Alterations in Cell Cycle and Induction of Apoptotic Cell Death in Breast Cancer Cells Treated with α-Mangostin Extracted from Mangosteen Pericarp

The development of molecularly targeted drugs has greatly advanced cancer therapy, despite these drugs being associated with some serious problems. Recently, increasing attention has been paid to the anticancer effects of natural products. α-Mangostin, a xanthone isolated from the pericarp of mangosteen fruit, has been shown to induce apoptosis in various cancer cell lines and to exhibit antitumor activity in a mouse mammary cancer model. In this study, we investigated the influence of α-mangostin on apoptosis and cell cycle in the human breast cancer cell line MDA-MB231 (carrying a p53 mutation, and HER2, ER, and PgR negative) in order to elucidate its anticancer mechanisms. In α-mangostin-treated cells, induction of mitochondria-mediated apoptosis was observed. On cell-cycle analysis, G1-phase arrest, increased p21cip1 expression and decreases in cyclins, cdc(s), CDKs and PCNA were observed. In conclusion, α-mangostin may be useful as a therapeutic agent for breast cancer carrying a p53 mutation and having HER2- and hormone receptor-negative subtypes

Nasal displacement of retinal vessels on the optic disc in glaucoma associated with a nasally angled passage through lamina cribrosa

To investigate nasal displacement of central retinal vessel (CRV) on the optic nerve head (ONH) in glaucoma in association with its passage through lamina cribrosa (LC). This cross-sectional study included 113 eyes with glaucoma and 60 normal eyes. Horizontal spectral-domain optical coherence tomography (SD-OCT) scans of the ONH were acquired, and point where CRV emerged on the ONH surface was defined as the position of the CRV. Next, radial scans of the ONH were acquired, and angle of the CRV passing through the LC was measured. These parameters were compared between glaucomatous and normal eyes by t-test, and their relationship with possible confounders was assessed by multiple regression analyses. In glaucoma, CRV was significantly more nasally displaced than it was in normal eyes (66.0 +/- 8.6 vs. 54.3 +/- 9.5, P<0.0001), and eyes with more vessel displacement exhibited significantly worse glaucomatous visual field defects (P=0.0004). Greater nasal displacement of the CRV was significantly associated with a more nasally angled path through the LC (rs=0.569, P<0.0001). By using SD-OCT, we confirmed that nasal displacement of the CRV on the ONH was associated with glaucoma and was induced by its nasally angled path through the LC

Effective and convenient treatment of Xultophy with lower doses for elderly diabetic patient

The case is an 82-year-old female patient with Type 2 Diabetes Mellitus (T2DM) for 22 years. She developed right empyema in early January, 2021 and was treated by antibiotics and CT-guided drainage. After improving the status, she was transferred to Hayashi hospital, Tokushima, Japan. Treatment for T2DM was initially multiple daily insulin injection (MDI), but it could not continue because of injection several times a day by the family. Then, Xultophy was started once a day, which brought satisfactory glucose variability with lower doses. Consequently, Xultophy would be effective and useful agent from bio-psycho-social points of view

Alternative mRNA Splicing in Three Venom Families Underlying a Possible Production of Divergent Venom Proteins of the Habu Snake, Protobothrops flavoviridis

Snake venoms are complex mixtures of toxic proteins encoded by various gene families that function synergistically to incapacitate prey. A huge repertoire of snake venom genes and proteins have been reported, and alternative splicing is suggested to be involved in the production of divergent gene transcripts. However, a genome-wide survey of the transcript repertoire and the extent of alternative splicing still remains to be determined. In this study, the comprehensive analysis of transcriptomes in the venom gland was achieved by using PacBio sequencing. Extensive alternative splicing was observed in three venom protein gene families, metalloproteinase (MP), serine protease (SP), and vascular endothelial growth factors (VEGF). Eleven MP and SP genes and a VEGF gene are expressed as a total of 81, 61, and 8 transcript variants, respectively. In the MP gene family, individual genes are transcribed into different classes of MPs by alternative splicing. We also observed trans-splicing among the clustered SP genes. No other venom genes as well as non-venom counterpart genes exhibited alternative splicing. Our results thus indicate a potential contribution of mRNA alternative and trans-splicing in the production of highly variable transcripts of venom genes in the habu snake

