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1.
J Alzheimers Dis ; 97(1): 31-74, 2024.
Article in English | MEDLINE | ID: mdl-38007653

ABSTRACT

Alzheimer's disease (AD) affects more women than men, with women throughout the menopausal transition potentially being the most under researched and at-risk group. Sleep disruptions, which are an established risk factor for AD, increase in prevalence with normal aging and are exacerbated in women during menopause. Sex differences showing more disrupted sleep patterns and increased AD pathology in women and female animal models have been established in literature, with much emphasis placed on loss of circulating gonadal hormones with age. Interestingly, increases in gonadotropins such as follicle stimulating hormone are emerging to be a major contributor to AD pathogenesis and may also play a role in sleep disruption, perhaps in combination with other lesser studied hormones. Several sleep influencing regions of the brain appear to be affected early in AD progression and some may exhibit sexual dimorphisms that may contribute to increased sleep disruptions in women with age. Additionally, some of the most common sleep disorders, as well as multiple health conditions that impair sleep quality, are more prevalent and more severe in women. These conditions are often comorbid with AD and have bi-directional relationships that contribute synergistically to cognitive decline and neuropathology. The association during aging of increased sleep disruption and sleep disorders, dramatic hormonal changes during and after menopause, and increased AD pathology may be interacting and contributing factors that lead to the increased number of women living with AD.


Subject(s)
Alzheimer Disease , Sleep Wake Disorders , Animals , Female , Humans , Male , Alzheimer Disease/epidemiology , Alzheimer Disease/etiology , Cross-Sectional Studies , Multimorbidity , Sleep , Sleep Wake Disorders/epidemiology , Sleep Wake Disorders/complications , Sex Factors
2.
Biochim Biophys Acta Mol Basis Dis ; 1870(2): 166945, 2024 02.
Article in English | MEDLINE | ID: mdl-37935338

ABSTRACT

Recent years have seen both considerable progress and controversy in the Alzheimer's disease (AD) field. After decades of slow to negligible movement towards the development of disease modifying therapies, promising outcomes in recent clinical trials with several monoclonal antibodies targeting various forms of the amyloid-ß (Aß) peptide have at last opened a possible way forward. In fact, at this point multiple anti-Aß therapeutics are close to receiving (or have already received) regulatory approval. Although these outcomes are not without some degree of divisiveness, the fact remains that targeting amyloid for removal has finally shown at least modest efficacy in slowing the otherwise relentless progression of the disease. Although the validation of the long standing amyloid cascade hypothesis would seem to be at hand, what remains is the puzzling issue of why - if Aß indeed causes AD - does removing it from the brain not stop the disease entirely.


Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Humans , Amyloid beta-Peptides/metabolism , Alzheimer Disease/drug therapy , Brain/metabolism , Antibodies, Monoclonal/therapeutic use , Cognition
3.
J Appl Biobehav Res ; 22(4)2017 Dec.
Article in English | MEDLINE | ID: mdl-29230086

ABSTRACT

PURPOSE: The objectives of the study were to (1) assess the extent to which interrater reliability of pain drawing location and dispersion scoring methods are similar across pain disciplines in a sample of patients with cancer treatment-induced neuropathic pain (N = 56) and (2) investigate indicators of validity of the pain drawing in this unique sample. METHODS: Patients undergoing cancer therapy completed the Brief Pain Inventory Body Map, the MD Anderson Symptom Inventory, and the McGill Pain Questionnaire. RESULTS: Intraclass correlation coefficients among medical and psychology professionals ranged from .93-.99. Correlations between pain drawing score and symptom burden severity ranged from .29-.39; correlations between pain drawing score and symptom burden interference ranged from .28-.34. Patients who endorsed pain in the hands and feet more often described their pain as electric, numb, and shooting than patients without pain in the hands and feet. They also endorsed significantly more descriptors of neuropathic pain. CONCLUSIONS: Results suggest a similar understanding among members of a multidisciplinary pain team as to the location and dispersion of pain as represented by patients' pain drawings. In addition, pain drawing scores were related to symptom burden severity and interference and descriptors of neuropathic pain in expected ways.

