Neuroprotective potentials of ferulic acid against intracerebral hemorrhage COVID-19 through using network pharmacology approach and molecular docking analysis.

Intracerebral hemorrhage (ICH) refers to severe stroke subtype that may be life-threatening or even cause death. It is clinically observed that coronavirus disease 2019 (COVID-19) may be associated with the high mortality in ICH patients. Ferulic acid, one of the functional bioactive ingredients from medicinal herbs, has been preclinically proven with beneficial activities, including neuroprotection and anti-inflammation actions. Based on current findings, we assumed that ferulic acid may play the potentials against COVID-19 when ICH. In this study, preclinical approach including network pharmacology and molecular docking was applied to detect and identify the core targets and pharmacological mechanisms involved in ferulic acid on COVID-19 and ICH. The network pharmacology analysis identified total eleven core targets in ferulic acid and COVID-19/ICH. The molecular mechanisms of ferulic acid against COVID-19 and ICH were mostly involved in induction of antiviral activity, modulation of inflammatory reaction. Molecular docking model revealed that ferulic acid might effectively bind to epidermal growth factor receptor (EGFR) protein based on strong binding capability. Current findings reflected the preclinical pharmacological activities of ferulic acid that might use for management of COVID-19 and ICH. Although there are the limitations that are absence of experimental validation, these bioinformatic results underline that ferulic acid may exert simultaneous potentials against COVID-19 and ICH through modulating integrative mechanisms and key biotargets.

Ce6/Mn2+-chelated polydopamine@black-TiO2 nanoprobes for enhanced synergistic phototherapy and magnetic resonance imaging in 4T1 breast cancer.

Black titanium dioxide (TiO2) nanoparticles have attracted great attention due to their application in photothermal therapy (PTT). However, single-mode phototherapy has the risk of recurrence, and the high-dose laser usually imposed to improve the PTT performance can bring a potential threat to security. Here, polydopamine (PDA)-coated black TiO2 (b-P25@PDA) nanoparticles with a core-shell structure were synthesized for enhanced PTT; then, synergistic phototherapy nanoprobes (b-P25@PDA-Ce6 (Mn)) were constructed by coupling chlorin e6 (Ce6) and chelating Mn2+ for simultaneous photodynamic therapy (PDT)/PTT and magnetic resonance (MR) imaging, in which a low-dose laser was used and imaging-guided phototherapy with high efficiency and high safety was achieved. The prepared nanoprobes showed high photothermal conversion efficiency (32.12%), high reactive oxygen generation and excellent MR imaging. In the 4T1 tumor-bearing nude mouse model, the tumors completely disappeared under the combination of PDT/PTT with a low-dose laser but were only partially inhibited by single PDT and single PTT. The current work developed a multifunctional black TiO2-based nanoprobe for enhanced synergistic PDT/PTT and MR imaging, which will be important for the safe and efficient visualized theranostics of cancers.

Icariin suppresses cell cycle transition and cell migration in ovarian cancer cells.

Ovarian cancer is the third most common type of gynecological tumor, in addition to being the most lethal. Cytoreductive surgery with chemotherapy is the standard treatment for ovarian cancer. It is necessary to identify novel chemotherapeutic methods, since current chemotherapy treatments are rarely effective for patients with advanced­stage or recurrent ovarian cancer and may cause acute systemic toxicity. Icariin (ICA) is a prenylated flavonol glycoside derived from Herba Epimedii, a medicinal plant with a variety of pharmacological activities, including anticancer, antidiabetic and anti­obesity effects. By analyzing cell viability, cell cycle and cell migration, the present study demonstrated that ICA inhibited the cell viability of the ovarian cancer cell line, SKOV3, and blocked cell cycle transition. ICA inhibited the expression of fuse binding protein 1 (FBP1), a critical regulator of proliferation and tumorigenesis through binding to the c­Myc promoter, as well as ß­catenin, a key regulator in ovarian cancer initiation, metastasis, chemoresistance and recurrence. Furthermore, it was indicated that ICA inhibited the migration of SKOV3 cells. In accordance with our previous findings on high FBP1 expression in ovarian cancer, FBP1 was a potential target of ICA in ovarian cancer cells. Based on these results, the present study demonstrated that ICA may be a potential therapeutic agent for ovarian cancer treatment.