Modeling and Prediction of Driving Behaviors Using a Nonparametric Bayesian Method with AR Models

To develop a new generation advanced driver assistance system that avoids a dangerous condition in advance, we need to predict driving behaviors. Since a nonparametric Bayesian method with a two-level structure successfully predicted the symbolized behaviors only, we applied a nonparametric Bayesian method with linear dynamical systems to predicting the driving behavior. The method called the beta process autoregressive hidden Markov model (BP-AR-HMM) segments driving behaviors into states each of which corresponds to an AR model and it predicts future behaviors using the estimated future state sequence and the dynamical systems therein. Here, the segmentation as well as the parameters of the dynamical systems are determined using given training data in an unsupervised way. We carried out experiments with real driving data and found that the BP-AR-HMM predicted driving behaviors better than other methods

Association between Hardness (Difficulty of Chewing) of the Habitual Diet and Premenstrual Symptoms in Young Japanese Women

Recent evidence suggests that voluntary rhythmic movements such as chewing may increase blood serotonin and subsequently brain serotonin, which in turn acts to alleviate premenstrual symptoms. In this observational cross-sectional study, we tested the hypothesis that hardness (difficulty of chewing) of the habitual diet (i.e. dietary hardness) is associated with decreased premenstrual symptoms. Subjects were 640 female Japanese dietetic students aged 18–22 years. Dietary hardness was assessed as an estimate of masticatory muscle activity for the habitual diet (i.e. the difficulty of chewing the food). The consumption of a total of 107 foods was estimated by means of a self-administered, comprehensive diet history questionnaire, and masticatory muscle activity during the ingestion of these foods was estimated according to published equations. Menstrual cycle symptoms were assessed using the retrospective version of the Moos Menstrual Distress Questionnaire, from which total score and subscale scores (i.e. pain, concentration, behavioral change, autonomic reactions, water retention, and negative affect) in the premenstrual phase were calculated and expressed as percentages relative to those in the intermenstrual phase. Dietary hardness was not associated with total score in the premenstrual phase (P for trend = 0.48). Further, no association was seen for any subscale score in the premenstrual phase (P for trend = 0.18–0.91). In conclusion, this preliminary study failed to substantiate a hypothesized inverse relationship between hardness of the habitual diet and premenstrual symptoms. Considering the plausibility of the putative mechanism, however, further investigation using more relevant measures of chewing and premenstrual symptoms is warranted

Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer

<p>Abstract</p> <p>Background</p> <p>The effects of raloxifene, a novel selective estrogen receptor modulator, were studied in a mouse metastatic mammary cancer model expressing cytoplasmic ERα.</p> <p>Methods</p> <p>Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879luc2 cells, were subsequently treated with raloxifene at 0, 18 and 27 mg/kg/day using mini-osmotic pumps.</p> <p>Results</p> <p><it>In vitro </it>study demonstrated that the ERα in BJMC3879luc2 cells was smaller (between 50 and 64 kDa) than the normal-sized ERα (66 kDa) and showed cytoplasmic localization. A statistically significant but weak estradiol response was observed in this cell line. When BJMC3879luc2 tumors were implanted into mice, the ERα mRNA levels were significantly higher in females than in males. <it>In vitro </it>studies showed that raloxifene induced mitochondria-mediated apoptosis and cell-cycle arrest in the G1-phase and a decrease in the cell population in the S-phase. In animal experiments, tumor volumes were significantly suppressed in the raloxifene-treated groups. The multiplicity of lymph node metastasis was significantly decreased in the 27 mg/kg group. Levels of apoptosis were significantly increased in the raloxifene-treated groups, whereas the levels of DNA synthesis were significantly decreased in these groups. No differences in microvessel density in tumors were observed between the control and raloxifene-treated groups. The numbers of dilated lymphatic vessels containing intraluminal tumor cells were significantly reduced in mammary tumors in the raloxifene-treated groups. The levels of ERα mRNA in mammary tumors tended to be decreased in the raloxifene-treated groups.</p> <p>Conclusion</p> <p>These results suggest that the antimetastatic activity of raloxifene in mammary cancer expressing cytoplasmic ERα may be a crucial finding with clinical applications and that raloxifene may be useful as an adjuvant therapy and for the chemoprevention of breast cancer development.</p

