Coulomb blockade and Coulomb staircases in CoBi nanoislands on SrTiO3(001).

We successfully fabricated two-dimensional metallic CoBi nanoislands on SrTiO3(001) substrate by molecular beam epitaxy, and systematically investigated their electronic structures by scanning tunneling microscopy and spectroscopyin situat 4.2 K. Coulomb blockade and Coulomb staircases with discrete and well-separated levels are observed for the individual nanoisland, which is attributed to single-electron tunneling via two tunnel junction barriers. They are in excellent agreement with the simulations based on orthodox theory. Furthermore, we demonstrated that the Coulomb blockade becomes weaker with increasing temperature and almost disappears at ∼22 K in our variable temperature experiment, and its full-width at half-maximum of dI/dVpeaks with temperature is ∼6 mV. Our results provide a new platform for designing single-electron transistors that have potential applications in future microelectronics.

Carrier-Free Binary Self-Assembled Nanomedicines Originated from Traditional Herb Medicine with Multifunction to Accelerate MRSA-Infected Wound Healing by Antibacterial, Anti-Inflammation and Promoting Angiogenesis.

Background: Deaths from bacterial infections have risen year by year. This trend is further aggravated as the overuse antibiotics and the bacterial resistance to all known antibacterial agents. Therefore, new therapeutic alternatives are urgently needed. Methods: Enlightenment the combination usage of traditional herb medicine, one carrier-free binary nanoparticles (GA-BBR NPs) was discovered, which was self-assembled from gallic acid and berberine through electrostatic interaction, π-π stacking and hydrophobic interaction; and it could be successfully prepared by a green, cost-effective and "one-pot" preparation process. Results: The nanoparticles exhibited strong antibacterial activity and biofilm removal ability against multidrug-resistant S. aureus (MRSA) by downregulating mRNA expression of rpsF, rplC, rplN, rplX, rpsC, rpmC and rpsH to block bacterial translation mechanisms in vitro and in vivo, and it had well anti-inflammatory activity and a promising role in promoting angiogenesis to accelerate the wound healing on MRSA-infected wounds model in vivo. Additionally, the nanoparticles displayed well biocompatibility without cytotoxicity, hemolytic activity, and tissue or organ toxicity. Conclusion: GA-BBR NPs originated from the drug combination has potential clinical transformation value, and this study provides a new idea for the design of carrier-free nanomedicine derived from natural herbals.

Design and synthesis of novel anti-multidrug-resistant staphylococcus aureus derivatives of glycyrrhetinic acid by blocking arginine biosynthesis, metabolic and H2S biogenesis.

With the soaring number of multidrug-resistant bacteria, it is imperative to develop novel efficient antibacterial agents and discovery new antibacterial pathways. Herein, we designed and synthesized a series of structurally novel glycyrrhetinic acid (GA) derivatives against multidrug-resistant Staphylococcus aureus (MRSA). The in vitro antibacterial activity of these compounds was evaluated using the microbroth dilution method, agar plate coating experiments and real-time growth curves, respectively. Most of the target derivatives showed moderate antibacterial activity against Staphylococcus aureus (S. aureus) and MRSA (MIC = 3.125-25 µM), but inactivity against Escherichia coli (E. Coli) and Pseudomonas aeruginosa (P. aeruginosa) (MIC > 200 µM). Among them, compound 11 had the strongest antibacterial activity against MRSA, with an MIC value of 3.125 µM, which was 32 times and 64 times than the first-line antibiotics penicillin and norfloxacin, respectively. Additionally, transcriptomic (RNA-seq) and quantitative polymerase chain reaction (qPCR) analysis revealed that the antibacterial mechanism of compound 11 was through blocking the arginine biosynthesis and metabolic and the H2S biogenesis. Importantly, compound 11 was confirmed to have good biocompatibility through the in vitro hemolysis tests, cytotoxicity assays and the in vivo quail chicken chorioallantoic membrane (qCAM) experiments. Current study provided new potential antibacterial candidates from glycyrrhetinic acid derivatives for clinical treatment of MRSA infections.

