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Keywords = actin-polymerization inhibitor

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10 pages, 1373 KiB  
Communication
Phosphoinositide Signaling and Actin Polymerization Are Critical for Tip Growth in the Marine Red Alga Pyropia yezoensis
by Ryunosuke Irie and Koji Mikami
Plants 2025, 14(14), 2194; https://doi.org/10.3390/plants14142194 - 15 Jul 2025
Viewed by 299
Abstract
In the marine red alga Pyropia yezoensis, filamentous phases of the life cycle, e.g., the conchocelis (sporophyte) and conchosporangium (conchosporophyte), proliferate by tip growth. In this study, we investigated the possible involvement of phosphoinositide turnover and actin polymerization in the spontaneous initiation [...] Read more.
In the marine red alga Pyropia yezoensis, filamentous phases of the life cycle, e.g., the conchocelis (sporophyte) and conchosporangium (conchosporophyte), proliferate by tip growth. In this study, we investigated the possible involvement of phosphoinositide turnover and actin polymerization in the spontaneous initiation and tip growth of new branches in isolated single-celled conchocelis cells using pharmacological treatments. Treatment with LY294002 and U73122, specific inhibitors of phosphoinositide-phosphate 3-kinase and phospholipase C, respectively, reduced side-branch formation and inhibited the elongation of branches. In addition, two inhibitors of the actin cytoskeleton, cytochalasin B (CCB) and latrunculin B (LAT-B), had similar effects on tip growth. However, CCB did not alter the branching rate of single-celled conchocelis, whereas LAT-B did. As CCB and LAT-B affect actin polymerization through different mechanisms, this result suggests differences in the contributions of actin polymerization to branch initiation versus tip growth. These findings demonstrate the critical and diverse functional roles played by phosphoinositide turnover and actin polymerization in the regulation of the initiation and maintenance of tip growth in the conchocelis phase of P. yezoensis. Full article
(This article belongs to the Special Issue Algal Morphogenesis and Response to Abiotic Stresses)
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18 pages, 2726 KiB  
Article
TMEM16A Maintains Acrosomal Integrity Through ERK1/2, RhoA, and Actin Cytoskeleton During Capacitation
by Ana L. Roa-Espitia, Tania Reyes-Miguel, Monica L. Salgado-Lucio, Joaquín Cordero-Martínez, Dennis Tafoya-Domínguez and Enrique O. Hernández-González
Int. J. Mol. Sci. 2025, 26(8), 3750; https://doi.org/10.3390/ijms26083750 - 16 Apr 2025
Viewed by 569
Abstract
Mammalian spermatozoa undergo a series of physiological and biochemical changes in the oviduct that lead them to acquire the ability to fertilize eggs. During their transit in the oviduct, spermatozoa face a series of environmental changes that can affect sperm viability. A series [...] Read more.
Mammalian spermatozoa undergo a series of physiological and biochemical changes in the oviduct that lead them to acquire the ability to fertilize eggs. During their transit in the oviduct, spermatozoa face a series of environmental changes that can affect sperm viability. A series of ion channels and transporters, as well as the sperm cytoskeleton, allow spermatozoa to remain viable and functional. Cl channels such as TMEM16A (calcium-activated chloride channel), CFTR (cystic fibrosis transmembrane conductance regulator), and ClC3 (chloride voltage-gated channel 3) are some of the ion transporters involved in maintaining cellular homeostasis. They are expressed in mammalian spermatozoa and are associated with capacitation, acrosomal reaction, and motility. However, little is known about their role in maintaining sperm volume. Therefore, this study aimed to determine the mechanism through which TMEM16A maintains sperm volume during capacitation. The effects of TMEM16A were compared to those of CFTR and ClC3. Spermatozoa were capacitated in the presence of specific TMEM16A, CFTR, and ClC3 inhibitors, and the results showed that only TMEM16A inhibition increased acrosomal volume, leading to changes within the acrosome. Similarly, only TMEM16A inhibition prevented actin polymerization during capacitation. Further analysis showed that TMEM16A inhibition also prevented ERK1/2 and RhoA activation. On the other hand, TMEM16A and CFTR inhibition affected both capacitation and spontaneous acrosomal reaction, whereas ClC3 inhibition only affected the spontaneous acrosomal reaction. In conclusion, during capacitation, TMEM16A activity regulates acrosomal structure through actin polymerization and by regulating ERK1/2 and RhoA activities. Full article
(This article belongs to the Section Biochemistry)
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17 pages, 3110 KiB  
Article
Antagonistic Effects of Actin-Specific Toxins on Salmonella Typhimurium Invasion into Mammalian Cells
by David B. Heisler, Elena Kudryashova, Regan Hitt, Blake Williams, Michelle Dziejman, John Gunn and Dmitri S. Kudryashov
Biomolecules 2024, 14(11), 1428; https://doi.org/10.3390/biom14111428 - 9 Nov 2024
Viewed by 1453
Abstract
Competition between bacterial species is a major factor shaping microbial communities. It is possible but remains largely unexplored that competition between bacterial pathogens can be mediated through antagonistic effects of bacterial effector proteins on host systems, particularly the actin cytoskeleton. Using Salmonella Typhimurium [...] Read more.
