Critical Growth Factor Research Articles

Prospects of competitive process innovation business in Brazil: critical factors for competitiveness, productivity and growth

The economic conditions of recent times require a structural changing and, mainly, behavioral ones of Brazilian business. The scenario created by big economic powers shows the difference between Brazilian industries and service sectors when it is compared business issues, for example, competitiveness, productivity and innovation, with others countries. The technological innovation consists in a critical factor for competitiveness and for the global economic development; moreover, it can be found in industrial sectors (responsible for materialization and organization of operational system of production process) and in service sectors (which make planning of the contracted activity). Innovation should not be included only in these two economic sectors; however, it has to be included in the economic thought of countries. It has to be highlighted the fact that innovation is not the unique factor of competitiveness, but, productivity and knowledge make the same impact in competitiveness as innovation does. Besides, external and internal demands predict trends in terms of searching products, process an strategies, which can promote a better interaction between market and productivity control. In a global context, Brazil, specially, has a lot of techniques to learn in terms of how to use its resources in a adequate way, independently if they are natural or not. That is why studies about critical factors for competitiveness are determined for the Brazil's sustainable growth.

Critical challenges affecting Islamic banking growth in India using Analytical Hierarchy Process (AHP)

The banking sector plays a vital role in growth-supporting factor for economic growth in the world’s fastest-growing economies like India. Recently, Islamic banking has become an increasingly popular method for alleviating poverty, financial inclusion and economic development around the world. Its importance is highly needed in developing and emerging countries such as India. The main purpose of the paper is to identify and prioritize the critical impeding factors for Islamic banking growth in India. The study is conducted in two stages: the first stage involves investigating the current literature works regarding the challenges facing Islamic banking industry in India, while the second stage is based on identifying and prioritizing these challenges according to its importance in hindering Islamic banking growth by Analytic Hierarchy Process (AHP). AHP is a multi-criterion decision making tool for organizing and analyzing decisions, based on qualitative and quantitative measures. The results show that the regulatory environmental challenge is the most significant factor among other factors in impeding the growth of Islamic banking in India followed by lack of Islamic banking experts and scholars. The third main challenge is lack of awareness for Islamic banking instruments followed by lack of standardization and the last is lack of cooperation and coordination between Islamic banking authorities. This study is considered the first one to address empirically the challenges facing Islamic banking industry in the world and particularly in India.

EPA + DHA supplementation reduces PMN activation in microenvironment of chronic venous leg ulcers: A randomized, double-blind, controlled study.

Sustained high levels of activated polymorphonuclear leukocytes (PMNs) and PMN-derived proteases in the microenvironment of chronic venous leg ulcers (CVLUs) are linked to chronic inflammation and delayed healing. Uncontrolled PMN activity eventually destroys newly developed tissue and degrades critical growth factors. The bioactive components of fish oil (n-3 eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) have strong inflammation-resolving actions and have been shown to assuage PMN activity, but have not been tested in CVLU patients. This randomized controlled study compared the effectiveness of oral EPA + DHA therapy to a placebo for reducing PMN activation in CVLU microenvironments. At Days 0, 28, and 56, markers of PMNs (CD15) and activated PMNs (CD66b), and levels of PMN-derived proteases human neutrophil elastase and matrix metalloproteinase-8 were measured in CVLU fluid from patients receiving standard compression therapy and (1) EPA + DHA therapy (n = 16) or (2) placebo (n = 19). By Day 56, the EPA + DHA Group had a significantly lower percentage of CD66b+ cells in CVLU fluid compared to Day 0 (p = 0.02) and to Day 28 (p = 0.05). Importantly, there were downward trends in levels of both matrix metalloproteinase-8 and human neutrophil elastase over time in the EPA + DHA Group, which also demonstrated greater reductions in wound area by Day 28 (57% reduction) and Day 56 (76% reduction) than the Control Group (35% and 59%, respectively). Moreover, reductions in wound area had significant negative relationships with CD15+ cells in wound fluid at Days 28 (p = 0.008) and 56 (p < 0.001), and CD66b+ cells at Days 28 (p = 0.04) and 56 (p = 0.009). The collective findings provide supplemental evidence that high levels of activated PMNs in CVLU microenvironments inhibit healing, and suggest that EPA + DHA oral therapy may modulate PMN activity and facilitate healing of CVLUs when added to standard care regimens.