Integrative multi-omics unravels the amelioration effects of Zanthoxylum bungeanum Maxim. on non-alcoholic fatty liver disease.

BACKGROUND: The effect of Zanthoxylum bungeanum Maxim. (ZBM) on anti-obesity, lipid-lowering and liver protection has been identified, but the effect on the development of NAFLD induced by high-fat diet remains unclear. PURPOSE: To evaluate the alleviation effect of ZBM on NAFLD in vivo and explore the mechanisms by analyzing the liver transcriptome, microbiota and fecal metabolites. METHODS: NAFLD model was induced in C57BL/6J mice by feeding with high-fat diet (HFD). The potential mechanism of ZBM in improving NAFLD was studied by liver transcriptome analysis, real-time PCR, immunofluorescence, 16s rRNA sequencing and non-targeted metabonomics. RESULTS: ZBM has alleviation effects on HFD-induced NAFLD. The liver transcriptome, real-time PCR and immunofluorescence analysis showed that ZBM could efficiently regulate fatty acid and cholesterol metabolism. The 16S rRNA sequencing and LC-MS based metabonomic demonstrated that ZBM could rebalance gut microbiota dysbiosis and regulate metabolic profiles in HFD-induced NAFLD mice. Spearman correlation analysis revealed a strong correlation between gut microbiota and biochemical, pathological indexes and differential metabolic biomarkers. CONCLUSION: ZBM ameliorates HFD-induced NAFLD by regulating fatty acid and cholesterol metabolism, gut microbiota and metabolic profile.

Synthesis and biological evaluation of novel sinomenine derivatives as anti-inflammatory and analgesic agent.

Sinomenine (SIN) has long been known as an anti-inflammatory drug, while poor efficiency and large-dose treatment had limited its further application. A series of novel SIN derivatives 1-26 were designed and synthesized to improve its anti-inflammatory activity. The anti-inflammatory activity evaluation showed most of the derivatives exhibited enhanced anti-inflammatory activity in vitro compared to SIN. Compound 17 significantly inhibited LPS-induced secretion of pro-inflammatory factors NO (IC50 = 30.28 ± 1.70 µM), and suppressed the expression of iNOS, IL-6 and TNF-α in RAW264.7 cells. Moreover, compound 17 showed excellent anti-inflammatory in mouse paw edema. Immunohistochemistry results revealed that compound 17 exerted anti-inflammatory activity by inhibiting the pro-inflammatory cytokine TNF-α. Furthermore, compound 17 exhibited an analgesic effect in vivo. The results attained in this study indicated that compound 17 had the potential to be developed into an anti-inflammation and analgesic agent.

Injectable Carrier-Free Hydrogel Dressing with Anti-Multidrug-Resistant Staphylococcus aureus and Anti-Inflammatory Capabilities for Accelerated Wound Healing.

Antibacterial hydrogels have gradually become a powerful weapon to treat bacterially infected wounds and accelerate healing. In this paper, we designed a small-molecule self-healing antibacterial hydrogel containing 100% drug-loaded benzyl 3ß-amino-11-oxo-olean-12-en-30-oate (GN-Bn), which was governed by π-π stacking, hydrogen bonding, and van der Waals forces. Due to the carrier-free design concept, the problems of interbatch variability during sample preparation and carrier-related toxicity can be effectively avoided. Moreover, the GN-Bn hydrogel exhibited promising antibacterial activities against multidrug-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentration (MIC) of the GN-Bn hydrogel was 1.5625 nmol/mL, which was lower than those against clinical agents such as norfloxacin, penicillin, and tetracycline. This is attributed to its unique antibacterial mechanism that aims at killing bacteria or preventing their growth by regulating arginine biosynthesis and metabolism through both transcriptomic (RNA-seq) analysis and quantitative polymerase chain reaction (qPCR) analysis. In addition, the GN-Bn hydrogel can also inhibit proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) to promote wound healing. Collectively, the GN-Bn hydrogel elicited dual therapeutic effects on an MRSA-infected full-thickness skin wound model through its antibacterial and anti-inflammatory activities, which is attributed to the fact that the GN-Bn hydrogel has multiple advantages including sufficient mechanical stability, biocompatibility, and unique antibacterial mechanisms, making it significantly accelerate MRSA-infected full-thickness skin wound healing as a wound dressing. In a word, the GN-Bn antibacterial hydrogel dressing with an anti-inflammatory and antibacterial bifunctional material holds great potential in clinical application.