4.
Curr Opin Anaesthesiol ; 30(5): 570-576, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28708674

ABSTRACT

PURPOSE OF REVIEW: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, frequently chronic condition characterized by pain and decreased function. Given the growing number of cancer survivors and an increasing recognition of opioid therapy limitations, there is a need for critical analysis of the literature in directing an informed and thoughtful approach for the management of painful CIPN. RECENT FINDINGS: A PubMed search for 'chemotherapy-induced peripheral neuropathy AND pain' identifies 259 publications between 1 January 2016 and 31 March 2017. Based on review of this literature, we aim to present a clinically relevant update of painful CIPN. Notably, the use of duloxetine as a first-line agent in treatment of CIPN is confirmed. Moreover, clinical trials focus on nonpharmacologic strategies for managing painful CIPN. SUMMARY: Despite the volume of recent publications, there are limited preventive or therapeutic strategies for CIPN supported by high-level evidence. Duloxetine remains the only pharmacologic agent with demonstrated benefit; its clinical use should be routinely considered. Moving forward, nonopioid analgesic therapies will likely play an increasing role in CIPN treatment, but further research is necessary to confirm their utility. Promising therapies include vitamin B12 supplementation, physical therapy, and various forms of neuromodulation.


Subject(s)
Peripheral Nervous System Diseases/chemically induced , Duloxetine Hydrochloride/therapeutic use , Humans , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/prevention & control , Peripheral Nervous System Diseases/therapy , Vitamin B 12/administration & dosage
5.
EMBO J ; 31(5): 1279-92, 2012 Mar 07.
Article in English | MEDLINE | ID: mdl-22246185

ABSTRACT

Many pro-apoptotic signals trigger mitochondrial cytochrome c release, leading to caspase activation and ultimate cellular breakdown. Cell survival pathways, including the mitogen-activated protein kinase (MAPK) cascade, promote cell viability by impeding mitochondrial cytochrome c release and by inhibiting subsequent caspase activation. Here, we describe a mechanism for the inhibition of cytochrome c-induced caspase activation by MAPK signalling, identifying a novel mode of apoptotic regulation exerted through Apaf-1 phosphorylation by the 90-kDa ribosomal S6 kinase (Rsk). Recruitment of 14-3-3ɛ to phosphorylated Ser268 impedes the ability of cytochrome c to nucleate apoptosome formation and activate downstream caspases. High endogenous levels of Rsk in PC3 prostate cancer cells or Rsk activation in other cell types promoted 14-3-3ɛ binding to Apaf-1 and rendered the cells insensitive to cytochrome c, suggesting a potential role for Rsk signalling in apoptotic resistance of prostate cancers and other cancers with elevated Rsk activity. Collectively, these results identify a novel locus of apoptosomal regulation wherein MAPK signalling promotes Rsk-catalysed Apaf-1 phosphorylation and consequent binding of 14-3-3ɛ, resulting in decreased cellular responsiveness to cytochrome c.


Subject(s)
14-3-3 Proteins/metabolism , Apoptosis , Apoptotic Protease-Activating Factor 1/metabolism , Cytochromes c/antagonists & inhibitors , Cytochromes c/metabolism , Ribosomal Protein S6 Kinases/metabolism , Amino Acid Sequence , Animals , Cell Line , Chlorocebus aethiops , Humans , Models, Biological , Molecular Sequence Data , Phosphorylation , Protein Binding
6.
EMBO J ; 28(20): 3216-27, 2009 Oct 21.
Article in English | MEDLINE | ID: mdl-19730412

ABSTRACT

The apoptotic initiator caspase-2 has been implicated in oocyte death, in DNA damage- and heat shock-induced death, and in mitotic catastrophe. We show here that the mitosis-promoting kinase, cdk1-cyclin B1, suppresses apoptosis upstream of mitochondrial cytochrome c release by phosphorylating caspase-2 within an evolutionarily conserved sequence at Ser 340. Phosphorylation of this residue, situated in the caspase-2 interdomain, prevents caspase-2 activation. S340 was susceptible to phosphatase 1 dephosphorylation, and an interaction between phosphatase 1 and caspase-2 detected during interphase was lost in mitosis. Expression of S340A non-phosphorylatable caspase-2 abrogated mitotic suppression of caspase-2 and apoptosis in various settings, including oocytes induced to undergo cdk1-dependent maturation. Moreover, U2OS cells treated with nocodazole were found to undergo mitotic catastrophe more readily when endogenous caspase-2 was replaced with the S340A mutant to lift mitotic inhibition. These data demonstrate that for apoptotic stimuli transduced by caspase-2, cell death is prevented during mitosis through the inhibitory phosphorylation of caspase-2 and suggest that under conditions of mitotic arrest, cdk1-cyclin B1 activity must be overcome for apoptosis to occur.