Abstract 2497: Differential requirement of amino acids on cell survival of ovarian cancer cells

Abstract Amino acids (AAs) are traditionally classified into nutritionally essential AAs (EAAs) or nonessential AAs (NEAAs) for animals and humans. Recent studies have demonstrated that not only EAAs but also NEAAs play important roles on energy metabolisms in cancer cells. However, which AAs are indispensable for human cancer cell survival has not been fully elucidated. The purposes of this study were 1) to determine the indispensable AAs for ovarian cancer (OVC) cells and 2) to investigate the relationship between the AAs synthetase and cancer cell survival. Firstly, OVC cell lines were cultured with different medium in which each AA was depleted and cancer cell survival was examined. Among 17 OVC cell lines, EAAs were required in 12 cell lines, whereas others did not require EAAs for cell survival. Interestingly, cancer cell lines which required EAA also required at least one NEAAs, including arginine, cystine, glutamine, serine and tyrosine. Although extracellular glutamine has been known to be a critical factor for cancer cell survival and growth, 3 OVC cell lines did not require extracellular glutamine. Hence, we next examined glutamine synthetase (GS) gene, which is a critical enzyme for production of endogenous glutamine from glutamate. In OVC cell lines which did not require extracellular glutamine, GS expression level was positively correlated with cell survival rate under glutamine-depleted condition. Furthermore, we found that the expression of GS protein was negative in 38 of 645 primary OV tumors (5.9 %). Taken together, these results suggest that GS-down-regulated OVC cells require extracellular glutamine for their survival. Therefore, uptake inhibition of extracellular glutamine or reduction of extracellular glutamine level may be a novel therapeutic strategy for patients with ovarian cancer with “GS down-regulation”, as well as development of an AA-based precision medicine of OVC. Citation Format: Akiko Furusawa, Jun Inoue, Hitoshi Tsuda, Naoyuki Miyasaka, Johji Inazawa. Differential requirement of amino acids on cell survival of ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2497. doi:10.1158/1538-7445.AM2017-2497

Espousal of Welfare Schemes

Employee welfare is a prerequisite and critical factor for growth of any organization. The welfare facilities improve the organizational relations, and also enhance the competence and effectiveness of the employees. The employees' work life is vital, as they are the pillars of an organization. The main aim of implementing the welfare schemes in any organization is to secure the labour force by providing proper human condition of work and minimizing its hazardous effect on the life of the employees and their family members. The present study is an attempt to determine the various employee welfare schemes adopted by different private pharmaceutical companies, and its impact on the employee's satisfaction on work life.

Abstract SY28-01: Stromal contributions of adipocytes to cancer

Abstract The past few years have provided substantial evidence for the vital role of the local tumor microenvironment in various aspects of tumorigenesis. With obesity and its pathophysiologic sequelae still on the rise, the adipocyte is increasingly moving to center stage in the context of tumor stroma-related studies. To date, we have limited insights into how systemic changes associated with obesity and altered adipokine secretion influence the incidence and progression of obesity-associated cancers. Adipocytes are the major constituents of adipose tissue and play a key role in whole body metabolism. They not only fulfill an important role as a buffer for excess triglycerides, but they also secrete many lipid and protein factors and are therefore considered major endocrine cells that influence metabolism of other tissues, including liver, muscle, brain, and pancreatic β-cells. With chronic excess of energy intake, adipocytes develop hypertrophy and face various physiologic insults, such as hypoxia, oxidative stress, and disruptions in the protein secretory pathway due to ER stress. As a result, adipocytes become dysfunctional and less efficient at fulfilling their primary function of storing and neutralizing potentially toxic free fatty acids. Adipocyte dysfunction has been widely appreciated as a major cause underlying obesity-related metabolic disorders, including insulin resistance, type 2 diabetes, cardiovascular disease, chronic inflammation, and cancers due to inappropriate release of mitogenic and inflammatory factors. As a result, these dysfunctional adipocytes also support the growth of infiltrating transformed ductal epithelial cells in the mammary gland, at the level of secretion of critical growth factors, proinflammatory cytokines, increased ECM production, and support of tumor lesion growth through release of critical metabolites. Therefore, the adipocyte with its paracrine influence on the microenvironment as well as its endocrine functions is an important area of research for both primary and metastatic tumor growth. Citation Format: Philipp E. Scherer. Stromal contributions of adipocytes to cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY28-01. doi:10.1158/1538-7445.AM2017-SY28-01