Competition between bacterial species is a major factor shaping microbial communities. It is possible but remains largely unexplored that competition between bacterial pathogens can be mediated through antagonistic effects of bacterial effector proteins on host systems, particularly the actin cytoskeleton. Using Salmonella Typhimurium invasion into cells as a model, we demonstrate that invasion is inhibited if the host actin cytoskeleton is disturbed by actin-specific toxins, namely, Vibrio cholerae MARTX actin crosslinking (ACD) and Rho GTPase inactivation (RID) domains, Photorhabdus luminescens TccC3, and Salmonella’s own SpvB. We noticed that ACD, being an effective inhibitor of tandem G-actin-binding assembly factors, is likely to inhibit the activity of another Vibrio effector, VopF. In reconstituted actin polymerization assays and by live-cell microscopy, we confirmed that ACD potently halted the actin nucleation and pointed-end elongation activities of VopF, revealing competition between these two V. cholerae effectors. These results suggest that bacterial effectors from different species that target the same host machinery or proteins may represent an effective but largely overlooked mechanism of indirect bacterial competition in host-associated microbial communities. Whether the proposed inhibition mechanism involves the actin cytoskeleton or other host cell compartments, such inhibition deserves investigation and may contribute to a documented scarcity of human enteric co-infections by different pathogenic bacteria. Full article
(This article belongs to the Section Cellular Biochemistry)
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18 pages, 9498 KiB  
Article
Dennd2c Negatively Controls Multinucleation and Differentiation in Osteoclasts by Regulating Actin Polymerization and Protrusion Formation
by Yu Koyanagi, Eiko Sakai, Yu Yamaguchi, Fatima Farhana, Yohsuke Taira, Kuniaki Okamoto, Hiroshi Murata and Takayuki Tsukuba
Int. J. Mol. Sci. 2024, 25(21), 11479; https://doi.org/10.3390/ijms252111479 - 25 Oct 2024
Viewed by 1263
Abstract
Osteoclasts are bone-resorbing multinucleated giant cells formed by the fusion of monocyte/macrophage lineages. Various small GTPases are involved in the multinucleation and differentiation of osteoclasts. However, the roles of small GTPases regulatory molecules in osteoclast differentiation remain unclear. In the present study, we [...] Read more.
