scholarly journals Chemotherapy-Induced Peripheral Neuropathy and Changes in Cytoskeleton

2019 ◽  
Vol 20 (9) ◽  
pp. 2287 ◽  
Author(s):  
Alessio Malacrida ◽  
Cristina Meregalli ◽  
Virginia Rodriguez-Menendez ◽  
Gabriella Nicolini
Keyword(s):  
Morphological Changes ◽  
Proteasome Inhibitors ◽  
Sensory Nerves ◽  
Microtubule Organization ◽  
Peripheral Neurotoxicity ◽  
Chemotherapy Drugs ◽  
Associated Proteins ◽  
Dying Back

Despite the different antineoplastic mechanisms of action, peripheral neurotoxicity induced by all chemotherapy drugs (anti-tubulin agents, platinum compounds, proteasome inhibitors, thalidomide) is associated with neuron morphological changes ascribable to cytoskeleton modifications. The “dying back” degeneration of distal terminals (sensory nerves) of dorsal root ganglia sensory neurons, observed in animal models, in in vitro cultures and biopsies of patients is the most evident hallmark of the perturbation of the cytoskeleton. On the other hand, in highly polarized cells like neurons, the cytoskeleton carries out its role not only in axons but also has a fundamental role in dendrite plasticity and in the organization of soma. In the literature, there are many studies focused on the antineoplastic-induced alteration of microtubule organization (and consequently, fast axonal transport defects) while very few studies have investigated the effect of the different classes of drugs on microfilaments, intermediate filaments and associated proteins. Therefore, in this review, we will focus on: (1) Highlighting the fundamental role of the crosstalk among the three filamentous subsystems and (2) investigating pivotal cytoskeleton-associated proteins.

The Role of Microtubule Organization in Chondrocyte Response to Osmotic Loading

2007 ◽  
Author(s):  
Elizabeth S. Oswald ◽  
Pen-hsiu Grace Chao ◽  
J. Chloe Bulinski ◽  
Gerard A. Ateshian ◽  
Clark T. Hung
Keyword(s):  
Intracellular Transport ◽  
Morphological Changes ◽  
Cellular Responses ◽  
Microtubule Organization ◽  
Osmotic Loading ◽  
Volume Response ◽  
Cytoplasmic Organization

The cytoskeleton, including actin filaments and microtubules, provides chondrocytes with structure, cytoplasmic organization, and intracellular transport. The cytoskeleton is known to be involved in cellular responses to physiologic mechanical and osmotic loading signals, including morphological changes and mechanostransduction [1, 2]. Here, we examine microtubule (MT) involvement in volume response of chondrocytes to osmotic loading, as well as organization of stable MT with hypoosmotic loading. We also explore the hypothesis that chondrocytes from different zones of cartilage possess cytoskeletons with different properties, which help explain variations in their volume response to osmotic loading in situ and in vitro [3].

scholarly journals Membrane-associated phase separation: organization and function emerge from a two-dimensional milieu

2021 ◽  
Author(s):  
Jonathon A Ditlev
Keyword(s):  
Phase Separation ◽  
Cell Biology ◽  
Cellular Environment ◽  
Condensate Formation ◽  
Associated Proteins ◽  
Available Technology ◽  
And Function ◽  
Surrounding Membrane

Abstract Liquid‒liquid phase separation (LLPS) of biomolecules has emerged as an important mechanism that contributes to cellular organization. Phase separated biomolecular condensates, or membrane-less organelles, are compartments composed of specific biomolecules without a surrounding membrane in the nucleus and cytoplasm. LLPS also occurs at membranes, where both lipids and membrane-associated proteins can de-mix to form phase separated compartments. Investigation of these membrane-associated condensates using in vitro biochemical reconstitution and cell biology has provided key insights into the role of phase separation in membrane domain formation and function. However, these studies have generally been limited by available technology to study LLPS on model membranes and the complex cellular environment that regulates condensate formation, composition, and function. Here, I briefly review our current understanding of membrane-associated condensates, establish why LLPS can be advantageous for certain membrane-associated condensates, and offer a perspective for how these condensates may be studied in the future.

scholarly journals The Neuroinflammatory Role of Pericytes in Epilepsy

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 759
Author(s):  
Gaku Yamanaka ◽  
Fuyuko Takata ◽  
Yasufumi Kataoka ◽  
Kanako Kanou ◽  
Shinichiro Morichi ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Current Knowledge ◽  
Morphological Changes ◽  
Cell Damage ◽  
Neurovascular Unit ◽  
Experimental Studies ◽  
Intractable Epilepsy ◽  
In Vivo Studies

