Next Article in Journal
Terminalia chebula-Assisted Silver Nanoparticles: Biological Potential, Synthesis, Characterization, and Ecotoxicity
Previous Article in Journal
Targeting of microRNA-22 Suppresses Tumor Spread in a Mouse Model of Triple-Negative Breast Cancer
Previous Article in Special Issue
Immunomodulatory Effects of Non-Thermal Plasma in a Model for Latent HIV-1 Infection: Implications for an HIV-1-Specific Immunotherapy
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 11
Issue 5
10.3390/biomedicines11051471
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Opinion

Impact of Non-Invasive Physical Plasma on Heat Shock Protein Functionality in Eukaryotic Cells

by
Yanqing Wang
1,
Alexander Abazid
2,
Steffen Badendieck
2,
Alexander Mustea
1 and
Matthias B. Stope
1,*
1
Department of Gynecology and Gynecological Oncology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
2
Department of General, Visceral and Thorax Surgery, Bundeswehr Hospital Berlin, Scharnhorststrasse 13, 10115 Berlin, Germany
*
Author to whom correspondence should be addressed.
Biomedicines 2023, 11(5), 1471; https://doi.org/10.3390/biomedicines11051471
Submission received: 4 April 2023 / Revised: 6 May 2023 / Accepted: 11 May 2023 / Published: 18 May 2023
(This article belongs to the Special Issue Nonthermal Plasma-Based Immunotherapy)
Browse Figures
Review Reports Versions Notes

Abstract

:
Recently, biomedical research has increasingly investigated physical plasma as an innovative therapeutic approach with a number of therapeutic biomedical effects. It is known from radiation and chemotherapy that these applications can lead to the induction and activation of primarily cytoprotective heat shock proteins (HSP). HSP protect cells and tissues from physical, (bio)chemical, and physiological stress and, ultimately, along with other mechanisms, govern resistance and treatment failure. These mechanisms are well known and comparatively well studied in drug therapy. For therapies in the field of physical plasma medicine, however, extremely little data are available to date. In this review article, we provide an overview of the current studies on the interaction of physical plasma with the cellular HSP system.

Graphical Abstract

1. Introduction

Physical plasma describes a gas with a sufficient degree of ionization, which makes it conductive and capable of exhibiting a collective response to electromagnetic fields [1]. In addition to solid, liquid, and gas, physical plasma forms the fourth state of matter in physics. Physical plasma can be generated by microwaves, ionizing radiation, or high electric voltages [2]. For use in medicine, electrons are accelerated in an electric field so that they can impact atoms. This impact ionization leads to an avalanche charge multiplication, in which the free electrons are constantly accelerated in the electric field, and thus continue the process [3]. In addition to the generation of free electrons, ions, excited atoms and molecules, radicals and electromagnetic radiation, UVC radiation, for example, are also generated. In the atmosphere, some of the energy is also transferred to the particles in the ambient air so that energized oxygen particles are also formed, primarily reactive oxygen species (ROS) [4]. For application to patients, non-thermal physical plasmas are used with temperatures barely above human body temperature [1]. For this purpose, the physical plasmas are ionized only to a small extent, and free electrons are additionally stopped by dielectric materials. In this dielectric barrier discharge technology, the large, slow atoms and molecules are only slightly accelerated and the overall temperature of the physics plasma remains low [3]. Physical plasma administered in medical therapy is particularly gentle on tissues compared to other physical therapy methods such as ionizing radiation and laser. The biomedical effects are not induced by the introduction of high energies into the tissue, but are mainly transferred by biochemical mechanisms. The physically developed terms for such medically used physical plasmas such as ‘cold atmospheric plasma’ or ‘cold atmospheric pressure gas plasma’ do not indicate any medical properties. Therefore, the term ‘non-invasive physical plasma’ seems to be more suitable. This reflects the tissue-preserving properties of physical plasma and the initial confusion with blood plasma can be ruled out from the outset. In the following, the term ‘non-invasive physical plasma’ (NIPP) will therefore be used when referring to non-thermal physical plasma for medical use.
As early as 1996, it was demonstrated that NIPP can inactivate microorganisms very efficiently [4]. Subsequent studies have shown that a number of medically relevant pathogens, including multi-resistant bacteria, can be eradicated by treatment with NIPP. These include, for example, bacteria of the genera Escherichia, Streptococcus, Staphylococcus and Pseudomona, but also fungi and multicellular parasites [4,5,6]. Furthermore, NIPP is markedly beneficial to wound healing. The combination of antimicrobial and regenerative effects made NIPP an excellent therapeutic modality for the treatment of acute and chronic wounds including ulcers [7,8,9,10,11,12,13,14,15]. NIPP interacts with the ambient atmosphere resulting in the formation of ROS in the gas phase [16,17]. These diffuse into the aqueous extracellular space of tissues [18] and lead to a local increase in ROS concentration. The resulting redox stress leads to the oxidation of cellular lipids, proteins, and nucleic acids. This impairs cellular structures and limits their functions including, for example, ATP biosynthesis at the mitochondrial membrane [19]. Cells react to this with stress-induced responses such as the reduction of cell growth, cell motility, and induction of apoptosis [18,19,20]. Taken together, the cellular and molecular NIPP effects often lead to devitalizing effects that can be used to treat neoplasms, especially cancer [21,22]. Eukaryotic cells respond precisely to environmental influences, physiological stress, and therapeutic interventions. Chemical factors such as drugs, but also physical noxae—including, for instance, ionizing radiation—facilitate the expression of stress-induced cytoprotective proteins, primarily belonging to the heat shock protein (HSP) family. HSP are classified into six families based on their molecular weight [23]. HSP represent stress-induced cell survival factors involved in various cell responses (Figure 1).
In tumors, HSP are usually upregulated compared to non-malignant tissue areas and ensure the survival of the metabolically highly active cancer cells. Anticancer therapies typically further enhance HSP induction [24,25]. Thus, cancer cells protect themselves from the cytotoxic effects of the therapeutic agent and HSP-mediated resistance to the therapeutic agent occurs [26,27,28]. Accordingly, HSP inhibitors can be administered as an anticancer drug or to support chemotherapy [29]. Pharmacological inhibition of HSP70 in prostate cancer cells also leads to the downregulation of other HSP, revealing the regulatory interplay of different HSP family members in pathological processes [30]. Furthermore, HSP can suppress mechanisms of cell death such as necrosis and apoptosis [31,32,33], and buffer redox stress by ROS [34]. HSP functions have been implicated in numerous pathological processes beyond cancer, including ischaemic injury, inflammatory and infectious conditions, transplant complications, and immune disorders [35,36,37,38,39,40].
HSPs are also known to be involved in the immune response, which is believed to play a critical role in immune regulation by interacting with the immune system in several ways. For example, they are chaperones for antigenic peptides, which are fragments of proteins that are recognized by the immune system [41,42]. HSP can mediate the transport of these peptides to antigen-presenting cells, which are specialized immune cells that present the peptides to other immune cells, such as T-cells [43]. This process can stimulate an immune response to the antigenic peptide. In addition, HSP have been shown to have immunomodulatory effects on immune cells. For example, HSP can induce the maturation of dendritic cells, which are important antigen-presenting cells [44,45], and the activation of T-cells, which are crucial for the adaptive immune response [46]. Moreover, HSPs have been shown to have anti-inflammatory effects, which can help to prevent or reduce inflammation caused by the immune system [47]. Meanwhile, studies have shown that NIPP can modulate the activity of immune cells in several ways. For example, NIPP has been shown to increase the migration of immune cells, such as macrophages and neutrophils, to the site of inflammation or injury [48,49,50]. Additionally, NIPP also stimulates the production of cytokines and chemokines, which are signaling molecules that play important roles in the immune regulatory network [51,52]. These molecules can help to attract immune cells to the site of injury or infection and activate them to eliminate pathogens or damaged tissue [51,52]. NIPP has also been shown to induce apoptosis in certain types of immune cells, such as T- and B-cells [53,54].
In accordance with these important physiological and pathological HSP functions, it seems important to also consider potential influences on HSP expression and functionality after NIPP exposition. NIPP has been proven by many studies promoting tissue regeneration, wound healing, and cell repair [55,56]. ROS has been proved by many studies to have an adverse effect on cell survival and cause a stress response in cells [57,58], which can be produced in large quantities by NIPP [4,16,17]. However, NIPP was demonstrated to promote wound healing and cell proliferation and protect against cell damage. In tumor cells, NIPP can selectively kill tumor cells, and HSP have been proven to be highly expressed in most tumor cells and are thus related to their prognosis and malignancy. As a cytoprotective protein, HSP are also a marker protein of malignant tumors. Therefore, it is of great significance to characterize the effect of NIPP on HSP expression in cells after NIPP exposure using various NIPP devices (Table 1).

