Editorial

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3 pages, 169 KiB

Open AccessEditorial

HSP70: From Signaling Mechanisms to Therapeutics

by Kenia Pedrosa Nunes and Amanda Almeida de Oliveira

Biomolecules 2023, 13(7), 1141; https://doi.org/10.3390/biom13071141 - 17 Jul 2023

Viewed by 971

Abstract

Heat-shock proteins (HSPs) are primary stress responders that are vital to maintaining homeostasis [...] Full article

(This article belongs to the Special Issue HSP70: From Signaling Mechanisms to Therapeutics)

Research

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18 pages, 3951 KiB

Open AccessEditor’s ChoiceArticle

Circulating Hsp70 Levels and the Immunophenotype of Peripheral Blood Lymphocytes as Potential Biomarkers for Advanced Lung Cancer and Therapy Failure after Surgery

by Seyer Safi, Luis Messner, Merten Kliebisch, Linn Eggert, Ceyra Ceylangil, Philipp Lennartz, Benedict Jefferies, Henriette Klein, Moritz Schirren, Michael Dommasch, Dominik Lobinger and Gabriele Multhoff

Biomolecules 2023, 13(5), 874; https://doi.org/10.3390/biom13050874 - 22 May 2023

Cited by 2 | Viewed by 1519

Abstract

Lung cancer remains a devastating disease with a poor clinical outcome. A biomarker signature which could distinguish lung cancer from metastatic disease and detect therapeutic failure would significantly improve patient management and allow for individualized, risk-adjusted therapeutic decisions. In this study, circulating Hsp70 [...] Read more.

Lung cancer remains a devastating disease with a poor clinical outcome. A biomarker signature which could distinguish lung cancer from metastatic disease and detect therapeutic failure would significantly improve patient management and allow for individualized, risk-adjusted therapeutic decisions. In this study, circulating Hsp70 levels were measured using ELISA, and the immunophenotype of the peripheral blood lymphocytes were measured using multiparameter flow cytometry, to identify a predictive biomarker signature for lung cancer patients pre- and post-operatively, in patients with lung metastases and in patients with COPD as an inflammatory lung disease. The lowest Hsp70 concentrations were found in the healthy controls followed by the patients with advanced COPD. Hsp70 levels sequentially increased with an advancing tumor stage and metastatic disease. In the early-recurrence patients, Hsp70 levels started to increase within the first three months after surgery, but remained unaltered in the recurrence-free patients. An early recurrence was associated with a significant drop in B cells and an increase in Tregs, whereas the recurrence-free patients had elevated T and NK cell levels. We conclude that circulating Hsp70 concentrations might have the potential to distinguish lung cancer from metastatic disease, and might be able to predict an advanced tumor stage and early recurrence in lung cancer patients. Further studies with larger patient cohorts and longer follow-up periods are needed to validate Hsp70 and immunophenotypic profiles as predictive biomarker signatures. Full article

(This article belongs to the Special Issue HSP70: From Signaling Mechanisms to Therapeutics)

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16 pages, 2871 KiB

Open AccessFeature PaperArticle

Elevated Extracellular HSP72 and Blunted Heat Shock Response in Severe COVID-19 Patients

by Mariana Kras Borges Russo, Lucas Stahlhöfer Kowalewski, Gabriella Richter da Natividade, Carlos Henrique de Lemos Muller, Helena Trevisan Schroeder, Patrícia Martins Bock, Layane Ramos Ayres, Bernardo Urbano Cardoso, Caroline Zanotto, Julia Tsao Schein, Tatiana Helena Rech, Daisy Crispim, Luis Henrique Canani, Rogério Friedman, Cristiane Bauermann Leitão, Fernando Gerchman and Mauricio Krause

Biomolecules 2022, 12(10), 1374; https://doi.org/10.3390/biom12101374 - 26 Sep 2022

Cited by 5 | Viewed by 2079

Abstract

Aims: We hypothesized that critically ill patients with SARS-CoV-2 infection and insulin resistance would present a reduced Heat Shock Response (HSR), which is a pathway involved in proteostasis and anti-inflammation, subsequently leading to worse outcomes and higher inflammation. In this work we aimed: [...] Read more.

Aims: We hypothesized that critically ill patients with SARS-CoV-2 infection and insulin resistance would present a reduced Heat Shock Response (HSR), which is a pathway involved in proteostasis and anti-inflammation, subsequently leading to worse outcomes and higher inflammation. In this work we aimed: (i) to measure the concentration of extracellular HSP72 (eHSP72) in patients with severe COVID-19 and in comparison with noninfected patients; (ii) to compare the HSR between critically ill patients with COVID-19 (with and without diabetes); and (iii) to compare the HSR in these patients with noninfected individuals. Methods: Sixty critically ill adults with acute respiratory failure with SARS-CoV-2, with or without diabetes, were selected. Noninfected subjects were included for comparison (healthy, n = 19 and patients with diabetes, n = 22). Blood samples were collected to measure metabolism (glucose and HbA1c); oxidative stress (lypoperoxidation and carbonyls); cytokine profile (IL-10 and TNF); eHSP72; and the HSR (in vitro). Results: Patients with severe COVID-19 presented higher plasma eHSP72 compared with healthy individuals and noninfected patients with diabetes. Despite the high level of plasma cytokines, no differences were found between critically ill patients with COVID-19 with or without diabetes. Critically ill patients, when compared to noninfected, presented a blunted HSR. Oxidative stress markers followed the same pattern. No differences in the HSR (extracellular/intracellular level) were found between critically ill patients, with or without diabetes. Conclusions: We demonstrated that patients with severe COVID-19 have elevated plasma eHSP72 and that their HSR is blunted, regardless of the presence of diabetes. These results might explain the uncontrolled inflammation and also provide insights on the increased risk in developing type 2 diabetes after SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue HSP70: From Signaling Mechanisms to Therapeutics)

