Structure-based design and synthesis of anti-fibrotic compounds derived from para-positioned 3,4,5-trisubstituted benzene.

Liver fibrosis is an abnormal wound-healing response to liver injuries. It can lead to liver cirrhosis, and even liver cancer and liver failure. There is a lack of treatment for liver fibrosis and it is of great importance to develop anti-fibrotic drugs. A pivotal event in the process of developing liver fibrosis is the activation of hepatic stellate cells (HSCs), in which the nuclear receptor Nur77 plays a crucial role. This study aimed to develop novel anti-fibrotic agents with Nur77 as the drug target by modifying the structure of THPN, a Nur77-binding and anti-melanoma compound. Specifically, a series of para-positioned 3,4,5-trisubstituted benzene ring compounds with long-chain backbone were generated and tested for anti-fibrotic activity. Among these compounds, compound A8 was with the most potent and Nur77-dependent inhibitory activity against TGF-ß1-induced activation of HSCs. In a crystal structure analysis, compound A8 bound Nur77 in a peg-in-hole mode as THPN did but adopted a different conformation that could interfere the Nur77 interaction with AKT, which was previous shown to be important for an anti-fibrotic activity. In a cell-based assay, compound A8 indeed impeded the interaction between Nur77 and AKT leading to the stabilization of Nur77 without the activation of AKT. In a mouse model, compound A8 effectively suppressed the activation of AKT signaling pathway and up-regulated the cellular level of Nur77 to attenuate the HSCs activation and ameliorate liver fibrosis with no significant toxic side effects. Collectively, this work demonstrated that Nur77-targeting compound A8 is a promising anti-fibrotic drug candidate.

Overexpression of phosphatidylethanolamine-binding protein 4 (PEBP4) associates with recurrence of meningiomas.

BACKGROUND AND PURPOSE: Abnormal expression of phosphatidylethanolamine-binding protein 4 (PEBP4) has been identified in various types of malignant tumors. In the present study, we investigated the expression of PEBP4 in meningioma cases and examined whether PEBP4 expression was correlated with outcomes among these patients. MATERIALS AND METHODS: The expression levels of PEBP4 and Ki-67 in human meningioma tissues from 65 patients were evaluated by immunohistochemical staining. The correlation between PEBP4 immunoreactivity in meningioma samples and patients' clinical outcomes was examined using the Kruskal-Wallis correlation test. The prognostic value of PEBP4 expression in meningiomas patients also was investigated. RESULTS: Immunohistochemical analysis revealed up-regulated PEBP4 expression in both atypical and anaplastic meningiomas compared with classical meningiomas (13.38 ± 4.19% vs. 3.64 ± 2.04%, P < 0.001). PEBP4 immunoreactivity in meningioma samples was closely correlated with that for Ki-67 (Spearman r = 0.7922, P < 0.0001). PEBP4 expression was also associated with tumor differentiation grade and clinical recurrence (P < 0.05). Multivariate regression analysis showed with high PEBP4 expression was associated with a longer recurrence-free survival (hazard ratio=0.252, 95% confidence interval: 0.067-0.940, P = 0.040). CONCLUSION: PEBP4 may play an important role in the progression of meningioma, as high PEBP4 expression was associated with a higher pathological grade of meningioma. Moreover, PEBP4 expression may be a meaningful prognostic biomarker in meningioma.

Clinical efficacy and mechanism of mesenchymal stromal cells in treatment of COVID-19.

Coronavirus disease 2019 (COVID-19) is a highly infectious epidemic disease that has seriously affected human health worldwide. To date, however, there is still no definitive drug for the treatment of COVID-19. Cell-based therapies could represent a new breakthrough. Over the past several decades, mesenchymal stromal cells (MSCs) have proven to be ideal candidates for the treatment of many viral infectious diseases due to their immunomodulatory and tissue repair or regeneration promoting properties, and several relevant clinical trials for the treatment of COVID-19 have been registered internationally. Herein, we systematically summarize the clinical efficacy of MSCs in the treatment of COVID-19 based on published results, including mortality, time to symptom improvement, computed tomography (CT) imaging, cytokines, and safety, while elaborating on the possible mechanisms underpinning the effects of MSCs, to provide a reference for subsequent studies.

Knockdown of PEBP4 inhibits human glioma cell growth and invasive potential via ERK1/2 signaling pathway.

Phosphatidylethanolamine (PE)-binding protein 4 (PEBP4) is an antiapoptotic protein that is aberrantly expressed in various malignancies. We previously demonstrated that PEBP4 expression is dramatically induced in human gliomas and positively correlated with tumor grade and patient survival. However, the function of PEBP4 in human glioma development and underlying mechanisms remain largely unknown. By stable lentiviral vector-mediated silencing of PEBP4, we examined the effects of PEBP4 knockdown on the growth, apoptosis, and invasion of U251 and U373 human glioma cell lines using MTT, Transwell, colony formation, and flow cytometric assays. We examined the in vivo role of PEBP4 in tumor growth by inoculation of BALB/c nu/nu male mice with PEBP4-deficient U251 and U373 cells. The expression of cell cycle- and apoptosis-related proteins was analyzed by Western blotting and immunostaining. Knockdown of PEBP4 significantly reduced the proliferation and invasion of human glioma cells while inducing cell apoptosis by altering the expression of cell cycle- and apoptosis-related proteins. Mechanistically, PEBP4 knockdown led to activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway, an effect that could be reversed by U0126, a selective inhibitor of MEK1/2 (upstream of ERK1/2), suggesting involvement of ERK1/2 signaling in the regulation of glioma development and progression by PEBP4. We identified PEBP4 as a novel regulator mediating human glioma cell proliferation, invasion, and apoptosis as well as tumor formation and growth. Therefore, PEBP4 may be a potential therapeutic target in human glioma treatment.