2. HSP27

HSP27 is encoded by the HSPB1 gene located on human chromosome 7. The HSP27 gene contains three exons encoding 205 amino acids [68]. The structure of HSP27 mainly includes an α-crystallin domain, a WDPF domain, a partially conserved domain amino-terminal sequence, and a flexible carboxyl-terminal domain [69,70,71]. In contrast to large HSP, HSP27 is ATP-independent [69]. The phosphorylated forms of HSP27 are present in the nucleus and cytoplasm with a concomitant degradation of cytoplasmic and nuclear proteins [72], which may involve different cellular signaling networks.
The phosphorylation of HSP27 promotes the formation of small oligomers, whereas dephosphorylation promotes the formation of large oligomers, and this process is dynamically reversible [73]. It is widely believed that strong phosphorylation of three serine sites (Ser15, Ser78, and Ser82) present in the N-terminal domain induces dissociation of large HSP27 oligomers [74,75]. Under physiological conditions, when HSP27 is not phosphorylated, HSP27 exists as large oligomers (up to 1000 kDa) with molecular chaperone functions including refolding of unfolded proteins, regulation of cytoskeletal dynamics, and involvement in cell cycle regulation [76,77]. Under cellular stimulation conditions (high temperature, chemical toxins, radiation, etc.), HSP27 can be phosphorylated and activated by the p38 mitogen-activated protein kinase (p38 MAPK) pathway [26,78,79,80], protein kinase B (PKB) [81], protein kinase C (PKC) [82], protein kinase D (PKD) [83,84], protein kinase G (PKG), PKC-beta/ERK1/2, and PKC-beta/p38 MAPK [80,81], causing conformational changes and dissociation of oligomers into smaller HSP27 aggregates. Furthermore, it is controlled by various factors, such as tumor necrosis factor-α (TNFα) [85], transforming growth factor-β (TGFβ) [86,87], insulin-like growth factor-1 (IGF1) [88], and steroid hormones [89,90]. Studies have shown that HSP27 expression, which is not upregulated under oxidative stress, reduces intracellular ROS levels [91]. It also supports reduced forms of glutathione and mitochondrial membrane potential. Furthermore, it consolidates intracellular redox homeostasis by reducing intracellular iron levels and thus generating hydrogen radicals through the Fenton reaction, the acid oxidation with hydrogen peroxide catalyzed by iron salts. HSP27 stimulates glucose 6-phosphate dehydrogenase (G6PD) activity through the interaction of this reductase with its small and highly phosphorylated oligomers. Thus, the presence of HSP27 strongly attenuated protein oxidation, DNA damage, lipid peroxidation, and cytoskeletal structure disruption. The signaling mechanism of HSP27 phosphorylation does not depend on ROS but depends on the redox state. Pro-inflammatory cytokines induce the formation of ROS and reduce HSP27 content by promoting the formation of peroxynitrite, ultimately leading to retinal capillary endothelial cell apoptosis [92]. Schmidt et al. showed that in epithelial HaCaT keratinocytes, MAP kinases and ROS-associated HSP27, a downstream effector of the p38 signaling cascade, showed a clear correlation of phosphorylation level with NIPP treatment time. Similar to p38, the maximal phosphorylation level was reached after 180 s of treatment. Compared with H2O2-treated cells, phosphorylation of HSP27 was only slightly stimulated [93,94]. Debora et al. demonstrated that HSP27 release was enhanced upon the NIPP treatment of LNCaP and PC-3 cells [66,94]. After NIPP treatment, increased release of HSP27 was also found in OVCAR3 cells [67]. Furthermore, HSP27 is also involved in cytoskeleton remodeling and cell migration, which is modulated by NIPP treatment [59]. Furthermore, the two immune cell lines CD4+ T helper cell line Jurkat and monocyte cell line THP-1 were exposed to NIPP, and THP-1 cells were less sensitive to NIPP treatment in a pro-apoptotic and pro-proliferative manner than Jurkat cells [65]. Activation of HSP27 was detectable in THP-1 monocytes. The authors speculated that one of the reasons why THP-1 cells are more resistant to NIPP treatment than Jurkat cells might be the expression of cytoprotective HSP27. HSP27 activation, however, may play a key role in cellular escape from apoptosis after NIPP treatment.

