Correction to: Search of anti-allodynic compounds from Plantaginis Semen, a crude drug ingredient of Kampo formula "Goshajinkigan".

The article Search of anti-allodynic compounds from Plantaginis Semen, a crude drug ingredient of Kampo formula "Goshajinkigan".

Search of anti-allodynic compounds from Plantaginis Semen, a crude drug ingredient of Kampo formula "Goshajinkigan".

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the dose-limiting side effects of cancer chemotherapy. Although the control of CIPN is important, it is difficult to manage with currently available therapeutic drugs. Therefore, there is a need for novel therapeutic agents for treating CIPN. Goshajinkigan (GJG) is a Kampo formula composed of ten crude drugs. While GJG has been used for the treatment of CIPN, the active constituents of GJG and their underlying mechanisms of pharmacological effects are still unknown. Our previous study revealed that repetitive oral administration of the water extract of Plantaginis Semen, a crude drug ingredient of GJG, inhibited the mechanical allodynia induced by an intraperitoneal injection of paclitaxel in mice. To elucidate the active compounds of Plantaginis Semen, activity-guided separation of the water extract of Plantaginis Semen was performed. From the active fraction, four iridoids (1-4) were identified. Repetitive oral administration of aucubin (1) at 100 or 30 mg/kg and 100 mg/kg of the fraction crude 3 [primarily comprised of pedicularis-lactone (3)], showed anti-allodynic activity, suggesting 1 and 3 could be some of the active compounds responsible for the anti-allodynic property of Plantaginis Semen and GJG. Our study establishes that oral administration of 1 has potent anti-allodynic effect in addition to the activity of intraperitoneally administered 1 reported previously. Identification of active anti-allodynic compounds found in Kampo formulations will support the development of novel therapies for the management of CIPN in cancer patients.

Prophylactic Administration of Aucubin Inhibits Paclitaxel-Induced Mechanical Allodynia via the Inhibition of Endoplasmic Reticulum Stress in Peripheral Schwann Cells.

Paclitaxel is a chemotherapeutic agent that causes peripheral neuropathy as its major dose-limiting side effect. However, the peripheral neuropathy is difficult to manage. A study we recently conducted showed that repetitive administration of aucubin as a prophylactic inhibits paclitaxel-induced mechanical allodynia. However, the mechanisms underlying the anti-allodynic activity of aucubin, which is a major component of Plantaginis Semen, was unclear. In addition to mechanical allodynia, aucubin inhibited spontaneous and mechanical stimuli-induced firing in spinal dorsal horn neurons; however, catalpol, a metabolite of aucubin, did not show these effects. Furthermore, paclitaxel induced the expression of CCAAT/enhancer-binding protein homologous protein, a marker of endoplasmic reticulum (ER) stress, in the sciatic nerve and a Schwann cell line (LY-PPB6 cells); however, this effect was inhibited by aucubin. These results suggest that aucubin inhibits paclitaxel-induced mechanical allodynia through the inhibition of ER stress in peripheral Schwann cells.

Prophylactic administration of an extract from Plantaginis Semen and its major component aucubin inhibits mechanical allodynia caused by paclitaxel in mice.

The chemotherapeutic agent paclitaxel (PTX) causes peripheral neuropathy as a major dose-limiting side effect, and this peripheral neuropathy is difficult to control. Our previous report showed that prophylactic repetitive administration of goshajinkigan ( niú che shèn qì wán), but not hachimijiogan ( ba wèi dì huáng wán), which lacks two of the constituents of goshajinkigan, inhibited PTX-induced mechanical allodynia in mice. Thus, the herbal medicines Plantaginis Semen ( che qián zǐ) or Achyranthis Radix ( niú xi) may contribute to the inhibitory action of goshajinkigan on the exacerbation of PTX-induced mechanical allodynia [Andoh et al, J. Tradit. Complement. Med. 2014; 4: 293-297]. Therefore, in this study, we examined whether an extract of Plantaginis Semen (EPS) or Achyranthis Radix (EAR) would relieve PTX-induced mechanical allodynia in mice. A single intraperitoneal injection of PTX caused mechanical allodynia, which peaked on day 14 after injection. Repetitive oral administration of EPS, but not EAR, starting from the day after PTX injection significantly inhibited the exacerbation of PTX-induced mechanical allodynia. Repetitive intraperitoneal injection of aucubin, one of the main components of EPS, starting from the day after PTX injection also significantly reduced PTX-induced mechanical allodynia. However, repetitive intraperitoneal injection of geniposide acid (a precursor of aucubin) or catalpol (a metabolite of aucubin) did not prevent the exacerbation of mechanical allodynia. These results suggest that prophylactic administration of EPS is effective for preventing the exacerbation of PTX-induced allodynia. Aucubin may contribute to the inhibitory action of EPS on the exacerbation of PTX-induced allodynia.

Factors affecting the technical difficulty and clinical outcome of endoscopic submucosal dissection for colorectal tumors.