ZD2-Engineered Gold Nanostar@Metal-Organic Framework Nanoprobes for T1 -Weighted Magnetic Resonance Imaging and Photothermal Therapy Specifically Toward Triple-Negative Breast Cancer.

Compared with other subtypes of breast cancer, triple-negative breast cancer (TNBC) is seriously threatening to human life. Therefore, it is a matter of urgency to develop multifunctional nanoprobes for visualized theranostics of TNBC, achieving specific targeting toward only TNBC, but not other subtypes. Nanoscale metal-organic frameworks (MOFs) show important potential in visualized theranostics of tumors, but it is critical to synthesize well-defined core-shell MOF-based nanocomposites by encapsulating a single nanoparticle within MOF. In this study, a TNBC-targeted peptide (ZD2)-engineered, and a single gold nanostar (AuNS) coated within MIL-101-NH2 (Fe) by coating MOF with four cycles, obtain well-defined core-shell AuNS@MOF-ZD2 nanocomposites, which are expected to achieve T1 -weighted magnetic resonance imaging and photothermal therapy (PTT) specifically targeting toward TNBC. The prepared AuNS@MOF-ZD2 nanocomposites possess good biocompatibility, efficient T1 -weighted magnetic resonance (MR) relaxivity and stable photothermal conversion ability with an efficiency of 40.5%. The in vitro and in vivo characterizations prove their performances of T1 -weighted MR and PTT with a low power density of 808 nm laser, achieving excellent theranostic efficacy in TNBC. Importantly, it is demonstrated that the prepared AuNS@MOF-ZD2 nanoprobes can specifically target TNBC cells (MDA-MB-231), but not other subtypes of breast cancer cells (MDA-MB-435, MDA-MB-468, and MCF-7), indicating their promising application in visualized theranostics of breast cancers with molecular classification.

Black TiO2-based nanoprobes for T1-weighted MRI-guided photothermal therapy in CD133 high expressed pancreatic cancer stem-like cells.

At present, transmembrane glycoprotein CD133 highly expressed pancreatic cancer stem cells (PCSCs), with the features of chemotherapeutic/radiotherapeutic resistance and exclusive tumorigenic potential, are considered as the primary cause of metastasis and recurrence in pancreatic cancer, and therefore are an effective target in the disease treatment. Furthermore, with the launch of precision medicine, multifunctional nanoprobes have been applied as an efficient strategy for the magnetic resonance imaging (MRI)-guided photothermal therapy (PTT) of pancreatic cancer. In this research, with the aim of achieving precise MRI-guided PTT in CD133 highly expressed PCSCs, novel bTiO2-Gd-CD133mAb nanoprobes were designed and successfully prepared by loading Gd-DOTA and CD133 monoclonal antibodies on black TiO2 nanoparticles. It was very interesting to find that the r1 relaxivity value of the nanoprobes was 34.394 mM-1 s-1, about 7.5 times that of commercial Magnevist (4.5624 mM-1 s-1), which indicates that the nanoprobes have good potential as MRI T1 contrast agents with excellent performance. Herein, CD133 highly expressed PANC-1 cells were selected and verified as PCSCs model. In vitro experiments demonstrated that the nanoprobes exhibited active-targeting ability in PANC-1 cells, and consequently could specially enhance T1-weighted MR imaging and 808 nm near-infrared (NIR)-triggered PTT efficiency in the PCSCs model. Our study not only provides a new strategy for the effective treatment of pancreatic cancer and its' stem cells, but also further broadens the application of black TiO2 in the field of cancer theranostics.

Effect of Free Nitrous Acid on Nitrous Oxide Production and Denitrifying Phosphorus Removal by Polyphosphorus-Accumulating Organisms in Wastewater Treatment.

The inhibition of free nitrous acid (FNA) on denitrifying phosphorus removal has been widely reported for enhanced biological phosphorus removal; however, few studies focus on the nitrous oxide (N2O) production involved in this process. In this study, the effects of FNA on N2O production and anoxic phosphorus metabolism were investigated using phosphorus-accumulating organisms (PAOs) culture highly enriched (91 ± 4%) in Candidatus Accumulibacter phosphatis. Results show that the FNA concentration notably inhibited anoxic phosphorus metabolism and phosphorus uptake. Poly-ß-hydroxyalkanoate (PHA) degradation was completely inhibited when the FNA concentration was approximately 0.0923 mgHNO2-N/L. Higher initial FNA concentrations (0.00035 to 0.0103 mgHNO2-N/L) led to more PHA consumption/TN (0.444 to 0.916 mmol-C/(mmol-N·gVSS)). Moreover, it was found that FNA, rather than nitrite and pH, was likely the true inhibitor of N2O production. The highest proportion of N2O to TN was 78.42% at 0.0031 mgHNO2-N/L (equivalent to 42.44 mgNO2-N/L at pH 7.5), due to the simultaneous effects of FNA on the subsequent conversion of NO2 into N2O and then into N2. The traditional nitrite knee point can only indicate the exhaustion of nitrite, instead of the complete removal of TN.