Subject(s)
Apoptosis/physiology , Caspase 2/metabolism , Mitosis/physiology , Animals , Apoptosis/genetics , CDC2 Protein Kinase/genetics , CDC2 Protein Kinase/metabolism , Caspase 2/genetics , Cell Line , Cell Line, Tumor , Cyclin B/genetics , Cyclin B/metabolism , Cyclin B1 , Electrophoresis, Polyacrylamide Gel , Genetic Vectors , Humans , Lentivirus , Mitosis/drug effects , Mitosis/genetics , Nocodazole/pharmacology , Oocytes , Phosphorylation , RNA, Small Interfering , Serine/genetics , Serine/metabolism , Serine/physiology , Xenopus
7.
Cell ; 134(5): 720-1, 2008 Sep 05.
Article in English | MEDLINE | ID: mdl-18775303

ABSTRACT

During apoptosis, caspases cleave cellular substrates to break down and package the apoptotic cell for removal. Reporting in Cell, Mahrus et al. (2008) and Dix et al. (2008) use new approaches that identify hundreds of previously unrecognized caspase substrates, many of which appear to produce polypeptide fragments with potentially new functional activities.


Subject(s)
Apoptosis , Caspases/metabolism , Proteins/analysis , Proteins/metabolism , Humans , Jurkat Cells , Substrate Specificity
8.
Proc Natl Acad Sci U S A ; 104(52): 20820-5, 2007 Dec 26.
Article in English | MEDLINE | ID: mdl-18093951

ABSTRACT

Brain tumors are typically resistant to conventional chemotherapeutics, most of which initiate apoptosis upstream of mitochondrial cytochrome c release. In this study, we demonstrate that directly activating apoptosis downstream of the mitochondria, with cytosolic cytochrome c, kills brain tumor cells but not normal brain tissue. Specifically, cytosolic cytochrome c is sufficient to induce apoptosis in glioblastoma and medulloblastoma cell lines. In contrast, primary neurons from the cerebellum and cortex are remarkably resistant to cytosolic cytochrome c. Importantly, tumor tissue from mouse models of both high-grade astrocytoma and medulloblastoma display hypersensitivity to cytochrome c when compared with surrounding brain tissue. This differential sensitivity to cytochrome c is attributed to high Apaf-1 levels in the tumor tissue compared with low Apaf-1 levels in the adjacent brain tissue. These differences in Apaf-1 abundance correlate with differences in the levels of E2F1, a previously identified activator of Apaf-1 transcription. ChIP assays reveal that E2F1 binds the Apaf-1 promoter specifically in tumor tissue, suggesting that E2F1 contributes to the expression of Apaf-1 in brain tumors. Together, these results demonstrate an unexpected sensitivity of brain tumors to postmitochondrial induction of apoptosis. Moreover, they raise the possibility that this phenomenon could be exploited therapeutically to selectively kill brain cancer cells while sparing the surrounding brain parenchyma.


Subject(s)
Apoptotic Protease-Activating Factor 1/metabolism , Brain Neoplasms/metabolism , Brain/metabolism , Cytochromes c/metabolism , Gene Expression Regulation, Neoplastic , Apoptosis , Astrocytoma/metabolism , Caspases/metabolism , Cytochromes c/chemistry , E2F1 Transcription Factor/chemistry , Humans , Medulloblastoma/metabolism , Neurons/metabolism , Oligonucleotide Array Sequence Analysis , Promoter Regions, Genetic , Transcription, Genetic
9.
Cancer Res ; 67(10): 4716-24, 2007 May 15.
Article in English | MEDLINE | ID: mdl-17510399

