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Article ; Online: Withaferin A and Celastrol Overwhelm Proteostasis.

Vilaboa, Nuria / Voellmy, Richard

International journal of molecular sciences

2023 Volume 25, Issue 1

Abstract: Withaferin A (WA) and celastrol (CEL) are major bioactive components of plants that have been widely employed in traditional medicine. The pleiotropic activities of plant preparations and the isolated compounds in vitro and in vivo have been documented ... ...

Abstract	Withaferin A (WA) and celastrol (CEL) are major bioactive components of plants that have been widely employed in traditional medicine. The pleiotropic activities of plant preparations and the isolated compounds in vitro and in vivo have been documented in hundreds of studies. Both WA and CEL were shown to have anticancer activity. Although WA and CEL belong to different chemical classes, our synthesis of the available information suggests that the compounds share basic mechanisms of action. Both WA and CEL bind covalently to numerous proteins, causing the partial unfolding of some of these proteins and of many bystander proteins. The resulting proteotoxic stress, when excessive, leads to cell death. Both WA and CEL trigger the activation of the unfolded protein response (UPR) which, if the proteotoxic stress persists, results in apoptosis mediated by the PERK/eIF-2/ATF4/CHOP pathway or another UPR-dependent pathway. Other mechanisms of cell death may play contributory or even dominant roles depending on cell type. As shown in a proteomic study with WA, the compounds appear to function largely as electrophilic reactants, indiscriminately modifying reachable nucleophilic amino acid side chains of proteins. However, a remarkable degree of target specificity is imparted by the cellular context.
MeSH term(s)	Proteostasis ; Proteomics ; Pentacyclic Triterpenes ; Withanolides
Chemical Substances	celastrol (L8GG98663L) ; withaferin A (L6DO3QW4K5) ; Pentacyclic Triterpenes ; Withanolides
Language	English
Publishing date	2023-12-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25010367
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Withaferin A and Celastrol Overwhelm Proteostasis

Nuria Vilaboa / Richard Voellmy

International Journal of Molecular Sciences, Vol 25, Iss 1, p

2023 Volume 367

Abstract	Withaferin A (WA) and celastrol (CEL) are major bioactive components of plants that have been widely employed in traditional medicine. The pleiotropic activities of plant preparations and the isolated compounds in vitro and in vivo have been documented in hundreds of studies. Both WA and CEL were shown to have anticancer activity. Although WA and CEL belong to different chemical classes, our synthesis of the available information suggests that the compounds share basic mechanisms of action. Both WA and CEL bind covalently to numerous proteins, causing the partial unfolding of some of these proteins and of many bystander proteins. The resulting proteotoxic stress, when excessive, leads to cell death. Both WA and CEL trigger the activation of the unfolded protein response (UPR) which, if the proteotoxic stress persists, results in apoptosis mediated by the PERK/eIF-2/ATF4/CHOP pathway or another UPR-dependent pathway. Other mechanisms of cell death may play contributory or even dominant roles depending on cell type. As shown in a proteomic study with WA, the compounds appear to function largely as electrophilic reactants, indiscriminately modifying reachable nucleophilic amino acid side chains of proteins. However, a remarkable degree of target specificity is imparted by the cellular context.
Keywords	proteostasis ; protein unfolding ; protein aggregation ; Withaferin A ; celastrol ; IHSF ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	580
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Recent efforts in the development of nanomaterials to control transgene expression.

Escudero-Duch, Clara / Vilaboa, Nuria

Nanomedicine (London, England)

2020 Volume 15, Issue 21, Page(s) 2019–2022

MeSH term(s)	Gene Expression Regulation ; Hydrogels ; Nanostructures ; Transgenes
Chemical Substances	Hydrogels
Language	English
Publishing date	2020-08-11
Publishing country	England
Document type	Editorial ; Research Support, Non-U.S. Gov't
ZDB-ID	2277839-1
ISSN	1748-6963 ; 1743-5889
ISSN (online)	1748-6963
ISSN	1743-5889
DOI	10.2217/nnm-2020-0227
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Article: Herpes Simplex Viruses Whose Replication Can Be Deliberately Controlled as Candidate Vaccines.

Voellmy, Richard / Bloom, David C / Vilaboa, Nuria

Vaccines

2020 Volume 8, Issue 2

Abstract: Over the last few years, we have been evaluating a novel paradigm for immunization using viruses or virus-based vectors. Safety is provided not by attenuation or inactivation of vaccine viruses, but by the introduction into the viral genomes of genetic ... ...

