Cells

Research

16 pages, 4403 KiB

Open AccessArticle

A Charcot-Marie-Tooth-Causing Mutation in HSPB1 Decreases Cell Adaptation to Repeated Stress by Disrupting Autophagic Clearance of Misfolded Proteins

by Xuelian Zhang, Yaru Qiao, Ronglin Han, Yingjie Gao, Xun Yang, Ying Zhang, Ying Wan, Wei Yu, Xianchao Pan and Juan Xing

Cells 2022, 11(18), 2886; https://doi.org/10.3390/cells11182886 - 15 Sep 2022

Cited by 2 | Viewed by 2458

Abstract

Charcot-Marie-Tooth (CMT) disease is the most common inherited neurodegenerative disorder with selective degeneration of peripheral nerves. Despite advances in identifying CMT-causing genes, the underlying molecular mechanism, particularly of selective degeneration of peripheral neurons remains to be elucidated. Since peripheral neurons are sensitive to [...] Read more.

Charcot-Marie-Tooth (CMT) disease is the most common inherited neurodegenerative disorder with selective degeneration of peripheral nerves. Despite advances in identifying CMT-causing genes, the underlying molecular mechanism, particularly of selective degeneration of peripheral neurons remains to be elucidated. Since peripheral neurons are sensitive to multiple stresses, we hypothesized that daily repeated stress might be an essential contributor to the selective degeneration of peripheral neurons induced by CMT-causing mutations. Here, we mainly focused on the biological effects of the dominant missense mutation (S135F) in the 27-kDa small heat-shock protein HSPB1 under repeated heat shock. HSPB1^S135F presented hyperactive binding to both α-tubulin and acetylated α-tubulin during repeated heat shock when compared with the wild type. The aberrant interactions with tubulin prevented microtubule-based transport of heat shock-induced misfolded proteins for the formation of perinuclear aggresomes. Furthermore, the transport of autophagosomes along microtubules was also blocked. These results indicate that the autophagy pathway was disrupted, leading to an accumulation of ubiquitinated protein aggregates and a significant decrease in cell adaptation to repeated stress. Our findings provide novel insights into the molecular mechanisms of HSPB1^S135F-induced selective degeneration of peripheral neurons and perspectives for targeting autophagy as a promising therapeutic strategy for CMT neuropathy. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

19 pages, 3257 KiB

Open AccessArticle

Discovery of Novel HSP27 Inhibitors as Prospective Anti-Cancer Agents Utilizing Computer-Assisted Therapeutic Discovery Approaches

by Haruna Isiyaku Umar, Adeola Temitayo Ajayi, Nobendu Mukerjee, Abdullahi Tunde Aborode, Mohammad Mehedi Hasan, Swastika Maitra, Ridwan O. Bello, Hafsat O. Alabere, Afees A. Sanusi, Olamide O. Awolaja, Mohammed M. Alshehri, Prosper O. Chukwuemeka, Nada H. Aljarba, Saad Alkahtani, Sumira Malik, Athanasios Alexiou, Arabinda Ghosh and Md. Habibur Rahman

Cells 2022, 11(15), 2412; https://doi.org/10.3390/cells11152412 - 4 Aug 2022

Cited by 18 | Viewed by 3303

Abstract

Heat shock protein 27 (HSP27) is a protein that works as a chaperone and an antioxidant and is activated by heat shock, environmental stress, and pathophysiological stress. However, HSP27 dysregulation is a characteristic of many human cancers. HSP27 suppresses apoptosis and cytoskeletal reorganization. [...] Read more.

Heat shock protein 27 (HSP27) is a protein that works as a chaperone and an antioxidant and is activated by heat shock, environmental stress, and pathophysiological stress. However, HSP27 dysregulation is a characteristic of many human cancers. HSP27 suppresses apoptosis and cytoskeletal reorganization. As a result, it is recognized as a critical therapeutic target for effective cancer therapy. Despite the effectiveness of multiple HSP27 inhibitors in pre-clinical investigations and clinical trials, no HSP27 inhibitor has progressed to the anticancer phase of the development. These difficulties have mostly been attributable to existing anticancer therapies’ inability to target oncogenic HSP27. Highly selective HSP27 inhibitors with higher effective-ness and low toxicity led to the development of combination techniques that include computer-aided assisted therapeutic discovery and design. This study emphasizes the most recent results and roles of HSP27 in cancer and the potential for utilizing an anticancer chemical database to uncover novel compounds to inhibit HSP27. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Graphical abstract

16 pages, 2739 KiB

Open AccessArticle

PARP1 Might Substitute HSF1 to Reactivate Latent HIV-1 by Binding to Heat Shock Element

by Xinfeng Xu, Yingtong Lin, Xiaoyun Zeng, Chan Yang, Siqin Duan, Liqiong Ding, Wanzhen Lu, Jian Lin, Xiaoyan Pan, Xiancai Ma and Shuwen Liu

Cells 2022, 11(15), 2331; https://doi.org/10.3390/cells11152331 - 29 Jul 2022

Cited by 1 | Viewed by 2057

Abstract

At present, the barrier to HIV-1 functional cure is the persistence of HIV-1 reservoirs. The “shock (reversing latency) and kill (antiretroviral therapy)” strategy sheds light on reducing or eliminating the latent reservoir of HIV-1. However, the current limits of latency-reversing agents (LRAs) are [...] Read more.

At present, the barrier to HIV-1 functional cure is the persistence of HIV-1 reservoirs. The “shock (reversing latency) and kill (antiretroviral therapy)” strategy sheds light on reducing or eliminating the latent reservoir of HIV-1. However, the current limits of latency-reversing agents (LRAs) are their toxicity or side effects, which limit their practicability pharmacologically and immunologically. Our previous research found that HSF1 is a key transcriptional regulatory factor in the reversion of HIV-1 latency. We then constructed the in vitro HSF1-knockout (HSF1-KO) HIV-1 latency models and found that HSF1 depletion inhibited the reactivation ability of LRAs including salubrinal, carfizomib, bortezomib, PR-957 and resveratrol, respectively. Furthermore, bortezomib/carfizomib treatment induced the increase of heat shock elements (HSEs) activity after HSF1-KO, suggesting that HSEs participated in reversing the latent HIV-1. Subsequent investigation showed that latent HIV-1-reversal by H₂O₂-induced DNA damage was inhibited by PARP1 inhibitors, while PARP1 was unable to down-regulate HSF1-depleted HSE activity, indicating that PARP1 could serve as a replaceable protein for HSF1 in HIV-1 latent cells. In summary, we succeeded in finding the mechanisms by which HSF1 reactivates the latent HIV-1, which also provides a theoretical basis for the further development of LRAs that specifically target HSF1. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

11 pages, 3827 KiB

Open AccessArticle

Structural Alternation in Heat Shock Proteins of Activated Macrophages

by Wenhao Zhang, Ying Wei, Huaijin Zhang, Jing Liu, Zhaoyun Zong, Zongyuan Liu, Songbiao Zhu, Wenxuan Hou, Yuling Chen and Haiteng Deng

Cells 2021, 10(12), 3507; https://doi.org/10.3390/cells10123507 - 11 Dec 2021

Cited by 6 | Viewed by 2876

Abstract

The inflammatory response of macrophages is an orderly and complex process under strict regulation accompanied by drastic changes in morphology and functions. It is predicted that proteins will undergo structural changes during these finely regulated processes. However, changes in structural proteome in macrophages [...] Read more.