3. HSP40

HSP40 topology contains a highly conserved J-domain responsible for binding to HSP70 and stimulating ATPase activity as a co-chaperone. HSP40 proteins are divided into three groups: Class A (DNAJA), Class B (DNAJB), and Class C (DNAJC). Class A and B consist of an N-terminal J domain, a Gly-Phe-rich region, two C-terminal β-barrel domains for substrate-binding, and a dimerization domain. The J-domain of HSP40 can bind to the HSP70 ATPase domain, thereby stimulating the ATPase activity of HSP70 [95].
HSP40 is involved in protein translation, folding, unfolding, refolding, stabilization, and thus degradation [95,96]. HSP40 levels are elevated in human head and neck cancers, which correlates with decreased overall survival [97]. Parrales et al. [98] found that HSP40 also interacts with and stabilizes misfolded p53. Knockdown of HSP40 triggers ubiquitin ligase-mediated proteasomal degradation of mutated p53, thereby reducing malignant features of cancer cells and representing tumor-promoting efficacy. Co-expression of HSP70 and HSP40 prevents loss of mitochondrial membrane potential and follows apoptosis in RAW 264.7 cells [99]. In human lymphoma cells, U937, expression levels of HSP40 and Bcl-2 associated athanogene (BAG3) were significantly higher in cells exposed to MIPP compared to controls [61]. HSP40 and BAG3 are co-chaperones of HSP70 and are mainly regulated by heat shock transcription factor 1 (HSF1), an anti-apoptotic factor induced by various types of stress [100,101].

4. HSP60

HSP60 is located on chromosome 2 and is encoded by the gene HSPD1 [102]. HSP60 protein is mainly located in mitochondria and is required to maintain the integrity and function of the mitochondrial respiratory chain and cell survival [103,104]. HSP60 interacts with the accessory chaperone HSP10 to correct the folding of nascent proteins, restore the structure of misfolded proteins, and maintain the steady state of mitochondrial proteins [105]. Mitochondrial functionality appears to be the main activity of HSP60. Moreover, the protein has few functions in other typically HSP-dependent cell responses and HSP60 expression appears to be regulated very precisely [30,106,107]. Low levels of HSP60 are scattered in the cytoplasm, cell membrane surface, cell-derived exosomes, extracellular space, and the bloodstream [108,109]. Here, HSP60 is thought to be involved in membrane transport and signal transduction. In the absence of ATP, HSP60 exists in the form of a stable heptameric monocyclic ring. When ATP binds, HSP60 proteins form bicyclic structures followed by binding to HSP10 [105]. ATP hydrolysis can cause conformational changes in the apical domain and drive the folding and release of the bound protein [105,110,111]. Upregulation of HSP60 is considered an indicator of mitochondrial stress, such as increased mitochondrial ROS and mitochondrial DNA damage [112]. HSF1, a key regulator of heat shock response, controls HSP60 expression [113,114]. Due to dual subcellular localization, the function of HSP60 as an anti- and pro-apoptotic factor may depend on its cellular location and its ability to shuttle between mitochondria and cytosol [115,116,117]. Overexpression of mitochondrial HSP60 was able to inhibit doxorubicin-induced cardiomyocyte apoptosis by increasing anti-apoptotic Bcl-xL and Bcl-2, decreasing pro-apoptotic Bax, and inhibiting procaspase-3 activation. Among them, HSP60 not only interacts with Bax and Bcl-xL but also inhibits ubiquitination of Bcl-xL [118]. Loss of HSP60 is associated with altered levels of many mitochondrial proteins, including increased expression of pro-apoptotic Bax and decreased expression of anti-apoptotic Bcl-2 [119,120,121]. Furthermore, in cancer cells, mitochondrial HSP60 acts as a regulator of mitochondrial permeability transition by binding to cyclophilin D (CypD). HSP60 depletion induces CypD-dependent mitochondrial permeability transition, leading to apoptosis [122]. Following NIPP treatment, these liquids are known as NIPP-treated media and have been shown to have cytotoxic effects on cancer cells. Tornin et al. demonstrated that NIPP increases HSP60 expression by increasing H2O2 in cancer cells, and HSP60 expression was inhibited with catalase inhibitors and pyruvate [60]. They found that NIPP-treated media had greater cytotoxicity with loss of antitumor selectivity.