Novel Targeting of Transcription and Metabolism in Glioblastoma.

Purpose: Glioblastoma (GBM) is highly resistant to treatment, largely due to disease heterogeneity and resistance mechanisms. We sought to investigate a promising drug that can inhibit multiple aspects of cancer cell survival mechanisms and become an effective therapeutic for GBM patients.Experimental Design: To investigate TG02, an agent with known penetration of the blood-brain barrier, we examined the effects as single agent and in combination with temozolomide, a commonly used chemotherapy in GBM. We used human GBM cells and a syngeneic mouse orthotopic GBM model, evaluating survival and the pharmacodynamics of TG02. Mechanistic studies included TG02-induced transcriptional regulation, apoptosis, and RNA sequencing in treated GBM cells as well as the investigation of mitochondrial and glycolytic function assays.Results: We demonstrated that TG02 inhibited cell proliferation, induced cell death, and synergized with temozolomide in GBM cells with different genetic background but not in astrocytes. TG02-induced cytotoxicity was blocked by the overexpression of phosphorylated CDK9, suggesting a CDK9-dependent cell killing. TG02 suppressed transcriptional progression of antiapoptotic proteins and induced apoptosis in GBM cells. We further demonstrated that TG02 caused mitochondrial dysfunction and glycolytic suppression and ultimately ATP depletion in GBM. A prolonged survival was observed in GBM mice receiving combined treatment of TG02 and temozolomide. The TG02-induced decrease of CDK9 phosphorylation was confirmed in the brain tumor tissue.Conclusions: TG02 inhibits multiple survival mechanisms and synergistically decreases energy production with temozolomide, representing a promising therapeutic strategy in GBM, currently under investigation in an ongoing clinical trial. Clin Cancer Res; 24(5); 1124-37. ©2017 AACR.

Observation of a bi-critical point between antiferromagnetic and superconducting phases in pressurized single crystal Ca0.73La0.27FeAs2.

One of the most strikingly universal features of the high-temperature superconductors is that the superconducting phase emerges in the close proximity of the antiferromagnetic phase, and the interplay between these two phases poses a long-standing challenge. It is commonly believed that, as the antiferromagnetic transition temperature is continuously suppressed to zero, there appears a quantum critical point, around which the existence of antiferromagnetic fluctuation is responsible for the development of the superconductivity. In contrast to this scenario, we report the observation of a bi-critical point identified at 2.88GPa and 26.02K in the pressurized high-quality single crystal Ca0.73La0.27FeAs2 by complementary in-situ high pressure measurements. At the critical pressure, we find that the antiferromagnetism suddenly disappears and superconductivity simultaneously emerges at almost the same temperature, and that the external magnetic field suppresses the superconducting transition temperature but hardly affects the antiferromagnetic transition temperature.

Three dimensional plasmonic assemblies of AuNPs with an overall size of sub-200 nm for chemo-photothermal synergistic therapy of breast cancer.

Three dimensional plasmonic assemblies of gold nanoparticles (AuNPs) (gold 3D-PAs) have been recently developed for photothermal therapy, Raman imaging, photoacoustic imaging or X-ray computed tomography imaging because they can generate an enhanced electromagnetic field between the gaps of neighboring AuNPs and significantly improve the localized surface plasmon resonance (LSPR) effect in the near-infrared (NIR) region. However, the sizes of most reported gold 3D-PAs are too large (>300 nm) for in vivo applications as cancer theranostic agents because a size of about 200 nm is often considered to be the upper limit for successful drug delivery based on the enhanced permeation and retention (EPR) effect. Herein, we propose a novel strategy to fabricate the gold 3D-PAs with an overall size of sub-200 nm, whose self-assembly process was verified by TEM, DLS and UV-vis spectroscopy. The cell experiments demonstrate that our gold 3D-PAs allow combined chemotherapy and photothermal therapy. The histopathology assessments indicate that the toxicity of our gold 3D-PAs to normal tissues (side effect) is negligible. The animal experiments indicate that our gold 3D-PAs have a weak chemotherapeutic efficacy without NIR laser irradiation at a low DOX dosage, but shows an excellent therapeutic effect with NIR laser irradiation at the same DOX dosage due to the synergy of chemo-photothermal therapy.

