Induction of apoptosis in Lewis lung carcinoma cells by an intestinal bacterial metabolite produced from orally administered ginseng protopanaxadiol saponins

The present study demonstrated that oral administration of an intestinal bacterial metabolite (M1) of protopanaxadiol-type saponin significantly inhibited the tumor growth at the implantation site after intrapulmonary implantation of Lewis lung carcinoma (LLC) cells, and suppressed the metastasis to mediastinal lymph nodes. We also investigated the inhibitory mechanism of M1 on the growth of LLC cells. M1 inhibited the proliferation of LLC cells in a concentration-dependent manner, with characteristic morphological changes at the concentration of 30 μM. Treatment of LLC cells with M1 resulted in marked elevation of the caspase-3 activity, peaking at 2 h, and a subsequent time-dependent induction of apoptosis during the period from 3 to 24 h, as evidenced by DNA fragmentation analysis. Since M1-induced growth inhibition of LLC cells was completely abrogated by the pretreatment with a specific inhibitor of caspase-3, Z-DEVD-FMK, M1 functions via the activation of caspase-3 in the process of apoptosis in LLC cells. Thus, the anti-proliferative activity of M1 against LLC cells is primarily due to the induction of apoptosis via promotion of caspase-3 activity, and this induction may lead to the anti-tumor activity in vivo

An intestinal bacterial metabolite (M1) of ginseng protopanaxadiol saponins inhibits tumor-induced neovascularization

The present study demonstrated that an intestinal bacterial metabolite (M1) of protopanaxadiol-type ginsenosides significantly inhibited the growth of implanted tumor and the intrahepatic metastasis by the implantation of a small fragment of colon 26-L5 tumor into the liver when it was administered orally. These findings indicates that M1 was effective for the inhibition of the growth and metastasis of colon26-L5 cells in addition to lung metastasis of B16-BL6 melanoma cells as have been reported previously. The conditioned medium of colon 26-L5 cellS (CM-L5) induced in vitro tube formation of hepatic sinusoidal endothelial (HSE) cells on Matrigel-coated substrates, which is considered to be an important step in the processes of tumor angiogenesis. \u27This activity of CML5 was abrogated by noncytotoxic concentrations of M1 in a concentration-dependent manner. Similarly, M1 eliminated the ability of CM-L5 to promote the migration of HSE cells concentration-dependently. These findings indicate that M1-induced inhibition of tumor growth and intrahepatic metastasis may be partly related to the suppression of tumor angiogenic responses including capillary tube formation and migration of HSE cells. 本研究では,薬用人参(Panax ginseng C.A.MEYER)のprotopanaxadiol-type ginsenosidesの主要な腸内細菌代謝物M1の経口投与は,マウス結腸癌colon 26-L5細胞の腫瘍小片を肝へ直接移植した後の移植部位での増殖と肝内移転に対して有意に抑制効果を示すことを明らかにした。この結果は,B16-BL6メラノーマ細胞による肺転移を抑制した以前の報告と同様に,co1on 26-L5細胞に対しても有効であることが示された。肝類洞内度細胞(HSE細胞)をマトリゲルをコートした基質上で,colon 26-L5細胞の培養上清(CM-L5)とともに培養すると,腫瘍血管新生の週程における重要なステップのひとつである,内度細胞の菅腔形成を誘導した。CM-L5による菅形成能は,細胞傷害性を示さない濃度範囲のM1により,濃度依存的に抑制された。同様に,CM-L5によるHSE細胞の移動能の亢進を,M1は濃度に依存して抑制した。以上,M1による結腸癌の肝における増殖及び肝内転移の抑制は,内度細胞の骨腔形成及ぴ移動能を含む血管新生反応の抑制と部分的に関係していることが示唆された

Evaluation of Seismic Safety of a Large Caisson Structure

Some centrifugal shaking tests were carried out to clarify the mechanism of seismic interaction between a large caisson foundation and soil layers. Based on the test data, two-dimensional seismic effective stress FE analysis was applied, followed by verifying its applicability. Also, to clarify the flexural and shear behavior of the caisson structure members to the ultimate state and to evaluate the flexural and shear resistance, some large-scale model failure tests of poorly reinforced concrete in caisson foundation were carried out. Based on these test results above-mentioned, seismic analyses of an existing large caisson foundation to ground motion in level 2 earthquakes were carried out, adopting the above-mentioned analysis. As the results, it was concluded that the seismic safety on the caisson foundation was confirmed