Osteoclasts are bone-resorbing multinucleated giant cells formed by the fusion of monocyte/macrophage lineages. Various small GTPases are involved in the multinucleation and differentiation of osteoclasts. However, the roles of small GTPases regulatory molecules in osteoclast differentiation remain unclear. In the present study, we examined the role of Dennd2c, a putative guanine nucleotide exchange factor for Rab GTPases, in osteoclast differentiation. Knockdown of Dennd2c promoted osteoclast differentiation, resorption, and expression of osteoclast markers. Morphologically, Dennd2c knockdown induced the formation of larger osteoclasts with several protrusions. In contrast, overexpression of Dennd2c inhibited the multinucleation and differentiation of osteoclasts, bone resorption, and the expression of osteoclast markers. Dennd2c-overexpressing macrophages exhibited spindle-shaped mononuclear cells and long thin protrusions. Treatment of Dennd2c-overexpressing cells with the Cdc42 inhibitor ML-141 or the Rac1 inhibitor 6-thio-GTP prevented protrusion formation. Moreover, treatment of Dennd2c-overexpressing cells with the actin polymerization inhibitor latrunculin B restored multinucleated and TRAP-positive osteoclast formation. These results indicate that Dennd2c negatively regulates osteoclast differentiation and multinucleation by modulating protrusion formation in macrophages. Full article
(This article belongs to the Special Issue Molecular Studies of Bone Biology and Bone Tissue)
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20 pages, 3671 KiB  
Article
Aminopeptidase N/CD13 Crosslinking Promotes the Activation and Membrane Expression of Integrin CD11b/CD18
by Laura Díaz-Alvarez, Mariana Esther Martínez-Sánchez, Eleanor Gray, Erandi Pérez-Figueroa and Enrique Ortega
Biomolecules 2023, 13(10), 1488; https://doi.org/10.3390/biom13101488 - 6 Oct 2023
Viewed by 2223
Abstract
The β2 integrin CD11b/CD18, also known as complement receptor 3 (CR3), and the moonlighting protein aminopeptidase N (CD13), are two myeloid immune receptors with overlapping activities: adhesion, migration, phagocytosis of opsonized particles, and respiratory burst induction. Given their common functions, shared physical location, [...] Read more.
The β2 integrin CD11b/CD18, also known as complement receptor 3 (CR3), and the moonlighting protein aminopeptidase N (CD13), are two myeloid immune receptors with overlapping activities: adhesion, migration, phagocytosis of opsonized particles, and respiratory burst induction. Given their common functions, shared physical location, and the fact that some receptors can activate a selection of integrins, we hypothesized that CD13 could induce CR3 activation through an inside-out signaling mechanism and possibly have an influence on its membrane expression. We revealed that crosslinking CD13 on the surface of human macrophages not only activates CR3 but also influences its membrane expression. Both phenomena are affected by inhibitors of Src, PLCγ, Syk, and actin polymerization. Additionally, after only 10 min at 37 °C, cells with crosslinked CD13 start secreting pro-inflammatory cytokines like interferons type 1 and 2, IL-12p70, and IL-17a. We integrated our data with a bioinformatic analysis to confirm the connection between these receptors and to suggest the signaling cascade linking them. Our findings expand the list of features of CD13 by adding the activation of a different receptor via inside-out signaling. This opens the possibility of studying the joint contribution of CD13 and CR3 in contexts where either receptor has a recognized role, such as the progression of some leukemias. Full article
(This article belongs to the Section Cellular Biochemistry)
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20 pages, 4582 KiB  
Article
Mechanical Properties and Nanomotion of BT-20 and ZR-75 Breast Cancer Cells Studied by Atomic Force Microscopy and Optical Nanomotion Detection Method
by Maria N. Starodubtseva, Nastassia M. Shkliarava, Irina A. Chelnokova, María I. Villalba, Andrei Yu. Krylov, Eldar A. Nadyrov and Sandor Kasas
Cells 2023, 12(19), 2362; https://doi.org/10.3390/cells12192362 - 26 Sep 2023
Cited by 7 | Viewed by 2523
Abstract
Cells of two molecular genetic types of breast cancer—hormone-dependent breast cancer (ZR-75 cell line) and triple-negative breast cancer (BT-20 cell line)—were studied using atomic force microscopy and an optical nanomotion detection method. Using the Peak Force QNM and Force Volume AFM modes, we [...] Read more.
