Laurence Madera - Academia.edu (original) (raw)

Papers by Laurence Madera

The Journal of Immunology, Apr 1, 2010

Biochemical and biophysical research communications, Jan 28, 2015

Innate defense regulator (IDR) peptides are a class of immunomodulators which enhance and modulat... more Innate defense regulator (IDR) peptides are a class of immunomodulators which enhance and modulate host innate immune responses against microbial pathogens. While IDR-mediated protection against a range of bacterial pathogens is dependent on enhanced monocyte recruitment to the site of infection, the mechanisms through which they increase monocyte trafficking remain unclear. In this study, anti-infective peptide IDR-1002 was shown to enhance monocyte chemotaxis towards chemokines CCL3 and CCL5. This enhancement correlated with the selective upregulation of CCR5 surface expression by peptide-treated monocytes. It was found that IDR-1002 enhancement of monocyte chemotaxis was fully dependent on CCR5 function. Furthermore, IDR-1002 enhanced chemokine-induced monocyte p38 MAPK phosphorylation in a CCR5-dependent fashion. Overall, these results indicate that peptide IDR-1002 can selectively influence monocyte recruitment by host chemokines through the regulation of chemokine receptors.

Journal of Neuroimmunology, 2014

The Immune Response to Infection, 2011

Cancer Letters, 2015

Piperine, an alkaloid from black pepper, is reported to have anticancer activities. In this study... more Piperine, an alkaloid from black pepper, is reported to have anticancer activities. In this study, we investigated the effect of piperine on the growth and motility of triple-negative breast cancer (TNBC) cells. Piperine inhibited the in vitro growth of TNBC cells, as well as hormone-dependent breast cancer cells, without affecting normal mammary epithelial cell growth. Exposure to piperine decreased the percentage of TNBC cells in the G2 phase of the cell cycle. In addition, G1- and G2-associated protein expression was decreased and p21(Waf1/Cip1) expression was increased in piperine-treated TNBC cells. Piperine also inhibited survival-promoting Akt activation in TNBC cells and caused caspase-dependent apoptosis via the mitochondrial pathway. Interestingly, combined treatment with piperine and γ radiation was more cytotoxic for TNBC cells than γ radiation alone. The in vitro migration of piperine-treated TNBC cells was impaired and expression of matrix metalloproteinase-2 and -9 mRNA was decreased, suggesting an antimetastatic effect by piperine. Finally, intratumoral administration of piperine inhibited the growth of TNBC xenografts in immune-deficient mice. Taken together, these findings suggest that piperine may be useful in the treatment of TNBC.

PLoS ONE, 2013

Macrophages play a critical role in the innate immune response. To respond in a rapid and efficie... more Macrophages play a critical role in the innate immune response. To respond in a rapid and efficient manner to challenges in the micro-environment, macrophages are able to differentiate towards classically (M1) or alternatively (M2) activated phenotypes. Synthetic, innate defense regulators (IDR) peptides, designed based on natural host defence peptides, have enhanced immunomodulatory activities and reduced toxicity leading to protection in infection and inflammation models that is dependent on innate immune cells like monocytes/macrophages. Here we tested the effect of IDR-1018 on macrophage differentiation, a process essential to macrophage function and the immune response. Using transcriptional, protein and systems biology analysis, we observed that differentiation in the presence of IDR-1018 induced a unique signature of immune responses including the production of specific pro and anti-inflammatory mediators, expression of wound healing associated genes, and increased phagocytosis of apoptotic cells. Transcription factor IRF4 appeared to play an important role in promoting this IDR-1018-induced phenotype. The data suggests that IDR-1018 drives macrophage differentiation towards an intermediate M1-M2 state, enhancing anti-inflammatory functions while maintaining certain proinflammatory activities important to the resolution of infection. Synthetic peptides like IDR-1018, which act by modulating the immune system, could represent a powerful new class of therapeutics capable of treating the rising number of multidrug resistant infections as well as disorders associated with dysregulated immune responses.

Journal of Leukocyte Biology, 2013

Although HDPs were originally hypothesized to act as antimicrobial agents, they also have been sh... more Although HDPs were originally hypothesized to act as antimicrobial agents, they also have been shown to broadly modulate the immune response through the activation of different cell types. We recently developed a series of novel, synthetic peptides, termed IDRs, which are conceptually based on a natural HDP, bovine bactenecin. We showed that IDR-1 and IDR-1002 protect the host against bacterial infections through the induction of chemokines. The objective of this study was to investigate the effects of the IDRs on various functions of human neutrophils. Here, we demonstrated that IDR-HH2, IDR-1002, and IDR-1018 modulated the expression of neutrophil adhesion and activation markers. Moreover, these IDRs enhanced neutrophil adhesion to endothelial cells in a β₂ integrin-dependent manner and induced neutrophil migration and chemokine production. The IDR peptides also increased the release of the neutrophil-generated HDPs (antimicrobial), human α-defensins, and LL-37 and augmented neutrophil-mediated killing of Escherichia coli. Notably, the IDRs significantly suppressed LPS-mediated neutrophil degranulation, the release of ROS, and the production of the inflammatory cytokines TNF-α and IL-10, consistent with their ability to dampen inflammation. As evidenced by the inhibitory effects of MAPK-specific inhibitors, IDRs activated the MAPK pathway that was required for chemokine production. In conclusion, our study provides novel evidence regarding the contribution of the IDR peptides to the innate immune response through the modulation of neutrophil functions. The results described here may aid in the development of IDRs as novel, anti-infective and immunomodulatory agents.