Abstract	Over the last few years, we have been evaluating a novel paradigm for immunization using viruses or virus-based vectors. Safety is provided not by attenuation or inactivation of vaccine viruses, but by the introduction into the viral genomes of genetic mechanisms that allow for stringent, deliberate spatial and temporal control of virus replication. The resulting replication-competent controlled viruses (RCCVs) can be activated to undergo one or, if desired, several rounds of efficient replication at the inoculation site, but are nonreplicating in the absence of activation. Extrapolating from observations that attenuated replicating viruses are better immunogens than replication-defective or inactivated viruses, it was hypothesized that RCCVs that replicate with wild-type-like efficiency when activated will be even better immunogens. The vigorous replication of the RCCVs should also render heterologous antigens expressed from them highly immunogenic. RCCVs for administration to skin sites or mucosal membranes were constructed using a virulent wild-type HSV-1 strain as the backbone. The recombinants are activated by a localized heat treatment to the inoculation site in the presence of a small-molecule regulator (SMR). Derivatives expressing influenza virus antigens were also prepared. Immunization/challenge experiments in mouse models revealed that the activated RCCVs induced far better protective immune responses against themselves as well as against the heterologous antigens they express than unactivated RCCVs or a replication-defective HSV-1 strain. Neutralizing antibody and proliferation responses mirrored these findings. We believe that the data obtained so far warrant further research to explore the possibility of developing effective RCCV-based vaccines directed to herpetic diseases and/or diseases caused by other pathogens.
Keywords	covid19
Language	English
Publishing date	2020-05-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines8020230
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Article: A Narrative Review of Cell-Based Approaches for Cranial Bone Regeneration.

Falguera Uceda, Maria I / Sánchez-Casanova, Silvia / Escudero-Duch, Clara / Vilaboa, Nuria

Pharmaceutics

2022 Volume 14, Issue 1

Abstract: Current cranial repair techniques combine the use of autologous bone grafts and biomaterials. In addition to their association with harvesting morbidity, autografts are often limited by insufficient quantity of bone stock. Biomaterials lead to better ... ...

Abstract	Current cranial repair techniques combine the use of autologous bone grafts and biomaterials. In addition to their association with harvesting morbidity, autografts are often limited by insufficient quantity of bone stock. Biomaterials lead to better outcomes, but their effectiveness is often compromised by the unpredictable lack of integration and structural failure. Bone tissue engineering offers the promising alternative of generating constructs composed of instructive biomaterials including cells or cell-secreted products, which could enhance the outcome of reconstructive treatments. This review focuses on cell-based approaches with potential to regenerate calvarial bone defects, including human studies and preclinical research. Further, we discuss strategies to deliver extracellular matrix, conditioned media and extracellular vesicles derived from cell cultures. Recent advances in 3D printing and bioprinting techniques that appear to be promising for cranial reconstruction are also discussed. Finally, we review cell-based gene therapy approaches, covering both unregulated and regulated gene switches that can create spatiotemporal patterns of transgenic therapeutic molecules. In summary, this review provides an overview of the current developments in cell-based strategies with potential to enhance the surgical armamentarium for regenerating cranial vault defects.
Language	English
Publishing date	2022-01-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14010132
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Article: Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications.

Vilaboa, Nuria / Lopez, Juan Antonio / de Mesa, Marco / Escudero-Duch, Clara / Winfield, Natalie / Bayford, Melanie / Voellmy, Richard

Pharmaceuticals (Basel, Switzerland)

2023 Volume 16, Issue 4

Abstract: Exposure of many cancer cells, including multiple myeloma cells, to cytotoxic concentrations of natural products celastrol and withaferin A or synthetic compounds of the IHSF series resulted in denaturation of a luciferase reporter protein. Proteomic ... ...

Abstract	Exposure of many cancer cells, including multiple myeloma cells, to cytotoxic concentrations of natural products celastrol and withaferin A or synthetic compounds of the IHSF series resulted in denaturation of a luciferase reporter protein. Proteomic analysis of detergent-insoluble extract fractions from HeLa-derived cells revealed that withaferin A, IHSF058 and IHSF115 caused denaturation of 915, 722 and 991 of 5132 detected cellular proteins, respectively, of which 440 were targeted by all three compounds. Western blots showed that important fractions of these proteins, in some cases approaching half of total protein amounts, unfolded. Relatively indiscriminate covalent modification of target proteins was observed; 1178 different proteins were modified by IHSF058. Further illustrating the depth of the induced proteostasis crisis, only 13% of these proteins detectably aggregated, and 79% of the proteins that aggregated were not targets of covalent modification. Numerous proteostasis network components were modified and/or found in aggregates. Proteostasis disruption caused by the study compounds may be more profound than that mediated by proteasome inhibitors. The compounds act by a different mechanism that may be less susceptible to resistance development. Multiple myeloma cells were particularly sensitive to the compounds. Development of an additional proteostasis-disrupting therapy of multiple myeloma is suggested.
Language	English
Publishing date	2023-04-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph16040616
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Article ; Online: Remote control of transgene expression using noninvasive near-infrared irradiation.