Synthesis and biological activity evaluation of podophyllotoxin-linked bile acid derivatives as potential anti-liver cancer agents.

Podophyllotoxin's undifferentiated cytotoxicity and poor selectivity limit its clinical application. To improve above disadvantages, conjugation of bile acids with podophyllotoxin could improve cell line selectivity of liver cancer to achieve clinical translation further. Enlightened by the bile acids' moiety magic characters, thirty podophyllotoxin-linked bile acid derivatives had been designed and synthesized. The cytotoxicity of these compounds in vitro was evaluated on HepG2, HCT-116, A549 and MDCK cell lines. After conjunction with bile acids, most of the derivatives (IC50 = 0.066-0.831 µM) were more potent against above three types of tumor cells than Etoposide (VP-16, IC50 = 4.319-41.080 µM) and exhibited similar antitumor activity compared with doxorubicin (DOX, IC50 = 0.230-0.745 µM). Moreover, structure-activity relationship displayed the length of the linker chain between podophyllotoxin and bile acids affected the cytotoxicity. Especially, compound 23 exhibited strong activity against HepG2 cell lines (IC50 = 0.188 ± 0.01 µM) than MDCK cell lines (IC50 = 4.780 ± 0.50 µM) and its SI (IC50MDCK/IC50HepG2) value of compound 23 was 25.4. Further antitumor mechanism studies showed that compound 23 acted as Topo Ⅱ inhibition and induced cell apoptosis with S cell cycle arrest. In particular, compound 23 showed valid antitumor efficacy at 10 mg/kg by intraperitoneal administration with a tumor inhibition rate of 60.9% in the Hepa1-6 xenograft mice model. The current research displayed that introduction of bile acids contributed to improve selectivity and activity to cell, and compound 23 could be a promising anti-tumor candidate.

Collecting Duct Carcinoma of the Kidney: Analysis of 74 Cases From Multiple Centers.

OBJECTIVE: To comprehensively describe the manifestations, diagnosis, treatment and prognosis of the collecting duct carcinoma (CDC) of the kidney. MATERIALS AND METHODS: We retrospectively collected data from 74 patients with CDC from two centers between January 2001 and December 2020. The clinical characteristics, imaging and pathological features, and diagnostic and treatment methods were analyzed. RESULTS: The mean age of the patients was 61.5 years, and 54.1% were males. The most common symptoms were low back pain, hematuria, and fatigue. Computed tomography was not specific, with 10.8% of the patients diagnosed with urothelial carcinoma and 4.1% with infectious disease. Thirty-two patients had metastasis at presentation, while 17.6% had tumor thrombus in the venous system. Twenty-two patients underwent renal biopsy, and 50% of the patients were diagnosed with CDC. Sixty-one renal surgeries were performed, and the pathological median diameter was 6.5 cm. Eight patients received immune checkpoint inhibitors, and the objective remission rate was 50%. The median follow-up time was 16 months, while the median overall survival was 24.0 months. The univariate and multivariable analysis showed that sarcomatoid differentiation and absence of renal surgery were predictors of mortality. CONCLUSION: CDC is highly aggressive. Patients are commonly diagnosed at an advanced stage. Early surgical treatment can improve prognosis. Though there is still a lack of standard treatment, immune checkpoint inhibitors bring new hope for the treatment of CDC.