Cells of two molecular genetic types of breast cancer—hormone-dependent breast cancer (ZR-75 cell line) and triple-negative breast cancer (BT-20 cell line)—were studied using atomic force microscopy and an optical nanomotion detection method. Using the Peak Force QNM and Force Volume AFM modes, we revealed the unique patterns of the dependence of Young’s modulus on the indentation depth for two cancer cell lines that correlate with the features of the spatial organization of the actin cytoskeleton. Within a 200–300 nm layer just under the cell membrane, BT-20 cells are stiffer than ZR-75 cells, whereas in deeper cell regions, Young’s modulus of ZR-75 cells exceeds that of BT-20 cells. Two cancer cell lines also displayed a difference in cell nanomotion dynamics upon exposure to cytochalasin D, a potent actin polymerization inhibitor. The drug strongly modified the nanomotion pattern of BT-20 cells, whereas it had almost no effect on the ZR-75 cells. We are confident that nanomotion monitoring and measurement of the stiffness of cancer cells at various indentation depths deserve further studies to obtain effective predictive parameters for use in clinical practice. Full article
(This article belongs to the Special Issue Advances in Scanning Probe Microscopy in Cell Biology)
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43 pages, 3797 KiB  
Review
Cytochalasans and Their Impact on Actin Filament Remodeling
by Christopher Lambert, Katharina Schmidt, Marius Karger, Marc Stadler, Theresia E. B. Stradal and Klemens Rottner
Biomolecules 2023, 13(8), 1247; https://doi.org/10.3390/biom13081247 - 15 Aug 2023
Cited by 23 | Viewed by 5517 | Correction
Abstract
The eukaryotic actin cytoskeleton comprises the protein itself in its monomeric and filamentous forms, G- and F-actin, as well as multiple interaction partners (actin-binding proteins, ABPs). This gives rise to a temporally and spatially controlled, dynamic network, eliciting a plethora of motility-associated processes. [...] Read more.
The eukaryotic actin cytoskeleton comprises the protein itself in its monomeric and filamentous forms, G- and F-actin, as well as multiple interaction partners (actin-binding proteins, ABPs). This gives rise to a temporally and spatially controlled, dynamic network, eliciting a plethora of motility-associated processes. To interfere with the complex inter- and intracellular interactions the actin cytoskeleton confers, small molecular inhibitors have been used, foremost of all to study the relevance of actin filaments and their turnover for various cellular processes. The most prominent inhibitors act by, e.g., sequestering monomers or by interfering with the polymerization of new filaments and the elongation of existing filaments. Among these inhibitors used as tool compounds are the cytochalasans, fungal secondary metabolites known for decades and exploited for their F-actin polymerization inhibitory capabilities. In spite of their application as tool compounds for decades, comprehensive data are lacking that explain (i) how the structural deviances of the more than 400 cytochalasans described to date influence their bioactivity mechanistically and (ii) how the intricate network of ABPs reacts (or adapts) to cytochalasan binding. This review thus aims to summarize the information available concerning the structural features of cytochalasans and their influence on the described activities on cell morphology and actin cytoskeleton organization in eukaryotic cells. Full article
(This article belongs to the Special Issue Actin and Its Associates: Biophysical Aspects in Functional Roles)
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24 pages, 7443 KiB  
Article
Synthesis of New Chromene Derivatives Targeting Triple-Negative Breast Cancer Cells
by Aysha Alneyadi, Zohra Nausheen Nizami, Hanan E. Aburawi, Soleiman Hisaindee, Muhammad Nawaz, Samir Attoub, Gaber Ramadan, Nehla Benhalilou, Mazoun Al Azzani, Yassine Elmahi, Aysha Almeqbali, Khalid Muhammad, Ali H. Eid, Ranjit Vijayan and Rabah Iratni
Cancers 2023, 15(10), 2682; https://doi.org/10.3390/cancers15102682 - 9 May 2023
Cited by 8 | Viewed by 4266
Abstract
Breast cancer continues to be the leading cause of cancer-related deaths among women worldwide. The most aggressive type of breast cancer is triple-negative breast cancer (TNBC). Indeed, not only does TNBC not respond well to several chemotherapeutic agents, but it also frequently develops [...] Read more.
