Replacing the tropolonic methoxyl group of colchicine with methylamino increases tubulin binding affinity with improved therapeutic index and overcomes paclitaxel cross-resistance.

AIMS: Microtubule inhibitors are widely used in first line cancer therapy, though drug resistance often develops and causes treatment failure. Colchicine binds to tubulins and inhibits tumor growth, but is not approved for cancer therapy due to systemic toxicity. In this study, we aim to improve the therapeutic index of colchicine through structural modification. METHODS: The methoxyl group of the tropolonic ring in colchicine was replaced with amino groups. The cross-resistance of the derivatives with paclitaxel and vincristine was tested. Antitumor effects of target compounds were tested in vivo in A549 and paclitaxel-resistant A549/T xenografts. The interaction of target compounds with tubulins was measured using biological and chemical methods. RESULTS: Methylamino replacement of the tropolonic methoxyl group of colchicine increases, while demethylation loses, selective tubulin binding affinity, G2/M arrest and antiproliferation activity. Methylaminocolchicine is more potent than paclitaxel and vincristine to inhibit tumor growth in vitro and in vivo without showing cross-resistance to paclitaxel. Methylaminocolchicine binds to tubulins in unique patterns and inhibits P-gp with a stable pharmacokinetic profile. CONCLUSION: Methylanimo replacement of the tropolonic methoxyl group of colchicine increases antitumor activity with improved therapeutic index. Methylaminocolchicine represents a new type of mitotic inhibitor with the ability of overcoming paclitaxel and vincristine resistance.

Expression and mechanisms of interferon-stimulated genes in viral infection of the central nervous system (CNS) and neurological diseases.

Interferons (IFNs) bind to cell surface receptors and activate the expression of interferon-stimulated genes (ISGs) through intracellular signaling cascades. ISGs and their expression products have various biological functions, such as antiviral and immunomodulatory effects, and are essential effector molecules for IFN function. ISGs limit the invasion and replication of the virus in a cell-specific and region-specific manner in the central nervous system (CNS). In addition to participating in natural immunity against viral infections, studies have shown that ISGs are essential in the pathogenesis of CNS disorders such as neuroinflammation and neurodegenerative diseases. The aim of this review is to present a macroscopic overview of the characteristics of ISGs that restrict viral neural invasion and the expression of the ISGs underlying viral infection of CNS cells. Furthermore, we elucidate the characteristics of ISGs expression in neurological inflammation, neuropsychiatric disorders such as depression as well as neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Finally, we summarize several ISGs (ISG15, IFIT2, IFITM3) that have been studied more in recent years for their antiviral infection in the CNS and their research progress in neurological diseases.

Intestinal microbiota and melatonin in the treatment of secondary injury and complications after spinal cord injury.

Spinal cord injury (SCI) is a central nervous system (CNS) disease that can cause sensory and motor impairment below the level of injury. Currently, the treatment scheme for SCI mainly focuses on secondary injury and complications. Recent studies have shown that SCI leads to an imbalance of intestinal microbiota and the imbalance is also associated with complications after SCI, possibly through the microbial-brain-gut axis. Melatonin is secreted in many parts of the body including pineal gland and gut, effectively protecting the spinal cord from secondary damage. The secretion of melatonin is affected by circadian rhythms, known as the dark light cycle, and SCI would also cause dysregulation of melatonin secretion. In addition, melatonin is closely related to the intestinal microbiota, which protects the barrier function of the gut through its antioxidant and anti-inflammatory effects, and increases the abundance of intestinal microbiota by influencing the metabolism of the intestinal microbiota. Furthermore, the intestinal microbiota can influence melatonin formation by regulating tryptophan and serotonin metabolism. This paper summarizes and reviews the knowledge on the relationship among intestinal microbiota, melatonin, and SCI in recent years, to provide new theories and ideas for clinical research related to SCI treatment.

Reduced PTCH2 expression is associated with glioma development through its regulation of the PTEN/AKT signaling pathway.

Mutations in the human protein patched homolog (PTCH) gene have been demonstrated to be associated with cancer development in several types of malignancy. However, the underlying mechanism of PTCH-associated cancer development remains poorly understood, to the best of our knowledge. In the present study, the expression of PTCH2 in glioma tumor tissues from The Cancer Genome Atlas (TCGA) database and clinical patients with glioma were measured. Reduced expression levels of PTCH2 were observed in patients with glioma with poor prognose. In vitro, overexpression of PTCH2 significantly suppressed the proliferation and invasion of the glioma cell lines, LN229 and U87-MG. Mechanistically, PTCH2 upregulated the expression of tumor suppressor PTEN, thereby leading to the suppression of pro-survival AKT signals in glioma. Reduced expression of PTEN and enhanced expression of AKT promoted glioma development in vitro and in vivo. Blockade of PTCH2/AKT signals efficiently strengthened the anticancer effects of chemotherapy and prolonged the survival time in tumor-bearing mice, which provided a novel insight into potential treatment strategies for glioma in the clinic.

Neutrophils as emerging immunotherapeutic targets: Indirect treatment of tumors by regulating the tumor immune environment based on a sialic acid derivative-modified nanocomplex platform.