Prostate-Specific Membrane Antigen and Esterase Dual Responsive Camptothecin-Oligopeptide Self-Assembled Nanoparticles for Efficient Anticancer Drug Delivery.

BACKGROUND: The clinical utility of camptothecin (CPT) is restricted by poor aqueous solubility, high lipophilicity, active lactone ring instability, and off-targeted toxicities. We report here a prostate-specific membrane antigen (PSMA) and esterase dual responsive self-assembled nanoparticles (CPT-WT-H NPs) for highly efficient CPT delivery and effective cancer therapy. METHODS AND RESULTS: In this study, smart self-assembled nanoparticles CPT-WT-H NPs were elaborately designed and synthesized by combing hydrophobic CPT with hydrophilic PSMA-responsive penta-peptide via a cleavable ester bond. This dual responsive nanoparticle with negatively charged surface first respond to the extracellular PSMA and then to the intracellular esterase, achieving a programmable release of CPT at the tumor site and producing the byproducts of biocompatible glutamic acid and aspartic acid. Our data demonstrated that CPT-WT-H NPs exhibited greatly improved water solubility and stability. Results from MTT and flow cytometry showed CPT-WT-H NPs exhibited significantly higher cytotoxicity as well as apoptosis-inducing activity against PSMA-expressing LNCaP-FGC cells than the non-PSMA-expressing cancer cells, showing excellent cytotoxic selectivity. Moreover, the unique nanostructure provided the efficient transportation of CPT to tumor site, which resulted in the effective inhibition of tumor growth and low systemic toxicity in vivo. CONCLUSION: CPT-WT-H NPs exhibited excellent in vitro PSMA-response ability and in vivo antitumor activity and safety, holding the promise to become a new and potent anticancer drug. The current research presents a promising strategy for efficient drug delivery.

Tumor-Infiltrating CD8+ T Cells Driven by the Immune Checkpoint-Associated Gene IDO1 Are Associated With Cervical Cancer Prognosis.

Tumor-infiltrating immune cells, associated with tumor progression, are promising prognostic biomarkers. However, the relationship between levels of gene expression and that of immune cell infiltration in cervical cancer prognosis is unknown. In this study, three cervical cancer gene expression microarrays (GSE6791, GSE63678 and GSE55940) were obtained from the GEO database. The IDO1 gene was identified by differentially expressed gene screening. The gene expression profiles of TCGA and GTEx databases along with comprehensive bioinformatics analysis identified that the IDO1 gene was upregulated in cervical cancer with significant difference in expression at different N stages. In addition, it was also upregulated in HPV16 positive sample. The pan-cancer analysis identified that IDO1 was highly expressed in most cancers. TIMER analysis revealed that the expression of IDO1 in CESC shows positive correlation with CD8+ T cells, CD4+ T cells, neutrophils, dendritic cells. IDO1 expression showed remarkable positive correlation with all immune cell markers except M1 macrophages. CD8+ T cell infiltration GSEA results showed that IDO1 was mainly associated with tumor immune-related signaling pathways.

Prognostic Models for Patients With Gleason Score 9 Prostate Cancer: A Population-Based Study.