Pericytes are a component of the blood–brain barrier (BBB) neurovascular unit, in which they play a crucial role in BBB integrity and are also implicated in neuroinflammation. The association between pericytes, BBB dysfunction, and the pathophysiology of epilepsy has been investigated, and links between epilepsy and pericytes have been identified. Here, we review current knowledge about the role of pericytes in epilepsy. Clinical evidence has shown an accumulation of pericytes with altered morphology in the cerebral vascular territories of patients with intractable epilepsy. In vitro, proinflammatory cytokines, including IL-1β, TNFα, and IL-6, cause morphological changes in human-derived pericytes, where IL-6 leads to cell damage. Experimental studies using epileptic animal models have shown that cerebrovascular pericytes undergo redistribution and remodeling, potentially contributing to BBB permeability. These series of pericyte-related modifications are promoted by proinflammatory cytokines, of which the most pronounced alterations are caused by IL-1β, a cytokine involved in the pathogenesis of epilepsy. Furthermore, the pericyte-glial scarring process in leaky capillaries was detected in the hippocampus during seizure progression. In addition, pericytes respond more sensitively to proinflammatory cytokines than microglia and can also activate microglia. Thus, pericytes may function as sensors of the inflammatory response. Finally, both in vitro and in vivo studies have highlighted the potential of pericytes as a therapeutic target for seizure disorders.

Anti-Aging Effect of Siraitia grosuenorii by Enhancement of Hematopoietic Stem Cell Function

2016 ◽  
Vol 44 (04) ◽  
pp. 803-815 ◽  
Author(s):  
Lin Bai ◽  
Guiying Shi ◽  
Yajun Yang ◽  
Wei Chen ◽  
Lianfeng Zhang
Keyword(s):  
Aging Process ◽  
Cell Function ◽  
Whooping Cough ◽  
Aging Effect ◽  
Guangxi Province ◽  
Facs Analysis ◽  
Hematopoietic Stem ◽  
Associated Proteins

Anti-aging has always been a popular topic, and there are many claims about the existence of factors that can slow, stop, or even reverse the aging process. Siraitia grosuenorii, a local fruit in china, has been used for the treatment of gastritis, sore throats, and whooping cough in traditional Chinese medicine. The individuals who took the juice of Siraitia grosuenorii regularly had increased longevity in the Guangxi Province, which is located in the Southern part of China. In this paper, we fed mice with Siraitia grosuenorii for 10 months to identify the role of Siraitia grosuenorii in anti-aging and to investigate its corresponding mechanism. The results showed that mice fed with Siraitia grosuenorii displayed a slower aging process. The extension of the aging process was due to the enhanced function of HSCs. FACS analysis showed that the number of LSKs, LT-HSCs, ST-HSCs and MPPs from Siraitia grosuenorii mice was decreased. In vitro, a clonigenic assay showed that LT-HSCs from Siraitia grosuenorii mice increased the ability of self-renewal. Moreover, Siraitia grosuenorii mice maintained the quiescence of LSKs, decreased the level of ROS and reduced the amount of senescence associated β-gal positive cells. Furthermore, Siraitia grosuenorii mice decreased the expression of senescence-associated proteins. Siraitia grosuenorii maintained quiescence, decreased senescence and enhanced the function of HSCs, slowing the aging process of mice.

scholarly journals Intracellular Proadrenomedullin-Derived Peptides Decorate the Microtubules and Contribute to Cytoskeleton Function

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 2888-2898 ◽  
Author(s):  
Dan L. Sackett ◽  
Laurent Ozbun ◽  
Enrique Zudaire ◽  
Lisa Wessner ◽  
John M. Chirgwin ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Morphological Changes ◽  
Microtubule Associated Proteins ◽  
Microtubule Stabilization ◽  
Gene Coding ◽  
Intracellular Compartments ◽  
Associated Proteins ◽  
G2 Phase ◽  
Interfering Rna

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are secretory hormones, but it is not unusual to find them in intracellular compartments. Using yeast-2 hybrid technology, we found interactions between AM and several microtubule-associated proteins (MAPs), and between PAMP and tubulin. Expression of fluorescent-tagged AM and PAMP as well as immunofluorescence for the native peptides showed a complete decoration of the microtubules and colocalization with other MAPs. PAMP, but not AM, bound to tubulin in vitro and destabilized tubulin polymerization. Down-regulation of the gene coding for both AM and PAMP through small interfering RNA technology resulted in morphological changes, microtubule stabilization, increase in posttranslational modifications of tubulin such as acetylation and detyrosination, reduction in cell motility, and partial arrest at the G2 phase of the cell cycle, when compared with cells transfected with the same vector carrying a scrambled sequence. These results show that PAMP is a novel MAP, whereas AM may be exerting more subtle effects in regulating cytoskeleton function.

