The novel selective TLR7 agonist GY101 suppresses colon cancer growth by stimulating immune cells.

Toll-like receptor (TLR) 7, a transmembrane signal transduction receptor expressed on the surface of endosomes, has become an attractive target for antiviral and cancer immunotherapies. TLR7 can induce signal transduction by recognizing single-stranded RNA or its analogs, leading to the release of cytokines such as IL-6, IL-12, TNF-α and type-I IFN. Activation of TLR7 helps to enhance immunogenicity and immune memory by stimulating immune cells. Herein, we identified a novel selective TLR7 agonist, GY101, and determined its ability to activate TLR7. In summary, in vitro, compound GY101 significantly induced the secretion of IL-6, IL-12, TNF-α and IFN-γ in mouse splenic lymphocytes; in vivo, peritumoral injection of GY101 significantly suppressed colon cancer CT26, as well as poorly immunogenic B16-F10 and 4T1 cancer cell-derived tumor growth by activating the infiltration of lymphocytes and polarization of M2-like macrophages into M1-like macrophages. These results demonstrate that GY101, as a potent TLR7 agonist, holds great potential for cancer immunotherapy.

Treatment strategies for Parkinson's disease.

Parkinson's disease (PD) is caused by progressive degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in the deficiency of DA in the striatum. Thus, symptoms are developed, such as akinesia, rigidity and tremor. The aetiology of neuronal death in PD still remains unclear. Several possible mechanisms of the degeneration of dopaminergic neurons are still elusive. Various mechanisms of neuronal degeneration in PD have been proposed, including formation of free radicals, oxidative stress, mitochondrial dysfunction, excitotoxicity, calcium cytotoxicity, trophic factor deficiency, inflammatory processes, genetic factors, environmental factors, toxic action of nitric oxide, and apoptosis. All these factors interact with each other, inducing a vicious cycle of toxicity causing neuronal dysfunction, atrophy and finally cell death. Considerable evidence suggests that free radicals and oxidative stress may play key roles in the pathogenesis of PD. However, currently, drug therapy cannot completely cure the disease. DA replacement therapy with levodopa (L-Dopa), although still being a gold standard for symptomatic treatment of PD, only alleviates the clinical symptoms. Furthermore, patients usually experience severe side effects several years after the L-Dopa treatment. Until now, no therapy is available to stop or at least slow down the neurodegeneration in patients. Therefore, efforts are made not only to improve the effect of L-Dopa treatment for PD, but also to investigate new drugs with both antiparkinsonian and neuroprotective effects. Here, the advantages and limitations of current and future therapies for PD were dicussed. Current therapies include dopaminergic therapy, DA agonists, MAO-B inhibitor, COMT inhibitors, anticholinergic drugs, surgical procedures such as pallidotomy and more specifically deep brain stimulation of the globus pallidus pars interna (GPi) or subthalamic nucleus (STN), and stem cell transplantation.

Synthesis and antitumor activity of novel dibutyltin carboxylates of aminoglucosyl derivatives.

In this study, di-n-butyltin(IV) oxide was reacted with the amino glucose analog, cis-4-[N-(1',3',4',6'-tetra-O-benzoyl-2-deoxy-glucopyranosyl)imido]-4-oxo-2-butenoic acid (1a) and o-[N-(1',3',4',6'-tetra-O-benzoyl-2-deoxy-glucopyranosyl) carbamoyl] benzoic acid (2a) to give the complexes bis-{cis-4-[N-(1',3',4',6'-tetra-O-benzoyl-2-deoxy-glucopyranosyl)imido-4-oxo-2-butenoic acid]-di-n-butyltin} carboxylate (1) and bis-{o-[N-(1',3',4',6'-tetra-O-benzoyl-2-deoxy-glucopyranosyl) carbamoyl-benzoic acid]-di-n-butyltin}carboxylate (2). These two compounds were then characterized by IR, NMR and MS. In vitro tests showed that both compounds have high cytotoxicity in four tumor cell lines (P388, HL-60, A549 and BEL-7402). Clonogenic assays demonstrated that both compounds 1 and 2 have hematopoietic cell toxicity at 10(-6) M.

Synthesis and analysis of potential DNA intercalators containing quinoline-glucose hybrids.

A new series of potential DNA bisintercalators have been designed by linking 8-hydroxy-quinoline to the 6-CH(2)OH group of glucose and connecting the 1-OH group of glucose with various linkers, such as quinol, glycol, and triethylene glycol. These new compounds were well-synthesized and fully characterized. Preliminary binding assays of these compounds to calf thymus DNA (CT-DNA) were conducted using UV-absorption and fluorescence spectroscopy analysis. The primary antitumor activity of these compounds was also performed.

[Synthesis and spectral analysis of metal-N-glycoside complexes and studies of catalyzed ester hydrolytic kinetics].

Four new complexes of Ni(II), Cu(II), Zn(II) and Co(III) with HL (HL= N,N'-di-beta-D-glucosylethylenediamine) have been synthesized in methanol solutions. The compositions of the complexes determined by elementary analysis are [Ni(HL)(H2O)2]2+ Cl2.CH3OH.2H2O, [Cu(HL)]2+ Cl2.CH3CH2OH.3H2O, [Zn(HL)]2+ Cl2.H2O and [Co(HL)(H2O)(OH)]2+ Cl2.CH3OH.2H2O respectively. They were also characterized by IR, UV and NMR spectra which show that complexes of Ni(II) and Co(III) have octahedral configuration, while complexes of Cu(II) and Zn(II) have tetralhedral configuration. The hydrolytic kinetics of p-Nitrophenyl picolinate(PNPP) catalyzed by these complexes in buffer solution was also studied spectrophotometrically.

[Effect of femoral rotation on hip bone mineral density measurement].

OBJECTIVE: To measure hip bone mineral density (BMD) on different femoral rotations and to identify the influence of femoral rotation during hip densitometry. METHODS: Forty women were recruited at the out-department of orthopedic, with the average age of 60.7 years (45-85 years), the average height of 161.8 cm (150-175 cm), and the average weight of 67.4 kg (48-80 kg). BMD measurement of hip was done in neutral position (0 degrees), 15 degrees and 30 degrees of internal rotation under quality control of DXA machine. All the subjects were asked to get down scan table and reposition after each measuring in different rotation. RESULTS: Hip BMD of proximal femur (femoral neck, Ward's area and trochanter region) have significant variations in measurement (P < 0.01) among neutral position, 15 degrees and 30 degrees of internal rotation. There were more BMD change at the cancellous region (Ward's triangle and trochanter region) than at cortical bone area (femoral neck region). Statistical analysis showed a significant positive correlation for hip BMD change between neutral degrees to 15 degrees of internal rotation and 15 degrees to 30 degrees of internal rotation. But no correlation between neutral degrees to 30 degrees of internal rotation for hip BMD change. CONCLUSIONS: Femoral rotation was shown to have a significant effect on hip BMD measurements. Cortical bone region of hip have a less BMD change than cancellous bone region. Proper positioning of the femur during scan can improve precision significantly.