Purpose: Gleason score (GS) system is one of the most widely used histological grading methods for prostate cancer (PCa) all over the world. GS can be obtained by adding the primary Gleason pattern (GP) and secondary GP. Different proportions of GP 4 and GP 5 in prostate specimens can both lead to GS 9. In this study, we explored whether GP 5 + 4 or GP 4 + 5 was associated with different prognoses among patients with GS 9 PCa. Materials and methods: A retrospective population-based study was conducted on 10,124 subjects diagnosed with GS 9 PCa between 2004 and 2009 from the Surveillance, Epidemiology, and End Results program. A 1:1 propensity-score matching (PSM) was performed to balance the baseline characteristics between the GP 4 + 5 and 5 + 4 groups and to compare the prognoses between the two groups. Cox regression analysis and Fine-Gray competing risk regression models were adopted to screen the covariates significantly associated with all-cause mortality (ACM) and cancer-specific mortality (CAM). Results: GP 5 + 4 was associated with higher risks of ACM and CSM before or after PSM than GP 4 + 5. In the original cohort, there were eight independent predictors for ACM, which were age at diagnosis, race, AJCC NM stage, PSA levels, treatments, GP, and marital status, confirmed by the Cox analysis; and nine independent predictors for CSM, which were age at diagnosis, race, AJCC TNM stage, PSA levels, treatments, GP, and marital status, confirmed by the competing-risk model. Conclusion: GP 5 + 4 was associated with a poorer overall survival and cancer-specific survival compared with GP 4 + 5.

Revealing the Toxicity-Enhancing Essence of Glycyrrhiza on Genkwa Flos Based on Ultra-high-performance Liquid Chromatography Coupled With Quadrupole-Orbitrap High-Resolution Mass Spectrometry and Self-Assembled Supramolecular Technology.

Researchers often focus on the mechanisms of synergistic agents, a few explore drug combinations that enhance toxicity, while few have studied the internal mechanism of compatibility enhancement in chemical level. Herein, we present a comprehensive analysis based on ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) and a self-assembled supramolecular strategy, which reveals the toxicity-enhancing essence of glycyrrhizic acid originated in licorice when combined with Genkwa Flos. Through this method, we discovered the toxicity was enhanced through the formation of a supramolecular complex from Genkwa Flos/glycyrrhizic acid. The morphology and size distribution of the self-assembled nanoparticles were characterized by scanning electron microscopy and dynamic light scattering Furthermore, a total of 58 constituents (eight diterpenoids, 35 flavonoids, five phenylpropanoids, four nucleosides, two amino acids, and four other compounds) consisted from the supramolecular complex were identified through accurate-mass measurements in full-scan MS/data-dependent MS/MS mode. Based on the hydrophobic interaction of glycyrrhizic acid with yuanhuacine (one of main ingredients from Genkwa Flos), the supramolecular self-assembly mechanism was revealed with proton nuclear magnetic resonance (1H-NMR) and NOESY 2D NMR. The toxicity of Genkwa Flos and Genkwa Flos/glycyrrhizic acid supramolecular complex were compared through in vitro studies on L-02 cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; and 4',6-diamidino-2-phenylindole (DAPI) staining was performed to further confirm the enhancement inhibition of Genkwa Flos/glycyrrhizic acid supramolecular complex than Genkwa Flos. This study provides fundamental scientific evidence of the formation of a self-assembled phytochemical supramolecular when Genkwa Flos and glycyrrhizic acid are combined, enabling to understand their clinical incompatibility and contraindication.

Self-assembled natural phytochemicals for synergistically antibacterial application from the enlightenment of traditional Chinese medicine combination.

The application of nanotechnology for antimicrobial delivery has capacity to improve antibacterial efficacy. Currently, the usage of various inorganic and organic carriers, such as metal ions, nano-silicon and surfactants, might increase the potential toxicity of nanoparticles and make their clinical transformation more difficult. Herein, a nano-delivery system was constructed by direct self-assembly of antibacterial phytochemicals (berberine and rhein) originated from traditional Chinese medicine Coptis chinensis Franch. and Rheum palmatum L., respectively. Combining X-ray single crystal diffraction, nuclear magnetic resonance and other spectra characterizations, the stacked structure of nanoparticles was profoundly demonstrated. Briefly, rhein acted as the layered backbone and berberine embedded in it. In vitro bacteriostasis experiment showed the minimum bactericidal concentration of nanoparticles was 0.1 µmol/mL, which was lower than that of berberine and rhein. The results of confocal laser scanning microscope, biofilm quantitive assay and scanning electron microscopy indicated that nanoparticles had strong inhibitory effects on Staphylococcus aureus biofilm. More importantly, transmission electron microscopy and mass spectra indicated the further bacteriostatic mechanism of nanoparticles. Meanwhile, the nanoparticles had well biocompatibility and safety. Current study will open up new prospect that the design of self-assemblies between active phytochemicals can be originated from traditional Chinese medicine combination.

