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Search Results: 1 - 10 of 445973 matches for " Carlos M. Isales "
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Energy Balance, Myostatin, and GILZ: Factors Regulating Adipocyte Differentiation in Belly and Bone
Xingming Shi,Mark Hamrick,Carlos M. Isales
PPAR Research , 2007, DOI: 10.1155/2007/92501
Abstract: Peroxisome proliferator-activated receptor gamma (PPAR-γ) belongs to the nuclear hormone receptor subfamily of transcription factors. PPARs are expressed in key target tissues such as liver, fat, and muscle and thus they play a major role in the regulation of energy balance. Because of PPAR-γ's role in energy balance, signals originating from the gut (e.g., GIP), fat (e.g., leptin), muscle (e.g., myostatin), or bone (e.g., GILZ) can in turn modulate PPAR expression and/or function. Of the two PPAR-γ isoforms, PPAR-γ2 is the key regulator of adipogenesis and also plays a role in bone development. Activation of this receptor favors adipocyte differentiation of mesenchymal stem cells, while inhibition of PPAR-γ2 expression shifts the commitment towards the osteoblastogenic pathway. Clinically, activation of this receptor by antidiabetic agents of the thiazolidinedione class results in lower bone mass and increased fracture rates. We propose that inhibition of PPAR-γ2 expression in mesenchymal stem cells by use of some of the hormones/factors mentioned above may be a useful therapeutic strategy to favor bone formation.
Glucocorticoid-Induced Leucine Zipper (GILZ) Antagonizes TNF-α Inhibition of Mesenchymal Stem Cell Osteogenic Differentiation
Linlin He,Nianlan Yang,Carlos M. Isales,Xing-Ming Shi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031717
Abstract: Tumor necrosis factor-alpha (TNF-α) is a potent proinflammatory cytokine that inhibits osteoblast differentiation while stimulating osteoclast differentiation and bone resorption. TNF-α activates MAP kinase pathway leading to inhibition of osterix (Osx) expression. TNF-α also induces the expression of E3 ubiquitin ligase protein Smurf1 and Smurf2 and promotes degradation of Runx2, another key transcription factor regulating osteoblast differentiation and bone formation. We showed previously that overexpression of glucocorticoid (GC)-induced leucine zipper (GILZ) enhances osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs). We and others also showed that GILZ is a GC effecter and mediates GC anti-inflammatory activity. In this study, we asked the question whether GILZ retains its osteogenic activity while functioning as an anti-inflammatory mediator. To address this question, we infected mouse bone marrow MSCs with retroviruses expressing GILZ and induced them for osteogenic differentiation in the presence or absence of TNF-α. Our results show that overexpression of GILZ antagonized the inhibitory effects of TNF-α on MSC osteogenic differentiation and the mRNA and protein expression of Osx and Runx2, two pivotal osteogenic regulators. Further studies show that these antagonistic actions occur via mechanisms involving GILZ inhibition of TNF-α-induced ERK MAP kinase activation and protein degradation. These results suggest that GILZ may have therapeutic potential as a novel anti-inflammation therapy.
Stromal Cell-Derived Factor-1β Mediates Cell Survival through Enhancing Autophagy in Bone Marrow-Derived Mesenchymal Stem Cells
Samuel Herberg, Xingming Shi, Maribeth H. Johnson, Mark W. Hamrick, Carlos M. Isales, William D. Hill
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0058207
Abstract: Bone marrow-derived mesenchymal stem/stromal cells (BMSCs) hold great potential for cell-based therapy, yet the therapeutic efficacy remains uncertain. Transplanted BMSCs often fail to engraft within the bone marrow (BM), in part due to the poor survival of donor cells in response to inflammatory reactions, hypoxia, oxidative stress, or nutrient starvation. Two basic cell processes, apoptosis and autophagy, could potentially be responsible for the impaired survival of transplanted BMSCs. However, the functional relationship between apoptosis and autophagy in BMSC homeostasis is complex and not well understood. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) signaling axis appears to be critical in maintaining proliferation and survival of BM stem cell populations through improving cell proliferation and survival in response to stress; however, the exact mechanisms remain unclear. We recently described novel genetically engineered Tet-Off-SDF-1β BMSCs, which over-express SDF-1β under tight doxycycline-control, thus providing an ideal model system to investigate the isolated effects of SDF-1β. In this study we tested the hypothesis that SDF-1β can mediate cell survival of BMSCs in vitro through increasing autophagy. We found that SDF-1β had no effect on BMSC proliferation; however, SDF-1β significantly protected genetically engineered BMSCs from H2O2-induced cell death through increasing autophagy and decreasing caspase-3-dependent apoptosis. Taken together, we provide novel evidence that the SDF-1/CXCR4 axis, specifically activated by the SDF-1β isoform, plays a critical role in regulating BMSC survival under oxidative stress through increasing autophagy.