Escudero-Duch, Clara / Muñoz-Moreno, Laura / Martin-Saavedra, Francisco / Sanchez-Casanova, Silvia / Lerma-Juarez, Miguel Angel / Vilaboa, Nuria

Journal of photochemistry and photobiology. B, Biology

2023 Volume 242, Page(s) 112697

Abstract: This study investigated whether noninvasive near-infrared (NIR) energy could be transduced into heat in deep-seated organs in which adenovirus type-5 vectors tend to accumulate, thereby activating heat shock protein (HSP) promoter-mediated transgene ... ...

Abstract	This study investigated whether noninvasive near-infrared (NIR) energy could be transduced into heat in deep-seated organs in which adenovirus type-5 vectors tend to accumulate, thereby activating heat shock protein (HSP) promoter-mediated transgene expression, without local administration of photothermal agents. NIR irradiation of the subdiaphragmatic and left dorsocranial part of the abdominal cavity of adult immunocompetent C3H/HeNRj mice with an 808-nm laser effectively increased the temperature of the irradiated regions of the liver and spleen, respectively, resulting in the accumulation of the heat-inducible HSP70 protein. Spatial control of transgene expression was achieved in the NIR-irradiated regions of the mice administered an adenoviral vector carrying a firefly luciferase (fLuc) coding sequence controlled by a human HSP70B promoter, as assessed by bioluminescence and immunohistochemistry analyses. Levels of reporter gene expression were modulated by controlling NIR power density. Spatial control of transgene expression through NIR-focused activation of the HSP70B promoter, as well as temporal regulation by administering rapamycin was achieved in the spleens of mice inoculated with an adenoviral vector encoding a rapamycin-dependent transactivator driven by the HSP70B promoter and an adenoviral vector carrying a fLuc coding sequence controlled by the rapamycin-activated transactivator. Mice that were administered rapamycin and exposed to NIR light expressed fLuc activity in the splenic region, whereas no activity was detected in mice that were only administered rapamycin or vehicle or only NIR-irradiated. Thus, in the absence of any exogenously supplied photothermal material, remote control of heat-induced transgene expression can be achieved in the liver and spleen by means of noninvasive NIR irradiation.
MeSH term(s)	Humans ; Mice ; Animals ; Mice, Inbred C3H ; Transgenes ; HSP70 Heat-Shock Proteins/genetics ; Infrared Rays ; Trans-Activators/genetics ; Sirolimus
Chemical Substances	HSP70 Heat-Shock Proteins ; Trans-Activators ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2023-03-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	623022-2
ISSN	1873-2682 ; 1011-1344
ISSN (online)	1873-2682
ISSN	1011-1344
DOI	10.1016/j.jphotobiol.2023.112697
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Article ; Online: Herpes Simplex Viruses Whose Replication Can Be Deliberately Controlled as Candidate Vaccines

Richard Voellmy / David C Bloom / Nuria Vilaboa

Vaccines, Vol 8, Iss 230, p

2020 Volume 230

Abstract	Over the last few years, we have been evaluating a novel paradigm for immunization using viruses or virus-based vectors. Safety is provided not by attenuation or inactivation of vaccine viruses, but by the introduction into the viral genomes of genetic mechanisms that allow for stringent, deliberate spatial and temporal control of virus replication. The resulting replication-competent controlled viruses (RCCVs) can be activated to undergo one or, if desired, several rounds of efficient replication at the inoculation site, but are nonreplicating in the absence of activation. Extrapolating from observations that attenuated replicating viruses are better immunogens than replication-defective or inactivated viruses, it was hypothesized that RCCVs that replicate with wild-type-like efficiency when activated will be even better immunogens. The vigorous replication of the RCCVs should also render heterologous antigens expressed from them highly immunogenic. RCCVs for administration to skin sites or mucosal membranes were constructed using a virulent wild-type HSV-1 strain as the backbone. The recombinants are activated by a localized heat treatment to the inoculation site in the presence of a small-molecule regulator (SMR). Derivatives expressing influenza virus antigens were also prepared. Immunization/challenge experiments in mouse models revealed that the activated RCCVs induced far better protective immune responses against themselves as well as against the heterologous antigens they express than unactivated RCCVs or a replication-defective HSV-1 strain. Neutralizing antibody and proliferation responses mirrored these findings. We believe that the data obtained so far warrant further research to explore the possibility of developing effective RCCV-based vaccines directed to herpetic diseases and/or diseases caused by other pathogens.
Keywords	herpesvirus ; HSV-1 ; candidate vaccine ; vaccine vector ; live vaccine ; replication-competent controlled ; Medicine ; R
Subject code	570
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Wear of hip prostheses increases serum IGFBP-1 levels in patients with aseptic loosening.