Stereotactic radiosurgery for central nervous system hemangioblastoma in von Hippel-Lindau disease: A systematic review and meta-analysis.

Von Hippel-Lindau (VHL) disease is a dominantly inherited disorder marked by multiorgan tumors, such as central nervous system benign hemangioblastomas (CHB). Stereotactic radiosurgery (SRS) has also been used to treat CHB for a long time. The purpose of this meta-analysis is to provide a long-term outcome of SRS for VHL-associated CHB by reviewing published studies. We completed a Pubmed/Embase/SCOPUS/Cochrane Library literature search to get eligible studies published from January 1990 to December 2019 about using SRS to treat VHL-associated CHB. 15 studies met eligibility for qualitative systematic review, of which nine studies were ultimately eligible for quantity meta-analysis of 5-year tumor control rates (TCR), representing 170 subjects with a total of 660 lesions. Gamma Knife was the most published SRS method for VHL-associated CHB. The pooled 5-year TCR across the nine studies was 0.919 (95 %CI: 0.881-0.957). The pooled 5-year TCR for only intracranial lesions across eight studies was 0.917 (95 %CI: 0.876-0.957). Individual patient data were extracted from 9 studies, representing 298 lesions of 70 subjects. Sex, tumor volume, radiosurgery methods, marginal doses, maximum doses, the number of tumors for radiosurgery, age at the time of radiosurgery, tumor locations were not proven to be associated with tumor progression. SRS offered a satisfactory 5-year tumor control of CHB for VHL patients. Despite the paucity of randomized control trials, SRS is recommended to patients with limited surgical alternatives. However, the long-term outcomes and underlying factors associated with tumor progression remain to be investigated.

Design, synthesis, and biological evaluation of ligustrazine - betulin amino-acid/dipeptide derivatives as anti-tumor agents.

The ligustrazine - betulin derivative (TB), TB amino acids derivatives (TB-01 - TB-09) and TB dipeptide derivatives (TB-10 - TB-18) were designed and synthesized. And their in vitro cytotoxic activities were evaluated against four cancer cell lines (Hela, HepG2, BGC-823 and HT-29) and normal cells MDCK by standard methylthiazol tetrazolium (MTT) assay. Most of them demonstrated better antitumor activity than the relevant material betulin. Among them, compound TB-01 showed the best anti-tumor effect on the cancer cells and the lowest toxicity on the normal cells. For example, the cytotoxicity of TB-01 against the cancer cells (mean IC50 = 4.86 ±â€¯1.16 µM) was 3-fold higher than that against the normal cells MDCK (IC50 = 16.11 ±â€¯2.29 µM). Moreover, TB-01 showed better cytotoxic than positive drug cisplatin (DDP) on tumor cells. Besides, the Zebrafish toxicity evaluation test showed that TB-01 demonstrated high biosafety. Subsequently, fluorescent staining, apoptosis detection and cell cycle analysis indicated that TB-01 induced early apoptosis in HepG2 cells and blocked the cell cycle in the G1 phase. In addition, the structure-activity relationships of these derivatives were briefly discussed.

Self-Assemblies Based on Traditional Medicine Berberine and Cinnamic Acid for Adhesion-Induced Inhibition Multidrug-Resistant Staphylococcus aureus.

