Charlie Norwood VA Medical Center

About: Charlie Norwood VA Medical Center is a healthcare organization based out in Augusta, Georgia, United States. It is known for research contribution in the topics: Autophagy & Kidney. The organization has 349 authors who have published 490 publications receiving 16360 citations. The organization is also known as: Augusta VA Medical Center.

Osteopontin: A Key Regulator of Tumor Progression and Immunomodulation.

Abstract: OPN is a multifunctional phosphoglycoprotein expressed in a wide range of cells, including osteoclasts, osteoblasts, neurons, epithelial cells, T, B, NK, NK T, myeloid, and innate lymphoid cells. OPN plays an important role in diverse biological processes and is implicated in multiple diseases such as cardiovascular, diabetes, kidney, proinflammatory, fibrosis, nephrolithiasis, wound healing, and cancer. In cancer patients, overexpressed OPN is often detected in the tumor microenvironment and elevated serum OPN level is correlated with poor prognosis. Initially identified in activated T cells and termed as early T cell activation gene, OPN links innate cells to adaptive cells in immune response to infection and cancer. Recent single cell RNA sequencing revealed that OPN is primarily expressed in tumor cells and tumor-infiltrating myeloid cells in human cancer patients. Emerging experimental data reveal a key role of OPN is tumor immune evasion through regulating macrophage polarization, recruitment, and inhibition of T cell activation in the tumor microenvironment. Therefore, in addition to its well-established direct tumor cell promotion function, OPN also acts as an immune checkpoint to negatively regulate T cell activation. The OPN protein level is highly elevated in peripheral blood of human cancer patients. OPN blockade immunotherapy with OPN neutralization monoclonal antibodies (mAbs) thus represents an attractive approach in human cancer immunotherapy.

Loss of Hsp110 Leads to Age-Dependent Tau Hyperphosphorylation and Early Accumulation of Insoluble Amyloid β

Abstract: Diseases like Alzheimer's disease (AD) and other tauopathies are defined by the expression of neurofibrillary tangles (NFTs) deposited mainly in neurons The NFTs are aggregates of the hyperphosphorylated tau (p-tau) (3, 74) Normal tau increases microtubule stability, but tau can be hyperphosphorylated under disease conditions and released from microtubules (3, 5, 6) The molecular mechanisms involved in the formation of NFTs are not completely understood However, accumulation of abnormal p-tau and NFTs causes neurodegeneration (3) A number of protein kinases, including glycogen synthase kinase 3 (GSK3) and cyclin-dependent protein kinase 5 (CDK5), have been shown to phosphorylate tau at Thr231 and Ser262 as well as several other sites that flank the microtubule binding repeat, leading to tangles of paired helical filaments (PHFs) similar to those observed in the brains of patients with AD (54, 72) Evidence shows that GSK3 physically interacts with tau and is thought to be the main contributor to the formation of NFTs and amyloid β (Aβ) plaques in AD patients (18, 53, 54) Phosphorylation of GSK3a/b at S9/S21 which is inhibitory to its activity during insulin signaling, leads to phosphorylation of tau in neurons (80) GSK3a/b phospho-S9/S21, p-tau, and 14-3-3zeta have been isolated in a 500-kDa complex, and the interaction has been shown to result in tau phosphorylation by GSK3 (1, 80) Although not well characterized, p-tau has been shown to be dephosphorylated by the B family regulatory subunit of the heterotrimeric PP2A holoenzyme (76) There are two protein phosphatase 2A (PP2A) binding sites on microtubule tau binding repeats, perhaps allowing tau to be more efficiently dephosphorylated by PP2A catalytic subunit (76) Both GSK3 and CDK5 are also known to be involved in the phosphorylation of amyloid precursor protein (APP) at Thr668 and APP processing and Aβ production (53, 58) Studies suggest that amyloid peptide can activate GSK3 signaling, and the increase in GSK3 activity can then contribute to abnormal APP processing Indeed, reduction in GSK3 activity reduces amyloid peptide production in murine AD models (18, 53, 57, 71) Reduction in PP2A activity leads to altered APP regulation as well (26, 43) Additional molecules that affect tau hyperphosphorylation and APP processing are the peptidyl prolyl isomerases (9, 36, 51) Deletion of Pin1 isomerase in vivo leads to p-tau and neurodegeneration (42) Crossing Pin1-deficient mice with transgenic mice expressing mutant APP (APPβsw) leads to abnormal APP processing and accumulation of toxic amyloid β42 (Aβ42) species Pin1, therefore, is implicated in isomerization of tau, perhaps facilitating its dephosphorylation (42) The presence of Pin1 has been implicated in promoting nonamyloidogenic processing of APP and reduction in toxic Aβ42 production (51) Hsp70/Hsc70 has been shown to preferentially bind to a hyperphosphorylated form of tau in the diseased human brain (49) Cross talk between the ubiquitin proteasome system (UPS) and molecular chaperones might also be critical in regulating the deposition and toxicity of tau (8, 16) These results suggest that the activity of Hsp70 and Hsp90 preserve the native structure and function of tau protein Hsp70 and the C-terminal Hsp70-interacting protein (Chip) have been shown to regulate tau ubiquitination and degradation (11, 12, 21, 52, 65) Interestingly, Chip and βAPP interact, and Chip and Hsp70/90 expression have been shown to lower the cellular levels of Aβ and reduce Aβ toxicity in vitro (39) Misfolded proteins are either degraded through the UPS or are folded, at least in part, by the Hsps (4, 7) Eukaryotic cells possess a class of heat shock proteins (Hsps) related to the Hsp70 family This Hsp100 family of proteins contains Hspa41 (Apg1 or OSP94), Hsp94 (Apg2), and Hsp110 (2, 17, 28, 61, 70, 77, 78) They were initially considered to be “holdases” that keep denatured proteins in solution, and no client proteins have been described for them (14, 15, 56, 62) Hsp110 interacts with Hsp70 and increases its ATPase activity (15, 56, 62) The main function of Hsp110 appears to be a nucleotide exchange factor (NEF) for Hsp70 (14, 64) In general, Hsp110 is known to induce suppression of aggregation and protein refolding, and it protects proteins from the damaging effects of various stresses; however, its physiological function in mammalian cells remains unknown (15, 60) In these studies, we examined the role of Hsp110 in central nervous system (CNS) homeostasis in vivo We have found that hsp110−/− mice exhibit an age-dependent accumulation of p-tau that is associated with pathological features, such as the appearance of NFTs and neurodegeneration We also show that lack of Hsp110 leads to accelerated pathology as evidenced by the early appearance of senile plaques containing Aβ42 (a major toxic species [46]) in an AD transgenic mouse model At the biochemical level, we show that Hsp110 interacts with tau, a number of Hsps, GSK3, Pin1, and PP2A Furthermore, tau immunocomplexes pulled down from hsp110−/− brain extracts possess elevated levels of PP2A, but the pulled-down PP2A has significantly lower activity than the PP2A from wild-type mice Our studies therefore suggest a critical role for Hsp110 in maintaining the proper folding environment that is required for phosphorylation and dephosphorylation of tau and APP processing in vivo