Rocaglamide-A Potentiates Osteoblast Differentiation by Inhibiting NF-κB Signaling.

Rheumatoid arthritis is a chronic inflammatory disease that leads to bone and cartilage erosion. The inhibition of osteoblast differentiation by the inflammatory factor TNF-α is critical for the pathogenesis of rheumatoid arthritis. To modulate TNF-α mediated inhibition of osteoblast differentiation is required to improve therapeutic efficacy of rheumatoid arthritis. Here, we explored the potential role of rocaglamide-A, a component of Aglaia plant, in osteoblast differentiation. Rocaglamide-A prevented TNF-α mediated inhibition of osteoblast differentiation, and promoted osteoblast differentiation directly, in both C2C12 and primary mesenchymal stromal cells. Mechanistically, Rocaglamide-A inhibited the phosphorylation of NF-κB component p65 protein and the accumulation of p65 in nucleus, which resulted in the diminished NF-κB responsible transcriptional activity. Oppositely, overexpression of p65 reversed rocaglamide-A's protective effects on osteoblast differentiation. Collectively, rocaglamide-A protected and stimulated osteoblast differentiation via blocking NF-κB pathway. It suggests that rocaglamide-A may be a good candidate to develop as therapeutic drug for rheumatoid arthritis associated bone loss diseases.

[Pharmacokinetic studies of quercetin-hydroxypropyl-beta-cyclodextrin inclusion compound in rats].

To estabilish a HPLC method for determination of quercetin-hydroxypropyl-beta-cyclodextrin in rats plasma and investigate the pharmacokinetics characteristics of it in rats. The plasma was extracted with methanol-aceitc acid (9:1). The mobile phase was acetonitrilewater. Absorbance of the effluence was monitored at 360 nm. The linear limit of quercetin was within the range of 1 to 150 microg/ml. The lowest limit of quercetin was 0.5 microg/ml. The concentration-time curve of quercetin in rats was considered of a two-compartment open model, and the t1/2 (beta) of the inclusion compound when ig is 2.220 h, the t1/2 (beta) of the inclusion compound when iv is 90.871 min.

TCM treatment of infectious atypical pneumonia--a report of 16 cases.

OBJECTIVE: To probe into the mechanism on TCM treatment of infectious atypical pneumonia (severe acute respiratory syndrome, SARS) and evaluate its feasibility and effectiveness. METHOD: Twelve TCM prescriptions of herbal drugs (orally or i.v.) were used to treat 16 cases of SARS without using glucocorticoids, anti-viral agents, immune-regulators or antibiotics (in case there was no definite bacterial infections). The symptoms, signs, chest roentgenograms and lab examinations were carefully monitored and recorded for evaluation of the effectiveness. RESULTS: The average fever abatement time was 4.44 +/- 1.46 days and the mean absorption time of gross pulmonary infiltration was 10.87 +/- 2.92 days. No exacerbation occurred during the treatment. CONCLUSION: TCM intervention could effectively control and alleviate the symptoms and prevent the disease from exacerbation.

Nylon filter arrays reveal differential gene expression in proteoid roots of white lupin in response to phosphorus deficiency.

White lupin (Lupinus albus) adapts to phosphorus deficiency (-P) by the development of short, densely clustered lateral roots called proteoid (or cluster) roots. In an effort to better understand the molecular events mediating these adaptive responses, we have isolated and sequenced 2,102 expressed sequence tags (ESTs) from cDNA libraries prepared with RNA isolated at different stages of proteoid root development. Determination of overlapping regions revealed 322 contigs (redundant copy transcripts) and 1,126 singletons (single-copy transcripts) that compile to a total of 1,448 unique genes (unigenes). Nylon filter arrays with these 2,102 ESTs from proteoid roots were performed to evaluate global aspects of gene expression in response to -P stress. ESTs differentially expressed in P-deficient proteoid roots compared with +P and -P normal roots include genes involved in carbon metabolism, secondary metabolism, P scavenging and remobilization, plant hormone metabolism, and signal transduction.