S. aureus is resistant to various first-line antibiotics, and seeking multifarious strategies aimed at effective control of antibiotic-resistant behavior is urgently needed. Here, we report a two-component directed self-assembly mode: the phytochemicals berberine and cinnamic acid can directly self-assemble into nanoparticles (NPs) displaying good bacteriostastic activity. Compared with several first-line antibiotics, the obtained nanostructures have a better inhibitory effect on multidrug-resistant S. aureus (MRSA) and stronger ability for biofilm removal. These qualities are attributed to the fact that organic assemblies can first spontaneously adhere to the surface of the bacteria, infiltrate into the cell, and then lead to converging attack against MRSA; thereafter, multipath bactericidal mechanisms of NPs on MRSA are found by both transcriptomic analysis and quantitative Polymerase Chain Reaction analysis. Moreover, when combined with spectral data and single crystal X-ray diffraction, the NPs' self-assembly mechanism governed by hydrogen bonds and π-π stacking interactions is clearly elucidated. These non-covalent interactions induce the NPs' formation of butterfly-like one-dimensional self-assembled units and finally layered three-dimensional spatial configuration. In addition, biocompatibility tests show that the NPs are nonhemolytic with little toxicity in vitro and in vivo. This directed self-assembly mode can offer a new perspective toward the design of biocompatible antimicrobial nanomedicines for clinical translation.

Design, Synthesis and Biological Evaluation of Diosgenin-Amino Acid Derivatives with Dual Functions of Neuroprotection and Angiogenesis.

Diosgenin, a natural product with steroidal structure, has a wide range of clinical applications in China. It also shows great potential in the treatment of blood clots and nerve damage. To enhance the bioavailability as well as efficacy of diosgenin, eighteen diosgenin-amino acid derivatives were designed and synthesized. The neuroprotective effects of these compounds were evaluated by SH-SY5Y cell line and the biosafety was evaluated by H9c2 cell line. The results displayed that part of the derivatives' activities (EC50 < 20 µM) were higher than positive control edaravone (EC50 = 21.60 ± 3.04 µM), among which, DG-15 (EC50 = 6.86 ± 0.69 µM) exhibited the best neuroprotection. Meanwhile, biosafety evaluation showed that DG-15 had no cytotoxicity on H9c2 cell lines. Interestingly, combined neuroprotective and cytotoxic results, part of the derivatives without their protecting group were superior to compounds with protecting group. Subsequently, Giemsa staining and DAPI (4',6-diamidino-2-phenylindole) staining indicated that DG-15 had a protective effect on damaged SH-SY5Y cells by reducing apoptosis. Moreover, DG-15 showed a higher role in promoting angiogenesis at high concentrations (4 mg/mL) on the chorioallantoic membrane model. This finding displayed that DG-15 had dual functions of neuroprotection and angiogenesis, which provided further insight into designing agent for the application in treatment of ischemic stroke.

The Efficacy and Safety of Tyrosine Kinase Inhibitors for Von Hippel-Lindau Disease: A Retrospective Study of 32 Patients.

Background: Von Hippel-Lindau (VHL) disease is an autosomal-dominant hereditary cancer syndrome. Currently, studies on tyrosine kinase inhibitor (TKI) therapy for VHL disease are scarce. In this study, we retrospectively evaluated the efficacy and safety of four TKIs in patients with VHL disease. Methods: Patients diagnosed with VHL disease who were receiving TKIs were recruited. Patients were treated with sunitinib (n = 12), sorafenib (n = 11), axitinib (n = 6), or pazopanib (n = 3). The therapeutic response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: From July 2009 to September 2018, 32 patients with VHL disease were eligible and included in this study. The median duration of TKI therapy was 22 months (IQR 8.5-44.75), and the median follow-up period was 31.5 months (IQR 13.5-63.5). According to the RECIST, 9 (28%) of 32 patients showed a partial response, 15 (47%) achieved stable disease, and eight exhibited continued disease progression. A partial response was observed in 11 (31%) of 36 renal cell carcinomas, 4 (27%) of 15 pancreatic lesions, and 1 (20%) of five central nervous system (CNS) hemangioblastomas. The average tumor size decreased significantly for renal cell carcinomas (P = 0.0001), renal cysts (P = 0.027), and pancreatic lesions (P = 0.003) after TKI therapy. Common side effects included hand-foot skin reactions, diarrhea, alopecia, thrombocytopenia, and fatigue. Conclusions: Partial alleviation of VHL disease-related tumors can be achieved by TKI therapies in some patients, providing an alternative treatment strategy, and the side effects of TKIs are acceptable. Larger prospective studies are warranted to further evaluate the efficacy and safety of TKIs in patients with VHL disease.

