Plant-derived anticancer agents: Lessons from the pharmacology of geniposide and its aglycone, genipin

For centuries, plants have been exploited by mankind as sources of numerous cancer chemotherapeutic agents. Good examples of anticancer compounds of clinical significance today include the taxanes (e.g., taxol), vincristine, vinblastine, and the podophyllotoxin analogues that all trace their origin to higher plants. While all these drugs, along with the various other available therapeutic options, brought some relief in cancer management, a real breakthrough or cure has not yet been achieved. This critical review is a reflection on the lessons learnt from decades of research on the iridoid glycoside geniposide and its aglycone, genipin, which are currently used as gold standard reference compounds in cancer studies. Their effects on tumour development (carcinogenesis), cancer cell survival, and death, with particular emphasis on their mechanisms of actions, are discussed. Particular attention is also given to mechanisms related to the dual pro-oxidant and antioxidant effects of these compounds, the mitochondrial mechanism of cancer cell killing through reactive oxygen species (ROS), including that generated through the uncoupling protein-2 (UCP-2), the inflammatory mechanism, and cell cycle regulation. The implications of various studies for the evaluation of glycosidic and aglycone forms of natural products in vitro and in vivo through pharmacokinetic scrutiny are also addressed

The Myxoma Poxvirus Protein, M11L, Prevents Apoptosis by Direct Interaction with the Mitochondrial Permeability Transition Pore

M11L, an antiapoptotic protein essential for the virulence of the myxoma poxvirus, is targeted to mitochondria and prevents the loss of mitochondrial membrane potential that accompanies cell death. In this study we show, using a cross-linking approach, that M11L physically associates with the mitochondrial peripheral benzodiazepine receptor (PBR) component of the permeability transition (PT) pore. Close association of M11L and the PBR is also indicated by fluorescence resonance energy transfer (FRET) analysis. Stable expression of M11L prevents the release of mitochondrial cytochrome c induced by staurosporine or protoporphyrin IX (PPIX), a ligand of the PBR. Transiently expressed M11L also prevents mitochondrial membrane potential loss induced by PPIX, or induced by staurosporine in combination with PK11195, another ligand of the PBR. Myxoma virus infection and the associated expression of early proteins, including M11L, protects cells from staurosporine- and Fas-mediated mitochondrial membrane potential loss and this effect is augmented by the presence of PBR. We conclude that M11L regulates the mitochondrial permeability transition pore complex, most likely by direct modulation of the PBR

Implications for ID practice of Instructional Designers' Cultural Identities

Are there social and political purposes for design that are culturally based? A growing body of research is concerned with the design of culturally-appropriate learning resources and environments, but the emphasis of this panel is on the instructional designer as the agent of the design. Colloquially put, if we design for ourselves, we should understand the sociocultural influences on us and how they inform our practices. We should also develop respect for, and learn from, how various global cultures address similar design problems differently. This panel includes instructional design scholars and practitioners from a range of geopolitical regions, who will share culturally-based narratives and metaphors of ID, and invite participants to do the same. (Authors' abstract

Neural EGFL-Like 1 Regulates Cartilage Maturation through Runt-Related Transcription Factor 3–Mediated Indian Hedgehog Signaling

The pro-chondrogenic function of runt-related transcription factor 2 (Runx2) was previously considered to be dependent on direct binding with the promoter of Indian hedgehog (Ihh)—the major regulator of chondrocyte differentiation, proliferation, and maturation. The authors’ previous studies identified neural EGFL like 1 (Nell-1) as a Runx2-responsive growth factor for chondrogenic differentiation and maturation. In this study, it was further revealed that the pro-chondrogenic activities of Nell-1 also rely on Ihh signaling, by showing: i) Nell-1 significantly elevated Ihh signal transduction; ii) Nell-1 deficiency markedly reduced Ihh activation in chondrocytes; and iii) Nell-1–stimulated chondrogenesis was significantly reduced by the specific hedgehog inhibitor cyclopamine. Importantly, the authors demonstrated that Nell-1–responsive Ihh signaling and chondrogenic differentiation extended to Runx2 −/− models in vitro and in vivo. In Runx2 −/− chondrocytes, Nell-1 stimulated the expression and signal transduction of Runx3, another transcription factor required for complete chondrogenic differentiation and maturation. Furthermore, knocking down Runx3 in Runx2 −/− chondrocytes abolished Nell-1\u27s stimulation of Ihh-associated molecule expression, which validates Runx3 as a major mediator of Nell-1–stimulated Ihh activation. For the first time, the Runx2→Nell-1→Runx3→Ihh signaling cascade during chondrogenic differentiation and maturation has been identified as an alternative, but critical, pathway for Runx2 to function as a pro-chondrogenic molecule via Nell-1. © 2018 American Society for Investigative Patholog