5. HSP70

The sequence and protein structure of HSP70 are highly conserved in all species examined. All HSP70 isoforms contain two functional domains: the N-terminal nucleotide-binding domain (NBD) and the C-terminal substrate-binding domain (SBD). The factor regulates various mechanisms of cellular protein processing, including folding of nascent and misfolded proteins, protein assembly, transport, degradation, and prevention and disassembly of protein aggregates. This chaperone activity of HSP70 is achieved through an ATP-regulated cycle of polypeptide substrate binding and release. HSP70 have two intrinsic activities: first, as an ATPase, and second, to bind polypeptide substrates. These two activities are tightly coupled, and the chaperone activity strictly depends on this allosteric coupling. The chaperone activity of HSP70 is aided by two well-characterized accessory chaperones: Hsp40s and nucleotide exchange factors (NEF) [123]. HSP40 accelerates ATP hydrolysis by HSP70, while NEF mediate the regeneration of ADP by ATP. Taken together, HSP70, HSP40, and NEF constitute the most important chaperone mechanisms for protein folding and protein stabilization in cells [124,125].
HSP70 blocks apoptotic pathways by interacting with significant signaling proteins upstream, downstream, and within mitochondrial regulatory processes. Upstream of mitochondria, HSP70 binds and blocks c-Jun N-terminal kinase (JNK) activity. HSP70 inhibits apoptosis in a caspase-dependent mechanism by inhibiting JNK. For example, in hypertonicity-induced apoptosis, HSP70 deficiency induces JNK activation and caspase-3 activation [126]. HSP70 has also been shown to bind and stabilize non-phosphorylated PKC and Akt [127]. At the mitochondrial level, HSP70 inhibits Bax translocation and insertion into the mitochondrial outer membrane. Thus, HSP70 prevents mitochondrial membrane permeabilization and the release of cytochrome c and apoptosis-inducing factor (AIF) [128]. At the mitochondrial level, HSP70 blocks coupled Bax translocation with HSP40, thereby preventing mitochondrial outer membrane permeability and inhibiting the release of cytochrome c and other mitochondrial apoptotic molecules such as AIF. HSP70 also acts at the post-mitochondrial level. It has been consistently found that HSP70 inhibits the release of cytochrome c downstream of apoptosis and upstream of caspase-3 activation. Indeed, HSP70 has been shown to bind directly to Apaf-1, thereby preventing the recruitment of procaspase-9 to apoptotic bodies [129,130].
In human lymphoma cells U937, NIPP treatment resulted in a significant increase in apoptosis. Expression levels of HSP40 and BAG3 were significantly enhanced [96,131], suggesting that NIPP exposure expands ROS levels inhibiting NIPP-induced apoptosis. Previous studies have shown that nitric oxide (NO) is produced during NIPP treatment and rapidly converted to other ROS, including NOX [132,133]. NO induces HSF1-regulated HSP70 expression and subsequent cytoprotection [125,126,134].

6. HSP90

Similar to HSP70, HSP90 is also a highly conserved ATP-dependent chaperone that binds to client proteins to enable their appropriate folding [135]. Structurally, this HSP90 is a dimer. The monomeric subunits contain the four domains N-terminal dimerization domain (NTD), intermediate domain (MD), charged variable length region (CR), and C-terminal domain (CTD) [23,136]. HSP90 exists in several isomers sharing high degrees of homology. These isoforms exist both intracellularly and extracellularly. Five functional HSP90 members have been identified in mammalian cells, including the major cytoplasmic isoforms HSP90α1/α2 and HSP90β, as well as glucose-regulated protein 94 (GRP94), and tumor necrosis factor receptor-associated protein 1 (TRAP1) in the endoplasmic reticulum and mitochondria, respectively [135]. The two cytoplasmic isoforms of HSP90, HSP90α, and HSP90β, share 85% sequence identity. HSP90β is constitutively expressed under normal physiological conditions. However, HSP90α is stress-regulated, and elevated levels of HSP90α are associated with poor cancer prognosis [136,137]. HSP90 is also liberated into the extracellular environment through an exosomal pathway distinct from the classical secretion pathway.
Under non-stress conditions, the master regulator HSF-1 is inactive and binds to HSP90-containing protein complexes. Hypoxia, hyperthermia, trauma, and metabolic stress conditions disrupt the HSP90-HSF-1 complex, prompting the formation of HSF-1 homotrimers that translocate to the nucleus and stimulate rapid transcription of heat shock genes, and HSP90 expression increases [138]. HSF-1 is modified by post-translational regulation, and its transcriptional activation depends on the state of hyperphosphorylation. When sufficient levels of cytosolic HSP90 are reached and the denatured protein is metabolized or reconfigured, the HSP90 binding site again becomes available to stabilize HSF-1 in an inactive form [139,140].
HSP90 has more than 300 client proteins, including protein kinases, transcription factors, oncoproteins and tumor suppressors. Nima et al. showed the aggregation of platelets treated with NIPP and methylcellulose loaded with polyethyleneimine-polypyrrole nanoparticles. The treatment of burn wounds with a compound system can significantly increase the expression level of HSP90 and promote wound healing [62,64]. Schmidt et al. showed that HSP90A, HSP90AB, and HSP90B were significantly up-regulated after treatment of epithelial keratinocyte HaCaT cells with NIPP [59]. Another study showed that NIPP-treated cancer cells (colon, prostate, breast) not only led to the cleavage of HSP90 but also related to the degradation of PKD2. Their results demonstrate that HSP90 cleavage following NIPP treatment causes degradation of its client protein PKD2 and leads to impaired proliferation and increased cancer cell death in cancer cells (Figure 2). Interestingly, the level of cell death following NIPP treatment was comparable to that achieved by lentivirus-mediated knockdown of HSP90 [63].
HSP are regulated by heat shock transcription factor 1 (HSF1) and serve as stress-induced cytoprotective factors. As little as 20 min incubation of cells at 39 °C activates the heat shock element-binding activity of HSF1 [141,142]. HSF1, however, is also activated by oxidative stress [143], as also occurs during exposure to NIPP. Thus, the presence of NO and NOx in cells leads to HSF1-dependent induction of HSP70 [144,145,146]. This is accompanied by protein stabilization and refolding as well as modulation of immune processes. The physiological effects depend on the HSP superfamily members involved and are likely to be cell type and tissue specific. In addition, the NIPP device applied must be considered. The NIPP technology used and the specific technical characteristics of the device determine the properties of the NIPP, thus affecting the concentrations and composition of the ROS formed and, ultimately, their biological effects. The existing studies on the interaction of NIPP and HSP systems indicate that HSP plays a significant role. However, current studies still need to answer numerous questions to paint a generalized picture.