GIP-Overexpressing Mice Demonstrate Reduced Diet-Induced Obesity and Steatosis, and Improved Glucose Homeostasis
Su-Jin Kim, Cuilan Nian, Subashini Karunakaran, Susanne M. Clee, Carlos M. Isales, Christopher H. S. McIntosh
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040156
Abstract: Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that potentiates glucose-stimulated insulin secretion during a meal. Since GIP has also been shown to exert β-cell prosurvival and adipocyte lipogenic effects in rodents, both GIP receptor agonists and antagonists have been considered as potential therapeutics in type 2 diabetes (T2DM). In the present study, we tested the hypothesis that chronically elevating GIP levels in a transgenic (Tg) mouse model would increase adipose tissue expansion and exert beneficial effects on glucose homeostasis. In contrast, although GIP Tg mice demonstrated enhanced β-cell function, resulting in improved glucose tolerance and insulin sensitivity, they exhibited reduced diet-induced obesity. Adipose tissue macrophage infiltration and hepatic steatosis were both greatly reduced, and a number of genes involved in lipid metabolism/inflammatory signaling pathways were found to be down-regulated. Reduced adiposity in GIP Tg mice was associated with decreased energy intake, involving overexpression of hypothalamic GIP. Together, these studies suggest that, in the context of over-nutrition, transgenic GIP overexpression has the potential to improve hepatic and adipocyte function as well as glucose homeostasis.
Absence of Functional Leptin Receptor Isoforms in the POUND (Leprdb/lb) Mouse Is Associated with Muscle Atrophy and Altered Myoblast Proliferation and Differentiation
Phonepasong Arounleut, Matthew Bowser, Sunil Upadhyay, Xing-Ming Shi, Sadanand Fulzele, Maribeth H. Johnson, Alexis M. Stranahan, William D. Hill, Carlos M. Isales, Mark W. Hamrick
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072330
Abstract: Objective Leptin receptors are abundant in human skeletal muscle, but the role of leptin in muscle growth, development and aging is not well understood. Here we utilized a novel mouse model lacking all functional leptin receptor isoforms (POUND mouse, Leprdb/lb) to determine the role of leptin in skeletal muscle. Methods and Findings Skeletal muscle mass and fiber diameters were examined in POUND mice, and primary myoblast cultures were used to determine the effects of altered leptin signaling on myoblast proliferation and differentiation. ELISA assays, integrated pathway analysis of mRNA microarrays, and reverse phase protein analysis were performed to identify signaling pathways impacted by leptin receptor deficiency. Results show that skeletal muscle mass and fiber diameter are reduced 30–40% in POUND mice relative to wild-type controls. Primary myoblast cultures demonstrate decreased proliferation and decreased expression of both MyoD and myogenin in POUND mice compared to normal mice. Leptin treatment increased proliferation in primary myoblasts from muscles of both adult (12 months) and aged (24 months) wild-type mice, and leptin increased expression of MyoD and myogenin in aged primary myoblasts. ELISA assays and protein arrays revealed altered expression of molecules associated with the IGF-1/Akt and MAPK/MEK signaling pathways in muscle from the hindlimbs of mice lacking functional leptin receptors. Conclusion These data support the hypothesis that the adipokine leptin is a key factor important for the regulation of skeletal muscle mass, and that leptin can act directly on its receptors in peripheral tissues to regulate cell proliferation and differentiation.
The Knee Joint Tissues Differ Significantly in TGFβ1 Expression and Its Sensitivity  [PDF]
Sadanand Fulzele, Monte Hunter, Rajnikumar Sangani, Norman Chutkan, Carlos Isales, Mark W. Hamrick
CellBio (CellBio) , 2013, DOI: 10.4236/cellbio.2013.24022

The knee joint is the largest and most complex joint in the human body. In this study, we investigated TGFβ1 expression in the outer meniscus, inner meniscus and articular cartilage of rabbit and human knee tissue (outer and inner menisci) in order to determine the potential role of this factor in normal meniscal function. We also examined the potential of TGF-β1 stimulation to promote tissue regeneration in the two different regions of rabbit knee meniscus tissue. Immunohistochemical investigations of TGF-β1 were performed on rabbit and human knee tissue. The rabbit outer, inner and articular cartilage cells were culture and stimulated with TGF-β1 followed by cell proliferation assay and extracellular matrix analysis. Regulatory studies were performed using TGF-β1 inhibitors SB-431542 and PD98059. Gene expression was analyzed by quantitative polymerase chain reaction. We found marked regional variation in the expression of TGF-β1 in rabbit and human knee. TGF-β1 expressions are relatively greater in the outer meniscus than inner meniscus. Furthermore, we found that exogenous TGF-β1 stimulation increased cell proliferation and aggrecan synthesis more so in the outer than in the inner meniscus. Articular cartilage tissue shows moderate levels of cell proliferation and ECM synthesis when compared with outer and inner meniscus. These findings suggest that growth factors used to enhance the repair and regeneration of meniscal tissue should be tailored to enhance region-specific variation in cell proliferation and extracellular matrix synthesis.