The inflammatory response of macrophages is an orderly and complex process under strict regulation accompanied by drastic changes in morphology and functions. It is predicted that proteins will undergo structural changes during these finely regulated processes. However, changes in structural proteome in macrophages during the inflammatory response remain poorly characterized. In the present study, we applied limited proteolysis coupled mass spectrometry (LiP-MS) to identify proteome-wide structural changes in lipopolysaccharide (LPS)-activated macrophages. We identified 386 structure-specific proteolytic fingerprints from 230 proteins. Using the Gene Ontology (GO) biological process enrichment, we discovered that proteins with altered structures were enriched into protein folding-related terms, in which HSP60 was ranked as the most changed protein. We verified the structural changes in HSP60 by using cellular thermal shift assay (CETSA) and native CETSA. Our results showed that the thermal stability of HSP60 was enhanced in activated macrophages and formed an HSP10-less complex. In conclusion, we demonstrate that in situ structural systems biology is an effective method to characterize proteomic structural changes and reveal that the structures of chaperone proteins vary significantly during macrophage activation. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

14 pages, 2347 KiB

Open AccessArticle

The GRP94 Inhibitor PU-WS13 Decreases M2-like Macrophages in Murine TNBC Tumors: A Pharmaco-Imaging Study with ^99mTc-Tilmanocept SPECT

by Alexanne Bouchard, Hugo Sikner, Valentin Baverel, Anaïs-Rachel Garnier, Marie Monterrat, Mathieu Moreau, Emeric Limagne, Carmen Garrido, Evelyne Kohli, Bertrand Collin and Pierre-Simon Bellaye

Cells 2021, 10(12), 3393; https://doi.org/10.3390/cells10123393 - 2 Dec 2021

Cited by 7 | Viewed by 3038

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancers and is not eligible for hormone and anti-HER2 therapies. Identifying therapeutic targets and associated biomarkers in TNBC is a clinical challenge to improve patients’ outcome and management. High infiltration of CD206 [...] Read more.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancers and is not eligible for hormone and anti-HER2 therapies. Identifying therapeutic targets and associated biomarkers in TNBC is a clinical challenge to improve patients’ outcome and management. High infiltration of CD206⁺ M2-like macrophages in the tumor microenvironment (TME) indicates poor prognosis and survival in TNBC patients. As we previously showed that membrane expression of GRP94, an endoplasmic reticulum chaperone, was associated with the anti-inflammatory profile of human PBMC-derived M2 macrophages, we hypothesized that intra-tumoral CD206⁺ M2 macrophages expressing GRP94 may represent innovative targets in TNBC for theranostic purposes. We demonstrate in a preclinical model of 4T1 breast tumor-bearing BALB/c mice that (i) CD206-expressing M2-like macrophages in the TME of TNBC can be specifically detected and quantified using in vivo SPECT imaging with ^99mTc-Tilmanocept, and (ii) the inhibition of GRP94 with the chemical inhibitor PU-WS13 induces a decrease in CD206-expressing M2-like macrophages in TME. This result correlated with reduced tumor growth and collagen content, as well as an increase in CD8⁺ cells in the TME. ^99mTc-Tilmanocept SPECT imaging might represent an innovative non-invasive strategy to quantify CD206⁺ tumor-associated macrophages as a biomarker of anti-GRP94 therapy efficacy and TNBC tumor aggressiveness. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

12 pages, 2264 KiB

Open AccessArticle

Overexpression of Heat Shock Protein 70 Improves Cardiac Remodeling and Survival in Protein Phosphatase 2A-Expressing Transgenic Mice with Chronic Heart Failure

by Somy Yoon, Ulrich Gergs, Julie R. McMullen and Gwang Hyeon Eom

Cells 2021, 10(11), 3180; https://doi.org/10.3390/cells10113180 - 15 Nov 2021

Cited by 4 | Viewed by 2099

Abstract

Heat shock protein (HSP) 70 is a molecular chaperone that regulates protein structure in response to thermal stress. In addition, HSP70 is involved in post-translational modification and is related to the severity of some diseases. Here, we tested the functional relevance of long-lasting [...] Read more.

Heat shock protein (HSP) 70 is a molecular chaperone that regulates protein structure in response to thermal stress. In addition, HSP70 is involved in post-translational modification and is related to the severity of some diseases. Here, we tested the functional relevance of long-lasting HSP70 expression in a model of nonischemic heart failure using protein phosphatase 2 catalytic subunit A (PP2CA)-expressing transgenic mice. These transgenic mice, with cardiac-specific overexpression of PP2CA, abruptly died after 12 weeks of postnatal life. Serial echocardiograms to assess cardiac function revealed that the ejection fraction (EF) was gradually decreased in transgenic PP2CA (TgPP2CA) mice. In addition, PP2CA expression exacerbated systolic dysfunction and LV dilatation, with free wall thinning, which are indicators of fatal dilated cardiomyopathy. Interestingly, simultaneous expression of HSP70 in double transgenic mice (dTg) significantly improved the dilated cardiomyopathy phenotype of TgPP2CA mice. We observed better survival, preserved EF, reduced chamber enlargement, and suppression of free wall thinning. In the proposed molecular mechanism, HSP70 preferentially regulates the phosphorylation of AKT. Phosphorylation of AKT was significantly reduced in TgPP2CA mice but was not significantly lower in dTg mice. Signal crosstalk between AKT and its substrates, in association with HSP70, might be a useful intervention for patients with nonischemic heart failure to suppress cardiac remodeling and improve survival. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

15 pages, 3123 KiB

Open AccessArticle

by Abu Saleh Md Moin, Manjula Nandakumar, Hassan Kahal, Thozhukat Sathyapalan, Stephen L. Atkin and Alexandra E. Butler

Cells 2021, 10(11), 3109; https://doi.org/10.3390/cells10113109 - 10 Nov 2021

Cited by 5 | Viewed by 2706

Abstract

Mild hypoglycemia is common in clinical practice. Severe hypoglycemia results in heat shock protein and associate co-chaperone changes. Whether mild prolonged hypoglycemia elicits a similar response with inflammatory and oxidative-stress responses compared with a severe hypoglycemic event is unclear; therefore, this pilot exploratory [...] Read more.

Mild hypoglycemia is common in clinical practice. Severe hypoglycemia results in heat shock protein and associate co-chaperone changes. Whether mild prolonged hypoglycemia elicits a similar response with inflammatory and oxidative-stress responses compared with a severe hypoglycemic event is unclear; therefore, this pilot exploratory study was undertaken. We performed a case–control induced hypoglycemia clamp study, maintaining blood glucose at 2.8 mmol/L (50 mg/dL) for 1 h in 17 subjects (T2D (n = 10); controls (n = 7)). Blood sampling was performed at baseline, hypoglycemia, and 24 h; slow off-rate modified aptamer (SOMA)-scan plasma protein analysis of HSP-related proteins, inflammatory stress markers, and oxidative stress markers was performed. In total, 16 HSPs were analyzed. At baseline, TLR4:MD-2 complex was elevated (p = 0.01), whilst HSPA8 was lower (p < 0.05) in T2D. At hypoglycemia, UBE2N, STIP1, and UBE2L3 increased (all p < 0.05), whilst TLR4:MD-2 and HSPA8 decreased (p < 0.05) in T2D versus baseline. In follow-up after hypoglycemia, HSPs normalized to baseline by 24 h, except UBE2L3 (p < 0.05), which was decreased in controls versus baseline. Correlation of altered inflammatory markers with HSPs revealed the following: at baseline, TLR4:MD-2 correlated with CXCL10 (p < 0.01) and SIGLEC1 (p < 0.05) in controls; HSPA8 negatively correlated with IL5 (p < 0.05) in T2D. A negative correlation between urinary isoprostane 8-iso PGF2α, a marker of oxidative stress, and HSPA1A was seen at 24 h in T2D only (p < 0.05). In conclusion, the HSP changes seen for mild prolonged hypoglycemia were similar to those previously reported for a severe event. However, mild prolonged hypoglycemia appeared to elicit an increased inflammatory response that was associated with heat shock and related proteins. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Graphical abstract

23 pages, 5427 KiB

Open AccessArticle

CDK1-Mediated Phosphorylation of BAG3 Promotes Mitotic Cell Shape Remodeling and the Molecular Assembly of Mitotic p62 Bodies

by Carole Luthold, Herman Lambert, Solenn M. Guilbert, Marc-Antoine Rodrigue, Margit Fuchs, Alice-Anaïs Varlet, Amélie Fradet-Turcotte and Josée N. Lavoie

Cells 2021, 10(10), 2638; https://doi.org/10.3390/cells10102638 - 2 Oct 2021

Cited by 7 | Viewed by 2928

Abstract

The cochaperone BCL2-associated athanogene 3 (BAG3), in complex with the heat shock protein HSPB8, facilitates mitotic rounding, spindle orientation, and proper abscission of daughter cells. BAG3 and HSPB8 mitotic functions implicate the sequestosome p62/SQSTM1, suggesting a role for protein quality control. However, the [...] Read more.