Design and optimization of PLGA microparticles for controlled and local delivery of Neuregulin-1 in traumatic spinal cord injury

Spinal cord injury (SCI) results in significant tissue damage that underlies functional impairments. Pharmacological interventions to confer neuroprotection and promote cell replacement are essential for SCI repair. We previously reported that Neuregulin-1 (Nrg-1) is acutely and permanently downregulated after SCI. Nrg-1 is a critical growth factor for differentiation of neural precursor cells (NPCs) into myelinating oligodendrocytes. We showed that intrathecal delivery of Nrg-1 enhances oligodendrocyte replacement following SCI. While an effective delivery system, intrathecal and systemic administration of growth factors with diverse biological targets may pose adverse off-target effects. Here, we have developed and optimized an injectable biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles system for sustained and prolonged intraspinal delivery of Nrg-1 in SCI. Recombinant human Nrg-1β1 peptide was encapsulated into PLGA microparticles. Optimal Nrg-1 release rate and duration were achieved by manipulating the porosity and size of PLGA particles. Our in vitro analysis showed a direct correlation between particle size and porosity with Nrg-1 release rate, while Nrg-1 loading efficiency in PLGA microparticles was inversely correlated with particle porosity. In SCI, local intraspinal injection of PLGA-Nrg-1 microparticles maintained significantly higher tissue levels of Nrg-1 for a long-term duration compared to Nrg-1 delivered intrathecally by osmotic pumps. Bioactivity of Nrg-1 in PLGA microparticles was verified by promoting oligodendrocyte differentiation of NPCs in vitro, and preservation of oligodendrocytes and axons in SCI. PLGA-Nrg-1 also attenuated neuroinflammation and glial scarring following SCI. We show, for the first time, the feasibility, efficacy and safety of PLGA microparticle system for local and controlled administration of Nrg-1 in SCI.

Role of vitamin A in the healing process of alkali caused corneal injury of adult male albino rat: Histological and immunohistochemical study

Background and Aim: Alkali burn of the cornea is considered as the most dangerous injury to the eye. It causes cornealinfection, ulceration, perforation, neovascularization (NV) and opacification. Vitamin A is necessary for the normal growth and differentiation of epithelium; it is expected to promote the mechanical repair of corneal epithelial defectsThe present study is planned to investigate the effect of vitamin A eyegel on wound healing of the corneal alkali burn in rats. Materials and Methods: A total of thirty male albino rats were used. Rats were divided randomly into four groups: Group I,the control group; included three rats, received distilled water. Each of group II, III, IV included 9 rats: their central corneas of the right eyes were injured by contacting them with filter paper saturated with 0.01 m NaOH for 45 seconds. Group II, the non-treated group, injured and received distilled water. Group III, the antibiotic treated group, received antibiotic eye drops (lincomycin hydrochloride eye drops) 3 times per day for 3 days. Group IV, vitamin A treated group, received the same course of antibiotic and vitamin A eye gel (Hypotear gel 1000 IU/g) three times per day. for 3 days. The eyeball was taken out, rapidly fixed and processed for light microscopic, immunohistochemical and morphometric studies. Specimens were taken after 24,48 and 72 hr. post-injury for tissue preparation and study of structural changes and immuno-histochemical analysis using Ki67 (detection of cellular proliferation) and transforming growth factor – beta (TGF-β) which is one of the most critical growth factors in establishing the pathologic lesion after corneal alkali burn. Results: Hematoxylin and eosin stained sections showed rapid healing of corneal ulcer in vitamin A treated group, with absence of neo-vasculariztion and inflammatory cellular infiltration. Immunohistochemical results showed that the use of vitamin A enhance cell proliferation (detected with Ki67) and decrease the expression of TGF-β which is one of the most critical growth factors in establishing the pathological lesion after corneal alkali burn.Conclusions: Vitamin A eye gel helped rapid healing of corneal alkali burn. This effect may be due to its anti-inflammatoryeffect and stimulation of cell proliferation.

Biologically Triggered Delivery of EGF from Polymer Fiber Patches.