Structure-based optimization of salt-bridge network across the complex interface of PTPN4 PDZ domain with its peptide ligands in neuroglioma.

The PTP non-receptor type 4 (PTPN4) is an important regulator protein in learning, spatial memory and cerebellar synaptic plasticity; targeting the PDZ domain of PTPN4 has become as attractive therapeutic strategy for human neuroglioma. Here, we systematically examined the complex crystal structures of PTPN4 PDZ domain with its known peptide ligands; a number of charged amino acid residues were identified in these ligands and in the peptide-binding pocket of PDZ domain, which can constitute a complicated salt-bridge network across the complex interface. Molecular dynamics (MD) simulations, binding free energy calculations and continuum model analysis revealed that the electrostatic effect plays a predominant role in domain-peptide binding, while other noncovalent interactions such as hydrogen bonds and hydrophobic forces are also responsible for the binding. The computational findings were then used to guide structure-based optimization of the interfacial salt-bridge network. Consequently, five peptides were rationally designed using the high-affinity binder Cyto8-RETEV (RETEV-COOH) as template, including four single-point mutants (i.e. Cyto8-mtxe0: RETEE-COOH, Cyto8-mtxd-1: RETDV-COOH, Cyto8-mtxd-3: RDTEV-COOH and Cyto8-mtxk-4: KETEV-COOH) and one double-point mutant (i.e. Cyto8-mtxd-1k-4: KETDV-COOH). Binding assays confirmed that three (Cyto8-mtxd-1, Cyto8-mtxk-4 and Cyto8-mtxd-1k-4) out of the five designed peptides exhibit moderately or considerably increased affinity as compared to the native peptide Cyto8-RETEV.

Highly water-soluble platinum(II) complexes as GLUT substrates for targeted therapy: improved anticancer efficacy and transporter-mediated cytotoxic properties.

Glucose-conjugated malonato-platinum(II) complexes are designed and synthesized to target tumor-specific active transporters, namely, glucose transporters (GLUTs); the complexes exhibit much higher aqueous solubility by 150 times, improved potency in cytotoxicities by 10 times, and increased therapeutic index by over 30 fold compared to the newest generation of clinical drugs oxaliplatin.

Synthesis, characterization and in vitro anti-tumor activities of matrine derivatives.

Nineteen previously unreported matrine derivatives were synthesized and characterized using elemental analysis, infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and mass spectrometry. Target compounds 6a-6l and 7a-7c showed stronger inhibitory activities than matrine in the in vitro antitumor tests and inhibited the growth of the Hep7402, B16-F10, A549, and TW03 cell lines. In addition, compound 6i exhibited a potent antitumor activity similar to that of colchicine.

3D-pharmacophore models for selective A2A and A2B adenosine receptor antagonists.

Three-dimensional pharmacophore models were generated for A2A and A2B adenosine receptors (ARs) based on highly selective A2A and A2B antagonists using the Catalyst program. The best pharmacophore model for selective A2A antagonists (Hypo-A2A) was obtained through a careful validation process. Four features contained in Hypo-A2A (one ring aromatic feature (R), one positively ionizable feature (P), one hydrogen bond acceptor lipid feature (L), and one hydrophobic feature (H)) seem to be essential for antagonists in terms of binding activity and A2A AR selectivity. The best pharmacophore model for selective A2B antagonists (Hypo-A2B) was elaborated by modifying the Catalyst common features (HipHop) hypotheses generated from the selective A2B antagonists training set. Hypo-A2B also consists of four features: one ring aromatic feature (R), one hydrophobic aliphatic feature (Z), and two hydrogen bond acceptor lipid features (L). All features play an important role in A2B AR binding affinity and are essential for A2B selectivity. Both A2A and A2B pharmacophore models have been validated toward a wide set of test molecules containing structurally diverse selective antagonists of all AR subtypes. They are capable of identifying correspondingly high potent antagonists and differentiating antagonists between subtypes. The results of our study will act as a valuable tool for retrieving structurally diverse compounds with desired biological activities and designing novel selective adenosine receptor ligands.

[Effect of photodynamic therapy combined with interstitial chemotherapy for gliomas].

OBJECTIVE: To investigate the therapeutic effect of photodynamic therapy (PDT) combined with interstitial chemo- therapy on gliomas after microsurgery. METHODS: Twenty-eight patients with glioma received microsurgery for glioma resection as much as possible, during which PDT was carried out and an Ommaya bursa implanted into the cavity left by the resected tumor. PDT was performed again 24 h after the operation and carmustine injected into the Ommaya bursa for interstitial chemotherapy at the different time after the operation. The follow-up study lasted for 2 years. RESULTS: Two of the 28 patients had relapse of glioma within 1 year after the operation, with the 1-year survival rate of 89.3% (25/28) and 2-year survival rate of 65.7% (17/28). CONCLUSIONS: PDT combined with interstitial chemotherapy following microsurgery provides a safe and effective treatment of glioma, which can inhibit glioma growth, decrease the recurrence rate, prolong the patients' survival and improve their quality of live.