The cochaperone BCL2-associated athanogene 3 (BAG3), in complex with the heat shock protein HSPB8, facilitates mitotic rounding, spindle orientation, and proper abscission of daughter cells. BAG3 and HSPB8 mitotic functions implicate the sequestosome p62/SQSTM1, suggesting a role for protein quality control. However, the interplay between this chaperone-assisted pathway and the mitotic machinery is not known. Here, we show that BAG3 phosphorylation at the conserved T285 is regulated by CDK1 and activates its function in mitotic cell shape remodeling. BAG3 phosphorylation exhibited a high dynamic at mitotic entry and both a non-phosphorylatable BAG3^T285A and a phosphomimetic BAG3^T285D protein were unable to correct the mitotic defects in BAG3-depleted HeLa cells. We also demonstrate that BAG3 phosphorylation, HSPB8, and CDK1 activity modulate the molecular assembly of p62/SQSTM1 into mitotic bodies containing K63 polyubiquitinated chains. These findings suggest the existence of a mitotically regulated spatial quality control mechanism for the fidelity of cell shape remodeling in highly dividing cells. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

16 pages, 2914 KiB

Open AccessArticle

HSPB1 Is Essential for Inducing Resistance to Proteotoxic Stress in Beta-Cells

by Vinícius M. Gomes, Rosangela A. M. Wailemann, Gabriel S. Arini, Talita C. Oliveira, Daria R. Q. Almeida, Ancély F. dos Santos, Letícia F. Terra, Stephan Lortz and Leticia Labriola

Cells 2021, 10(9), 2178; https://doi.org/10.3390/cells10092178 - 24 Aug 2021

Cited by 8 | Viewed by 3542

Abstract

During type 1 diabetes mellitus (T1DM) development, beta-cells undergo intense endoplasmic reticulum (ER) stress that could result in apoptosis through the failure of adaptation to the unfolded protein response (UPR). Islet transplantation is considered an attractive alternative among beta-cell replacement therapies for T1DM. [...] Read more.

During type 1 diabetes mellitus (T1DM) development, beta-cells undergo intense endoplasmic reticulum (ER) stress that could result in apoptosis through the failure of adaptation to the unfolded protein response (UPR). Islet transplantation is considered an attractive alternative among beta-cell replacement therapies for T1DM. To avoid the loss of beta-cells that will jeopardize the transplant’s outcome, several strategies are being studied. We have previously shown that prolactin induces protection against proinflammatory cytokines and redox imbalance-induced beta-cell death by increasing heat-shock protein B1 (HSPB1) levels. Since the role of HSPB1 in beta cells has not been deeply studied, we investigated the mechanisms involved in unbalanced protein homeostasis caused by intense ER stress and overload of the proteasomal protein degradation pathway. We tested whether HSPB1-mediated cytoprotective effects involved UPR modulation and improvement of protein degradation via the ubiquitin-proteasome system. We demonstrated that increased levels of HSPB1 attenuated levels of pro-apoptotic proteins such as CHOP and BIM, as well as increased protein ubiquitination and the speed of proteasomal protein degradation. Our data showed that HSPB1 induced resistance to proteotoxic stress and, thus, enhanced cell survival via an increase in beta-cell proteolytic capacity. These results could contribute to generate strategies aimed at the optimization of beta-cell replacement therapies. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Graphical abstract

24 pages, 2397 KiB

Open AccessArticle

Phosphorylation in the Charged Linker Modulates Interactions and Secretion of Hsp90β

by Lorenz Weidenauer and Manfredo Quadroni

Cells 2021, 10(7), 1701; https://doi.org/10.3390/cells10071701 - 5 Jul 2021

Cited by 7 | Viewed by 3147

Abstract

Hsp90β is a major chaperone involved in numerous cellular processes. Hundreds of client proteins depend on Hsp90β for proper folding and/or activity. Regulation of Hsp90β is critical to coordinate its tasks and is mediated by several post-translational modifications. Here, we focus on two [...] Read more.

Hsp90β is a major chaperone involved in numerous cellular processes. Hundreds of client proteins depend on Hsp90β for proper folding and/or activity. Regulation of Hsp90β is critical to coordinate its tasks and is mediated by several post-translational modifications. Here, we focus on two phosphorylation sites located in the charged linker region of human Hsp90β, Ser226 and Ser255, which have been frequently reported but whose function remains unclear. Targeted measurements by mass spectrometry indicated that intracellular Hsp90β is highly phosphorylated on both sites (>90%). The level of phosphorylation was unaffected by various stresses (e.g., heat shock, inhibition with drugs) that impact Hsp90β activity. Mutating the two serines to alanines increased the amount of proteins interacting with Hsp90β globally and increased the sensitivity to tryptic cleavage in the C-terminal domain. Further investigation revealed that phosphorylation on Ser255 and to a lesser extent on Ser226 is decreased in the conditioned medium of cultured K562 cells, and that a non-phosphorylatable double alanine mutant was secreted more efficiently than the wild type. Overall, our results show that phosphorylation events in the charged linker regulate both the interactions of Hsp90β and its secretion, through changes in the conformation of the chaperone. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

15 pages, 3698 KiB

Open AccessArticle

Inhibition of the Heat Shock Protein A (HSPA) Family Potentiates the Anticancer Effects of Manumycin A

by Damian Robert Sojka, Sylwia Hasterok, Natalia Vydra, Agnieszka Toma-Jonik, Anna Wieczorek, Agnieszka Gogler-Pigłowska and Dorota Scieglinska

Cells 2021, 10(6), 1418; https://doi.org/10.3390/cells10061418 - 7 Jun 2021

Cited by 13 | Viewed by 4737

Abstract

Manumycin A (MA) is a well-tolerated natural antibiotic showing pleiotropic anticancer effects in various preclinical in vitro and in vivo models. Anticancer drugs may themselves act as stressors to induce the cellular adaptive mechanism that can minimize their cytotoxicity. Heat shock proteins (HSPs) [...] Read more.

Manumycin A (MA) is a well-tolerated natural antibiotic showing pleiotropic anticancer effects in various preclinical in vitro and in vivo models. Anticancer drugs may themselves act as stressors to induce the cellular adaptive mechanism that can minimize their cytotoxicity. Heat shock proteins (HSPs) as cytoprotective factors can counteract the deleterious effects of various stressful stimuli. In this study, we examined whether the anticancer effects of MA can be counteracted by the mechanism related to HSPs belonging to the HSPA (HSP70) family. We found that MA caused cell type-specific alterations in the levels of HSPAs. These changes included concomitant upregulation of the stress-inducible (HSPA1 and HSPA6) and downregulation of the non-stress-inducible (HSPA2) paralogs. However, neither HSPA1 nor HSPA2 were necessary to provide protection against MA in lung cancer cells. Conversely, the simultaneous repression of several HSPA paralogs using pan-HSPA inhibitors (VER-155008 or JG-98) sensitized cancer cells to MA. We also observed that genetic ablation of the heat shock factor 1 (HSF1) transcription factor, a main transactivator of HSPAs expression, sensitized MCF7 cells to MA treatment. Our study reveals that inhibition of HSF1-mediated heat shock response (HSR) can improve the anticancer effect of MA. These observations suggest that targeting the HSR- or HSPA-mediated adaptive mechanisms may be a promising strategy for further preclinical developments. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

18 pages, 5737 KiB

Open AccessArticle

Regional Differences in Heat Shock Protein 25 Expression in Brain and Spinal Cord Astrocytes of Wild-Type and SOD1 ^G93A Mice

by Rebecca San Gil, Benjamin E. Clarke, Heath Ecroyd, Bernadett Kalmar and Linda Greensmith

Cells 2021, 10(5), 1257; https://doi.org/10.3390/cells10051257 - 19 May 2021

Cited by 3 | Viewed by 3240

Abstract

Heterogeneity of glia in different CNS regions may contribute to the selective vulnerability of neuronal populations in neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). Here, we explored regional variations in the expression of heat shock protein 25 in glia under conditions of [...] Read more.