7. Conclusions

Current evidence on the functionality of HSP clearly demonstrates that they have important functions in cell protection and survival. This is evident in the inhibition of apoptosis, but also in controlling other cellular responses such as proliferation, motility, protein stability, degradation and turnover. NIPP-induced modulation of these HSP functions, therefore, has a major impact on the viability of cells and tissues.
As with other therapeutic modalities, HSP are potential targets in NIPP therapy (Figure 2). The mostly observed induction of HSP expression could be a cell response to NIPP-induced (redox) stress and may contribute to cell survival. Degradation of HSP90, however, also shows that NIPP action can inactivate HSP and suppress entire downstream signaling and effector cascades. Data published so far on the anticancer effects of NIPP demonstrate that cancer cells can be eradicated depending on the duration of treatment. Therefore, it is quite conceivable that the cellular HSP protection system cannot compensate for the therapeutic NIPP effects at various physiological levels.
However, this review article also clearly shows that data on the interaction of NIPP and HSP systems are strictly limited. The available studies only provide a vague idea about the modulation of HSP after NIPP treatment. It must be considered as a limitation that exclusively jet and jet-like devices have been used for NIPP formation (Table 2). In biomedical studies, it has always been shown that NIPP properties and biomedical NIPP effects always depend on the technology being used for NIPP generation. In addition, HSP10, as a binding partner of HSP60, is involved in the folding and stabilization of client proteins, particularly those that are newly synthesized or damaged due to stress [147,148]. In addition to its chaperone activity, HSP10 has also been implicated in other cellular processes, including regulation of gene expression, cell growth, and apoptosis [149]. Aberrant expression or function of HSP10 has been associated with various diseases, including cancer, neurodegenerative disorders, and autoimmune diseases. However, there are no studies related to NIPP and HSP10 so far. Furthermore, the different biological model systems of the investigations hamper the comparison of the results. Here, systematic studies on the most important members of the HSP superfamily would be desirable in the future.

