyperpermeability in both the endothelial cells and mice. Similar responses were not observed in the forsythoside E-treated animals and cells. These differences may be related to the potential of the tested compounds to react with RhoA-GTPγS and form stable interactions. This study innovatively revealed that some forsythosides may cause vascular leakage, and therefore, limiting their contents in injections should be considered.

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The binding affinity of a series of benzhydrylpiperazine δ opioid receptor agonists were pooled and evaluated by using 3D-QSAR and homology modeling/molecular docking methods. Ligand-based CoMFA and CoMSIA 3D-QSAR analyses with 46 compounds were performed on benzhydrylpiperazine analogues by taking the most active compound BW373U86 as the template. The models were generated successfully with q2 value of 0.508 and r2 value of 0.964 for CoMFA, and q2 value of 0.530 and r2 value of 0.927 for CoMSIA. The predictive capabilities of the two models were validated on the test set with R2pred value of 0.720 and 0.814, respectively. The CoMSIA model appeared to work better in this case. A homology model of active form of δ opioid receptor was established by Swiss-Model using a reported crystal structure of active µ opioid receptor as a template, and was further optimized using nanosecond scale molecular dynamics simulation. The most active compound BW373U86 was docked to the active site of δ opioid receptor and the lowest energy binding pose was then used to identify binding residues such as s Gln105, Lys108, Leu125, Asp128, Tyr129, Leu200, Met132, Met199, Lys214, Trp274, Ile277, Ile304 and Tyr308. The docking and 3D-QSAR results showed that hydrogen bond and hydrophobic interactions played major roles in ligand-receptor interactions. Our results highlight that an approach combining structure-based homology modeling/molecular docking and ligand-based 3D-QSAR methods could be useful in designing of new opioid receptor agonists.

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Opioid analgesics remain the first choice for the treatment of moderate to severe pain, but they are also notorious for their respiratory depression and addictive effects. This study focused on the pharmacology of a novel opioid receptor mixed agonist DPI-125 and attempted to elucidate the relationship between the δ-, µ- and κ-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds (DPI-125, DPI-3290, DPI-130, KUST202 and KUST13T02) were selected for this study. PKA fluorescence redistribution assays in CHO cells individually expressing δ-, µ- or κ-receptors were used to measure the agonist potency. The respiratory safety profiles were estimated in rats by the ratio of ED50 (pCO2 increase)/ED50 (antinociception). The abuse liability of DPI-125 was evaluated with a self-administration model in rhesus monkeys. The observed agonist potencies of DPI-125 for δ-, µ- and κ-opioid receptors were 4.29±0.36, 11.10±3.04, and 16.57±4.14 nmol/L, respectively. The other four compounds were also mixed agonists with varying potencies. DPI-125 exhibited a high respiratory safety profile, clearly related to its high δ-receptor potency. The ratio of the EC50 potencies for the µ- and δ-receptors was found to be positively correlated with the respiratory safety ratio. DPI-125 has similar potencies for µ- and κ-receptors, which is likely the reason for its reduced abuse potential. Our results demonstrate that the opioid receptor mixed agonist DPI-125 is safer and less addictive than traditional µ-agonist analgesics. These findings suggest that the development of δ>µâˆ¼κ opioid receptor mixed agonists is feasible, and such compounds could represent a promising class of potent analgesics with wider therapeutic windows.

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The objective of this study was to investigate cognitive dysfunction in 24-60-year-old neuromyelitis optica (NMO) patients, demographically matched healthy subjects, and MS patients. We conducted a comprehensive literature review of the PubMed, Medline, EMBASE, CNKI, Wan Fang Date, Web of Science, and Cochrane Library databases from inception to May 2016 for case-control studies that reported cognitive test scores in NMO patients, healthy subjects, and MS patients. Outcome measures were cognitive function evaluations, including performance on attention, language, memory, information processing speed, and executive function tests. The meta-analysis included eight studies. NMO patients performed significantly worse on attention (P < 0.00001), language (P = 0.00008), memory (P = 0.00004), information processing speed (P < 0.00001), and executive function tests (P = 0.00009) than healthy subjects. There were no significant differences in performance between NMO patients and MS patients on these tests. This meta-analysis indicates that NMO patients aged 24-60 years have significantly worse cognitive performance than demographically matched healthy subjects. However, this was comparable to the performance of demographically matched MS patients. There is a need for further rigorous randomized controlled trials with focus on elucidating the underlying mechanism of cognitive dysfunction in NMO patients.

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Four novel diimine rhenium(I) carbonyl complexes with the formula [Re(CO)3(L)Br], where L = 2-(4-(9H-carbazol-9-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (P1), 2-(4-(3,6-di-tert-butyl-9H-carbazol-9-yl)phenyl)-1H-imidazo-[4,5-f][1,10]phenanthroline (P2), 2-(4-(6-(9H-carbazol-9-yl)-9H-3,9-bicarbazol-9-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (D1), and 2-(4-(3',6'-di-tert-butyl-6-(3,6-di-tert-butyl-9H-carbazol-9-yl)-9H-3,9-bicarbazol-9-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (D2), have been successfully synthesized and fully characterized by 1H NMR, IR, and UV-Vis, etc. The luminescence quantum yields (LQYs) of the parent Re(I) complexes P1 and P2 are 0.13 and 0.16, respectively, which are much higher than the previously reported Re(I) dendrimers. The HOMOs and the LUMOs of P1 and P2 are calculated to be mainly composed of [d(Re) + pi(CO + Br)] and pi*(L) orbital, respectively. However, those of the Re(I) dendrimers D1 (LQY = 0.066) and D2 (LQY = 0.0048) are mainly localized on ligand L, indicating that the component of the metal-to-ligand charge-transfer d pi (Re) --> pi*(N-N) (MLCT) transitions in P1 and P2 should be more than those in D1 and D2. As a result, the higher LQYs of P1 and P2 are tentatively assigned to the disturbance of the MLCT transitions during the photoluminescence process.