Breast cancer continues to be the leading cause of cancer-related deaths among women worldwide. The most aggressive type of breast cancer is triple-negative breast cancer (TNBC). Indeed, not only does TNBC not respond well to several chemotherapeutic agents, but it also frequently develops resistance to various anti-cancer drugs, including taxane mitotic inhibitors. This necessitates the search for newer, more efficacious drugs. In this study, we synthesized two novel chromene derivatives (C1 and C2) and tested their efficacy against a battery of luminal type A and TNBC cell lines. Our results show that C1 and C2 significantly and specifically inhibited TNBC cell viability but had no effect on the luminal A cell type. In addition, these novel compounds induced mitotic arrest, cell multinucleation leading to senescence, and apoptotic cell death through the activation of the extrinsic pathway. We also showed that the underlying mechanisms for these actions of C1 and C2 involved inhibition of microtubule polymerization and disruption of the F-actin cytoskeleton. Furthermore, both compounds significantly attenuated migration of TNBC cells and inhibited angiogenesis in vitro. Finally, we performed an in silico analysis, which revealed that these novel variants bind to the colchicine binding site in β-tubulin. Taken together, our data highlight the potential chemotherapeutic properties of two novel chromene compounds against TNBC. Full article
(This article belongs to the Special Issue Advances in Anticancer Drugs and Pharmacotherapy of Cancer)
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19 pages, 9438 KiB  
Article
Uptake of Tropheryma whipplei by Intestinal Epithelia
by Julian Friebel, Katina Schinnerling, Kathleen Weigt, Claudia Heldt, Anja Fromm, Christian Bojarski, Britta Siegmund, Hans-Jörg Epple, Judith Kikhney, Annette Moter, Thomas Schneider, Jörg D. Schulzke, Verena Moos and Michael Schumann
Int. J. Mol. Sci. 2023, 24(7), 6197; https://doi.org/10.3390/ijms24076197 - 24 Mar 2023
Cited by 1 | Viewed by 3149
Abstract
Background: Tropheryma whipplei (TW) can cause different pathologies, e.g., Whipple’s disease and transient gastroenteritis. The mechanism by which the bacteria pass the intestinal epithelial barrier, and the mechanism of TW-induced gastroenteritis are currently unknown. Methods: Using ex vivo disease models [...] Read more.
Background: Tropheryma whipplei (TW) can cause different pathologies, e.g., Whipple’s disease and transient gastroenteritis. The mechanism by which the bacteria pass the intestinal epithelial barrier, and the mechanism of TW-induced gastroenteritis are currently unknown. Methods: Using ex vivo disease models comprising human duodenal mucosa exposed to TW in Ussing chambers, various intestinal epithelial cell (IEC) cultures exposed to TW and a macrophage/IEC coculture model served to characterize endocytic uptake mechanisms and barrier function. Results: TW exposed ex vivo to human small intestinal mucosae is capable of autonomously entering IECs, thereby invading the mucosa. Using dominant-negative mutants, TW uptake was shown to be dynamin- and caveolin-dependent but independent of clathrin-mediated endocytosis. Complementary inhibitor experiments suggested a role for the activation of the Ras/Rac1 pathway and actin polymerization. TW-invaded IECs underwent apoptosis, thereby causing an epithelial barrier defect, and were subsequently subject to phagocytosis by macrophages. Conclusions: TW enters epithelia via an actin-, dynamin-, caveolin-, and Ras-Rac1-dependent endocytosis mechanism and consecutively causes IEC apoptosis primarily in IECs invaded by multiple TW bacteria. This results in a barrier leak. Moreover, we propose that TW-packed IECs can be subject to phagocytic uptake by macrophages, thereby opening a potential entry point of TW into intestinal macrophages. Full article
(This article belongs to the Special Issue Biological Barriers)
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24 pages, 8393 KiB  
Article
P38 Mediates Tumor Suppression through Reduced Autophagy and Actin Cytoskeleton Changes in NRAS-Mutant Melanoma
by Ishani Banik, Adhideb Ghosh, Erin Beebe, Blaž Burja, Mojca Frank Bertoncelj, Christopher M. Dooley, Enni Markkanen, Reinhard Dummer, Elisabeth M. Busch-Nentwich and Mitchell P. Levesque
Cancers 2023, 15(3), 877; https://doi.org/10.3390/cancers15030877 - 31 Jan 2023
Cited by 4 | Viewed by 3234
Abstract
Hotspot mutations in the NRAS gene are causative genetic events associated with the development of melanoma. Currently, there are no FDA-approved drugs directly targeting NRAS mutations. Previously, we showed that p38 acts as a tumor suppressor in vitro and in vivo with respect [...] Read more.