Heterogeneity of glia in different CNS regions may contribute to the selective vulnerability of neuronal populations in neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). Here, we explored regional variations in the expression of heat shock protein 25 in glia under conditions of acute and chronic stress. Hsp27 (Hsp27; murine orthologue: Hsp25) fulfils a number of cytoprotective functions and may therefore be a possible therapeutic target in ALS. We identified a subpopulation of astrocytes in primary murine mixed glial cultures that expressed Hsp25. Under basal conditions, the proportion of Hsp25-positive astrocytes was twice as high in spinal cord cultures than in cortical cultures. To explore the physiological role of the elevated Hsp25 expression in spinal cord astrocytes, we exposed cortical and spinal cord glia to acute stress, using heat stress and pro-inflammatory stimuli. Surprisingly, we observed no stress-induced increase in Hsp25 expression in either cortical or spinal cord astrocytes. Similarly, exposure to endogenous stress, as modelled in glial cultures from SOD1 ^G93A-ALS mice, did not increase Hsp25 expression above that observed in astrocytes from wild-type mice. In vivo, Hsp25 expression was greater under conditions of chronic stress present in the spinal cord of SOD1 ^G93A mice than in wild-type mice, although this increase in expression is likely to be due to the extensive gliosis that occurs in this model. Together, these results show that there are differences in the expression of Hsp25 in astrocytes in different regions of the central nervous system, but Hsp25 expression is not upregulated under acute or chronic stress conditions. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

8 pages, 307 KiB

Open AccessArticle

Heat Shock Protein 27 Is an Emerging Predictor of Contrast-Induced Acute Kidney Injury on Patients Subjected to Percutaneous Coronary Interventions

by Andrzej Jaroszyński, Tomasz Zaborowski, Stanisław Głuszek, Tomasz Zapolski, Marcin Sadowski, Wojciech Załuska, Anna Cedro, Teresa Małecka-Massalska and Wojciech Dąbrowski

Cells 2021, 10(3), 684; https://doi.org/10.3390/cells10030684 - 19 Mar 2021

Cited by 5 | Viewed by 2008

Abstract

Contrast-induced acute kidney injury (CI-AKI) is a serious complication associated with considerable morbidity and mortality. Heat-shock protein 27 (HSP27) plays a role in the defense of the kidney tissue against various forms of cellular stress, including hypoxia and oxydative stress, both features associated [...] Read more.

Contrast-induced acute kidney injury (CI-AKI) is a serious complication associated with considerable morbidity and mortality. Heat-shock protein 27 (HSP27) plays a role in the defense of the kidney tissue against various forms of cellular stress, including hypoxia and oxydative stress, both features associated with CI-AKI. The aim of our study was to evaluate a potential predictive value of HSP27 for CI-AKI in patients subjected to percutaneous coronary interventions (PCI). Included were 343 selected patients subjected to PCI. Exclusion criteria were conditions that potentially might influence HSP27 levels. HSP27 serum levels were evaluated prior to PCI, together with serum creatinine, the concentration of which was also evaluated twice at 48 and 72 h post PCI. CI-AKI was diagnosed in 9.3% of patients. Patients in whom CI-AKI was diagnosed were older (p < 0.001), were more often females (p = 0.021), had higher prevalence of diabetes (p = 0.011), hypotension during PCI (p < 0.001), albuminuria (p = 0.004) as well as multivessel disease (p = 0.002), received higher contrast volume (p = 0.006), more often received contrast volume (CV) above the maximum allowed contrast dose (MACD) (p < 0.001), and had lower HSP27 level (p < 0.001). On multivariate analysis, CV > MACD (OR 1.23, p = 0.001), number of diseased vessels (OR 1.27, p = 0.006), and HSP27 (OR 0.81, p = 0.001) remained independent predictors of CI-AKI. Low concentration of HSP27 is an emerging, strong and independent predictor of CI-AKI in patients subjected to PCI. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

Review

Jump to: Research, Other

15 pages, 1538 KiB

Open AccessReview

The Distinct Assignments for Hsp90α and Hsp90β: More Than Skin Deep

by Cheng Chang, Xin Tang, David T. Woodley, Mei Chen and Wei Li

Cells 2023, 12(2), 277; https://doi.org/10.3390/cells12020277 - 11 Jan 2023

Cited by 10 | Viewed by 2640

Abstract

For decades, the undisputable definition of the cytosolic Hsp90α and hsp90β proteins being evolutionarily conserved, ATP-driven chaperones has ruled basic research and clinical trials. The results of recent studies, however, have fundamentally challenged this paradigm, not to mention the spectacular failures of the [...] Read more.

For decades, the undisputable definition of the cytosolic Hsp90α and hsp90β proteins being evolutionarily conserved, ATP-driven chaperones has ruled basic research and clinical trials. The results of recent studies, however, have fundamentally challenged this paradigm, not to mention the spectacular failures of the paradigm-based clinical trials in cancer and beyond. We now know that Hsp90α and Hsp90β are both ubiquitously expressed in all cell types but assigned for distinct and irreplaceable functions. Hsp90β is essential during mouse development and Hsp90α only maintains male reproductivity in adult mice. Neither Hsp90β nor Hsp90α could substitute each other under these biological processes. Hsp90β alone maintains cell survival in culture and Hsp90α cannot substitute it. Hsp90α also has extracellular functions under stress and Hsp90β does not. The dramatic difference in the steady-state expression of Hsp90 in different mouse organs is due to the variable expressions of Hsp90α. The lowest expression of Hsp90 is less than 2% and the highest expression of Hsp90 is 9% among non-transformed cell lines. The two linker regions only take up less than 5% of the Hsp90 proteins, but harbor 21% of the total amino acid substitutions, i.e., 40% in comparison to the 86% overall amino acid homology. A full understanding of the distinctions between Hsp90α and Hsp90β could lead to new, safe and effective therapeutics targeting Hsp90 in human disorders such as cancer. This is the first comprehensive review of a comparison between the two cytosolic Hsp90 isoforms. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

14 pages, 707 KiB

Open AccessReview

Role of Heat Shock Proteins in Atrial Fibrillation: From Molecular Mechanisms to Diagnostic and Therapeutic Opportunities

by Daiqi Liu, Xuyao Han, Zhiwei Zhang, Gary Tse, Qingmiao Shao and Tong Liu

Cells 2023, 12(1), 151; https://doi.org/10.3390/cells12010151 - 30 Dec 2022

Cited by 7 | Viewed by 3126

Abstract

Heat shock proteins (HSPs) are endogenous protective proteins and biomarkers of cell stress response, of which examples are HSP70, HSP60, HSP90, and small HSPs (HSPB). HSPs protect cells and organs, especially the cardiovascular system, against harmful and cytotoxic conditions. More recent attention has [...] Read more.

Heat shock proteins (HSPs) are endogenous protective proteins and biomarkers of cell stress response, of which examples are HSP70, HSP60, HSP90, and small HSPs (HSPB). HSPs protect cells and organs, especially the cardiovascular system, against harmful and cytotoxic conditions. More recent attention has focused on the roles of HSPs in the irreversible remodeling of atrial fibrillation (AF), which is the most common arrhythmia in clinical practice and a significant contributor to mortality. In this review, we investigated the relationship between HSPs and atrial remodeling mechanisms in AF. PubMed was searched for studies using the terms “Heat Shock Proteins” and “Atrial Fibrillation” and their relevant abbreviations up to 10 July 2022. The results showed that HSPs have cytoprotective roles in atrial cardiomyocytes during AF by promoting reverse electrical and structural remodeling. Heat shock response (HSR) exhaustion, followed by low levels of HSPs, causes proteostasis derailment in cardiomyocytes, which is the basis of AF. Furthermore, potential implications of HSPs in the management of AF are discussed in detail. HSPs represent reliable biomarkers for predicting and staging AF. HSP inducers may serve as novel therapeutic modalities in postoperative AF. HSP induction, either by geranylgeranylacetone (GGA) or by other compounds presently in development, may therefore be an interesting new approach for upstream therapy for AF, a strategy that aims to prevent AF whilst minimizing the ventricular proarrhythmic risks of traditional anti-arrhythmic agents. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

20 pages, 1077 KiB

Open AccessReview

The Role of HSP90 Inhibitors in the Treatment of Cardiovascular Diseases

by Shiyu Qi, Guang Yi, Kun Yu, Chong Feng and Shoulong Deng

Cells 2022, 11(21), 3444; https://doi.org/10.3390/cells11213444 - 31 Oct 2022

Cited by 11 | Viewed by 3302

Abstract

Cardiovascular disease is the result of complicated pathophysiological processes in the tissues that make up the blood vessels and heart. Heat shock protein 90 (HSP90) can interact with 10% of the proteome and is the most widely studied molecular chaperone in recent years. [...] Read more.