Aromatic Amino Acid Activation of Signaling Pathways in Bone Marrow Mesenchymal Stem Cells Depends on Oxygen Tension
Mona El Refaey, Qing Zhong, William D. Hill, Xing-Ming Shi, Mark W. Hamrick, Lakiea Bailey, Maribeth Johnson, Jianrui Xu, Wendy B. Bollag, Norman Chutkan, Carlos M. Isales
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091108
Abstract: The physiologic oxygen pressures inside the bone marrow environment are much lower than what is present in the peripheral circulation, ranging from 1–7%, compared to values as high as 10–13% in the arteries, lungs and liver. Thus, experiments done with bone marrow mesenchymal stem cells (BMMSCs) using standard culture conditions may not accurately reflect the true hypoxic bone marrow microenvironment. However, since aging is associated with an increased generation of reactive oxygen species, experiments done under 21%O2 conditions may actually more closely resemble that of the aging bone marrow environment. Aromatic amino acids are known to be natural anti-oxidants. We have previously reported that aromatic amino acids are potent agonists for stimulating increases in intracellular calcium and phospho-c-Raf and in promoting BMMSC differentiation down the osteogenic pathway. Our previous experiments were performed under normoxic conditions. Thus, we next decided to compare a normoxic (21% O2) vs. a hypoxic environment (3% O2) alone or after treatment with aromatic amino acids. Reverse-phase protein arrays showed that 3% O2 itself up-regulated proliferative pathways. Aromatic amino acids had no additional effect on signaling pathways under these conditions. However, under 21%O2 conditions, aromatic amino acids could now significantly increase these proliferative pathways over this “normoxic” baseline. Pharmacologic studies are consistent with the aromatic amino acids activating the extracellular calcium-sensing receptor. The effects of aromatic amino acids on BMMSC function in the 21% O2 environment is consistent with a potential role for these amino acids in an aging environment as functional anti oxidants.
Freedom of Conscience is Freedom of Choice: Women’s Reproductive Needs, Rights, and their Therapeutic Implications  [PDF]
Carlos M. Del Rio
Advances in Applied Sociology (AASoci) , 2012, DOI: 10.4236/aasoci.2012.23028
Abstract: Using reasonableness, we examine the U.S. Catholic bishops’ opposition to provisions of the Affordable Care Act of 2010. Weaving contributions from theology, philosophy, and jurisprudence, we emphasize the reasonable importance of mental health therapy for women within a relevant Catholic/Christian dialogue, particularly in the wake of the U.S. Supreme Court’s decision on healthcare. We principally identify socially imbedded factors that contribute to ending unwanted pregnancies, and argue that freedom of conscience is indeed freedom of choice within which women’s reproductive needs lie under protections of the U.S. Constitution. We recognize that Catholic tradition originates in the words and behaviors of Jesus. Examining closely these actions toward women, we find no reasonable justification for the bishops’ position against women’s freedom of conscience. We also discovered that revelation does not belong exclusively to the bishops; truth continues to be revealed to all human consciences, and true freedom does not allow for coercion/castigation of dogmatic import. We advocate for women’s ability to openly discuss their struggles to meet their reproductive condundra and to deconstruct their sexual stereotypes in mental health therapy. We provide crucial recommendations to augment choices for women’s reproduction condundra, and incite the need for new epistemic frameworks to address the complexity of female sexuality.
Brand Relationships: A Personality-Based Approach  [PDF]
Helena M. Nobre, Kip Becker, Carlos Brito
Journal of Service Science and Management (JSSM) , 2010, DOI: 10.4236/jssm.2010.32026
Abstract: The authors investigated the relationship between brand personality and brand relationships. The conceptual model was based on the hypothesis that brand personality may nurture specific consumer-brand relationships and that these relationships may influence the quality of the ties that consumers develop with brands. An instrument from intimate interpersonal relationships was used to measure consumer-brand relationships. An SEM analysis conducted on a sample of 733 consumer-brand relationships, involving nine highly known brands of different product categories, gave support to the theory. The research offers two significant contributions by: 1) Emphasizing the role of consumer-brand relationship in understanding multi-brand, symbolic consumption and 2) Offering a holistic perspective in the understanding of brand personality.
CT Guided Bone Marrow Aspiration and Core Biopsy  [PDF]
Carlos M. Badiola, Folco Scappaticci, Driola Brahaj
Open Journal of Radiology (OJRad) , 2012, DOI: 10.4236/ojrad.2012.22010
Abstract: Hemorrhagic complications related to bone marrow aspiration and trephine biopsy are uncommon. Risk factors include thrombocytopenia, myeloproliferative disorders, concurrent use of anticoagulants, and obesity. Here we describe our technique for bone marrow aspiration and biopsy of the posterior iliac crest using CT guidance. Our technique ensures needle passage only through subcutaneous fat and bone, avoiding muscle and neurovascular structures, as well as controlled and precise needle advancement within bone. This technique should be considered for use in patients that are at increased risk for procedure related complications, particularly obese patients, where surface anatomical landmarks may prove unreliable.
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