Wound healing is modulated by complex spatial and temporal regulation of growth factors within a wound site. Regenerative medicine seeks to generate materials that can mimic this environment for the healing of chronic or traumatic wounds. Herein, we report a programmed release of epidermal growth factor (EGF) from coextruded polymer fiber patches, which is triggered by the natural biological cascade of wound healing. Genetically engineered EGF containing a matrix metalloproteinase (MMP) cleavage site was covalently conjugated to a nonwoven poly(ε-caprolactone) (PCL) fiber mat fabricated by multilayered melt coextrusion. The genetically modified EGF showed rapid release in the presence of a biological trigger, MMP-9, while a control protein showed negligible release. The biologically responsive fiber mat dramatically enhanced proliferation and migration of human keratinocytes in the presence of MMP-9. This study describes the release of a critical wound-healing growth factor as triggered by the biology inherent in the healing process.

Th17 cell-mediated immune responses promote mast cell proliferation by triggering stem cell factor in keratinocytes

Although mast cells are traditionally thought to function as effector cells in allergic responses, they have increasingly been recognized as important regulators of various immune responses. Mast cells mature locally; thus, tissue-specific influences are important for promoting mast cell accumulation and survival in the skin and the gastrointestinal tract. In this study, we determined the effects of keratinocytes on mast cell accumulation during Th17-mediated skin inflammation. We observed increases in dermal mast cells in imiquimod-induced psoriatic dermatitis in mice accompanied by the expression of epidermal stem cell factor (SCF), a critical mast cell growth factor. Similar to mouse epidermal keratinocytes, SCF was highly expressed in the human HaCaT keratinocyte cell line following stimulation with IL−17. Further, keratinocytes promoted mast cell proliferation following stimulation with IL−17 in vitro. However, the effects of keratinocytes on mast cells were significantly diminished in the presence of anti−CD117 (stem cell factor receptor) blocking antibodies. Taken together, our results revealed that the Th17-mediated inflammatory environment promotes mast cell accumulation through keratinocyte-derived SCF.

Dietary Diversity of Children 6–23 months Is Limited by Age Related Complementary Feeding Practices as well as Household Dietary Diversity in Peru, Bangladesh and Sierra Leone

BackgroundComplementary feeding of infants and young children (IYC) 6–23 months is a critical factor for healthy growth and development. Dietary diversity (DD)‐‐the number of different food groups consumed‐‐is a proxy for micronutrient adequacy; minimum dietary diversity (MDD) is a WHO indicator used to assess the adequacy of complementary feeding in an IYC population. DD at the household level provides a measure of the food groups consumed in the home and thus potentially available for children. The comparison of household with child DD permits exploration of whether inadequate child DD is due to lack of availability in the home or intra‐household distribution to the child. Although a number of factors have been described in relation to child DD, the literature is limited regarding its relation with household DD.ObjectivesThis study examined firstly, the association between household and child DD in poor, mostly rural areas of 3 diverse countries: Peru—a middle income country, Bangladesh and Sierra Leone—both low‐income countries; and secondly, this same association across three IYC age groups (6–8 months, 9–11 months, 12–23 months) in each country.MethodsData were collected as part of the endline surveys following implementation of CARE's Window of Opportunity intervention which aimed to improve the diet and growth of children 0–23 months. Randomly sampled households in the intervention districts were selected (Peru n=402, Bangladesh n=1905, Sierra Leone n=585). DD was derived from 24 hour dietary recalls of the child's intake and HH food group consumption. The foods consumed in each case were assigned to 7 food groups (WHO): cereals/tubers/roots, flesh foods, eggs, dairy, legumes, vitamin A fruits/vegetables and other fruits/vegetables. Household and IYC consumption were compared in bivariate analysis. Generalized linear modeling (GLM) was used to examine MDD (a dichotomous variable)—which was met when IYC consumed 4 or more of the 7 groups.ResultsMDD was met by 89% of children in Peru, 61% in Bangladesh, and 53% in Sierra Leone. For each food group, with the exception of dairy, more households than IYC consumed them in all 3 countries. A clear and steep increase in consumption of each food group was seen by child's age group in all countries; youngest children had the lowest frequency of consumption (Table 1). In country specific GLM models, increasing household DD was significantly associated with meeting MDD (Odds Ratio (OR) range 2.0 to 3.0), controlling for mother's education, household food security and child's age group. In these same models, compared to IYC 6–8 months, older children had strong, independent associations with meeting MDD; 9–11 months (OR range 3.2 to 5.3), and 12–23 months (OR range 6.0 to 10.7).ConclusionsInfants 6–8 months were at significantly greater risk for not meeting MDD compared to children 9–11 and 12–23 months. While greater household DD decreased IYC risk for not meeting MDD, the comparison of foods consumed in the household versus the child's diet suggests that household DD, representing availability of foods, was not necessarily the main limiting factor. The variety of available food groups within the household, intra‐household distribution and/or caregiver selection of foods may all limit IYC DD. Future work should focus on understanding the barriers and facilitators for providing children with the full range of foods available so that DD among IYC, especially those in the youngest age group, can be improved.Support or Funding InformationCARE USA; The Catholic University of America Household and Child Consumption of Food Groups in 3 Countries image