Tumor cells are dependent on their microenvironment; thus, targeting the non-cancerous components surrounding the tumor may be beneficial. Neutrophils are important inflammatory cells in the tumor microenvironment that significantly affect tumor cell proliferation, metastasis, and immune regulation. Targeted regulation of tumor-associated neutrophil-related pathways is expected to become a new therapeutic approach. Colchicine compounds are powerful anti-inflammatory drugs that strongly inhibit the chemotaxis of neutrophils to the inflammatory site. We attempted to achieve anticancer effects by utilizing its ability to inhibit neutrophil recruitment rather than killing tumor cells. As such drugs are likely to cause non-specific damages due to the lack of selectivity, we synthesized and used sialic acid and cholesterol derivatives (SA-CH) for surface modification of the newly synthesized low-toxic colchicine derivative (BCS) nanocomposite to improve neutrophil targeting. In vivo and in vitro experiments have shown that SA-CH-modified BCS preparations are effectively absorbed by neutrophils, inhibit cell migration, reduce infiltration of tumor-associated neutrophils, enhance T lymphocyte function, and exhibit good anti-S180 early tumor effect. In addition, in a triple-negative breast cancer model, the agent could strongly inhibit tumor metastasis to the lungs.

Design, synthesis and evaluation of N-hydroxypropenamides based on adamantane to overcome resistance in NSCLC.

A series of novel N-hydroxypropenamides containing adamantane moiety were identified and most of them exhibited HDAC inhibitory activity and could reverse the resistance of cisplatin in NSCLC cell lines. In this process, molecular docking was employed to verify the rationality of designing, subsequently, target compounds were synthesized and conducted to enzyme- and cell-based biological evaluation. Most of synthesized compounds could inhibit HDAC activity with the IC50 values lower than 50 nM and result in the increase of Ac-H4 and p21 in A549 cells. Importantly, we assessed the reversal effect of those compounds and found several compounds display an anti-resistant effect in lung cancer cells, especially compound 8f. As compared to belinostat and cisplatin, compound 8f showed improved inhibitory activity against A549/CDDP cell lines with IC50 value of 5.76 µM, and far lower resistance index of 1.24. Moreover, the structure-activity relationships of these compounds were summarized and compound 8f could serve as a research tool for identifying the mechanism of reversing resistance and a template for designing novel compounds to reverse cisplatin resistance.

Blockade of Interleukin-7 Receptor Shapes Macrophage Alternative Activation and Promotes Functional Recovery After Spinal Cord Injury.

Macrophages are implicated in the pathological processes and functional recovery of spinal cord injury (SCI). Macrophage activation following inflammation depends on networks of interferons and cytokines. Recent evidence indicate that IL-7 signaling can influence the release of proinflammatory factors, however, its roles in modulating macrophage phenotype and function and whether it could affect the functional recovery of SCI are poorly understood. Here, we show that, in a murine SCI model, IL-7 is promptly and vastly induced in injured spinal cord, and that blockade of IL-7 signaling with anti-IL-7Rα mAb (A7R34) favors the generation of M2 phenotype macrophages by affecting the cytokine productions in T helper (Th)1 and Th2 cells. Furthermore, IL-7 displays strong chemotactic property for macrophages and A7R34 treatment inhibits their infiltration into injured sites in vivo. More importantly, the A7R34 treatment promotes functional recovery after SCI, indicating its therapeutic effects on spinal cord repair. Hence, our study proposes a new therapeutic strategy to treat SCI by blocking IL-7 signaling.

Laminoplasty using the Posterior Midline Approach in the Treatment of C1-2 Spinal Tumors.

AIM: This study aimed to investigate the method and efficacy of vertebral reconstruction using the posterior midline approach (PMA) in the treatment of C1-2 spinal tumors. MATERIAL AND METHODS: Twenty-seven patients with C1-2 spinal tumors from the Affiliated Hospital of Luzhou Medical College, who underwent microsurgical tumor resection through an occipitocervical PMA and spinal reset-reconstruction from January 2007 to December 2013, were enrolled in the study. The clinical data and results of these patients were analyzed and summarized. RESULTS: All patients underwent a successful complete tumor resection, with no operative deaths. The postoperative pathological diagnoses were schwannoma, neurofibroma, and meningioma in 21, 1, and 5 cases, respectively. The follow-up period was 4-48 months. Postoperatively, 1 patient was independent in daily activities, and 26 patients were able to live and work normally. No significant change was found between preoperative and postoperative MRI sequences of the cervical spine, and no cervical instability and tumor recurrence had occurred. CONCLUSION: PMA is suitable as the preferred approach for resection of C1-2 spinal tumors, and the vertebral reconstruction maintains spinal stability.

Surgical treatment of Chiari I malformation complicated with syringomyelia.

The aim of this study was to evaluate the curative effects of various surgical procedures on Chiari I malformation (CMI) complicated with syringomyelia. A total of 185 patients with CMI complicated with syringomyelia who received treatment between January 1997 and December 2011 were recruited. All patients underwent posterior fossa decompression in which the lamina of the first cervical vertebra was removed, with the removal of the second or third depending on the severity of the cerebellar tonsil herniation. Of the patients, 76 underwent large-bone-window decompression and duraplasty, while 109 underwent small-bone-window decompression, displaced cerebellar tonsil resection and duraplasty. The curative effects of the different surgical procedures were analyzed retrospectively. Clinical symptoms were eliminated or improved in 156 patients (84.3%) by the time of discharge from hospital. A total of 148 patients were evaluated using magnetic resonance imaging (MRI) which revealed that the cisterna magna was reconstructed in 92 patients and spinal syrinx was reduced in 75. Follow-up was performed on 147 patients (79.5%) for between 3 months and 12 years. During the follow-up, symptoms were eliminated or improved in 110 patients (74.8%), not improved in 26 (17.7%) and deteriorated in 11 (7.5%). MRI was performed on 95 patients during follow-up examinations and the cisterna magna was reconstructed in 87 patients and spinal syrinx was reduced in 79. Small-bone-window decompression plus duraplasty is an effective surgical procedure for treating CMI complicated with syringomyelia and intraoperative cerebellar tonsillectomy significantly aids patient recovery.