Hotspot mutations in the NRAS gene are causative genetic events associated with the development of melanoma. Currently, there are no FDA-approved drugs directly targeting NRAS mutations. Previously, we showed that p38 acts as a tumor suppressor in vitro and in vivo with respect to NRAS-mutant melanoma. We observed that because of p38 activation through treatment with the protein synthesis inhibitor, anisomycin leads to a transient upregulation of several targets of the cAMP pathway, representing a stressed cancer cell state that is often observed by therapeutic doses of MAPK inhibitors in melanoma patients. Meanwhile, genetically induced p38 or its stable transduction leads to a distinct cellular transcriptional state. Contrary to previous work showing an association of invasiveness with high p38 levels in BRAF-mutated melanoma, there was no correlation of p38 expression with NRAS-mutant melanoma invasion, highlighting the difference in BRAF and NRAS-driven melanomas. Although the role of p38 has been reported to be that of both tumor suppressor and oncogene, we show here that p38 specifically plays the role of a tumor suppressor in NRAS-mutant melanoma. Both the transient and stable activation of p38 elicits phosphorylation of mTOR, reported to be a master switch in regulating autophagy. Indeed, we observed a correlation between elevated levels of phosphorylated mTOR and a reduction in LC3 conversion (LCII/LCI), indicative of suppressed autophagy. Furthermore, a reduction in actin intensity in p38–high cells strongly suggests a role of mTOR in regulating actin and a remodeling in the NRAS-mutant melanoma cells. Therefore, p38 plays a tumor suppressive role in NRAS-mutant melanomas at least partially through the mechanism of mTOR upregulation, suppressed autophagy, and reduced actin polymerization. One or more combinations of MEK inhibitors with either anisomycin, rapamycin, chloroquine/bafilomycin, and cytochalasin modulate p38 activation, mTOR phosphorylation, autophagy, and actin polymerization, respectively, and they may provide an alternate route to targeting NRAS-mutant melanoma. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Signaling Pathways in Melanoma)
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14 pages, 1424 KiB  
Article
The Soluble Fms-like Tyrosine Kinase-1 Contributes to Structural and Functional Changes in Endothelial Cells in Chronic Kidney Disease
by Annika Schulz, Carolin Christina Drost, Bettina Hesse, Katrin Beul, Marcus Brand and Giovana Seno Di Marco
Int. J. Mol. Sci. 2022, 23(24), 16059; https://doi.org/10.3390/ijms232416059 - 16 Dec 2022
Cited by 6 | Viewed by 2144
Abstract
Endothelial cells are a critical target of the soluble Fms-like tyrosine kinase-1 (sFlt-1), a soluble factor increased in different diseases with varying degrees of renal impairment and endothelial dysfunction, including chronic kidney disease (CKD). Although the mechanisms underlying endothelial dysfunction are multifactorial and [...] Read more.
Endothelial cells are a critical target of the soluble Fms-like tyrosine kinase-1 (sFlt-1), a soluble factor increased in different diseases with varying degrees of renal impairment and endothelial dysfunction, including chronic kidney disease (CKD). Although the mechanisms underlying endothelial dysfunction are multifactorial and complex, herein, we investigated the damaging effects of sFlt-1 on structural and functional changes in endothelial cells. Our results evidenced that sera from patients with CKD stiffen the endothelial cell cortex in vitro, an effect correlated with sFlt-1 levels and prevented by sFlt-1 neutralization. Besides, we could show that recombinant sFlt-1 leads to endothelial stiffening in vitro and in vivo. This was accompanied by cytoskeleton reorganization and changes in the endothelial barrier function, as observed by increased actin polymerization and endothelial cell permeability, respectively. These results depended on the activation of the p38 MAPK and were blocked by the specific inhibitor SB203580. However, sFlt-1 only minimally affected the expression of stiffness-sensitive genes. These findings bring new insight into the mechanism of action of sFlt-1 and its biological effects that cannot be exclusively ascribed to the regulation of angiogenesis. Full article
(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)
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18 pages, 3633 KiB  
Article
S-Benproperine, an Active Stereoisomer of Benproperine, Suppresses Cancer Migration and Tumor Metastasis by Targeting ARPC2
by Hyun-Jin Jang, Yae Jin Yoon, Jiyeon Choi, Yu-Jin Lee, Sangku Lee, Wansang Cho, Wan Gi Byun, Seung Bum Park, Dong Cho Han and Byoung-Mog Kwon
Pharmaceuticals 2022, 15(12), 1462; https://doi.org/10.3390/ph15121462 - 25 Nov 2022
Cited by 2 | Viewed by 2850
Abstract
Metastasis, in which cancer cells migrate to other tissues and form new tumors, is a major cause of both cancer death and treatment failure. In a previous study, benproperine (Benp) was identified as a cancer cell migration inhibitor and an inhibitor of actin-related [...] Read more.