Peritoneal dissemination of high-grade serous ovarian cancer: pivotal roles of chromosomal instability and epigenetic dynamics

Epithelial ovarian cancer remains the lethal gynecological malignancy in women. The representative histotype is high-grade serous carcinoma (HGSC), and most patients with HGSC present at advanced stages with peritoneal dissemination. Since the peritoneal dissemination is the most important factor for poor prognosis of the patients, complete exploration for its molecular mechanisms is mandatory. In this narrative review, being based on the clinical, pathologic, and genomic findings of HGSC, chromosomal instability and epigenetic dynamics have been discussed as the potential drivers for cancer development in the fallopian tube, acquisition of cancer stem cell (CSC)-like properties, and peritoneal metastasis of HGSC. The natural history of carcinogenesis with clonal evolution, and adaptation to microenvironment of peritoneal dissemination of HGSC should be targeted in the novel development of strategies for prevention, early detection, and precision treatment for patients with HGSC

Application of Level-Set Type Topology Optimization Analysis for Cavity Shape Estimation Problem in Structures Based On Non-Destructive Hammering Test

In this study, we present application of the level-set type topology optimization analysis for the cavity shape estimation problem in structures based on the non-destructive hammering test. The cavity shape is identified so as to minimize a performance function. The performance function is defined as the square sum of the residual between computed and the observed displacements on structure surface. In this study, accuracy of identified cavity shape is investigated by changing numerical parameters in the topology optimization

1-Methyl-2-undecyl-4(1H)-quinolone, a derivative of quinolone alkaloid evocarpine, attenuates high phosphate-induced calcification of human aortic valve interstitial cells by inhibiting phosphate cotransporter PiT-1

AbstractAn abnormally high serum phosphate level induces calcific aortic stenosis (CAS), which is characterized by ectopic valve calcification and stenosis of the orifice area. Inhibition of ectopic calcification is a critical function of any internal medical therapy for CAS disease. The aim of the present study was to investigate the inhibitory effects of several derivatives of evocarpine, methanolic extracts from the fruits of Evodia rutaecarpa Bentham (Japanese name: Go-Shu-Yu) on the high phosphate-induced calcification of human aortic valve interstitial cells (HAVICs) obtained from patients with CAS. High phosphate (3.2 mM) concentrations significantly increased the calcification of HAVICs after 7 days of culture. This calcification was completely inhibited in the presence of sodium phosphonoformate (PFA), a selective inhibitor of the type III sodium-dependent phosphate cotransporter (PiT-1). PiT-1 contributes to phosphate uptake, resulting in calcification. 1-Methyl-2-undecyl-4(1H)-quinolone (MUQ; 30–300 nM), but not evocarpine or its derivatives dihydroevocarpine and 1-methyl-2-nonyl-4(1H)-quinolone, inhibited the high phosphate-induced HAVICs calcification in a concentration-dependent manner. Although all of the evocarpine derivatives attenuated alkaline phosphatase activity, only MUQ also decreased PiT-1 gene expression with cellular PiT-1 protein diminution. These results suggest that MUQ mitigated high phosphate-induced HAVICs calcification by inhibiting PiT-1 gene expression

Polymorphism of the Tryptophan Hydroxylase 2 (TPH2) Gene Is Associated with Chimpanzee Neuroticism

In the brain, serotonin production is controlled by tryptophan hydroxylase 2 (TPH2), a genotype. Previous studies found that mutations on the TPH2 locus in humans were associated with depression and studies of mice and studies of rhesus macaques have shown that the TPH2 locus was involved with aggressive behavior. We previously reported a functional single nucleotide polymorphism (SNP) in the form of an amino acid substitution, Q468R, in the chimpanzee TPH2 gene coding region. In the present study we tested whether this SNP was associated with neuroticism in captive and wild-born chimpanzees living in Japan and Guinea, respectively. Even after correcting for multiple tests (Bonferroni p = 0.05/6 = 0.008), Q468R was significantly related to higher neuroticism (β = 0.372, p = 0.005). This study is the first to identify a genotype linked to a personality trait in chimpanzees. In light of the prior studies on humans, mice, and rhesus macaques, these findings suggest that the relationship between neuroticism and TPH2 has deep phylogenetic roots