Biomechanics of the Lumbar Disc

1997 ◽  
Vol 01 (02) ◽  
pp. 81-94 ◽  
Author(s):  
V. K. Goel ◽  
N. M. Grosland ◽  
J. Scifert
Keyword(s):  
Morphological Changes ◽  
Imaging Techniques ◽  
Lumbar Disc ◽  
Analytical Models ◽  
Clinical Observations ◽  
Disc Bulge ◽  
Mechanical Factors ◽  
Methods Analytical

The human disc and the facets work in unison to transmit loads across a lumbar motion segment. For this reason, if one component is affected by the degenerative process, the other follows. Modern imaging techniques and clinical observations have adequately delineated morphological changes in the spinal structures, while in vitro biomechanical studies have revealed that repetitive complex loads may lead to loosening of spinal structures, annular tears, and herniated discs. In addition to such experimental methods, analytical models have been able to explain the role of mechanical factors in producing disc degeneration and herniation. Furthermore, these techniques are applicable to investigating various surgical stabilization procedures. From a biomechanical perspective, surgical procedures such as discectomy are effective in reducing pain due to a decrease in disc bulge following surgery. Excessive instability across the disc, however, may require the use of bone grafts, cages or other types of interbody spacers to restore disc height. Efforts are currently underway to restore disc mechanics via an artificial disc. The following review is aimed at outlining the role of mechanical foctors in both inducing and stabilizing the degenerated/herniated intervertebral disc.

scholarly journals SHP-2 phosphatase is required for hematopoietic cell transformation by Bcr-Abl

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 778-785 ◽  
Author(s):  
Jing Chen ◽  
Wen-Mei Yu ◽  
Hanako Daino ◽  
Hal E. Broxmeyer ◽  
Brian J. Druker ◽  
...  
Keyword(s):  
Cell Transformation ◽  
Biological Effects ◽  
Present Report ◽  
Proteasome Inhibitors ◽  
Heat Shock Protein 90 ◽  
Hematopoietic Cell ◽  
Serum Starvation ◽  
Oncogenic Signaling

Abstract SHP-2 phosphatase forms a stable protein complex with and is heavily tyrosine-phosphorylated by the oncogenic tyrosine kinase Bcr-Abl. However, the role of SHP-2 in Bcr-Abl–mediated leukemogenesis is unclear. In the present report, we provide evidence that SHP-2 is required for hematopoietic cell transformation by Bcr-Abl. In vitro biological effects of Bcr-Abl transduction were diminished in SHP-2Δ/Δ hematopoietic cells, and the leukemic potential of Bcr-Abl–transduced SHP-2Δ/Δ cells in recipient animals was compromised. Further analyses showed that Bcr-Abl protein (p210) was degraded, and its oncogenic signaling was greatly decreased in SHP-2Δ/Δ cells. Treatment with proteasome inhibitors or reintroduction of SHP-2 restored p210 level in Bcr-Abl–transduced SHP-2Δ/Δ cells. Subsequent investigation revealed that SHP-2 interacted with heat shock protein 90, an important chaperone protein protecting p210 from proteasome-mediated degradation. The role of SHP-2 in the stability of p210 is independent of its catalytic activity. Blockade of SHP-2 expression in p210-expressing cells by antisense or small-interfering RNA approaches decreased p210 level, causing cell death. Inhibition of SHP-2 enzymatic activity by overexpression of catalytically inactive SHP-2 mutant did not destabilize p210 but enhanced serum starvation-induced apoptosis, suggesting that SHP-2 also plays an important role in downstream signaling of p210 kinase. These studies identified a novel function of SHP-2 and suggest that SHP-2 might be a useful target for controlling Bcr-Abl–positive leukemias.

scholarly journals Direct and indirect interactions promote complexes of the lipoprotein LbcA, the CtpA protease and its substrates, and other cell wall proteins in Pseudomonas aeruginosa

2021 ◽  
Author(s):  
Dolonchapa Chakraborty ◽  
Andrew J. Darwin
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Cell Wall ◽  
Protein Complexes ◽  
Associated Proteins ◽  
Carboxyl Terminal ◽  
Multiple Species ◽  
Processing Protease ◽  
Enzyme Complexes