BACKGROUND: Endoscopic submucosal dissection (ESD) for colorectal tumors is technically difficult due to the anatomy of the large intestine, with its narrow lumen, thin walls, and redundancy. Here, we assessed factors associated with incomplete resection and difficult colorectal ESD. METHODS: Between November 2009 and April 2013, we performed ESD on 151 consecutive colorectal tumors in 147 patients. We evaluated the clinical outcomes of all cases and conducted multiple logistic regression analysis of the following factors related to incomplete resection and difficult procedure: age, gender, location (right colon, left colon or rectum), tumor size (diameter ≥40 or <40 mm), operation time, morphology [granular-type laterally spreading tumor (LST-G), non-granular-type laterally spreading tumor (LST-NG), or protruded type], fibrosis, and paradoxical movement during the procedure. A procedure that required more than 120 min was defined as a difficult colorectal ESD. RESULTS: Average tumor size was 32.1 ± 10.7 mm, and the average procedure length was 71.8 ± 49.5 min. The rate of en bloc resection was 94.7%, while that of en bloc curative resection was 86.8%. Perforation occurred in 1.3% of the ESD procedures. Multivariate logistic regression analysis revealed that only severe fibrosis [odds ratio (OR) 4.51; 95% confidence interval (CI) 1.36-14.91, p = 0.014] contributed to incomplete resection and that a tumor size exceeding 40 mm (OR 5.73 [95% CI 1.66-19.74], p = 0.006), severe fibrosis (OR 23.31 [95% CI 6.59-82.54], p < 0.001), and paradoxical movement (OR 4.26 [95% CI 1.11-16.44], p = 0.035) were independent factors exacerbating the difficulty of colorectal ESD. CONCLUSIONS: Severe fibrosis contributed to both incomplete resection and difficult colorectal ESD. Larger tumor size and paradoxical movement during the procedure were independent factors contributing to the difficulty of colorectal ESD. These factors might enable endoscopists to develop strategies for treating colorectal ESD.

An efficient grid layout algorithm for biological networks utilizing various biological attributes.

BACKGROUND: Clearly visualized biopathways provide a great help in understanding biological systems. However, manual drawing of large-scale biopathways is time consuming. We proposed a grid layout algorithm that can handle gene-regulatory networks and signal transduction pathways by considering edge-edge crossing, node-edge crossing, distance measure between nodes, and subcellular localization information from Gene Ontology. Consequently, the layout algorithm succeeded in drastically reducing these crossings in the apoptosis model. However, for larger-scale networks, we encountered three problems: (i) the initial layout is often very far from any local optimum because nodes are initially placed at random, (ii) from a biological viewpoint, human layouts still exceed automatic layouts in understanding because except subcellular localization, it does not fully utilize biological information of pathways, and (iii) it employs a local search strategy in which the neighborhood is obtained by moving one node at each step, and automatic layouts suggest that simultaneous movements of multiple nodes are necessary for better layouts, while such extension may face worsening the time complexity. RESULTS: We propose a new grid layout algorithm. To address problem (i), we devised a new force-directed algorithm whose output is suitable as the initial layout. For (ii), we considered that an appropriate alignment of nodes having the same biological attribute is one of the most important factors of the comprehension, and we defined a new score function that gives an advantage to such configurations. For solving problem (iii), we developed a search strategy that considers swapping nodes as well as moving a node, while keeping the order of the time complexity. Though a naïve implementation increases by one order, the time complexity, we solved this difficulty by devising a method that caches differences between scores of a layout and its possible updates. CONCLUSION: Layouts of the new grid layout algorithm are compared with that of the previous algorithm and human layout in an endothelial cell model, three times as large as the apoptosis model. The total cost of the result from the new grid layout algorithm is similar to that of the human layout. In addition, its convergence time is drastically reduced (40% reduction).

Automatic drawing of biological networks using cross cost and subcomponent data.

Automatic graph drawing function for biopathways is indispensable for biopathway databases and softwares. This paper proposes a new grid-based algorithm for biopathway layout that considers (a) edge-edge crossing, (b) node-edge crossing, (c) distance measures between nodes, as its costs, and (d) subcellular localization information from Gene Ontology, as its constraints. For this algorithm, we newly define cost functions, devise an efficient method for computing the costs (a)-(c) by employing a matrix representing the difference between two layouts, and take a steepest descent method for searching locally optimal solutions and multi-step layout method for finding better solutions. We implemented this algorithm on Cell Illustrator which is a biopathway modeling and simulation software. The algorithm is applied to a signal transduction pathway of apoptosis induced by fas ligand. We compare our layout with that of the grid-based algorithm by Li and Kurata (Bioinformatics 21 (9):2036-2042, 2005). The result shows that our algorithm reduces edge-edge crossings and node-edge crossings, and solves the ''isolated island problem'', that is, despite the intension, some groups of nodes are apart from other nodes in the layout. As a result, the biological understandability of the layout is fairly improved.

Ground deformation characteristics caused by lateral spreading during the 1995 Hanshin - Awaji earthquake

Attempts were made to investigate features of ground displacements and settlements caused by the lateral spreading of liquefied soil during the earthquake in the wharf areas along peripheries of Port Island, Rokko Island and Fukae Island. Measurements were made at a number of locations of width of open craks and vertical offset across the cracks on the ground surface along alignments in the direction perpendicular to the revetment line.(AU)