@misc{sheats_yin_fang_park_crews_parikh_dickson_adler_2019, title={MARCKS and Lung Disease}, volume={60}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2018-0285TR}, abstractNote={MARCKS (myristoylated alanine-rich C kinase substrate) is a prominent PKC substrate expressed in all eukaryotic cells. It is known to bind to and cross-link actin filaments, to serve as a bridge between Ca2+/calmodulin and PKC signaling, and to sequester the signaling molecule phosphatidylinositol 4,5-bisphosphate in the plasma membrane. Since the mid-1980s, this evolutionarily conserved and ubiquitously expressed protein has been associated with regulating cellular events that require dynamic actin reorganization, including cellular adhesion, migration, and exocytosis. More recently, translational studies have implicated MARCKS in the pathophysiology of a number of airway diseases, including chronic obstructive pulmonary disease, asthma, lung cancer, and acute lung injury/acute respiratory distress syndrome. This article summarizes the structure and cellular function of MARCKS (also including MARCKS family proteins and MARCKSL1 [MARCKS-like protein 1]). Evidence for MARCKS's role in several lung diseases is discussed, as are the technological innovations that took MARCKS-targeting strategies from theoretical to therapeutic. Descriptions and updates derived from ongoing clinical trials that are investigating inhalation of a MARCKS-targeting peptide as therapy for patients with chronic bronchitis, lung cancer, and ARDS are provided.}, number={1}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Sheats, Mary K. and Yin, Qi and Fang, Shijing and Park, Joungjoa and Crews, Anne L. and Parikh, Indu and Dickson, Brian and Adler, Kenneth B.}, year={2019}, month={Jan}, pages={16–27} }
 @article{su_huang_ma_liang_dinh_chen_shen_allen_qiao_li_et al._2019, title={Platelet-Inspired Nanocells for Targeted Heart Repair After Ischemia/Reperfusion Injury}, volume={29}, ISSN={["1616-3028"]}, DOI={10.1002/adfm.201803567}, abstractNote={Cardiovascular disease is the leading cause of mortality worldwide. While reperfusion therapy is vital for patient survival post-heart attack, it also causes further tissue injury, known as myocardial ischemia/reperfusion (I/R) injury in clinical practice. Exploring ways to attenuate I/R injury is of clinical interest for improving post-ischemic recovery. A platelet-inspired nanocell (PINC) that incorporates both prostaglandin E2 (PGE2)-modified platelet membrane and cardiac stromal cell-secreted factors to target the heart after I/R injury is introduced. By taking advantage of the natural infarct-homing ability of platelet membrane and the overexpression of PGE2 receptors (EPs) in the pathological cardiac microenvironment after I/R injury, the PINCs can achieve targeted delivery of therapeutic payload to the injured heart. Furthermore, a synergistic treatment efficacy can be achieved by PINC, which combines the paracrine mechanism of cell therapy with the PGE2/EP receptor signaling that is involved in the repair and regeneration of multiple tissues. In a mouse model of myocardial I/R injury, intravenous injection of PINCs results in augmented cardiac function and mitigated heart remodeling, which is accompanied by the increase in cycling cardiomyocytes, activation of endogenous stem/progenitor cells, and promotion of angiogenesis. This approach represents a promising therapeutic delivery platform for treating I/R injury.}, number={4}, journal={ADVANCED FUNCTIONAL MATERIALS}, author={Su, Teng and Huang, Ke and Ma, Hong and Liang, Hongxia and Dinh, Phuong-Uyen and Chen, Justin and Shen, Deliang and Allen, Tyler A. and Qiao, Li and Li, Zhenhua and et al.}, year={2019}, month={Jan} }
 @article{qiao_hu_liu_zhang_ma_huang_li_su_vandergrif_tang_et al._2019, title={microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential}, volume={129}, ISSN={["1558-8238"]}, url={https://doi.org/10.1172/JCI123135}, DOI={10.1172/JCI123135}, abstractNote={Exosomes, as functional paracrine units of therapeutic cells, can partially reproduce the reparative properties of their parental cells. The constitution of exosomes, as well as their biological activity, largely depends on the cells that secrete them. We isolated exosomes from explant-derived cardiac stromal cells from patients with heart failure (FEXO) or from normal donor hearts (NEXO) and compared their regenerative activities in vitro and in vivo. Patients in the FEXO group exhibited an impaired ability to promote endothelial tube formation and cardiomyocyte proliferation in vitro. Intramyocardial injection of NEXO resulted in structural and functional improvements in a murine model of acute myocardial infarction. In contrast, FEXO therapy exacerbated cardiac function and left ventricular remodeling. microRNA array and PCR analysis revealed dysregulation of miR-21-5p in FEXO. Restoring miR-21-5p expression rescued FEXO's reparative function, whereas blunting miR-21-5p expression in NEXO diminished its therapeutic benefits. Further mechanistic studies revealed that miR-21-5p augmented Akt kinase activity through the inhibition of phosphatase and tensin homolog. Taken together, the heart failure pathological condition altered the miR cargos of cardiac-derived exosomes and impaired their regenerative activities. miR-21-5p contributes to exosome-mediated heart repair by enhancing angiogenesis and cardiomyocyte survival through the phosphatase and tensin homolog/Akt pathway.}, number={6}, journal={JOURNAL OF CLINICAL INVESTIGATION}, publisher={American Society for Clinical Investigation}, author={Qiao, Li and Hu, Shiqi and Liu, Suyun and Zhang, Hui and Ma, Hong and Huang, Ke and Li, Zhenhua and Su, Teng and Vandergrif, Adam and Tang, Junnan and et al.}, year={2019}, month={Jun}, pages={2237–2250} }
 @article{yin_fang_park_crews_parikh_adler_2016, title={An Inhaled Inhibitor of Myristoylated Alanine-Rich C Kinase Substrate Reverses LPS-Induced Acute Lung Injury in Mice}, volume={55}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2016-0236rc}, abstractNote={Section:ChooseTop of pageAbstract <<Materials and MethodsResultsDiscussionReferencesCITING ARTICLES}, number={5}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Yin, Qi and Fang, Shijing and Park, Joungjoa and Crews, Anne L. and Parikh, Indu and Adler, Kenneth B.}, year={2016}, month={Nov}, pages={617–622} }
 @article{li_d’annibale-tolhurst_adler_fang_yin_birkenheuer_levy_jones_sung_hawkins_et al._2013, title={A Myristoylated Alanine-Rich C Kinase Substrate–Related Peptide Suppresses Cytokine mRNA and Protein Expression in LPS-Activated Canine Neutrophils}, volume={48}, ISSN={1044-1549 1535-4989}, url={http://dx.doi.org/10.1165/rcmb.2012-0278OC}, DOI={10.1165/rcmb.2012-0278oc}, abstractNote={Myristoylated alanine-rich C kinase substrate (MARCKS) is a ubiquitously expressed protein kinase C substrate that has emerged as a potential therapeutic target for the amelioration of mucin secretion and inflammation in patients with chronic obstructive pulmonary disease. MARCKS also plays a key role in regulating the adhesion, migration, and degranulation of neutrophils. Moreover, given its biological role in epithelial and immune cells, we hypothesized that MARCKS may play an integral role in cytokine secretion by neutrophils. Because the amino terminus of MARCKS is highly conserved across vertebrate species, we successfully applied the well-characterized human MARCKS inhibitory peptide, myristoylated N-terminal sequence (MANS), to attenuate the function of MARCKS in isolated canine neutrophils. Pretreatment of canine neutrophils with MANS peptide significantly reduced both mRNA and protein expression in a broad range of LPS-induced cytokines, including IL-8, a chemokine (C-X-C motif) ligand-1 orthologue, and TNF-α, in comparison with untreated cells or those treated with a control peptide. This reduction in cytokine expression was observed even when neutrophils were treated with MANS 2 hours after LPS exposure. The observed reduction in cytokine secretion was not attributable to protein retention or cell death, but was associated with reduced cytokine transcript synthesis. These observations identify MARCKS protein as a promising therapeutic target in the treatment of inflammatory diseases or syndromes attributed to neutrophil influx and inflammatory cytokine production, such as sepsis, acute lung injury, and acute respiratory distress syndrome.}, number={3}, journal={American Journal of Respiratory Cell and Molecular Biology}, publisher={American Thoracic Society}, author={Li, Jingjing and D’Annibale-Tolhurst, Melissa A. and Adler, Kenneth B. and Fang, Shijing and Yin, Qui and Birkenheuer, Adam J. and Levy, Michael G. and Jones, Samuel L. and Sung, Eui Jae and Hawkins, Eleanor C. and et al.}, year={2013}, month={Mar}, pages={314–321} }
 @article{fang_crews_chen_park_yin_ren_adler_2013, title={MARCKS and HSP70 interactions regulate mucin secretion by human airway epithelial cells in vitro}, volume={304}, ISSN={["1522-1504"]}, DOI={10.1152/ajplung.00337.2012}, abstractNote={Myristoylated alanine-rich C kinase substrate (MARCKS) protein has been recognized as a key regulatory molecule controlling mucin secretion by airway epithelial cells in vitro and in vivo. We recently showed that two intracellular chaperones, heat shock protein 70 (HSP70) and cysteine string protein (CSP), associate with MARCKS in the secretory mechanism. To elucidate more fully MARCKS-HSP70 interactions in this process, studies were performed in well-differentiated normal human bronchial epithelial (NHBE) cells maintained in air-liquid interface culture utilizing specific pharmacological inhibition of HSP70 with pyrimidinone MAL3-101 and siRNA approaches. The results indicate that HSP70 interaction with MARCKS is enhanced after exposure of the cells to the protein kinase C activator/mucin secretagogue, phorbol 12-myristate 13-acetate (PMA). Pretreatment of NHBEs with MAL3-101 attenuated in a concentration-dependent manner PMA-stimulated mucin secretion and interactions among HSP70, MARCKS, and CSP. In additional studies, trafficking of MARCKS in living NHBE cells was investigated after transfecting cells with fluorescently tagged DNA constructs: MARCKS-yellow fluorescent protein, and/or HSP70-cyan fluorescent protein. Cells were treated with PMA 48 h posttransfection, and trafficking of the constructs was examined by confocal microscopy. MARCKS translocated rapidly from plasma membrane to cytoplasm, whereas HSP70 was observed in the cytoplasm and appeared to associate with MARCKS after PMA exposure. Pretreatment of cells with either MAL3-101 or HSP70 siRNA inhibited translocation of MARCKS. These results provide evidence of a role for HSP70 in mediating mucin secretion via interactions with MARCKS and that these interactions are critical for the cytoplasmic translocation of MARCKS upon its phosphorylation.}, number={8}, journal={AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY}, author={Fang, Shijing and Crews, Anne L. and Chen, Wei and Park, Joungjoa and Yin, Qi and Ren, Xiu-Rong and Adler, Kenneth B.}, year={2013}, month={Apr}, pages={L511–L518} }
 @article{green_park_yin_fang_crews_jones_adler_2012, title={Directed migration of mouse macrophages in vitro involves myristoylated alanine-rich C-kinase substrate (MARCKS) protein}, volume={92}, ISSN={0741-5400}, url={http://dx.doi.org/10.1189/jlb.1211604}, DOI={10.1189/jlb.1211604}, abstractNote={A role for MARCKS protein in directed migration of macrophages toward a chemoattractant was investigated. A peptide identical to the N-terminus of MARCKS (the MANS peptide), shown previously to inhibit the function of MARCKS in various cell types, was used. We investigated whether this MARCKS-related peptide could affect migration of macrophages, using the mouse macrophage-like J774A.1 cell line and primary murine macrophages. Both of these cell types migrated in response to the chemoattractants macrophage/MCPs, MCP-1 (25-100 ng/ml) or C5a (5-20 ng/ml). Cells were preincubated (15 min) with MANS or a mis-sense control peptide (RNS), both at 50 μM, and effects on migration determined 3 h after addition of chemoattractants. The movement and interactions of MARCKS and actin also were followed visually via confocal microscopy using a fluorescently labeled antibody to MARCKS and fluorescently tagged phalloidin to identify actin. MANS, but not RNS, attenuated migration of J774A.1 cells and primary macrophages in response to MCP-1 or C5a, implicating MARCKS in the cellular mechanism of directed migration. Exposure of cells to MCP-1 resulted in rapid phosphorylation and translocation of MARCKS from plasma membrane to cytosol, whereas actin appeared to spread through the cell and into cell protrusions; there was visual and biochemical evidence of a transient interaction between MARCKS and actin during the process of migration. These results suggest that MARCKS is involved in directed migration of macrophages via a process involving its phosphorylation, cytoplasmic translocation, and interaction with actin.}, number={3}, journal={Journal of Leukocyte Biology}, publisher={Wiley}, author={Green, T. D. and Park, J. and Yin, Q. and Fang, S. and Crews, A. L. and Jones, S. L. and Adler, K. B.}, year={2012}, month={May}, pages={633–639} }