Neural EGFL Like 1 as a Potential Pro-Chondrogenic, Anti-Inflammatory Dual-Functional Disease-Modifying Osteoarthritis Drug

Arthritis, an inflammatory condition that causes pain and cartilage destruction in joints, affects over 54.4 million people in the US alone. Here, for the first time, we demonstrated the emerging role of neural EGFL like 1 (NELL-1) in arthritis pathogenesis by showing that Nell-1-haploinsufficient (Nell-1+/6R) mice had accelerated and aggravated osteoarthritis (OA) progression with elevated inflammatory markers in both spontaneous primary OA and chemical-induced secondary OA models. In the chemical-induced OA model, intra-articular injection of interleukin (IL)1β induced more severe inflammation and cartilage degradation in the knee joints of Nell-1+/6R mice than in wildtype animals. Mechanistically, in addition to its pro-chondrogenic potency, NELL-1 also effectively suppressed the expression of inflammatory cytokines and their downstream cartilage catabolic enzymes by upregulating runt-related transcription factor (RUNX)1 in mouse and human articular cartilage chondrocytes. Notably, NELL-1 significantly reduced IL1β-stimulated inflammation and damage to articular cartilage in vivo. In particular, NELL-1 administration markedly reduced the symptoms of antalgic gait observed in IL1β-challenged Nell-1+/6R mice. Therefore, NELL-1 is a promising pro-chondrogenic, anti-inflammatory dual-functional disease-modifying osteoarthritis drug (DMOAD) candidate for preventing and suppressing arthritis-related cartilage damage. © 2019 Elsevier Lt

Mesoscopic superpositions of vibronic collective states of N trapped ions

We propose a scalable procedure to generate entangled superpositions of motional coherent states and electronic states in N trapped ions. Beyond their fundamental importance, these states may be of interest for quantum information processing and may be used in experimental studies of decoherence.Comment: Final version, as published in Physical Review Letters. See also further developments and applications in quant-ph/020207

Fibromodulin Reduces Scar Formation in Adult Cutaneous Wounds by Eliciting a Fetal-Like Phenotype

Blocking transforming growth factor (TGF)β1 signal transduction has been a central strategy for scar reduction; however, this approach appears to be minimally effective. Here, we show that fibromodulin (FMOD), a 59-kD small leucine-rich proteoglycan critical for normal collagen fibrillogenesis, significantly reduces scar formation while simultaneously increasing scar strength in both adult rodent models and porcine wounds, which simulate human cutaneous scar repair. Mechanistically, FMOD uncouples pro-migration/contraction cellular signals from pro-fibrotic signaling by selectively enhancing SMAD3-mediated signal transduction, while reducing AP-1-mediated TGFβ1 auto-induction and fibrotic extracellular matrix accumulation. Consequently, FMOD accelerates TGFβ1-responsive adult fibroblast migration, myofibroblast conversion, and function. Furthermore, our findings strongly indicate that, by delicately orchestrating TGFβ1 activities rather than indiscriminately blocking TGFβ1, FMOD elicits fetal-like cellular and molecular phenotypes in adult dermal fibroblasts in vitro and adult cutaneous wounds in vivo, which is a unique response of living system undescribed previously. Taken together, this study illuminates the signal modulating activities of FMOD beyond its structural support functions, and highlights the potential for FMOD-based therapies to be used in cutaneous wound repair. © The Author(s) 2017

Lean and obese Zucker rats exhibit different patterns of p70s6 kinase regulation in the tibialis anterior muscle in response to high-force muscle contraction