ABSTRACT

The antiangiogenic protein angiostatin inhibits ATP synthase on the endothelial cell surface, blocking cellular proliferation. To examine the specificity of this interaction, we generated monoclonal antibodies (mAb) directed against ATP synthase. mAb directed against the beta-catalytic subunit of ATP synthase (MAb3D5AB1) inhibits the activity of the F(1) domain of ATP synthase and recognizes the catalytic beta-subunit of ATP synthase. We located the antibody recognition site of MAb3D5AB1 in domains containing the active site of the beta-subunit. MAb3D5AB1 also binds to purified Escherichia coli F(1) with an affinity 25-fold higher than the affinity of angiostatin for this protein. MAb3D5AB1 inhibits the hydrolytic activity of F(1) ATP synthase at lower concentrations than angiostatin. Like angiostatin, MAb3D5AB1 inhibits ATP generation by ATP synthase on the endothelial cell surface in acidic conditions, the typical tumor microenvironment where cell surface ATP synthase exhibits greater activity. MAb3D5AB1 disrupts tube formation and decreases intracellular pH in endothelial cells exposed to low extracellular pH. Neither angiostatin nor MAb3D5AB1 showed an antiangiogenic effect in the corneal neovascularization assay; however, both were effective in the low-pH environment of the chicken chorioallantoic membrane assay. Thus, MAb3D5AB1 shows angiostatin-like properties superior to angiostatin and may be exploited in cancer chemotherapy.


Subject(s)
Angiostatins/metabolism , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Mitochondrial Proton-Translocating ATPases/immunology , Adenosine Triphosphate/biosynthesis , Animals , Antibodies, Monoclonal/metabolism , Binding Sites, Antibody , Biomimetic Materials , Catalytic Domain/immunology , Cattle , Chorioallantoic Membrane/blood supply , Corneal Neovascularization/drug therapy , Endothelial Cells/cytology , Endothelial Cells/drug effects , Epitope Mapping , Female , Humans , Hydrogen-Ion Concentration , Mice , Mice, Inbred BALB C , Mitochondrial Proton-Translocating ATPases/antagonists & inhibitors , Mitochondrial Proton-Translocating ATPases/metabolism , Models, Molecular , Neovascularization, Physiologic/drug effects , Rats , Rats, Inbred F344
10.
J Biol Chem ; 282(23): 17259-71, 2007 Jun 08.
Article in English | MEDLINE | ID: mdl-17426020

ABSTRACT

We have shown that Wnt5A increases the motility of melanoma cells. To explore cellular pathways involving Wnt5A, we compared gain-of-function (WNT5A stable transfectants) versus loss-of-function (siRNA knockdown) of WNT5A by microarray analysis. Increasing WNT5A suppressed the expression of several genes, which were re-expressed after small interference RNA-mediated knockdown of WNT5A. Genes affected by WNT5A include KISS-1, a metastasis suppressor, and CD44, involved in tumor cell homing during metastasis. This could be validated at the protein level using both small interference RNA and recombinant Wnt5A (rWnt5A). Among the genes up-regulated by WNT5A was the gene vimentin, associated with an epithelial to mesenchymal transition (EMT), which involves decreases in E-cadherin, due to up-regulation of the transcriptional repressor, Snail. rWnt5A treatment increases Snail and vimentin expression, and decreases E-cadherin, even in the presence of dominant-negativeTCF4, suggesting that this activation is independent of Wnt/beta-catenin signaling. Because Wnt5A can signal via protein kinase C (PKC), the role of PKC in Wnt5A-mediated motility and EMT was also assessed using PKC inhibition and activation studies. Treating cells expressing low levels of Wnt5A with phorbol ester increased Snail expression inhibiting PKC in cells expressing high levels of Wnt5A decreased Snail. Furthermore, inhibition of PKC before Wnt5A treatment blocked Snail expression, implying that Wnt5A can potentiate melanoma metastasis via the induction of EMT in a PKC-dependent manner.


Subject(s)
Epithelial Cells/cytology , Melanoma/metabolism , Mesoderm/cytology , Protein Kinase C/metabolism , Proto-Oncogene Proteins/metabolism , Wnt Proteins/metabolism , Base Sequence , Cell Line, Tumor , DNA Primers , Fluorescent Antibody Technique , Humans , Melanoma/enzymology , Melanoma/pathology , Neoplasm Metastasis , Proto-Oncogene Proteins/genetics , RNA, Small Interfering , Wnt Proteins/genetics , Wnt-5a Protein
11.
J Biol Chem ; 278(29): 27312-8, 2003 Jul 18.
Article in English | MEDLINE | ID: mdl-12736244