Cardiovascular disease is the result of complicated pathophysiological processes in the tissues that make up the blood vessels and heart. Heat shock protein 90 (HSP90) can interact with 10% of the proteome and is the most widely studied molecular chaperone in recent years. HSP90 is extensively involved in the regulation of protein folding and intracellular protein stability, making HSP90 a hopeful target for the treatment of multiple cardiovascular diseases. Numerous client proteins of HSP90 have been identified in known cardiac disease pathways, including MAPK signaling, PI3K/AKT (PKB)/mTOR, and TNF-α signaling. Therefore, these pathways can be controlled by regulating HSP90. Among them, the activity of HSP90 can be regulated via numerous inhibitors. In this review, first, we will discuss the function of HSP90 and its role in pathological pathways. In addition, HSP90 plays a significant role in most cardiovascular diseases, including hypertension, pulmonary venous hypertension, atherosclerosis, and heart failure; next we will focus on this part. Finally, we will summarize the currently known HSP90 inhibitors and their potential in the treatment of heart disease. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

32 pages, 2912 KiB

Open AccessReview

Targeting HSP90 as a Novel Therapy for Cancer: Mechanistic Insights and Translational Relevance

by Jian Zhang, Houde Li, Yu Liu, Kejia Zhao, Shiyou Wei, Eric T. Sugarman, Lunxu Liu and Gao Zhang

Cells 2022, 11(18), 2778; https://doi.org/10.3390/cells11182778 - 6 Sep 2022

Cited by 28 | Viewed by 6474

Abstract

Heat shock protein (HSP90), a highly conserved molecular chaperon, is indispensable for the maturation of newly synthesized poly-peptides and provides a shelter for the turnover of misfolded or denatured proteins. In cancers, the client proteins of HSP90 extend to the entire process of [...] Read more.

Heat shock protein (HSP90), a highly conserved molecular chaperon, is indispensable for the maturation of newly synthesized poly-peptides and provides a shelter for the turnover of misfolded or denatured proteins. In cancers, the client proteins of HSP90 extend to the entire process of oncogenesis that are associated with all hallmarks of cancer. Accumulating evidence has demonstrated that the client proteins are guided for proteasomal degradation when their complexes with HSP90 are disrupted. Accordingly, HSP90 and its co-chaperones have emerged as viable targets for the development of cancer therapeutics. Consequently, a number of natural products and their analogs targeting HSP90 have been identified. They have shown a strong inhibitory effect on various cancer types through different mechanisms. The inhibitors act by directly binding to either HSP90 or its co-chaperones/client proteins. Several HSP90 inhibitors—such as geldanamycin and its derivatives, gamitrinib and shepherdin—are under clinical evaluation with promising results. Here, we review the subcellular localization of HSP90, its corresponding mechanism of action in the malignant phenotypes, and the recent progress on the development of HSP90 inhibitors. Hopefully, this comprehensive review will shed light on the translational potential of HSP90 inhibitors as novel cancer therapeutics. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Graphical abstract

13 pages, 1358 KiB

Open AccessReview

The Role of the Heat-Shock Proteins in Esophagogastric Cancer

by Francisco Tustumi, Gabriel Andrade Agareno, Ricardo Purchio Galletti, Rafael Benjamim Rosa da Silva, Julia Grams Quintas, Lucas de Abreu Sesconetto, Daniel José Szor and Nelson Wolosker

Cells 2022, 11(17), 2664; https://doi.org/10.3390/cells11172664 - 27 Aug 2022

Cited by 8 | Viewed by 2527

Abstract

Heat-shock proteins (HSPs) are a family of proteins that have received considerable attention over the last several years. They have been classified into six prominent families: high-molecular-mass HSP, 90, 70, 60, 40, and small heat shock proteins. HSPs participate in protein folding, stability, [...] Read more.

Heat-shock proteins (HSPs) are a family of proteins that have received considerable attention over the last several years. They have been classified into six prominent families: high-molecular-mass HSP, 90, 70, 60, 40, and small heat shock proteins. HSPs participate in protein folding, stability, and maturation of several proteins during stress, such as in heat, oxidative stress, fever, and inflammation. Due to the immunogenic host’s role in the combat against cancer cells and the role of the inflammation in the cancer control or progression, abnormal expression of these proteins has been associated with many types of cancer, including esophagogastric cancer. This study aims to review all the evidence concerning the role of HSPs in the pathogenesis and prognosis of esophagogastric cancer and their potential role in future treatment options. This narrative review gathers scientific evidence concerning HSPs in relation to esophagus and gastric cancer. All esophagogastric cancer subtypes are included. The role of HSPs in carcinogenesis, prognostication, and therapy for esophagogastric cancer are discussed. The main topics covered are premalignant conditions for gastric cancer atrophic gastritis, Barrett esophagus, and some viral infections such as human papillomavirus (HPV) and Epstein–Barr virus (EBV). HSPs represent new perspectives on the development, prognostication, and treatment of esophagogastric cancer. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

22 pages, 2076 KiB

Open AccessFeature PaperReview

Targeting Heat-Shock Protein 90 in Cancer: An Update on Combination Therapy

by Xiude Ren, Tao Li, Wei Zhang and Xuejun Yang

Cells 2022, 11(16), 2556; https://doi.org/10.3390/cells11162556 - 17 Aug 2022

Cited by 22 | Viewed by 3770

Abstract

Heat-shock protein 90 (HSP90) is an important molecule chaperone associated with tumorigenesis and malignancy. HSP90 is involved in the folding and maturation of a wide range of oncogenic clients, including diverse kinases, transcription factors and oncogenic fusion proteins. Therefore, it could be argued [...] Read more.

Heat-shock protein 90 (HSP90) is an important molecule chaperone associated with tumorigenesis and malignancy. HSP90 is involved in the folding and maturation of a wide range of oncogenic clients, including diverse kinases, transcription factors and oncogenic fusion proteins. Therefore, it could be argued that HSP90 facilitates the malignant behaviors of cancer cells, such as uncontrolled proliferation, chemo/radiotherapy resistance and immune evasion. The extensive associations between HSP90 and tumorigenesis indicate substantial therapeutic potential, and many HSP90 inhibitors have been developed. However, due to HSP90 inhibitor toxicity and limited efficiency, none have been approved for clinical use as single agents. Recent results suggest that combining HSP90 inhibitors with other anticancer therapies might be a more advisable strategy. This review illustrates the role of HSP90 in cancer biology and discusses the therapeutic value of Hsp90 inhibitors as complements to current anticancer therapies. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

15 pages, 859 KiB

Open AccessReview

The Role of Heat Shock Protein 70 Subfamily in the Hyperplastic Prostate: From Molecular Mechanisms to Therapeutic Opportunities

by Xun Fu, Huan Liu, Jiang Liu, Michael E. DiSanto and Xinhua Zhang

Cells 2022, 11(13), 2052; https://doi.org/10.3390/cells11132052 - 28 Jun 2022

Cited by 8 | Viewed by 2756

Abstract

Benign prostatic hyperplasia (BPH) is one of the most common causes of lower urinary tract symptoms (LUTS) in men, which is characterized by a noncancerous enlargement of the prostate. BPH troubles the vast majority of aging men worldwide; however, the pathogenetic factors of [...] Read more.

Benign prostatic hyperplasia (BPH) is one of the most common causes of lower urinary tract symptoms (LUTS) in men, which is characterized by a noncancerous enlargement of the prostate. BPH troubles the vast majority of aging men worldwide; however, the pathogenetic factors of BPH have not been completely identified. The heat shock protein 70 (HSP70) subfamily, which mainly includes HSP70, glucose-regulated protein 78 (GRP78) and GRP75, plays a crucial role in maintaining cellular homeostasis. HSP70s are overexpressed in the course of BPH and involved in a variety of biological processes, such as cell survival and proliferation, cell apoptosis, epithelial/mesenchymal transition (EMT) and fibrosis, contributing to the development and progress of prostate diseases. These chaperone proteins also participate in oxidative stress, a cellular stress response that takes place under stress conditions. In addition, HSP70s can bind to the androgen receptor (AR) and act as a regulator of AR activity. This interaction of HSP70s with AR provides insight into the importance of the HSP70 chaperone family in BPH pathogenesis. In this review, we discuss the function of the HSP70 family in prostate glands and the role of HSP70s in the course of BPH. We also review the potential applications of HSP70s as biomarkers of prostate diseases for targeted therapies. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

32 pages, 8882 KiB

Open AccessReview

Forcing the Antitumor Effects of HSPs Using a Modulated Electric Field

by Carrie Anne Minnaar and Andras Szasz

Cells 2022, 11(11), 1838; https://doi.org/10.3390/cells11111838 - 4 Jun 2022

Cited by 19 | Viewed by 3517

Abstract

The role of Heat Shock Proteins (HSPs) is a “double-edged sword” with regards to tumors. The location and interactions of HSPs determine their pro- or antitumor activity. The present review includes an overview of the relevant functions of HSPs, which could improve their [...] Read more.