α-Mangostin extracted from the pericarp of the mangosteen (Garcinia mangostana Linn) reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p53 mutation

<p>Abstract</p> <p>Background</p> <p>The mangosteen fruit has a long history of medicinal use in Chinese and Ayurvedic medicine. Recently, the compound α-mangostin, which is isolated from the pericarp of the fruit, was shown to induce cell death in various types of cancer cells in <it>in vitro </it>studies. This led us to investigate the antitumor growth and antimetastatic activities of α-mangostin in an immunocompetent xenograft model of mouse metastatic mammary cancer having a p53 mutation that induces a metastatic spectrum similar to that seen in human breast cancers.</p> <p>Methods</p> <p>Mammary tumors, induced by inoculation of BALB/c mice syngeneic with metastatic BJMC3879luc2 cells, were subsequently treated with α-mangostin at 0, 10 and 20 mg/kg/day using mini-osmotic pumps and histopathologically examined. To investigate the mechanisms of antitumor ability by α-mangostin, <it>in vitro </it>studies were also conducted.</p> <p>Results</p> <p>Not only were <it>in vivo </it>survival rates significantly higher in the 20 mg/kg/day α-mangostin group versus controls, but both tumor volume and the multiplicity of lymph node metastases were significantly suppressed. Apoptotic levels were significantly increased in the mammary tumors of mice receiving 20 mg/kg/day and were associated with increased expression of active caspase-3 and -9. Other significant effects noted at this dose level were decreased microvessel density and lower numbers of dilated lymphatic vessels containing intraluminal tumor cells in mammary carcinoma tissues.</p> <p><it>In vitro</it>, α-mangostin induced mitochondria-mediated apoptosis and G1-phase arrest and S-phase suppression in the cell cycle. Since activation by Akt phosphorylation plays a central role in a variety of oncogenic processes, including cell proliferation, anti-apoptotic cell death, angiogenesis and metastasis, we also investigated alterations in Akt phosphorylation induced by α-mangostin treatment both <it>in vitro </it>and <it>in vivo</it>. Quantitative analysis and immunohistochemistry showed that α-mangostin significantly decreased the levels of phospho-Akt-threonine 308 (Thr308), but not serine 473 (Ser473), in both mammary carcinoma cell cultures and mammary carcinoma tissues <it>in vivo</it>.</p> <p>Conclusions</p> <p>Since lymph node involvement is the most important prognostic factor in breast cancer patients, the antimetastatic activity of α-mangostin as detected in mammary cancers carrying a p53 mutation in the present study may have specific clinical applications. In addition, α-mangostin may have chemopreventive benefits and/or prove useful as an adjuvant therapy, or as a complementary alternative medicine in the treatment of breast cancer.</p

Flap endonucleases pass 5′-flaps through a flexible arch using a disorder-thread-order mechanism to confer specificity for free 5′-ends

Flap endonucleases (FENs), essential for DNA replication and repair, recognize and remove RNA or DNA 5′-flaps. Related to FEN specificity for substrates with free 5′-ends, but controversial, is the role of the helical arch observed in varying conformations in substrate-free FEN structures. Conflicting models suggest either 5′-flaps thread through the arch, which when structured can only accommodate single-stranded (ss) DNA, or the arch acts as a clamp. Here we show that free 5′-termini are selected using a disorder-thread-order mechanism. Adding short duplexes to 5′-flaps or 3′-streptavidin does not markedly impair the FEN reaction. In contrast, reactions of 5′-streptavidin substrates are drastically slowed. However, when added to premixed FEN and 5′-biotinylated substrate, streptavidin is not inhibitory and complexes persist after challenge with unlabelled competitor substrate, regardless of flap length or the presence of a short duplex. Cross-linked flap duplexes that cannot thread through the structured arch react at modestly reduced rate, ruling out mechanisms involving resolution of secondary structure. Combined results explain how FEN avoids cutting template DNA between Okazaki fragments and link local FEN folding to catalysis and specificity: the arch is disordered when flaps are threaded to confer specificity for free 5′-ends, with subsequent ordering of the arch to catalyze hydrolysis