ABSTRACT

Human plasminogen contains structural domains that are termed kringles. Proteolytic cleavage of plasminogen yields kringles 1-3 or 4 and kringle 5 (K5), which regulate endothelial cell proliferation. The receptor for kringles 1-3 or 4 has been identified as cell surface-associated ATP synthase; however, the receptor for K5 is not known. Sequence homology exists between the plasminogen activator streptokinase and the human voltage-dependent anion channel (VDAC); however, a functional relationship between these proteins has not been reported. A streptokinase binding site for K5 is located between residues Tyr252-Lys283, which is homologous to the primary sequence of VDAC residues Tyr224-Lys255. Antibodies against these sequences react with VDAC and detect this protein on the plasma membrane of human endothelial cells. K5 binds with high affinity (Kd of 28 nm) to endothelial cells, and binding is inhibited by these antibodies. Purified VDAC binds to K5 but only when reconstituted into liposomes. K5 also interferes with mechanisms controlling the regulation of intracellular Ca2+ via its interaction with VDAC. K5 binding to endothelial cells also induces a decrease in intracellular pH and hyperpolarization of the mitochondrial membrane. These studies suggest that VDAC is a receptor for K5.


Subject(s)
Endothelium, Vascular/metabolism , Plasminogen/chemistry , Plasminogen/metabolism , Porins/metabolism , Receptors, Cell Surface/metabolism , Amino Acid Sequence , Binding Sites/genetics , Cells, Cultured , Humans , Hydrogen-Ion Concentration , In Vitro Techniques , Kinetics , Kringles , Liposomes , Membrane Potentials , Mitochondria/metabolism , Models, Molecular , Molecular Sequence Data , Porins/chemistry , Porins/genetics , Protein Binding , Receptors, Cell Surface/chemistry , Receptors, Cell Surface/genetics , Receptors, Urokinase Plasminogen Activator , Sequence Homology, Amino Acid , Streptokinase/chemistry , Streptokinase/genetics , Streptokinase/metabolism , Voltage-Dependent Anion Channels
12.
J Biol Chem ; 277(44): 42082-7, 2002 Nov 01.
Article in English | MEDLINE | ID: mdl-12194978

ABSTRACT

The low density lipoprotein receptor-related protein (LRP) is a scavenger receptor that binds to many proteins, some of which trigger signal transduction. Receptor-recognized forms of alpha(2)-Macroglobulin (alpha(2)M*) bind to LRP, but the pattern of signal transduction differs significantly from that observed with other LRP ligands. For example, neither Ni(2+) nor the receptor-associated protein, which blocks binding of all known ligands to LRP, block alpha(2)M*-induced signal transduction. In the current study, we employed alpha(2)-macroglobulin (alpha(2)M)-agarose column chromatography to purify cell surface membrane binding proteins from 1-LN human prostate cancer cells and murine macrophages. The predominant binding protein purified from 1-LN prostate cancer cells was Grp 78 with small amounts of LRP, a fact that is consistent with our previous observations that there is little LRP present on the surface of these cells. The ratio of LRP:Grp 78 is much higher in macrophages. Flow cytometry was employed to demonstrate the presence of Grp 78 on the cell surface of 1-LN cells. Purified Grp 78 binds to alpha(2)M* with high affinity (K(d) approximately 150 pm). A monoclonal antibody directed against Grp 78 both abolished alpha(2)M*-induced signal transduction and co-precipitated LRP. Ligand blotting with alpha(2)M* showed binding to both Grp 78 and LRP heavy chains in these preparations. Use of RNA interference to silence LRP expression had no effect on alpha(2)M*-mediated signaling. We conclude that Grp 78 is essential for alpha(2)M*-induced signal transduction and that a "co-receptor" relationship exists with LRP like that seen with several other ligands and receptors such as the uPA/uPAR (urinary type plasminogen activator or urokinase/uPA receptor) system.


Subject(s)
Carrier Proteins/physiology , Heat-Shock Proteins , Low Density Lipoprotein Receptor-Related Protein-1/physiology , Molecular Chaperones/physiology , RNA Interference , Signal Transduction , alpha-Macroglobulins/physiology , Animals , Endoplasmic Reticulum Chaperone BiP , Humans , Low Density Lipoprotein Receptor-Related Protein-1/chemistry , Male , Mice , Tumor Cells, Cultured
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