Author Contributions

Conceptualization, Y.W., A.A. and M.B.S.; writing—original draft preparation, Y.W., A.A. and M.B.S.; writing—review and editing, Y.W., A.A., S.B., A.M. and M.B.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Isbary, G.; Shimizu, T.; Li, Y.F.; Stolz, W.; Thomas, H.M.; Morfill, G.E.; Zimmermann, J.L. Cold atmospheric plasma devices for medical issues. Expert Rev. Med. Devices 2013, 10, 367–377. [Google Scholar] [CrossRef] [PubMed]
  2. Kong, M.G.; Kroesen, G.; Morfill, G.; Nosenko, T.; Shimizu, T.; van Dijk, J.; Zimmermann, J.L. Plasma medicine: An introductory review. New J. Phys. 2009, 11, 115012. [Google Scholar] [CrossRef]
  3. Kletschkus, K.; Haralambiev, L.; Mustea, A.; Bekeschus, S.; Stope, M.B. Review of innovative physical therapy methods: Introduction to the principles of cold physical plasma. In Vivo 2020, 34, 3103–3107. [Google Scholar] [CrossRef]
  4. Laroussi, M. Sterilization of contaminated matter with an atmospheric pressure plasma. IEEE Trans. Plasma Sci. 1996, 24, 1188–1191. [Google Scholar] [CrossRef]
  5. Kramer, A.; Bekeschus, S.; Matthes, R.; Bender, C.; Stope, M.B.; Napp, M.; Lademann, O.; Lademann, J.; Weltmann, K.-D.; Schauer, F. Cold physical plasmas in the field of hygiene—Relevance, significance, and future applications. Plasma Process. Polym. 2015, 12, 1410–1422. [Google Scholar] [CrossRef]
  6. Daeschlein, G.; Scholz, S.; Arnold, A.; von Podewils, S.; Haase, H.; Emmert, S.; Woedtke, T.; von Weltmann, K.-D.; Jünger, M. In vitro susceptibility of important skin and wound pathogens against low temperature atmospheric pressure plasma jet (APPJ) and dielectric barrier discharge plasma (DBD). Plasma Process Polym. 2012, 9, 380–389. [Google Scholar] [CrossRef]
  7. Von Woedtke, T.; Schmidt, A.; Bekeschus, S.; Wende, K.; Weltmann, K.D. Plasma medicine: A field of applied redox biology. In Vivo 2019, 33, 1011–1026. [Google Scholar] [CrossRef] [PubMed]
  8. Bernhardt, T.; Semmler, M.L.; Schafer, M.; Bekeschus, S.; Emmert, S.; Boeckmann, L. Plasma medicine: Applications of cold atmospheric pressure plasma in dermatology. Oxid. Med. Cell Longev. 2019, 3, 3873928. [Google Scholar] [CrossRef]
  9. Chuangsuwanich, A.; Assadamongkol, T.; Boonyawan, D. The healing effect of low-temperature atmospheric-pressure plasma in pressure ulcer: A randomized controlled trial. Int. J. Low Extrem. Wounds 2016, 15, 313–319. [Google Scholar] [CrossRef] [PubMed]
  10. Ulrich, C.; Kluschke, F.; Patzelt, A.; Vandersee, S.; Czaika, V.A.; Richter, H.; Bob, A.; Hutten, J.; Painsi, C.; Huge, R.; et al. Clinical use of cold atmospheric pressure argon plasma in chronic leg ulcers: A pilot study. J. Wound Care 2015, 196, 198–200, 202–203. [Google Scholar] [CrossRef]
  11. Von Woedtke, T.; Reuter, S.; Masur, K.; Weltmann, K.-D. Plasmas for medicine. Phys. Rep. 2013, 530, 291–320. [Google Scholar] [CrossRef]
  12. Haertel, B.; Eiden, K.; Deuter, A.; Wende, K.; von Woedtke, T.; Lindequist, U. Differential effect of non-thermal atmospheric-pressure plasma on angiogenesis. Lett. Appl. NanoBioSci. 2014, 3, 159–166. [Google Scholar]
  13. Schmidt-Bleker, A.; Winter, J.; Bösel, A.; Reuter, S.; Weltmann, K.D. On the plasma chemistry of a cold atmospheric argon plasma jet with shielding gas device. Plasma Sources Sci. Technol. 2016, 25, 015005. [Google Scholar] [CrossRef]
  14. Arndt, S.; Unger, P.; Wacker, E.; Shimizu, T.; Heinlin, J.; Li, Y.F.; Thomas, H.M.; Morfill, G.E.; Zimmermann, J.L.; Bosserhoff, A.K.; et al. Cold atmospheric plasma (CAP) changes gene expression of key molecules of the wound healing machinery and improves wound healing in vitro and in vivo. PLoS ONE 2013, 8, e79325. [Google Scholar] [CrossRef] [PubMed]
  15. Bekeschus, S.; von Woedtke, T.; Kramer, A.; Weltmann, K.D.; Masur, K. Cold physical plasma treatment alters redox balance in human immune cells. Plasma Med. 2013, 4, 267–278. [Google Scholar] [CrossRef]
  16. Jablonowski, H.; von Woedtke, T. Research on plasma medicine-relevant plasma-liquid interaction: What happened in the past five years? Clin. Plasma Med. 2015, 2, 42–52. [Google Scholar] [CrossRef]
  17. Kalghatgi, S.; Friedman, G.; Fridman, A.; Clyne, A.M. Endothelial cell proliferation is enhanced by low dose non-thermal plasma through fibroblast growth factor-2 release. Ann. Biomed Eng. 2010, 38, 748–757. [Google Scholar] [CrossRef] [PubMed]
  18. Sander, C.; Nitsch, A.; Erb, H.H.H.; Egger, E.K.; Haralambiev, L.; Eggers, B.; Kramer, F.-J.; Weiss, M.; Mustea, A.; Stope, M.B. Non-invasive physical plasma enhances the membrane permeability to low molecular weight compounds and subsequently leads to the loss of cellular ATP and the devitalization of epithelial cancer cells. Appl. Sci. 2021, 21, 9801. [Google Scholar] [CrossRef]
  19. Haertel, B.; von Woedtke, T.; Weltmann, K.D.; Lindequist, U. Non-thermal atmospheric-pressure plasma possible application in wound healing. Biomol. Ther. 2014, 22, 477–490. [Google Scholar] [CrossRef]
  20. Stope, M.B. Plasma oncology—Physical plasma as innovative tumor therapy. J. Cancer Biol. 2020, 2, 53–56. [Google Scholar]
  21. Weiss, M.; Gumbel, D.; Hanschmann, E.M.; Mandelkow, R.; Gelbrich, N.; Zimmermann, U.; Walther, R.; Ekkernkamp, A.; Sckell, A.; Kramer, A.; et al. Cold atmospheric plasma treatment induces anti-proliferative effects in prostate cancer cells by redox and apoptotic signaling pathways. PLoS ONE 2015, 10, e0130350. [Google Scholar] [CrossRef] [PubMed]
  22. Marzi, J.; Stope, M.B.; Henes, M.; Koch, A.; Wenzel, T.; Holl, M.; Layland, S.L.; Neis, F.; Bosmuller, H.; Ruoff, F.; et al. Noninvasive physical plasma as innovative and tissue-preserving therapy for women positive for cervical intraepithelial neoplasia. Cancers 2022, 14, 1933. [Google Scholar] [CrossRef] [PubMed]
  23. Kampinga, H.H.; Hageman, J.; Vos, M.J.; Kubota, H.; Tanguay, R.M.; Bruford, E.A.; Cheetham, M.E.; Chen, B.; Hightower, L.E. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 2009, 14, 105–111. [Google Scholar] [CrossRef] [PubMed]