The role of Heat Shock Proteins (HSPs) is a “double-edged sword” with regards to tumors. The location and interactions of HSPs determine their pro- or antitumor activity. The present review includes an overview of the relevant functions of HSPs, which could improve their antitumor activity. Promoting the antitumor processes could assist in the local and systemic management of cancer. We explore the possibility of achieving this by manipulating the electromagnetic interactions within the tumor microenvironment. An appropriate electric field may select and affect the cancer cells using the electric heterogeneity of the tumor tissue. This review describes the method proposed to effect such changes: amplitude-modulated radiofrequency (amRF) applied with a 13.56 MHz carrier frequency. We summarize the preclinical investigations of the amRF on the HSPs in malignant cells. The preclinical studies show the promotion of the expression of HSP70 on the plasma membrane, participating in the immunogenic cell death (ICD) pathway. The sequence of guided molecular changes triggers innate and adaptive immune reactions. The amRF promotes the secretion of HSP70 also in the extracellular matrix. The extracellular HSP70 accompanied by free HMGB1 and membrane-expressed calreticulin (CRT) form damage-associated molecular patterns encouraging the dendritic cells’ maturing for antigen presentation. The process promotes CD8⁺ killer T-cells. Clinical results demonstrate the potential of this immune process to trigger a systemic effect. We conclude that the properly applied amRF promotes antitumor HSP activity, and in situ, it could support the tumor-specific immune effects produced locally but acting systemically for disseminated cells and metastatic lesions. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

20 pages, 2378 KiB

Open AccessReview

Hsp90 in Human Diseases: Molecular Mechanisms to Therapeutic Approaches

by Mamta P. Sumi and Arnab Ghosh

Cells 2022, 11(6), 976; https://doi.org/10.3390/cells11060976 - 12 Mar 2022

Cited by 19 | Viewed by 6861

Abstract

The maturation of hemeprotein dictates that they incorporate heme and become active, but knowledge of this essential cellular process remains incomplete. Studies on chaperon Hsp90 has revealed that it drives functional heme maturation of inducible nitric oxide synthase (iNOS), soluble guanylate cyclase (sGC) [...] Read more.

The maturation of hemeprotein dictates that they incorporate heme and become active, but knowledge of this essential cellular process remains incomplete. Studies on chaperon Hsp90 has revealed that it drives functional heme maturation of inducible nitric oxide synthase (iNOS), soluble guanylate cyclase (sGC) hemoglobin (Hb) and myoglobin (Mb) along with other proteins including GAPDH, while globin heme maturations also need an active sGC. In all these cases, Hsp90 interacts with the heme-free or apo-protein and then drives the heme maturation by an ATP dependent process before dissociating from the heme-replete proteins, suggesting that it is a key player in such heme-insertion processes. As the studies on globin maturation also need an active sGC, it connects the globin maturation to the NO-sGC (Nitric oxide-sGC) signal pathway, thereby constituting a novel NO-sGC-Globin axis. Since many aggressive cancer cells make Hbβ/Mb to survive, the dependence of the globin maturation of cancer cells places the NO-sGC signal pathway in a new light for therapeutic intervention. Given the ATPase function of Hsp90 in heme-maturation of client hemeproteins, Hsp90 inhibitors often cause serious side effects and this can encourage the alternate use of sGC activators/stimulators in combination with specific Hsp90 inhibitors for better therapeutic intervention. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Graphical abstract

18 pages, 1801 KiB

Open AccessReview

Hsp70 in Redox Homeostasis

by Hong Zhang, Weibin Gong, Si Wu and Sarah Perrett

Cells 2022, 11(5), 829; https://doi.org/10.3390/cells11050829 - 28 Feb 2022

Cited by 51 | Viewed by 5743

Abstract

Cellular redox homeostasis is precisely balanced by generation and elimination of reactive oxygen species (ROS). ROS are not only capable of causing oxidation of proteins, lipids and DNA to damage cells but can also act as signaling molecules to modulate transcription factors and [...] Read more.

Cellular redox homeostasis is precisely balanced by generation and elimination of reactive oxygen species (ROS). ROS are not only capable of causing oxidation of proteins, lipids and DNA to damage cells but can also act as signaling molecules to modulate transcription factors and epigenetic pathways that determine cell survival and death. Hsp70 proteins are central hubs for proteostasis and are important factors to ameliorate damage from different kinds of stress including oxidative stress. Hsp70 members often participate in different cellular signaling pathways via their clients and cochaperones. ROS can directly cause oxidative cysteine modifications of Hsp70 members to alter their structure and chaperone activity, resulting in changes in the interactions between Hsp70 and their clients or cochaperones, which can then transfer redox signals to Hsp70-related signaling pathways. On the other hand, ROS also activate some redox-related signaling pathways to indirectly modulate Hsp70 activity and expression. Post-translational modifications including phosphorylation together with elevated Hsp70 expression can expand the capacity of Hsp70 to deal with ROS-damaged proteins and support antioxidant enzymes. Knowledge about the response and role of Hsp70 in redox homeostasis will facilitate our understanding of the cellular knock-on effects of inhibitors targeting Hsp70 and the mechanisms of redox-related diseases and aging. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

13 pages, 689 KiB

Open AccessReview

Heat Shock Protein 22 in Physiological and Pathological Hearts: Small Molecule, Large Potentials

by Xiaonan Sun, Sharadhi Siri, Amirah Hurst and Hongyu Qiu

Cells 2022, 11(1), 114; https://doi.org/10.3390/cells11010114 - 30 Dec 2021

Cited by 9 | Viewed by 2882

Abstract

Small heat shock protein 22 (HSP22) belongs to the superfamily of heat shock proteins and is predominantly expressed in the heart, brain, skeletal muscle, and different types of cancers. It has been found that HSP22 is involved in variant cellular functions in cardiomyocytes [...] Read more.

Small heat shock protein 22 (HSP22) belongs to the superfamily of heat shock proteins and is predominantly expressed in the heart, brain, skeletal muscle, and different types of cancers. It has been found that HSP22 is involved in variant cellular functions in cardiomyocytes and plays a vital role in cardiac protection against cardiomyocyte injury under diverse stress. This review summarizes the multiple functions of HSP22 in the heart and the underlying molecular mechanisms through modulating gene transcription, post-translational modification, subcellular translocation of its interacting proteins, and protein degradation, facilitating mitochondrial function, cardiac metabolism, autophagy, and ROS production and antiapoptotic effect. We also discuss the association of HSP22 in cardiac pathologies, including human dilated cardiomyopathy, pressure overload-induced heart failure, ischemic heart diseases, and aging-related cardiac metabolism disorder. The collected information would provide insights into the understanding of the HSP22 in heart diseases and lead to discovering the therapeutic targets. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

44 pages, 1878 KiB

Open AccessReview

HSP70s in Breast Cancer: Promoters of Tumorigenesis and Potential Targets/Tools for Therapy

by Alexander E. Kabakov and Vladimir L. Gabai

Cells 2021, 10(12), 3446; https://doi.org/10.3390/cells10123446 - 7 Dec 2021

Cited by 31 | Viewed by 6837

Abstract

The high frequency of breast cancer worldwide and the high mortality among women with this malignancy are a serious challenge for modern medicine. A deeper understanding of the mechanisms of carcinogenesis and emergence of metastatic, therapy-resistant breast cancers would help development of novel [...] Read more.

The high frequency of breast cancer worldwide and the high mortality among women with this malignancy are a serious challenge for modern medicine. A deeper understanding of the mechanisms of carcinogenesis and emergence of metastatic, therapy-resistant breast cancers would help development of novel approaches to better treatment of this disease. The review is dedicated to the role of members of the heat shock protein 70 subfamily (HSP70s or HSPA), mainly inducible HSP70, glucose-regulated protein 78 (GRP78 or HSPA5) and GRP75 (HSPA9 or mortalin), in the development and pathogenesis of breast cancer. Various HSP70-mediated cellular mechanisms and pathways which contribute to the oncogenic transformation of mammary gland epithelium are reviewed, as well as their role in the development of human breast carcinomas with invasive, metastatic traits along with the resistance to host immunity and conventional therapeutics. Additionally, intracellular and cell surface HSP70s are considered as potential targets for therapy or sensitization of breast cancer. We also discuss a clinical implication of Hsp70s and approaches to targeting breast cancer with gene vectors or nanoparticles downregulating HSP70s, natural or synthetic (small molecule) inhibitors of HSP70s, HSP70-binding antibodies, HSP70-derived peptides, and HSP70-based vaccines. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

16 pages, 1425 KiB

Open AccessReview

Molecular Mechanisms of Hypertensive Nephropathy: Renoprotective Effect of Losartan through Hsp70

by Valeria Victoria Costantino, Andrea Fernanda Gil Lorenzo, Victoria Bocanegra and Patricia G. Vallés

Cells 2021, 10(11), 3146; https://doi.org/10.3390/cells10113146 - 12 Nov 2021

Cited by 42 | Viewed by 7268

Abstract

Hypertensive nephrosclerosis is the second most common cause of end-stage renal disease after diabetes. For years, hypertensive kidney disease has been focused on the afferent arterioles and glomeruli damage and the involvement of the renin angiotensin system (RAS). Nonetheless, in recent years, novel [...] Read more.