The Pseudomonas aeruginosa lipoprotein LbcA was discovered because it copurified with and promoted the activity of CtpA, a carboxyl-terminal processing protease (CTP) required for type III secretion system function, and for virulence in a mouse model of acute pneumonia. In this study we explored the role of LbcA by determining its effect on the proteome and its participation in protein complexes. lbcA and ctpA null mutations had strikingly similar effects on the proteome, suggesting that assisting CtpA might be the most impactful role of LbcA in the bacterial cell. Independent complexes containing LbcA and CtpA, or LbcA and substrate, were isolated from P. aeruginosa cells, indicating that LbcA facilitates proteolysis by recruiting the protease and its substrates independently. An unbiased examination of proteins that copurified with LbcA revealed an enrichment for proteins associated with the cell wall. One of these copurification partners was found to be a new CtpA substrate, and the first substrate that is not a peptidoglycan hydrolase. Many of the other LbcA copurification partners are known or predicted peptidoglycan hydrolases. However, some of these LbcA copurification partners were not cleaved by CtpA, and an in vitro assay revealed that while CtpA and all of its substrates bound to LbcA directly, these non-substrates did not. Subsequent experiments suggested that the non substrates might co-purify with LbcA by participating in multi-enzyme complexes containing LbcA-binding CtpA substrates. IMPORTANCE Carboxyl-terminal processing proteases (CTPs) are widely conserved and associated with the virulence of several bacteria, including CtpA in Pseudomonas aeruginosa . CtpA copurifies with the uncharacterized lipoprotein, LbcA. This study shows that the most impactful role of LbcA might be to promote CtpA-dependent proteolysis, and that it achieves this as a scaffold for CtpA and its substrates. It also reveals that LbcA copurification partners are enriched for cell wall-associated proteins, one of which is a novel CtpA substrate. Some of the LbcA copurification partners are not cleaved by CtpA, but might copurify with LbcA because they participate in multi-enzyme complexes containing CtpA substrates. These findings are important, because CTPs and their associated proteins affect peptidoglycan remodeling and virulence in multiple species.

scholarly journals DKK1 activates noncanonical NF-κB signaling via IL-6–induced CKAP4 receptor in multiple myeloma

2021 ◽  
Vol 5 (18) ◽  
pp. 3656-3667
Author(s):  
Xin Li ◽  
Jingjing Wang ◽  
Shuai Zhu ◽  
Jinxin Zheng ◽  
Ying Xie ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Wnt Signaling ◽  
Proteasome Inhibitors ◽  
Bone Destruction ◽  
Bortezomib Treatment ◽  
Canonical Wnt ◽  
Dickkopf 1

Abstract Proteasome inhibitors, such as bortezomib (BTZ), represent the key elements in chemotherapy regimens for multiple myeloma (MM), whereas acquired chemoresistance and ultimately relapse remain a major obstacle. In the current study, we screened differently expressed cytokines in bortezomib-resistant MM cells and found that Dickkopf-1 (DKK1) level was remarkably augmented, whereas CD138 level was significantly suppressed. DKK1 in vitro specifically enhanced the resistance of myeloma cells to bortezomib treatment, and excessive DKK1 drove CD138 downregulation via inhibition of canonical Wnt signaling. Notably, DKK1 mainly induced drug resistance in MM cells via the receptor of CKAP4. Mechanistically, CKAP4 transduced DKK1 signal and evoked NF-κB pathway through recruiting and preventing cullin associated and neddylation dissociated 1 from hampering the assembly of E3 ligase-mediated ubiquitination of IκBα. In addition, we found that interleukin-6 (IL-6) stimulated CKAP4 expression to generate drug resistance, and disturbance of DKK1-CKAP4 axis improved sensitivity to BTZ treatment of MM and attenuated bone destruction in a mouse model. Collectively, our study revealed the previously unidentified role of DKK1 in myeloma drug resistance via Wnt signaling dependent and independent manners, and clarified the importance of antagonism of DKK1-IL-6 loop in bone marrow microenvironment.

Targeting DNA Repair Systems in Antitubercular Drug Development

2019 ◽  
Vol 26 (8) ◽  
pp. 1494-1505 ◽  
Author(s):  
Alina Minias ◽  
Anna Brzostek ◽  
Jarosław Dziadek
Keyword(s):  
Dna Repair ◽  
Protein Crystal ◽  
Model Organisms ◽  
Dna Repair Genes ◽  
Associated Proteins ◽  
Related Proteins ◽  
Repair Genes

Infections with Mycobacterium tuberculosis, the causative agent of tuberculosis, are difficult to treat using currently available chemotherapeutics. Clinicians agree on the urgent need for novel drugs to treat tuberculosis. In this mini review, we summarize data that prompts the consideration of DNA repair-associated proteins as targets for the development of new antitubercular compounds. We discuss data, including gene expression data, that highlight the importance of DNA repair genes during the pathogenic cycle as well as after exposure to antimicrobials currently in use. Specifically, we report experiments on determining the essentiality of DNA repair-related genes. We report the availability of protein crystal structures and summarize discovered protein inhibitors. Further, we describe phenotypes of available gene mutants of M. tuberculosis and model organisms Mycobacterium bovis and Mycobacterium smegmatis. We summarize experiments regarding the role of DNA repair-related proteins in pathogenesis and virulence performed both in vitro and in vivo during the infection of macrophages and animals. We detail the role of DNA repair genes in acquiring mutations, which influence the rate of drug resistance acquisition.

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