  24. Stope, M.B.; Koensgen, D.; Burchardt, M.; Concin, N.; Zygmunt, M.; Mustea, A. Jump in the fire—Heat shock proteins and their impact on ovarian cancer therapy. Crit. Rev. Oncol. Hematol. 2016, 97, 152–156. [Google Scholar] [CrossRef] [PubMed]
  25. Lang, B.J.; Prince, T.L.; Okusha, Y.; Bunch, H.; Calderwood, S.K. Heat shock proteins in cell signaling and cancer. Biochim. Biophys. Acta Mol. Cell Res. 2022, 1869, 119187. [Google Scholar] [CrossRef] [PubMed]
  26. Stope, M.B.; Weiss, M.; Preuss, M.; Streitborger, A.; Ritter, C.A.; Zimmermann, U.; Walther, R.; Burchardt, M. Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells. Oncol. Rep. 2014, 32, 2380–2386. [Google Scholar] [CrossRef]
  27. Rocchi, P.; So, A.; Kojima, S.; Signaevsky, M.; Beraldi, E.; Fazli, L.; Hurtado-Coll, A.; Yamanaka, K.; Gleave, M. Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer. Cancer Res. 2004, 64, 6595–6602. [Google Scholar] [CrossRef]
  28. Grossebrummel, H.; Peter, T.; Mandelkow, R.; Weiss, M.; Muzzio, D.; Zimmermann, U.; Walther, R.; Jensen, F.; Knabbe, C.; Zygmunt, M.; et al. Cytochrome P450 17A1 inhibitor abiraterone attenuates cellular growth of prostate cancer cells independently from androgen receptor signaling by modulation of oncogenic and apoptotic pathways. Int. J. Oncol. 2016, 48, 793–800. [Google Scholar] [CrossRef]
  29. Banerji, U.; Sain, N.; Sharp, S.Y.; Valenti, M.; Asad, Y.; Ruddle, R.; Raynaud, F.; Walton, M.; Eccles, S.A.; Judson, I.; et al. An in vitro and in vivo study of the combination of the heat shock protein inhibitor 17-allylamino-17-demethoxygeldanamycin and carboplatin in human ovarian cancer models. Cancer Chemother. Pharmacol. 2008, 62, 769–778. [Google Scholar] [CrossRef]
  30. Brunnert, D.; Langer, C.; Zimmermann, L.; Bargou, R.C.; Burchardt, M.; Chatterjee, M.; Stope, M.B. The heat shock protein 70 inhibitor VER155008 suppresses the expression of HSP27, HOP and HSP90beta and the androgen receptor, induces apoptosis, and attenuates prostate cancer cell growth. J. Cell. Biochem. 2020, 121, 407–417. [Google Scholar] [CrossRef]
  31. Song, T.F.; Zhang, Z.F.; Liu, L.; Yang, T.; Jiang, J.; Li, P. Small interfering RNA-mediated silencing of heat shock protein 27 (HSP27) Increases chemosensitivity to paclitaxel by increasing production of reactive oxygen species in human ovarian cancer cells (HO8910). J. Int. Med. Res. 2009, 37, 1375–1388. [Google Scholar] [CrossRef] [PubMed]
  32. Buzzard, K.A.; Giaccia, A.J.; Killender, M.; Anderson, R.L. Heat shock protein 72 modulates pathways of stress-induced apoptosis. J. Biol. Chem. 1998, 273, 17147–17153. [Google Scholar] [CrossRef] [PubMed]
  33. Abazid, A.; Martin, B.; Choinowski, A.; McNeill, R.V.; Brandenburg, L.O.; Ziegler, P.; Zimmermann, U.; Burchardt, M.; Erb, H.; Stope, M.B. The androgen receptor antagonist enzalutamide induces apoptosis, dysregulates the heat shock protein system, and diminishes the androgen receptor and estrogen receptor beta1 expression in prostate cancer cells. J. Cell. Biochem. 2019, 120, 16711–16722. [Google Scholar] [CrossRef] [PubMed]
  34. Gabai, V.L.; Kabakov, A.E. Rise in heat-shock protein level confers tolerance to energy deprivation. FEBS Lett. 1993, 327, 247–250. [Google Scholar] [CrossRef] [PubMed]
  35. Preville, X.; Salvemini, F.; Giraud, S.; Chaufour, S.; Paul, C.; Stepien, G.; Ursini, M.V.; Arrigo, A.P. Mammalian small stress proteins protect against oxidative stress through their ability to increase glucose-6-phosphate dehydrogenase activity and by maintaining optimal cellular detoxifying machinery. Exp. Cell Res. 1999, 247, 61–78. [Google Scholar] [CrossRef]
  36. Benjamin, I.J.; McMillan, D.R. Stress (heat shock) proteins: Molecular chaperones in cardiovascular biology and disease. Circ. Res. 1998, 83, 117–132. [Google Scholar] [CrossRef] [PubMed]
  37. Polla, B.S.; Cossarizza, A. Stress proteins in inflammation. EXS 1996, 77, 375–391. [Google Scholar]
  38. Wong, H.R. Potential protective role of the heat shock response in sepsis. New Horiz. 1998, 6, 194–200. [Google Scholar]
  39. Gowda, A.; Yang, C.; Asimakis, G.K.; Rastegar, S.; Motamedi, M. Heat shock improves recovery and provides protection against global ischemia after hypothermic storage. Ann. Thorac. Surg. 1998, 66, 1991–1997. [Google Scholar] [CrossRef]
  40. Srivastava, P. Roles of heat-shock proteins in innate and adaptive immunity. Nat. Rev. Immunol. 2002, 2, 185–194. [Google Scholar] [CrossRef]
  41. Shevtsov, M.; Multhoff, G. Heat Shock Protein-Peptide and HSP-Based Immunotherapies for the Treatment of Cancer. Front. Immunol. 2016, 7, 171. [Google Scholar] [CrossRef] [PubMed]
  42. Hagymasi, A.T.; Dempsey, J.P.; Srivastava, P.K. Heat-Shock Proteins. Curr. Protoc. 2022, 2, e592. [Google Scholar] [CrossRef] [PubMed]
  43. van Eden, W. Immune tolerance therapies for autoimmune diseases based on heat shock protein T-cell epitopes. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2018, 373, 20160531. [Google Scholar] [CrossRef] [PubMed]
  44. Sun, Z.; Deng, G.; Peng, X.; Xu, X.; Liu, L.; Peng, J.; Ma, Y.; Zhang, P.; Wen, A.; Wang, Y.; et al. Intelligent photothermal dendritic cells restart the cancer immunity cycle through enhanced immunogenic cell death. Biomaterials 2021, 279, 121228. [Google Scholar] [CrossRef] [PubMed]
  45. Gulic, T.; Laskarin, G.; Glavan, L.; Grubic Kezele, T.; Haller, H.; Rukavina, D. Human Decidual CD1a(+) Dendritic Cells Undergo Functional Maturation Program Mediated by Gp96. Int. J. Mol. Sci. 2023, 24, 2278. [Google Scholar] [CrossRef]
  46. Spierings, J.; van Eden, W. Heat shock proteins and their immunomodulatory role in inflammatory arthritis. Rheumatology 2017, 56, 198–208. [Google Scholar] [CrossRef]
  47. Zininga, T.; Ramatsui, L.; Shonhai, A. Heat Shock Proteins as Immunomodulants. Molecules 2018, 23, 2846. [Google Scholar] [CrossRef]