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11 pages, 2260 KiB

Open AccessEditor’s ChoiceArticle

by Amanda A. de Oliveira, Valentina O. Mendoza, Fernanda Priviero, R. Clinton Webb and Kenia P. Nunes

Biomolecules 2022, 12(8), 1125; https://doi.org/10.3390/biom12081125 - 16 Aug 2022

Cited by 4 | Viewed by 1690

Abstract

Aging impairs the expression of HSP70, an emergent player in vascular biology. However, it is unknown if age-related alterations in HSP70 are linked to a decline in arterial function. In this study, we test the hypothesis that the contributions of HSP70 to vascular [...] Read more.

Aging impairs the expression of HSP70, an emergent player in vascular biology. However, it is unknown if age-related alterations in HSP70 are linked to a decline in arterial function. In this study, we test the hypothesis that the contributions of HSP70 to vascular contraction are diminished in middle-aged animals. We determined the basal levels of HSP70 in the aorta of young and middle-aged Sprague Dawley male rats using Western blotting. Functional studies were performed in a wire myograph system. Force development in response to phenylephrine was assessed in the presence or absence of extracellular calcium (Ca²⁺), and in aortic rings treated or non-treated with an HSP70 inhibitor. Fluorescent probes were used to evaluate vascular oxidative stress and nitric oxide levels. We report that middle-aged rats have significantly lower levels of HSP70. Blockade of HSP70 attenuated vascular phasic and tonic contraction in isolated aortas. It appears that a functional HSP70 is required for proper Ca²⁺ handling as inhibition of this protein led to reduced force–displacement in response to Ca²⁺ dynamics. Furthermore, middle-aged aortic rings exposed to the HSP70 inhibitor display higher reactive oxygen species levels without changes in nitric oxide. In summary, we show that middle-aged animals have lower levels of HSP70 in aortas, which associates with an age-related decline in vascular responses to α-1 adrenergic stimulation. Full article

(This article belongs to the Special Issue HSP70: From Signaling Mechanisms to Therapeutics)

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Review

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15 pages, 612 KiB

Open AccessEditor’s ChoiceReview

Thermal Effect on Heat Shock Protein 70 Family to Prevent Atherosclerotic Cardiovascular Disease

by Masayo Nagai and Hidesuke Kaji

Biomolecules 2023, 13(5), 867; https://doi.org/10.3390/biom13050867 - 20 May 2023

Cited by 3 | Viewed by 1311

Abstract

Heat shock protein 70 (HSP70) is a chaperone protein induced by various stresses on cells and is involved in various disease mechanisms. In recent years, the expression of HSP70 in skeletal muscle has attracted attention for its use as a prevention of atherosclerotic [...] Read more.

Heat shock protein 70 (HSP70) is a chaperone protein induced by various stresses on cells and is involved in various disease mechanisms. In recent years, the expression of HSP70 in skeletal muscle has attracted attention for its use as a prevention of atherosclerotic cardiovascular disease (ASCVD) and as a disease marker. We have previously reported the effect of thermal stimulation targeted to skeletal muscles and skeletal muscle-derived cells. In this article, we reported review articles including our research results. HSP70 contributes to the improvement of insulin resistance as well as chronic inflammation which are underlying pathologies of type 2 diabetes, obesity, and atherosclerosis. Thus, induction of HSP70 expression by external stimulation such as heat and exercise may be useful for ASCVD prevention. It may be possible to induce HSP70 by thermal stimulus in those who have difficulty in exercise because of obesity or locomotive syndrome. It requires further investigation to determine whether monitoring serum HSP70 concentration is useful for ASCVD prevention. Full article

(This article belongs to the Special Issue HSP70: From Signaling Mechanisms to Therapeutics)

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23 pages, 1183 KiB

Open AccessReview

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

by Nayla Mouawad, Guido Capasso, Edoardo Ruggeri, Leonardo Martinello, Filippo Severin, Andrea Visentin, Monica Facco, Livio Trentin and Federica Frezzato

Biomolecules 2023, 13(4), 604; https://doi.org/10.3390/biom13040604 - 28 Mar 2023

Cited by 4 | Viewed by 2228

Abstract

The search for molecules to be targeted that are involved in apoptosis resistance/increased survival and pathogenesis of onco-hematological malignancies is ongoing since these diseases are still not completely understood. Over the years, a good candidate has been identified in the Heat Shock Protein [...] Read more.