Synthesis of Novel Baicalein Amino Acid Derivatives and Biological Evaluation as Neuroprotective Agents.

Baicalein, a famously effective component of the traditional Chinese medicine Rhizoma Huang Qin (Scutellaria altissima L.), has been proved to have potent neuroprotection and anti-platelet aggregation effects with few side effects. Meanwhile, recent studies have revealed that the introduction of amino acid to baicalein could improve its neuroprotective activity. In the present study, a series of novel baicalein amino acid derivatives were designed, synthesized, and screened for their neuroprotective effect against tert-butyl, hydroperoxide-induced, SH-SY5Y neurotoxicity cells and toxicity on the normal H9C2 cell line by standard methylthiazol tetrazolium (MTT) assay. In addition, all of the newly synthesized compounds were characterized by 1H-NMR, 13C-NMR, and high resolution mass spectrometry (HR-MS). The results showed that most of the compounds provided more potent neuroprotection than baicalein, and were equivalent to the positive drug edaravin. They showed no obvious cytotoxicity on normal H9C2 cells. Notably, the most active compound 8 displayed the highest protective effect (50% effective concentration (EC50) = 4.31 µM) against tert-butyl, hydroperoxide-induced, SH-SY5Y neurotoxicity cells, which was much better than the baicalein (EC50 = 24.77 µM) and edaravin (EC50 = 5.62 µM). Further research on the chick chorioallantoic membrane (CAM) model indicated that compound 8 could significantly increase angiogenesis, which might promote neurovascular proliferation. The detection of apoptosis analysis showed that compound 8 could dramatically alleviate morphological manifestations of cell damage. Moreover, the benzyloxycarbonyl (cbz)-protected baicalein amino acid derivatives showed better neuroprotective activity than the t-Butyloxy carbonyl (boc)-protected derivatives.

Design, synthesis and biological evaluation of cinnamic acid derivatives with synergetic neuroprotection and angiogenesis effect.

As for complex brain diseases involved with multiple pathogenic factors, it is extremely difficult to achieve curative effect by acting on a single target. Multi-approach drugs provide a promising prospect in the treatment of complex brain diseases and have been attracting more and more interest. Enlightened by synergetic effect of combination in traditional herb medicines, forty-two novel cinnamic acid derivatives were designed and synthesized by introducing capsaicin and/or ligustrazine moieties to enhance biological activities in both neurological function and neurovascular protection. Elevated levels of cell viability on human brain microvascular endothelium cell line (HBMEC-2) and human neuroblastoma cell line (SH-SY5Y) against free radical injury were observed in most of compounds. Among them, compound 14a exhibited the most potent activities with a significant EC50 value of 3.26 ±â€¯0.16 µM (HBMEC-2) and 2.41 ±â€¯0.10 µM (SH-SY5Y). Subsequently, the results of morphological staining and flow cytometry analysis experiments on both cell lines showed that 14a had the potential to block apoptosis, maintain cell morphological integrity and protect physiological function of mitochondria. Moreover, 14a displayed specific angiogenesis effect in the chick chorioallantoic membrane (CAM) assay; and the results of RT-PCR suggested that the mechanism for angiogenesis effect was associated with the enhancement of the expressions of VEGFR2 mRNA in chick embryo. Preliminary structure-activity relationship was analyzed. The above evidences suggested that conjunctures gained by combining active ingredients in traditional herb medicines deserved further study and might provide references in discovering dual-effective lead compounds for brain diseases.