Metastasis, in which cancer cells migrate to other tissues and form new tumors, is a major cause of both cancer death and treatment failure. In a previous study, benproperine (Benp) was identified as a cancer cell migration inhibitor and an inhibitor of actin-related protein 2/3 complex subunit 2 (ARPC2). However, Benp is a racemic mixture, and which stereoisomer is the active isomer remains unclear. In this study, we found that S-Benp is an active isomer and inhibits the migration and invasion of cancer cells much more strongly than R-Benp, with no effect on normal cells. The metastasis inhibitory effect of S-Benp was also verified in an animal model. Validating that inhibitors bind to their targets in cells and tissues has been a very challenging task in drug discovery. The direct interactions between ARPC2 and S-Benp were verified by surface plasmon resonance analysis (SPR), a cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). In the mutant study with ARPC2F225A cells, S-Benp did not bind to ARPC2F225A according to CETSA and DARTS. Furthermore, we validated that S-Benp colocalized with ARPC2 in cancer cells and directly bound to ARPC2 in tumor tissues using Cy3-conjugated S-Benp according to CETSA. Finally, actin polymerization assays and immunocytochemistry showed that S-Benp suppressed actin remodeling such as lamellipodium formation. Taken together, our data suggest that S-Benp is an active stereoisomer of Benp and a potential metastasis inhibitor via ARPC2 binding. Full article
(This article belongs to the Topic Advances in Anti-Cancer Drugs)
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24 pages, 5870 KiB  
Article
The NIN-Like Protein OsNLP2 Negatively Regulates Ferroptotic Cell Death and Immune Responses to Magnaporthe oryzae in Rice
by Yafei Chen, Juan Wang, Nam Khoa Nguyen, Byung Kook Hwang and Nam Soo Jwa
Antioxidants 2022, 11(9), 1795; https://doi.org/10.3390/antiox11091795 - 12 Sep 2022
Cited by 10 | Viewed by 3373
Abstract
Nodule inception (NIN)-like proteins (NLPs) have a central role in nitrate signaling to mediate plant growth and development. Here, we report that OsNLP2 negatively regulates ferroptotic cell death and immune responses in rice during Magnaporthe oryzae infection. OsNLP2 was localized to the plant [...] Read more.
Nodule inception (NIN)-like proteins (NLPs) have a central role in nitrate signaling to mediate plant growth and development. Here, we report that OsNLP2 negatively regulates ferroptotic cell death and immune responses in rice during Magnaporthe oryzae infection. OsNLP2 was localized to the plant cell nucleus, suggesting that it acts as a transcription factor. OsNLP2 expression was involved in susceptible disease development. ΔOsnlp2 knockout mutants exhibited reactive oxygen species (ROS) and iron-dependent ferroptotic hypersensitive response (HR) cell death in response to M. oryzae. Treatments with the iron chelator deferoxamine, lipid-ROS scavenger ferrostatin-1, actin polymerization inhibitor cytochalasin A, and NADPH oxidase inhibitor diphenyleneiodonium suppressed the accumulation of ROS and ferric ions, lipid peroxidation, and HR cell death, which ultimately led to successful M. oryzae colonization in ΔOsnlp2 mutants. The loss-of-function of OsNLP2 triggered the expression of defense-related genes including OsPBZ1, OsPIP-3A, OsWRKY104, and OsRbohB in ΔOsnlp2 mutants. ΔOsnlp2 mutants exhibited broad-spectrum, nonspecific resistance to diverse M. oryzae strains. These combined results suggest that OsNLP2 acts as a negative regulator of ferroptotic HR cell death and defense responses in rice, and may be a valuable gene source for molecular breeding of rice with broad-spectrum resistance to blast disease. Full article
(This article belongs to the Special Issue Redox Biology in Plant Growth, Defence and Metabolism)
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14 pages, 7349 KiB  
Article
Mechanisms of Basement Membrane Micro-Perforation during Cancer Cell Invasion into a 3D Collagen Gel
by Shayan S. Nazari, Andrew D. Doyle and Kenneth M. Yamada
Gels 2022, 8(9), 567; https://doi.org/10.3390/gels8090567 - 7 Sep 2022
Cited by 10 | Viewed by 4541
Abstract
Cancer invasion through basement membranes represents the initial step of tumor dissemination and metastasis. However, little is known about how human cancer cells breach basement membranes. Here, we used a three-dimensional in vitro invasion model consisting of cancer spheroids encapsulated by a basement [...] Read more.