The search for molecules to be targeted that are involved in apoptosis resistance/increased survival and pathogenesis of onco-hematological malignancies is ongoing since these diseases are still not completely understood. Over the years, a good candidate has been identified in the Heat Shock Protein of 70kDa (HSP70), a molecule defined as “the most cytoprotective protein ever been described”. HSP70 is induced in response to a wide variety of physiological and environmental insults, allowing cells to survive lethal conditions. This molecular chaperone has been detected and studied in almost all the onco-hematological diseases and is also correlated to poor prognosis and resistance to therapy. In this review, we give an overview of the discoveries that have led us to consider HSP70 as a therapeutic target for mono- or combination-therapies in acute and chronic leukemias, multiple myeloma and different types of lymphomas. In this excursus, we will also consider HSP70 partners, such as its transcription factor HSF1 or its co-chaperones whose druggability could indirectly affect HSP70. Finally, we will try to answer the question asked in the title of this review considering that, despite the effort made by research in this field, HSP70 inhibitors never reached the clinic. Full article

(This article belongs to the Special Issue HSP70: From Signaling Mechanisms to Therapeutics)

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30 pages, 10899 KiB

Open AccessReview

HSP70 Family in Cancer: Signaling Mechanisms and Therapeutic Advances

by Kejia Zhao, Guanyu Zhou, Yu Liu, Jian Zhang, Yaohui Chen, Lunxu Liu and Gao Zhang

Biomolecules 2023, 13(4), 601; https://doi.org/10.3390/biom13040601 - 27 Mar 2023

Cited by 8 | Viewed by 3002

Abstract

The 70 kDa heat shock proteins (HSP70s) are a group of highly conserved and inducible heat shock proteins. One of the main functions of HSP70s is to act as molecular chaperones that are involved in a large variety of cellular protein folding and [...] Read more.

The 70 kDa heat shock proteins (HSP70s) are a group of highly conserved and inducible heat shock proteins. One of the main functions of HSP70s is to act as molecular chaperones that are involved in a large variety of cellular protein folding and remodeling processes. HSP70s are found to be over-expressed and may serve as prognostic markers in many types of cancers. HSP70s are also involved in most of the molecular processes of cancer hallmarks as well as the growth and survival of cancer cells. In fact, many effects of HSP70s on cancer cells are not only related to their chaperone activities but rather to their roles in regulating cancer cell signaling. Therefore, a number of drugs directly or indirectly targeting HSP70s, and their co-chaperones have been developed aiming to treat cancer. In this review, we summarized HSP70-related cancer signaling pathways and corresponding key proteins regulated by the family of HSP70s. In addition, we also summarized various treatment approaches and progress of anti-tumor therapy based on targeting HSP70 family proteins. Full article

(This article belongs to the Special Issue HSP70: From Signaling Mechanisms to Therapeutics)

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13 pages, 1252 KiB

Open AccessReview

HSP70 and Primary Arterial Hypertension

by Bernardo Rodriguez-Iturbe, Richard J. Johnson, Laura Gabriela Sanchez-Lozada and Hector Pons

Biomolecules 2023, 13(2), 272; https://doi.org/10.3390/biom13020272 - 01 Feb 2023

Cited by 5 | Viewed by 2079

Abstract

Heat shock protein 70 (HSP70) production is a stress-generated cellular response with high interspecies homology. HSP70 has both chaperone and cytokine functions and may induce, depending on the context, tolerogenic anti-inflammatory reactivity or immunogenic and autoimmune reactivity. Intracellular (chaperoning transit of antigens to [...] Read more.

Heat shock protein 70 (HSP70) production is a stress-generated cellular response with high interspecies homology. HSP70 has both chaperone and cytokine functions and may induce, depending on the context, tolerogenic anti-inflammatory reactivity or immunogenic and autoimmune reactivity. Intracellular (chaperoning transit of antigens to MHC in antigen-presenting cells) and extracellular HSP70-related effects are associated with hypertension, which is an inflammatory condition recognized as the most important risk factor for cardiovascular disease mortality. Here, we review (a) the relationship between HSP70, inflammation and immune reactivity, (b) clinical evidence relating to stress, HSP70 and anti-HSP70 reactivity with primary hypertension and (c) experimental data showing that salt-sensitive hypertension is associated with delayed hypersensitivity to HSP70. This is a consequence of anti-HSP70 reactivity in the kidneys and may be prevented and corrected by the T-cell-driven inhibition of kidney inflammation triggered by specific epitopes of HSP70. Finally, we discuss our postulate that lifelong stress signals and danger-associated molecular patterns stimulate HSP-70 and individual genetic and epigenetic characteristics determine whether the HSP70 response would drive inflammatory immune reactivity causing hypertension or, alternatively, would drive immunomodulatory responses that protect against hypertension. Full article

(This article belongs to the Special Issue HSP70: From Signaling Mechanisms to Therapeutics)

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