Journal of Innate Immunity, 2012

Regulation of the immune system by immunomodulatory agents, such as the synthetic innate defense ... more Regulation of the immune system by immunomodulatory agents, such as the synthetic innate defense regulator (IDR) peptides, has been proposed as a potential strategy to strengthen host immune responses against infection. IDR peptides confer protection in vivo against a range of bacterial infections and have been developed as components of single-dose vaccine adjuvants due to their ability to modulate innate immunity, correlating with an increased recruitment of monocytes to sites of infection or immunization. However, the mechanisms by which IDR peptides augment monocyte recruitment remain poorly defined. Anti-infective peptide IDR-1002 was demonstrated here to lack direct monocyte chemoattractive activity yet enhance, by up to 5-fold, the ability of human monocytes to migrate on fibronectin towards chemokines. This effect correlated with an increased adhesion of monocytes and THP-1 cells to fibronectin by IDR-1002 and other IDR peptides and the adhesion of THP-1 cells to fibronectin occurred in a β(1)-integrin-dependent manner, corresponding with an increased activation of β(1)-integrins and the phosphoinositide 3-kinase (PI3K)-Akt pathway. PI3K- and Akt-specific inhibitors abrogated IDR-1002-induced adhesion and activation of β(1)-integrins, whereas p38 and MEK1 inhibitors did not affect, or moderately inhibited, adhesion, respectively. Furthermore, IDR-1002 enhancement of monocyte migration towards chemokines and activation of β(1)-integrins was abrogated in the presence of PI3K- and Akt-specific inhibitors. In summary, IDR-1002 enhanced monocyte migration on fibronectin through promotion of β(1)-integrin-mediated interactions regulated by the PI3K-Akt pathway, revealing a mechanism by which IDR-1002 promotes monocyte recruitment.

The Journal of Immunology, 2010

The Journal of Immunology, 2013

Journal of Dermatological Science, 2013

Infection and Immunity, 2012

The adaptation of Pseudomonas aeruginosa to its environment, including the host, is tightly contr... more The adaptation of Pseudomonas aeruginosa to its environment, including the host, is tightly controlled by its network of regulatory systems. The two-component regulatory system PhoPQ has been shown to play a role in the virulence and polymyxin resistance of P. aeruginosa as well as several other Gram-negative species. Dysregulation of this system has been demonstrated in clinical isolates, yet how it affects virulence of P. aeruginosa is unknown. To investigate this, an assay was used whereby bacteria were cocultured with human bronchial epithelial cells. The interaction of wild-type (WT) bacteria that had adhered to epithelial cells led to a large upregulation of the expression of the oprH-phoP-phoQ operon and its target, the arn lipopolysaccharide (LPS) modification operon, in a PhoQ-dependent manner, compared to cells in the supernatant that had failed to adhere. Relative to the wild type, a phoQ mutant cocultured on epithelial cells produced less secreted protease and lipase and, like the phoQ mutant, piv, lipH, and lasB mutants demonstrated reduced cytotoxicity toward epithelial cells. Mutation in phoQ also resulted in alterations to lipid A and to increased inflammatory LPS. These data indicate that mutation of phoQ results in a phenotype that is similar to the less virulent but more inflammatory phenotype of clinical strains isolated from chronic-stage cystic fibrosis lung infections.

Annals of the New York Academy of Sciences, 2010

A highly effective strategy for combating infectious diseases is to enhance host defenses using i... more A highly effective strategy for combating infectious diseases is to enhance host defenses using immunomodulators, either preventatively, through vaccination, or therapeutically. The effectiveness of many vaccines currently in use is due in part to adjuvants, molecules that have little immunogenicity by themselves but which help enhance and appropriately skew the immune response to an antigen. The development of new vaccines necessitates the development of new types of adjuvants to ensure an appropriate immune response. Herein, we review commonly used vaccine adjuvants and discuss promising adjuvant candidates. We also discuss various other immunomodulators (namely cytokines, Toll-like receptor agonists, and host defense peptides) that are, or have potential to be, useful for antimicrobial therapies that exert their effects by boosting host immune responses rather than targeting pathogens directly.