Increased phosphorylation of the 70-kDa ribosomal S6 kinase (p70S6k) signaling is strongly correlated with the degree of muscle adaptation following exercise. Herein we compare the phosphorylation of p70S6k, Akt, and mammalian target of rapamycin (mTOR) in the tibialis anterior (TA) muscles of lean and obese Zucker rats following a bout of eccentric exercise. Exercise increased p70S6k (Thr389) phosphorylation immediately after (33.3 ± 7.2%) and during [1 h (24.0 ± 14.9%) and 3 h (24.6 ± 11.3%)] recovery in the lean TA and at 3 h (33.5 ± 8.0%) in the obese TA Zucker rats. mTOR (Ser2448) phosphorylation was elevated in the lean TA immediately after exercise (96.5 ± 40.3%) but remained unaltered in the obese TA. Exercise increased Akt (Thr308) and Akt (Ser473) phosphorylation in the lean but not the obese TA. These results suggest that insulin resistance is associated with alterations in the ability of muscle to activate p70S6k signaling following an acute bout of exercise. Muscle Nerve 39: 503–511 2009. Type 2 (non–insulin-dependent) diabetes mellitus (DM) is an emerging epidemic in Western cultures, and it is believed to afflict 150 million people worldwide.11 Insulin resistance is frequently accompanied by a variety of metabolic and cardiovascular abnormalities, including hypertension, glucose intolerance, type 2 diabetes, dyslipidemia, atherosclerosis, and central obesity. A number of studies that employ strength training regimens have been shown to improve glycemic control, increase skeletal muscle size and strength, and positively change body composition. The data suggest that anaerobic exercise may be an effective strategy for the treatment of insulin resistance and type 2 diabetes.6, 7, 49, 53 Recent reports have suggested that differences exist between normal and insulin-resistant muscle in their adaptation to an exercise regimen.5, 8, 20, 24, 48, 50 However, the direct effects of exercise on the phenotype of insulin-resistant muscle have not been widely studied. It is thought that the beneficial effects of exercise on muscle are mediated through activation of the various signaling cascades involved in regulating changes in gene expression, glucose uptake, and protein synthesis.2Whether insulin resistance alters exercise-induced signal transduction processes in muscle is unknown, but the differences, if present, may help to explain why exercise-induced skeletal muscle adaptations can differ between normal and insulin-resistant populations. It is well established that increased muscle loading increases the rates of muscle protein synthesis.27 This increase in protein synthesis, at least in part, is thought to be regulated by the phosphorylation of the p70 ribosomal protein S6 kinase (p70S6k),26 whose activation has been proposed to promote increased translation of messages that have a polypyrimide motif just downstream of the 5′ cap.45 It is believed that p70S6k activity is regulated by the mammalian target of rapamycin (mTOR), which functions as a growth factor and nutrient-sensing signaling molecule in mammalian cells.40 How mTOR activity is modulated is not clear; however, recent evidence suggests that mTOR is controlled by Akt or protein kinase B (PKB), which is activated in response to phospholipid products of the phosphatidylinositol 3-kinase (PI3K) reaction. It is well documented that binding of insulin to the membrane receptor stimulates a cascade of phosphorylation events resulting in activation of PI3K. It is likely that PKB/Akt directly increases mTOR activity by phosphorylating mTOR at Ser2448, and it has been hypothesized that this event is a critical point of control in the regulation of protein synthesis.4 It has been postulated that p70S6k signaling may be particularly important in mediating muscle adaptation given that the phosphorylation of this molecule following an exercise bout has been found to be strongly associated with the increase in muscle weight after 6 weeks of chronic stimulation. The purpose of the present study was to determine whether insulin resistance alters p70S6k signaling after an acute episode of contractile activity. To investigate this possibility, muscle signaling was examined in 12-week-old lean and obese Zucker rats, as it is widely accepted that the insulin resistance exhibited by these animals closely models the development of type 2 diabetes seen in humans.3, 18, 25, 39 We hypothesized that insulin resistance would be associated with differences in how muscle contraction regulates the phosphorylation of the Akt/TOR/p70S6k signaling cascade. To test this hypothesis, the contraction-mediated activation of Akt, mTOR, and p70S6k was assessed either immediately after or 1 or 3 h after a single bout of sciatic nerve stimulation. Taken together, our data suggest that insulin resistance alters contraction-induced p70S6k phosphorylation in skeletal muscle. These findings are consistent with the possibility that insulin resistance alters the way skeletal muscle “senses and responds” to contractile stimuli

Three-dimensional culture of human meniscal cells: Extracellular matrix and proteoglycan production

<p>Abstract</p> <p>Background</p> <p>The meniscus is a complex tissue whose cell biology has only recently begun to be explored. Published models rely upon initial culture in the presence of added growth factors. The aim of this study was to test a three-dimensional (3D) collagen sponge microenvironment (without added growth factors) for its ability to provide a microenvironment supportive for meniscal cell extracellular matrix (ECM) production, and to test the responsiveness of cells cultured in this manner to transforming growth factor-β (TGF-β).</p> <p>Methods</p> <p>Experimental studies were approved prospectively by the authors' Human Subjects Institutional Review Board. Human meniscal cells were isolated from surgical specimens, established in monolayer culture, seeded into a 3D scaffold, and cell morphology and extracellular matrix components (ECM) evaluated either under control condition or with addition of TGF-β. Outcome variables were evaluation of cultured cell morphology, quantitative measurement of total sulfated proteoglycan production, and immunohistochemical study of the ECM components chondroitin sulfate, keratan sulfate, and types I and II collagen.</p> <p>Result and Conclusion</p> <p>Meniscal cells attached well within the 3D microenvironment and expanded with culture time. The 3D microenvironment was permissive for production of chondroitin sulfate, types I and II collagen, and to a lesser degree keratan sulfate. This microenvironment was also permissive for growth factor responsiveness, as indicated by a significant increase in proteoglycan production when cells were exposed to TGF-β (2.48 μg/ml ± 1.00, mean ± S.D., vs control levels of 1.58 ± 0.79, p < 0.0001). Knowledge of how culture microenvironments influence meniscal cell ECM production is important; the collagen sponge culture methodology provides a useful in vitro tool for study of meniscal cell biology.</p