Cancer invasion through basement membranes represents the initial step of tumor dissemination and metastasis. However, little is known about how human cancer cells breach basement membranes. Here, we used a three-dimensional in vitro invasion model consisting of cancer spheroids encapsulated by a basement membrane and embedded in 3D collagen gels to visualize the early events of cancer invasion by confocal microscopy and live-cell imaging. Human breast cancer cells generated large numbers of basement membrane perforations, or holes, of varying sizes that expanded over time during cell invasion. We used a wide variety of small molecule inhibitors to probe the mechanisms of basement membrane perforation and hole expansion. Protease inhibitor treatment (BB94), led to a 63% decrease in perforation size. After myosin II inhibition (blebbistatin), the basement membrane perforation area decreased by only 15%. These treatments produced correspondingly decreased cellular breaching events. Interestingly, inhibition of actin polymerization dramatically decreased basement membrane perforation by 80% and blocked invasion. Our findings suggest that human cancer cells can primarily use proteolysis and actin polymerization to perforate the BM and to expand perforations for basement membrane breaching with a relatively small contribution from myosin II contractility. Full article
(This article belongs to the Special Issue Cancer Cell Biology in Biological Hydrogel)
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14 pages, 1757 KiB  
Communication
Interrelation between α-Cardiac Actin Treadmilling and Myocardin-Related Transcription Factor-A Nuclear Shuttling in Cardiomyocytes
by Mark-Alexander Gorey, Mathias Mericskay, Zhenlin Li and Jean-François Decaux
Int. J. Mol. Sci. 2022, 23(13), 7394; https://doi.org/10.3390/ijms23137394 - 2 Jul 2022
Viewed by 2524
Abstract
Myocardin-related transcription factors (MRTFs) play a central role in the regulation of actin expression and cytoskeletal dynamics that are controlled by Rho GTPases. SRF is a ubiquitous transcription factor strongly expressed in muscular tissues. The depletion of SRF in the adult mouse heart [...] Read more.
Myocardin-related transcription factors (MRTFs) play a central role in the regulation of actin expression and cytoskeletal dynamics that are controlled by Rho GTPases. SRF is a ubiquitous transcription factor strongly expressed in muscular tissues. The depletion of SRF in the adult mouse heart leads to severe dilated cardiomyopathy associated with the down-regulation of target genes encoding sarcomeric proteins including α-cardiac actin. The regulatory triad, composed of SRF, its cofactor MRTFA and actin, plays a major role in the coordination of the nuclear transcriptional response to adapt actin filament dynamics associated with changes in cell shape, and contractile and migratory activities. Most of the knowledge on the regulation of the SRF–MRTF–Actin axis has been obtained in non-muscle cells with α-actin and smooth muscle cells with α-smooth actin. Here, we visualized for the first time by a time-lapse video, the nucleocytoplasmic shuttling of MRTFA induced by serum or pro-hypertrophic agonists such as angiotensin II, phenylephrine and endothelin-1, using an MRTFA-GFP adenovirus in cultures of neonatal rat cardiomyocytes. We showed that an inhibitor of the RhoA/ROCK signaling pathway leads to an α-cardiac actin polymerization disruption and inhibition of MRTFA nucleocytoplasmic shuttling. Moreover, inhibition of the PI3K/Akt signaling pathway also prevents the entry of MRTFA into the nuclei. Our findings point out a central role of the SRF–MRTFA–actin axis in cardiac remodeling. Full article
(This article belongs to the Section Molecular Biology)
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