Hypertensive nephrosclerosis is the second most common cause of end-stage renal disease after diabetes. For years, hypertensive kidney disease has been focused on the afferent arterioles and glomeruli damage and the involvement of the renin angiotensin system (RAS). Nonetheless, in recent years, novel evidence has demonstrated that persistent high blood pressure injures tubular cells, leading to epithelial–mesenchymal transition (EMT) and tubulointerstitial fibrosis. Injury primarily determined at the glomerular level by hypertension causes changes in post-glomerular peritubular capillaries that in turn induce endothelial damage and hypoxia. Microvasculature dysfunction, by inducing hypoxic environment, triggers inflammation, EMT with epithelial cells dedifferentiation and fibrosis. Hypertensive kidney disease also includes podocyte effacement and loss, leading to disruption of the filtration barrier. This review highlights the molecular mechanisms and histologic aspects involved in the pathophysiology of hypertensive kidney disease incorporating knowledge about EMT and tubulointerstitial fibrosis. The role of the Hsp70 chaperone on the angiotensin II–induced EMT after angiotensin II type 1 receptor (AT₁R) blockage, as a possible molecular target for therapeutic strategy against hypertensive renal damage is discussed. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

33 pages, 2933 KiB

Open AccessReview

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

by Selin Altinok, Rebekah Sanchez-Hodge, Mariah Stewart, Kaitlan Smith and Jonathan C. Schisler

Cells 2021, 10(11), 3121; https://doi.org/10.3390/cells10113121 - 11 Nov 2021

Cited by 8 | Viewed by 4614

Abstract

Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting [...] Read more.

Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensure cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, with a concentration on cardioprotection, neuroprotection, cancer, and autoimmune diseases. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Graphical abstract

19 pages, 2290 KiB

Open AccessReview

by Rajani Rai, Amy L. Kennedy, Zitha Redempta Isingizwe, Pouya Javadian and Doris Mangiaracina Benbrook

Cells 2021, 10(11), 2996; https://doi.org/10.3390/cells10112996 - 3 Nov 2021

Cited by 31 | Viewed by 5154

Abstract

Background: Upregulation of Heath Shock Protein 70 (HSP70) chaperones supports cancer cell survival. Their high homology causes a challenge to differentiate them in experimental or prevention and treatment strategies. The objective of this investigation was to determine similarities and differences of Hsp70, [...] Read more.

Background: Upregulation of Heath Shock Protein 70 (HSP70) chaperones supports cancer cell survival. Their high homology causes a challenge to differentiate them in experimental or prevention and treatment strategies. The objective of this investigation was to determine similarities and differences of Hsp70, hsc70, Grp78 and Mortalin members of the HSP70 family encoded by HSPA1, HSPA8, HSPA5 and HSPA9 genes, respectively. Methods: Literature reviews were conducted using HSPA1, HSPA5, HSPA8 and HSPA9 gene or protein names or synonyms combined with biological or cancer-relevant terms. Ingenuity Pathway Analysis was used to identify and compare profiles of proteins that directly bind individual chaperones and their associated pathways. TCGA data was probed to identify associations of hsc70 with cancer patient survival. ClinicalTrials.gov was used to identify HSP70 family studies. Results: The chaperones have similar protein folding functions. Their different cellular effects are determined by co-chaperones and client proteins combined with their intra- and extra-cellular localizations. Their upregulation is associated with worse patient prognosis in multiple cancers and can stimulate tumor immune responses or drug resistance. Their inhibition selectively kills cancer over healthy cells. Conclusions: Differences in Hsp70, hsc70, Grp78 and mortalin provide opportunities to calibrate HSP70 inhibitors for individual cancers and combination therapies. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Graphical abstract

18 pages, 368 KiB

Open AccessReview

Ins and Outs of Heat Shock Proteins in Colorectal Carcinoma: Its Role in Carcinogenesis and Therapeutic Perspectives

by Batoul Abi Zamer, Waseem El-Huneidi, Mohamed Ahmed Eladl and Jibran Sualeh Muhammad

Cells 2021, 10(11), 2862; https://doi.org/10.3390/cells10112862 - 24 Oct 2021

Cited by 6 | Viewed by 2727

Abstract

Cancer cells can reprogram their metabolic activities and undergo uncontrolled proliferation by utilizing the power of heat shock proteins (HSPs). HSPs are highly conserved chaperones that facilitate the folding of intracellular proteins under stress. Constitutively, HSPs are expressed at low levels, but their [...] Read more.

Cancer cells can reprogram their metabolic activities and undergo uncontrolled proliferation by utilizing the power of heat shock proteins (HSPs). HSPs are highly conserved chaperones that facilitate the folding of intracellular proteins under stress. Constitutively, HSPs are expressed at low levels, but their expression upregulates in response to a wide variety of insults, including anticancer drugs, allowing cancer cells to develop chemoresistance. In recent years, several researchers have reported that HSPs could be an important therapeutic target in difficult-to-treat cancers such as colorectal carcinoma (CRC). Worldwide, CRC is the second most common type of cancer and the second leading cause of cancer-related deaths. The molecular complexity of CRC and the coexisting inflammatory conditions present a significant obstacle to developing effective treatment. Recently, considerable progress has been made in enhancing our understanding of the role of HSPs in CRC pathogenesis. Moreover, novel therapeutic strategies targeting HSPs, either alone or in combination with other anticancer agents, have been reported. Herein, we present an overview of the functional mechanisms and the diagnostic and prognostic potential of HSPs in CRC. We also discuss emerging anti-CRC strategies based on targeting HSPs. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

30 pages, 8533 KiB

Open AccessFeature PaperReview

Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future

by Melissa Louise Stofberg, Celine Caillet, Marianne de Villiers and Tawanda Zininga

Cells 2021, 10(11), 2849; https://doi.org/10.3390/cells10112849 - 22 Oct 2021

Cited by 11 | Viewed by 4688

Abstract

Malaria is still one of the major killer parasitic diseases in tropical settings, posing a public health threat. The development of antimalarial drug resistance is reversing the gains made in attempts to control the disease. The parasite leads a complex life cycle that [...] Read more.

Malaria is still one of the major killer parasitic diseases in tropical settings, posing a public health threat. The development of antimalarial drug resistance is reversing the gains made in attempts to control the disease. The parasite leads a complex life cycle that has adapted to outwit almost all known antimalarial drugs to date, including the first line of treatment, artesunate. There is a high unmet need to develop new strategies and identify novel therapeutics to reverse antimalarial drug resistance development. Among the strategies, here we focus and discuss the merits of the development of antimalarials targeting the Heat shock protein 90 (Hsp90) due to the central role it plays in protein quality control. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

16 pages, 2089 KiB

Open AccessReview

Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase

by Aitor Franco, Lorea Velasco-Carneros, Naiara Alvarez, Natalia Orozco, Fernando Moro, Adelina Prado and Arturo Muga

Cells 2021, 10(10), 2745; https://doi.org/10.3390/cells10102745 - 14 Oct 2021

Cited by 6 | Viewed by 3164

Abstract

Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an [...] Read more.

Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an urgent need for understanding the basic molecular mechanisms associated with such diseases. A major molecular hallmark of most NDs is the accumulation of insoluble and toxic protein aggregates, known as amyloids, in extracellular or intracellular deposits. Here, we review the current knowledge on how molecular chaperones, and more specifically a ternary protein complex referred to as the human disaggregase, deals with amyloids. This machinery, composed of the constitutive Hsp70 (Hsc70), the class B J-protein DnaJB1 and the nucleotide exchange factor Apg2 (Hsp110), disassembles amyloids of α-synuclein implicated in Parkinson’s disease as well as of other disease-associated proteins such as tau and huntingtin. We highlight recent studies that have led to the dissection of the mechanism used by this chaperone system to perform its disaggregase activity. We also discuss whether this chaperone-mediated disassembly mechanism could be used to solubilize other amyloidogenic substrates. Finally, we evaluate the implications of the chaperone system in amyloid clearance and associated toxicity, which could be critical for the development of new therapies. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

20 pages, 2932 KiB

Open AccessReview

The Pathophysiological Role of Heat Shock Response in Autoimmunity: A Literature Review

by Ariadni Androvitsanea, Kostas Stylianou, Eleni Drosataki and Ioannis Petrakis

Cells 2021, 10(10), 2626; https://doi.org/10.3390/cells10102626 - 1 Oct 2021

Cited by 15 | Viewed by 3894

Abstract

Within the last two decades, there has been increasing evidence that heat-shock proteins can have a differential influence on the immune system. They can either provoke or ameliorate immune responses. This review focuses on outlining the stimulatory as well as the inhibitory effects [...] Read more.

Within the last two decades, there has been increasing evidence that heat-shock proteins can have a differential influence on the immune system. They can either provoke or ameliorate immune responses. This review focuses on outlining the stimulatory as well as the inhibitory effects of heat-shock proteins 27, 40, 70, 65, 60, and 90 in experimental and clinical autoimmune settings. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Graphical abstract

28 pages, 4057 KiB

Open AccessReview

Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases

by Lisha Wang, Liza Bergkvist, Rajnish Kumar, Bengt Winblad and Pavel F. Pavlov

Cells 2021, 10(10), 2596; https://doi.org/10.3390/cells10102596 - 29 Sep 2021

Cited by 8 | Viewed by 4624

Abstract

The dysfunction of the proteostasis network is a molecular hallmark of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Molecular chaperones are a major component of the proteostasis network and maintain cellular homeostasis by folding client proteins, [...] Read more.

The dysfunction of the proteostasis network is a molecular hallmark of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Molecular chaperones are a major component of the proteostasis network and maintain cellular homeostasis by folding client proteins, assisting with intracellular transport, and interfering with protein aggregation or degradation. Heat shock protein 70 kDa (Hsp70) and 90 kDa (Hsp90) are two of the most important chaperones whose functions are dependent on ATP hydrolysis and collaboration with their co-chaperones. Numerous studies implicate Hsp70, Hsp90, and their co-chaperones in neurodegenerative diseases. Targeting the specific protein–protein interactions between chaperones and their particular partner co-chaperones with small molecules provides an opportunity to specifically modulate Hsp70 or Hsp90 function for neurodegenerative diseases. Here, we review the roles of co-chaperones in Hsp70 or Hsp90 chaperone cycles, the impacts of co-chaperones in neurodegenerative diseases, and the development of small molecules modulating chaperone/co-chaperone interactions. We also provide a future perspective of drug development targeting chaperone/co-chaperone interactions for neurodegenerative diseases. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

18 pages, 1584 KiB

Open AccessReview

Heat Shock Proteins: Connectors between Heart and Kidney

by Carolina Victória Cruz Junho, Carolina Amaral Bueno Azevedo, Regiane Stafim da Cunha, Ainhoa Rodriguez de Yurre, Emiliano Medei, Andréa Emilia Marques Stinghen and Marcela Sorelli Carneiro-Ramos

Cells 2021, 10(8), 1939; https://doi.org/10.3390/cells10081939 - 30 Jul 2021

Cited by 9 | Viewed by 5658

Abstract

Over the development of eukaryotic cells, intrinsic mechanisms have been developed in order to provide the ability to defend against aggressive agents. In this sense, a group of proteins plays a crucial role in controlling the production of several proteins, guaranteeing cell survival. [...] Read more.

Over the development of eukaryotic cells, intrinsic mechanisms have been developed in order to provide the ability to defend against aggressive agents. In this sense, a group of proteins plays a crucial role in controlling the production of several proteins, guaranteeing cell survival. The heat shock proteins (HSPs), are a family of proteins that have been linked to different cellular functions, being activated under conditions of cellular stress, not only imposed by thermal variation but also toxins, radiation, infectious agents, hypoxia, etc. Regarding pathological situations as seen in cardiorenal syndrome (CRS), HSPs have been shown to be important mediators involved in the control of gene transcription and intracellular signaling, in addition to be an important connector with the immune system. CRS is classified as acute or chronic and according to the first organ to suffer the injury, which can be the heart (CRS type 1 and type 2), kidneys (CRS type 3 and 4) or both (CRS type 5). In all types of CRS, the immune system, redox balance, mitochondrial dysfunction, and tissue remodeling have been the subject of numerous studies in the literature in order to elucidate mechanisms and propose new therapeutic strategies. In this sense, HSPs have been targeted by researchers as important connectors between kidney and heart. Thus, the present review has a focus to present the state of the art regarding the role of HSPs in the pathophysiology of cardiac and renal alterations, as well their role in the kidney–heart axis. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

23 pages, 23801 KiB

Open AccessReview

Role of a Heat Shock Transcription Factor and the Major Heat Shock Protein Hsp70 in Memory Formation and Neuroprotection

by Olga G. Zatsepina, Michael B. Evgen’ev and David G. Garbuz

Cells 2021, 10(7), 1638; https://doi.org/10.3390/cells10071638 - 29 Jun 2021

Cited by 39 | Viewed by 5339

Abstract

Heat shock proteins (Hsps) represent the most evolutionarily ancient, conserved, and universal system for protecting cells and the whole body from various types of stress. Among Hsps, the group of proteins with a molecular weight of 70 kDa (Hsp70) plays a particularly important [...] Read more.

Heat shock proteins (Hsps) represent the most evolutionarily ancient, conserved, and universal system for protecting cells and the whole body from various types of stress. Among Hsps, the group of proteins with a molecular weight of 70 kDa (Hsp70) plays a particularly important role. These proteins are molecular chaperones that restore the native conformation of partially denatured proteins after exposure to proteotoxic forms of stress and are critical for the folding and intracellular trafficking of de novo synthesized proteins under normal conditions. Hsp70s are expressed at high levels in the central nervous system (CNS) of various animals and protect neurons from various types of stress, including heat shock, hypoxia, and toxins. Numerous molecular and behavioral studies have indicated that Hsp70s expressed in the CNS are important for memory formation. These proteins contribute to the folding and transport of synaptic proteins, modulate signaling cascades associated with synaptic activation, and participate in mechanisms of neurotransmitter release. In addition, HSF1, a transcription factor that is activated under stress conditions and mediates Hsps transcription, is also involved in the transcription of genes encoding many synaptic proteins, whose levels are increased in neurons under stress and during memory formation. Thus, stress activates the molecular mechanisms of memory formation, thereby allowing animals to better remember and later avoid potentially dangerous stimuli. Finally, Hsp70 has significant protective potential in neurodegenerative diseases. Increasing the level of endogenous Hsp70 synthesis or injecting exogenous Hsp70 reduces neurodegeneration, stimulates neurogenesis, and restores memory in animal models of ischemia and Alzheimer’s disease. These findings allow us to consider recombinant Hsp70 and/or Hsp70 pharmacological inducers as potential drugs for use in the treatment of ischemic injury and neurodegenerative disorders. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

Other

Jump to: Research, Review

7 pages, 771 KiB

Open AccessCommentary

Tracking the Activation of Heat Shock Signaling in Cellular Protection and Damage

by Shisui Torii and Pasko Rakic

Cells 2022, 11(9), 1561; https://doi.org/10.3390/cells11091561 - 5 May 2022

Viewed by 1853

Abstract

Heat Shock (HS) signaling is activated in response to various types of cellular stress. This activation serves to protect cells from immediate threats in the surrounding environment. However, activation of HS signaling occurs in a heterogeneous manner within each cell population and can [...] Read more.

Heat Shock (HS) signaling is activated in response to various types of cellular stress. This activation serves to protect cells from immediate threats in the surrounding environment. However, activation of HS signaling occurs in a heterogeneous manner within each cell population and can alter the epigenetic state of the cell, ultimately leading to long-term abnormalities in body function. Here, we summarize recent research findings obtained using molecular and genetic tools to track cells where HS signaling is activated. We then discuss the potential further applications of these tools, their limitations, and the necessary caveats in interpreting data obtained with these tools. Full article

(This article belongs to the Special Issue Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Role of Heat Shock Proteins: From Molecular Mechanisms to Therapeutic Opportunities

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (36 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI