Medicine and Health Sciences Commons^™

Cd151-Α3Β1 Integrin Complexes Suppress Ovarian Tumor Growth By Repressing Slug-Mediated Emt And Canonical Wnt Signaling, Lauren A. Baldwin, John T. Hoff, Jason Lefringhouse, Michael Zhang, Changhe Jia, Zeyi Liu, Sonia Erfani, Hongyan Jin, Mei Xu, Qing-Bai She, John R. Van Nagell Jr., Chi Wang, Li Chen, Rina Plattner, David M. Kaetzel, Jia Luo, Michael Lu, Dava West, Chunming Liu, Fred R. Ueland, Ronny Drapkin, Binhua P. Zhou, Xiuwei H. Yang

Pharmacology and Nutritional Sciences Faculty Publications

Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-α3β1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or α3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by …

Long-Acting Antituberculous Therapeutic Nanoparticles Target Macrophage Endosomes., Benson J. Edagwa, Dongwei Guo, Pavan Puligujja, Han Chen, Joellyn Mcmillan, Xinming Liu, Howard Gendelman, Prabagaran Narayanasamy

Journal Articles: Pharmacology & Experimental Neuroscience

Eradication of Mycobacterium tuberculosis (MTB) infection requires daily administration of combinations of rifampin (RIF), isoniazid [isonicotinylhydrazine (INH)], pyrazinamide, and ethambutol, among other drug therapies. To facilitate and optimize MTB therapeutic selections, a mononuclear phagocyte (MP; monocyte, macrophage, and dendritic cell)-targeted drug delivery strategy was developed. Long-acting nanoformulations of RIF and an INH derivative, pentenyl-INH (INHP), were prepared, and their physicochemical properties were evaluated. This included the evaluation of MP particle uptake and retention, cell viability, and antimicrobial efficacy. Drug levels reached 6 μg/10(6) cells in human monocyte-derived macrophages (MDMs) for nanoparticle treatments compared with 0.1 μg/10(6) cells for native drugs. …

Pupillometry: A Non-Invasive Technique For Pain Assessment In Paediatric Patients., Mark A. Connelly, Jacob T. Brown, Gregory L. Kearns, Rawni A. Anderson, Shawn D. St Peter, Kathleen A. Neville

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: Pupillometry has been used to assess pain intensity and response to analgesic medications in adults. The aim of this observational study was to explore proof of concept for the use of this technique in paediatric patients. Changes in pupil parameters before and after opioid exposure also were evaluated.

DESIGN AND SETTING: This was a single-centre, prospective study conducted at an academic paediatric medical centre.

PATIENTS: Children 9-17 years of age undergoing elective surgical correction of pectus excavatum were enrolled into a protocol approved by the human ethical committee (institutional review board).

INTERVENTIONS: Pupil size and reactivity were measured using …

Neuroinflammation And Neurologic Deficits In Diabetes Linked To Brain Accumulation Of Amylin, Sarah Srodulski, Savita Sharma, Adam B. Bachstetter, Jennifer M. Brelsfoard, Conrado Pascual, Xinmin Simon Xie, Kathryn E. Saatman, Linda J. Van Eldik, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: We recently found that brain tissue from patients with type-2 diabetes (T2D) and cognitive impairment contains deposits of amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic β-cells. Amylin deposition is promoted by chronic hypersecretion of amylin (hyperamylinemia), which is common in humans with obesity or pre-diabetic insulin resistance. Human amylin oligomerizes quickly when oversecreted, which is toxic, induces inflammation in pancreatic islets and contributes to the development of T2D. Here, we tested the hypothesis that accumulation of oligomerized amylin affects brain function.

METHODS: In contrast to amylin from humans, rodent amylin is neither amyloidogenic nor cytotoxic. …

Cc2d1a Regulates Human Intellectual And Social Function As Well As Nf-Κb Signaling Homeostasis., M. Chiara Manzini, Lan Xiong, Ranad Shaheen, Dimira E Tambunan, Stefania Di Costanzo, Vanessa Mitisalis, +15 Additional Authors

Pharmacology and Physiology Faculty Publications

Autism spectrum disorder (ASD) and intellectual disability (ID) are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive "founder" mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB). Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intracellular signaling. Cc2d1a knockdown in neurons …

Cardioprotection By Controlling Hyperamylinemia In A "Humanized" Diabetic Rat Model, Sanda Despa, Savita Sharma, Todd R. Harris, Hua Dong, Ning Li, Nipavan Chiamvimonvat, Heinrich Taegtmeyer, Kenneth B. Margulies, Bruce D. Hammock, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Chronic hypersecretion of the pancreatic hormone amylin is common in humans with obesity or prediabetic insulin resistance and induces amylin aggregation and proteotoxicity in the pancreas. We recently showed that hyperamylinemia also affects the cardiovascular system. Here, we investigated whether amylin aggregates interact directly with cardiac myocytes and whether controlling hyperamylinemia protects the heart.

METHODS AND RESULTS: By Western blot, we found abundant amylin aggregates in lysates of cardiac myocytes from obese patients, but not in controls. Aggregated amylin was elevated in failing hearts, suggesting a role in myocyte injury. Using rats overexpressing human amylin in the pancreas (HIP …

The Rak/Frk Tyrosine Kinase Associates With And Internalizes The Epidermal Growth Factor Receptor, Ling Jin, Rolf J. Craven

Pharmacology and Nutritional Sciences Faculty Publications

Src is the founding member of a diverse family of intracellular tyrosine kinases, and Src has a key role in promoting cancer growth, in part, through its association with receptor tyrosine kinases. However, some Src-related proteins have widely divergent physiological roles, and these proteins include the Rak/Frk tyrosine kinase (Frk stands for Fyn-related kinase), which inhibits cancer cell growth and suppresses tumorigenesis. Rak/Frk phosphorylates and stabilizes the Pten tumor suppressor, protecting it from degradation, and Rak/Frk associates with the retinoblastoma (Rb) tumor suppressor. However, the role of Rak/Frk in receptor-mediated signaling is largely unknown. Here, we demonstrate that Rak/Frk associates …

The Evolutionary Young Mir-1290 Favors Mitotic Exit And Differentiation Of Human Neural Progenitors Through Altering The Cell Cycle Proteins., Sowmya V. Yelamanchili, Brenda M. Morsey, Emily B. Harrison, D. A. Rennard, Kathleen M. Emanuel, I Thapa, D. R. Bastola, H. S. Fox

Journal Articles: Pharmacology & Experimental Neuroscience

Regulation of cellular proliferation and differentiation during brain development results from processes requiring several regulatory networks to function in synchrony. MicroRNAs are part of this regulatory system. Although many microRNAs are evolutionarily conserved, recent evolution of such regulatory molecules can enable the acquisition of new means of attaining specialized functions. Here we identify and report the novel expression and functions of a human and higher primate-specific microRNA, miR-1290, in neurons. Using human fetal-derived neural progenitors, SH-SY5Y neuroblastoma cell line and H9-ESC-derived neural progenitors (H9-NPC), we found miR-1290 to be upregulated during neuronal differentiation, using microarray, northern blotting and qRT-PCR. We …