Vallés, Gema / García-Rey, Eduardo / Saldaña, Laura / García-Cimbrelo, Eduardo / Vilaboa, Nuria

Scientific reports

2021 Volume 11, Issue 1, Page(s) 576

Abstract: The biological mechanisms involved in aseptic loosening include inflammation-associated and bone resorption-associated processes. Coordinated cellular actions result in biochemical imbalances with devastating consequences for the joint. Given that this ... ...

Abstract	The biological mechanisms involved in aseptic loosening include inflammation-associated and bone resorption-associated processes. Coordinated cellular actions result in biochemical imbalances with devastating consequences for the joint. Given that this condition is not known for showing systemic signs, we investigated whether circulating levels of inflammation-related proteins are altered in patients with aseptic loosening. Our study included 37 patients who underwent revision surgery due to hip osteolysis and aseptic loosening and 31 patients who underwent primary total hip arthroplasty. Using antibody arrays, we evaluated the serum levels of 320 proteins in four patients from each group. The results showed differences in insulin-like growth factor-binding protein 1 (IGFBP-1) concentrations, which we then quantified using enzyme-linked immunosorbent assay tests in all study patients. The results confirmed that serum IGFBP-1 concentrations were higher in the revision surgery patients than in the hip arthroplasty patients. In vitro studies showed that exposure of human osteoblasts to titanium particles induced an IGFBP-1 release that further increased when exposure to particles was performed in media conditioned by human M1 macrophages. These findings suggest that elevated serum IGFBP-1 levels in patients with aseptic loosening can arise from increased local IGFBP-1 production in the inflammatory environment of the periprosthetic bed.
MeSH term(s)	Aged ; Arthroplasty, Replacement, Hip/adverse effects ; Enzyme-Linked Immunosorbent Assay ; Female ; Hip Prosthesis/adverse effects ; Humans ; In Vitro Techniques ; Insulin-Like Growth Factor Binding Protein 1/blood ; Insulin-Like Growth Factor Binding Protein 1/metabolism ; Macrophages ; Male ; Osteoblasts/metabolism ; Osteolysis/etiology ; Prosthesis Failure/adverse effects ; Prosthesis Failure/etiology ; Reoperation ; Titanium/adverse effects
Chemical Substances	IGFBP1 protein, human ; Insulin-Like Growth Factor Binding Protein 1 ; Titanium (D1JT611TNE)
Language	English
Publishing date	2021-01-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-79813-x
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Article ; Online: Remote Patterning of Transgene Expression Using Near Infrared-Responsive Plasmonic Hydrogels.

Martín-Saavedra, Francisco / Vilaboa, Nuria

Methods in molecular biology (Clifton, N.J.)

2016 Volume 1408, Page(s) 281–292

Abstract: The development of noninvasive technologies for remote control of gene expression has received increased attention for their therapeutic potential in clinical scenarios, including cancer, neurological disorders, immunology, tissue engineering, as well as ...

Abstract	The development of noninvasive technologies for remote control of gene expression has received increased attention for their therapeutic potential in clinical scenarios, including cancer, neurological disorders, immunology, tissue engineering, as well as developmental biology research. Near-infrared (NIR) light is a suitable source of energy that can be employed to pattern transgene expression in plasmonic cell constructs. Gold nanoparticles tailored to exhibit a plasmon surface band absorption peaking at NIR wavelengths within the so called tissue optical window (TOW) can be used as fillers in fibrin-based hydrogels. These biocompatible composites can be loaded with cells harboring heat-inducible gene switches. NIR laser irradiation of the resulting plasmonic cell constructs causes the local conversion of NIR photon energy into heat, achieving spatially restricted patterns of transgene expression that faithfully match the illuminated areas of the hydrogels. In combination with cells genetically engineered to harbor gene switches activated by heat and dependent on a small-molecule regulator (SMR), NIR-responsive hydrogels allow reliable and safe control of the spatiotemporal availability of therapeutic biomolecules in target tissues.
MeSH term(s)	Animals ; Animals, Genetically Modified/genetics ; Biocompatible Materials/chemistry ; Cells, Immobilized/cytology ; Cells, Immobilized/metabolism ; Cells, Immobilized/transplantation ; Fibrin/chemistry ; Gene Expression/radiation effects ; Genetic Engineering/instrumentation ; Genetic Engineering/methods ; Genetic Therapy/instrumentation ; Genetic Therapy/methods ; Gold/chemistry ; Hot Temperature ; Hydrogels/chemistry ; Infrared Rays ; Metal Nanoparticles/chemistry ; Tissue Scaffolds/chemistry ; Transgenes/radiation effects
Chemical Substances	Biocompatible Materials ; Hydrogels ; Gold (7440-57-5) ; Fibrin (9001-31-4)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-3512-3_19
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