Regulation of endometrial cell proliferation by estrogen-induced BDNF signaling pathway

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin growth factors family. Recent studies indicated that the level of BDNF in follicular fluid is a marker for oocyte quality and infertility. Here, we intend to further investigate the function of BDNF and its signaling pathway in the regulation of endometrial cells proliferation. We found that BDNF is a critical growth factor in endometrial cells. Activation of signal transducer and activator of transcription 3 signaling pathway is required for BNDF-regulated endometrial cell proliferation. Furthermore, BDNF is an effector of estrogen in endometrial cells. Finally, we investigated the different role of Val66Met, a single-nucleotide polymorphism of the BDNF gene, in regulating endometrial cells proliferation. The results showed that BDNFV66M polymorphism is a loss-of-function polymorphism in the regulation of endometrial cells growth. Given the correlation between endometriosis and infertility, it is important to understand the role of BDNF in regulating endometrial cells proliferation and to develop new therapeutic strategies for the treatment of endometriosis-related infertility.

The effects of perinatal steroid therapy on growth factor levels during different stages of the developing brain

Objective: Excess glucocorticoid (GC) exposure on the fetal brain during critical stages of development has considerable effects on the development of the central nervous system (CNS). This study thus aimed to evaluate the differential effects of GC exposure on critical growth factor levels during different stages of brain maturation.Methods: For this purpose, forty-two rat pups were divided into six groups based on the timing of betamethasone administration. Rats in the treatment groups were exposed to intraperitoneal betamethasone injections beginning at different time points (postnatal days 1, 2, and 3). Rats in the placebo group received the same volume of 0.9% saline via the same fashion. Pups were sacrificed at 24 h following the final injection for determining the neuronal density and immunohistochemical evaluation of critical growth factors.Results: In the groups treated with betamethasone on postnatal day 1 (P1) and P2, which correspond to 22–24 and 24–28 gestational weeks in humans, the neuronal count in the hippocampal regions was significantly lower than their control groups. However, if steroid therapy was administered on P3, corresponding to 28–32 weeks in humans, no difference was observed between the two groups. Growth factors were affected in different ways depending on the steroid administration time and evaluated region.Conclusions: The results suggest that the modulating effect of steroids on neuron count and growth factor response depends on the stage of brain development at the time of exposure. Therefore, this may be one of the key determinants affecting the deleterious and beneficial effects of GCs on the CNS.

A new hope for obesity management: Boron inhibits adipogenesis in progenitor cells through the Wnt/β-catenin pathway

Obesity is a worldwide medical problem resulting in serious morbidity and mortality involving differentiation of pre-adipocytes into mature adipocytes (adipogenesis). Boron treatment has been reported to be associated with weight reduction in experimental animals; however, its effects on pre-adipocyte differentiation and anti-adipogenic molecular mechanisms are unknown.In this study, we demonstrate the inhibitory activities of boric acid (BA) and sodium pentaborate pentahydrate (NaB) on adipogenesis using common cellular models. Boron treatment repressed the expression of adipogenesis-related genes and proteins, including CCAAT-enhancer-binding protein α and peroxisome proliferator-activated receptor γ, by regulating critical growth factors and the β-catenin, AKT, and extracellular signal-regulated kinase signaling pathways. In addition, although boron treatment did not induce apoptosis in pre-adipocytes, it depressed mitotic clonal expansion by regulation of cell cycle genes.Overall, these data offer promising insights into the prevention/treatment of obesity and associated diseases.

A Chemoattractant-Guided Walk Through Lymphopoiesis: From Hematopoietic Stem Cells to Mature B Lymphocytes.