VPS35-deficiency results in an impaired AMPA receptor trafficking and decreased dendritic spine maturation

Abstract: Background Vacuolar protein sorting 35 (VPS35), a key component of retromer, plays an important role in endosome-to-Golgi retrieval of membrane proteins. Dysfunction of VPS35/retromer is a risk factor for neurodegenerative disorders, including AD (Alzheimer’s disease) and PD (Parkinson’s disease). However, exactly how VPS35-deficiency contributes to AD or PD pathogenesis remains poorly understood.

Remote Ischemic Perconditioning is Effective After Embolic Stroke in Ovariectomized Female Mice

Abstract: Remote ischemic conditioning is neuroprotective in young male rodents after experimental stroke. However, it has never been tested in females whom remain at higher risk of stroke injury after menopause. We tested remote ischemic perconditioning therapy (RIPerC) at 2 h after embolic stroke in ovariectomized (OVX) female mice with and without intravenous tissue plasminogen activator (IV-tPA) treatment. We assessed cerebral blood flow (CBF), neurobehavioral outcomes, infarction, hemorrhage, edema, and survival. RIPerC therapy with and without IV-tPA improved the CBF and neurobehavioral outcomes and reduced the infarction, hemorrhage, and edema significantly. Late IV-tPA alone at 4 h post-stroke neither improved the neurobehavior nor reduced the infarction but aggravated hemorrhage and mortality in OVX mice. RIPerC therapy prevented the increased mortality during late IV-tPA. Our study demonstrates for the first time that RIPerC therapy is effective in OVX females.

Abnormal aquaporin-3 protein expression in hyperproliferative skin disorders

Abstract: Non-melanoma skin cancers (NMSCs) and psoriasis represent common hyperproliferative skin disorders, with approximately one million new NMSC diagnoses each year in the United States alone and a psoriasis prevalence of about 2% worldwide. We recently demonstrated that the glycerol channel, aquaporin-3 (AQP3) and the enzyme phospholipase D2 (PLD2) interact functionally in epidermal keratinocytes of the skin to inhibit their proliferation. However, others have suggested that AQP3 is pro-proliferative in keratinocytes and is upregulated in the NMSC, squamous cell carcinoma (SCC). To evaluate the AQP3/PLD2 signaling module in skin diseases, we determined their levels in SCC, basal cell carcinoma (BCC) and psoriasis as compared to normal epidermis. Skin biopsies with the appropriate diagnoses (10 normal, 5 SCC, 13 BCC and 10 plaque psoriasis samples) were obtained from the pathology archives and examined by immunohistochemistry using antibodies recognizing AQP3 and PLD2. In normal epidermis AQP3, an integral membrane protein, was localized mainly to the plasma membrane and PLD2 to the cell periphery, particularly in suprabasal layers. In BCC, AQP3 and PLD2 levels were reduced as compared to the normal-appearing overlying epidermis. In SCC, AQP3 staining was "patchy," with areas of reduced AQP3 immunoreactivity exhibiting positivity for Ki67, a marker of proliferation. PLD2 staining was unchanged in SCC. In psoriasis, AQP3 staining was usually observed in the cytoplasm rather than in the membrane. Also, in the majority of psoriatic samples, PLD2 showed weak immunoreactivity or aberrant localization. These results suggest that abnormalities in the AQP3/PLD2 signaling module correlate with hyperproliferation in psoriasis and the NMSCs.