B lymphocytes develop from hematopoietic stem cells (HSCs) in specialized bone marrow niches composed of rare mesenchymal lineage stem/progenitor cells (MSPCs) and sinusoidal endothelial cells. These niches are defined by function and location: MSPCs are mostly perisinusoidal cells that together with a small subset of sinusoidal endothelial cells express stem cell factor, interleukin-7 (IL-7), IL-15, and the highest amounts of CXCL12 in bone marrow. Though rare, MSPCs are morphologically heterogeneous, highly reticular, and form a vast cellular network in the bone marrow parenchyma capable of interacting with large numbers of hematopoietic cells. HSCs, downstream multipotent progenitor cells, and common lymphoid progenitor cells utilize CXCR4 to fine-tune access to critical short-range growth factors provided by MSPCs for their long-term maintenance and/or multilineage differentiation. In later stages, developing B lymphocytes use CXCR4 to navigate the bone marrow parenchyma, and predominantly cannabinoid receptor-2 for positioning within bone marrow sinusoids, prior to being released into peripheral blood circulation. In the final stages of differentiation, transitional B cells migrate to the spleen where they preferentially undergo further rounds of differentiation until selection into the mature B cell pool occurs. This bottleneck purges up to 97% of all developing B cells in a peripheral selection process that is heavily controlled not only by the intensity of BCR signaling and access to BAFF but also by the proper functioning of the B cell motility machinery.

Sirtuin-6 Preserves R-spondin-1 Expression and increases Resistance of intestinal Epithelium to injury in Mice

Sirtuin-6 (Sirt6) is a critical epigenetic regulator, but its function in the gut is unknown. Here, we studied the role of intestinal epithelial Sirt6 in colitis-associated intestinal epithelial injury. We found that Sirt6, which is predominantly expressed in epithelial cells in intestinal crypts, is decreased in colitis in both mice and humans. Colitis-derived inflammatory mediators including interferon-γ and reactive oxygen species strongly inhibited Sirt6 protein expression in young adult mouse colonocyte (YAMC) cells. The susceptibility of the cells to injurious insults was increased after knockdown of Sirt6 expression. In contrast, YAMC cells with Sirt6 overexpression exhibited more resistance to injurious insult. Furthermore, intestinal epithelial-specific Sirt6 (Sirt6IEC-KO) knockout mice exhibited greater susceptibility to dextran sulfate sodium (DSS)-induced colitis. RNA sequencing transcriptome analysis revealed that inflammatory mediators such as tumor necrosis factor (TNF)-α suppressed expression of R-spondin-1 (Rspo1, a critical growth factor for intestinal epithelial cells) in Sirt6-silenced YAMC cells in vitro. In addition, lipopolysaccharide was found to inhibit colonic Rspo1 expression in Sirt6IEC-KO mice but not their control littermates. Furthermore, Sirt6IEC-KO mice with DSS-induced colitis also exhibited in a significant decrease in Rspo1 expression in colons. In vitro, knockdown of Rspo1 attenuated the effect of ectopic expression of Sirt6 on protection of YAMC cells against cell death challenges. In conclusion, Sirt6 plays an important role in protecting intestinal epithelial cells against inflammatory injury in a mechanism associated with preserving Rspo1 levels in the cells.

The Pathways and Challenges of University Engagement: Comparative Case Studies in Austria

The Pathways and Challenges of University Engagement: Comparative Case Studies in Austria

Enhanced peripheral dopamine impairs post-ischemic healing by suppressing angiotensin receptor type 1 expression in endothelial cells and inhibiting angiogenesis.

Increased circulating catecholamines have been linked with cardiovascular anomalies as well as with peripheral vascular diseases. Although the roles of epinephrine and norepinephrine have received considerable attention, the role of the other catecholamine, dopamine, has been less studied. Since dopamine is a potent endogenous inhibitor of angiogenesis and as angiogenesis is essential for ischemic healing, we therefore studied the role played by dopamine during ischemic healing using dopamine D2 receptor knockout (KOD2) mice. Although concentration of dopamine and its rate-limiting enzyme, tyrosine hydroxylase, was considerably high in the muscle tissues of wild-type and KOD2 mice with unilateral hind limb ischemia (HLI), recovery was significantly faster in the KOD2 mice compared to the wild-type controls, thereby indicating that peripheral dopamine might have a role in this healing process. In addition, we observed significant differences in post-ischemic angiogenesis between these two groups. Our study further revealed that elevated dopamine independently suppressed activation of local tissue-based renin-angiotensin system (RAS), a critical growth factor system stimulating angiogenesis in ischemia. Angiotensin II (ATII) and its receptor, angiotensin receptor type 1 (AT1R), are the key players in RAS-mediated angiogenesis. Dopamine acting through its D2 receptors in endothelial cells inhibited ATII-mediated angiogenesis by suppressing the expression of AT1R in these cells. This study thus for the first time demonstrates the role played by dopamine in prolonging post-ischemic recovery. Therefore, pharmacological intervention inhibiting the action of dopamine holds promise as future therapeutic strategy for the treatment of HLI and other peripheral arterial diseases.

Synergistic targeting of Sp1, a critical transcription factor for myeloma cell growth and survival, by panobinostat and proteasome inhibitors.

Panobinostat, a pan-deacetylase inhibitor, synergistically elicits cytotoxic activity against myeloma (MM) cells in combination with the proteasome inhibitor bortezomib. Because precise mechanisms for panobinostat's anti-MM action still remain elusive, we aimed to clarify the mechanisms of anti-MM effects of panobinostat and its synergism with proteasome inhibitors. Although the transcription factor Sp1 was overexpressed in MM cells, the Sp1 inhibitor terameprocol induced MM cell death in parallel with reduction of IRF4 and cMyc. Panobinostat induced activation of caspase-8, which was inversely correlated with reduction of Sp1 protein levels in MM cells. The panobinostat-mediated effects were further potentiated to effectively induce MM cell death in combination with bortezomib or carfilzomib even at suboptimal concentrations as a single agent. Addition of the caspase-8 inhibitor z-IETD-FMK abolished the Sp1 reduction not only by panobinostat alone but also by its combination with bortezomib, suggesting caspase-8-mediated Sp1 degradation. The synergistic Sp1 reduction markedly suppressed Sp1-driven prosurvival factors, IRF4 and cMyc. Besides, the combinatory treatment reduced HDAC1, another Sp1 target, in MM cells, which may potentiate HDAC inhibition. Collectively, caspase-8-mediated post-translational Sp1 degradation appears to be among major mechanisms for synergistic anti-MM effects of panobinostat and proteasome inhibitors in combination.

PS 01-18] MECHANISM OF HYPERTENSIVE CARDIAC HYPERTROPHY IN CULTURED NEONATAL RAT VENTRICULAR CARDIAC MYOCYTES

Objective: hypertrophy and impaired cardiac function are commonly observed in some patients with hypertension. Angiotensin II is a critical growth factor to mediate cardiac hypertrophy. MicroRNAs (miRs) have been identified and associated with several cardiovascular diseases, including ischemic cardiomyopathy and cardiac hypertrophy. MiR-21 was reported to be upregulated during adult rat cardiac remodeling. The importance of miR-21* in cardiomyocyte hypertrophy has also been demonstrated. Design and Method: Wistar rats (weight, 120–150 g) were purchased. Ventricular cardiomyocytes were isolated from 1 to 2-day-old neonatal wistar rat as described previously with minor modification. After 24 h of serum starvation, the cardiomyocytes were stimulated with or without 1 umol/L Ang II for 48 h. The hypertrophy cardiomyocytes were identified by semi-quantitative RT-PCR assay. Total miRNAs were extracted using mirVANA miRNA isolation kit. The miRNAs quality and quantity were determined by a NanoDrop 1000 Spectrophotometer. The miRNAs were reverse transcribed by TaqMan MicroRNA Reverse Transcription Kit. qRT-PCR was performed using TaqMan Universal PCR Master Mix II on the ABI 7500 System according to the manufacturer's recommendations. Total proteins isolated from cultured cardiomyocytes, with or without 1 umlo/L Ang II for 48 h, were prepared by M-PER mammalian protein extraction reagent. SDS-polyacrylamide gel electrophoresis was performed using standard procedures. Results: We demonstrated that miR-21* was markedly upregualted in Ang II-induced neonatal rat cardiac myocytes, while miR-21 was reduced. We might speculate that the miRNA expression profile is different between neonatal rat and adult rat cardiac myocytes. Our results further showed that Ang II led to a significant reduction of PTEN expression level and a significant promotion of phosphorylation level of PI3K. In contrast, treatment with prohypertrophic molecule Ang II reduced the phosphorylation level of Akt. Conclusions: We therefore speculate that miR-21* might have two opposite effects on Ang II-induced cardiac hypertrophy through various signaling pathways.