  48. Duchesne, C.; Frescaline, N.; Blaise, O.; Lataillade, J.J.; Banzet, S.; Dussurget, O.; Rousseau, A. Cold Atmospheric Plasma Promotes Killing of Staphylococcus aureus by Macrophages. mSphere 2021, 6, e0021721. [Google Scholar] [CrossRef]
  49. Kaushik, N.K.; Kaushik, N.; Adhikari, M.; Ghimire, B.; Linh, N.N.; Mishra, Y.K.; Lee, S.J.; Choi, E.H. Preventing the Solid Cancer Progression via Release of Anticancer-Cytokines in Co-Culture with Cold Plasma-Stimulated Macrophages. Cancers 2019, 11, 842. [Google Scholar] [CrossRef]
  50. Bekeschus, S.; Winterbourn, C.C.; Kolata, J.; Masur, K.; Hasse, S.; Broker, B.M.; Parker, H.A. Neutrophil extracellular trap formation is elicited in response to cold physical plasma. J. Leukoc. Biol. 2016, 100, 791–799. [Google Scholar] [CrossRef]
  51. Haralambiev, L.; Wien, L.; Gelbrich, N.; Kramer, A.; Mustea, A.; Burchardt, M.; Ekkernkamp, A.; Stope, M.B.; Gumbel, D. Effects of Cold Atmospheric Plasma on the Expression of Chemokines, Growth Factors, TNF Superfamily Members, Interleukins, and Cytokines in Human Osteosarcoma Cells. Anticancer Res. 2019, 39, 151–157. [Google Scholar] [CrossRef] [PubMed]
  52. Arndt, S.; Landthaler, M.; Zimmermann, J.L.; Unger, P.; Wacker, E.; Shimizu, T.; Li, Y.F.; Morfill, G.E.; Bosserhoff, A.K.; Karrer, S. Effects of cold atmospheric plasma (CAP) on ss-defensins, inflammatory cytokines, and apoptosis-related molecules in keratinocytes in vitro and in vivo. PLoS ONE 2015, 10, e0120041. [Google Scholar] [CrossRef] [PubMed]
  53. Turrini, E.; Laurita, R.; Stancampiano, A.; Catanzaro, E.; Calcabrini, C.; Maffei, F.; Gherardi, M.; Colombo, V.; Fimognari, C. Cold Atmospheric Plasma Induces Apoptosis and Oxidative Stress Pathway Regulation in T-Lymphoblastoid Leukemia Cells. Oxid. Med. Cell Longev. 2017, 2017, 4271065. [Google Scholar] [CrossRef]
  54. Haertel, B.; Volkmann, F.; von Woedtke, T.; Lindequist, U. Differential sensitivity of lymphocyte subpopulations to non-thermal atmospheric-pressure plasma. Immunobiology 2012, 217, 628–633. [Google Scholar] [CrossRef]
  55. Stratmann, B.; Costea, T.C.; Nolte, C.; Hiller, J.; Schmidt, J.; Reindel, J.; Masur, K.; Motz, W.; Timm, J.; Kerner, W.; et al. Effect of Cold Atmospheric Plasma Therapy vs Standard Therapy Placebo on Wound Healing in Patients with Diabetic Foot Ulcers: A Randomized Clinical Trial. JAMA Netw. Open 2020, 3, e2010411. [Google Scholar] [CrossRef]
  56. Abbasi, E.; Mehrabadi, J.F.; Nourani, M.; Namini, Y.N.; Mohammadi, S.; Esmaeili, D.; Abbasi, A. Evaluation of cold atmospheric-pressure plasma against burn wound infections and gene silencing. Iran. J. Microbiol. 2021, 13, 544–552. [Google Scholar] [CrossRef]
  57. Sinha, K.; Das, J.; Pal, P.B.; Sil, P.C. Oxidative stress: The mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch. Toxicol. 2013, 87, 1157–1180. [Google Scholar] [CrossRef] [PubMed]
  58. Dimauro, I.; Mercatelli, N.; Caporossi, D. Exercise-induced ROS in heat shock proteins response. Free. Radic. Biol. Med. 2016, 98, 46–55. [Google Scholar] [CrossRef]
  59. Schmidt, A.; Bekeschus, S.; Wende, K.; Vollmar, B.; von Woedtke, T. A cold plasma jet accelerates wound healing in a murine model of full-thickness skin wounds. Exp. Dermatol. 2017, 26, 156–162. [Google Scholar] [CrossRef]
  60. Tornin, J.; Mateu-Sanz, M.; Rodriguez, A.; Labay, C.; Rodriguez, R.; Canal, C. Pyruvate plays a main role in the antitumoral selectivity of cold atmospheric plasma in osteosarcoma. Sci. Rep. 2019, 9, 10681. [Google Scholar] [CrossRef]
  61. Tabuchi, Y.; Uchiyama, H.; Zhao, Q.L.; Yunoki, T.; Andocs, G.; Nojima, N.; Takeda, K.; Ishikawa, K.; Hori, M.; Kondo, T. Effects of nitrogen on the apoptosis of and changes in gene expression in human lymphoma U937 cells exposed to argon-based cold atmospheric pressure plasma. Int. J. Mol. Med. 2016, 37, 1706–1714. [Google Scholar] [CrossRef] [PubMed]
  62. Bolouki, N.; Hsu, Y.N.; Hsiao, Y.C.; Jheng, P.R.; Hsieh, J.H.; Chen, H.L.; Mansel, B.W.; Yeh, Y.Y.; Chen, Y.H.; Lu, C.X.; et al. Cold atmospheric plasma physically reinforced substances of platelets-laden photothermal-responsive methylcellulose complex restores burn wounds. Int. J. Biol. Macromol. 2021, 192, 506–515. [Google Scholar] [CrossRef] [PubMed]
  63. Bekeschus, S.; Lippert, M.; Diepold, K.; Chiosis, G.; Seufferlein, T.; Azoitei, N. Physical plasma-triggered ROS induces tumor cell death upon cleavage of HSP90 chaperone. Sci. Rep. 2019, 9, 4112. [Google Scholar] [CrossRef] [PubMed]
  64. Chen, Y.H.; Chuang, E.Y.; Jheng, P.R.; Hao, P.C.; Hsieh, J.H.; Chen, H.L.; Mansel, B.W.; Yeh, Y.Y.; Lu, C.X.; Lee, J.W.; et al. Cold-atmospheric plasma augments functionalities of hybrid polymeric carriers regenerating chronic wounds: In vivo experiments. Mater. Sci. Eng. C Mater. Biol. Appl. 2021, 131, 112488. [Google Scholar] [CrossRef] [PubMed]
  65. Bundscherer, L.; Wende, K.; Ottmuller, K.; Barton, A.; Schmidt, A.; Bekeschus, S.; Hasse, S.; Weltmann, K.D.; Masur, K.; Lindequist, U. Impact of non-thermal plasma treatment on MAPK signaling pathways of human immune cell lines. Immunobiology 2013, 218, 1248–1255. [Google Scholar] [CrossRef]
  66. Singer, D.; Ressel, V.; Stope, M.B.; Bekeschus, S. Heat shock protein 27 affects myeloid cell activation and interaction with prostate cancer cells. Biomedicines 2022, 10, 2192. [Google Scholar] [CrossRef]
  67. Singer, D.; Wulff, C.P.; Stope, M.B.; Bekeschus, S. Extracellular heat shock protein 27 is released by plasma-treated ovarian cancer cells and affects THP-1 monocyte activity. Plasma 2022, 5, 569–578. [Google Scholar] [CrossRef]
  68. Stock, A.D.; Spallone, P.A.; Dennis, T.R.; Netski, D.; Morris, C.A.; Mervis, C.B.; Hobart, H.H. Heat shock protein 27 gene: Chromosomal and molecular location and relationship to Williams syndrome. Am. J. Med. Genet. A 2003, 120A, 320–325. [Google Scholar] [CrossRef]
  69. Choi, S.K.; Kam, H.; Kim, K.Y.; Park, S.I.; Lee, Y.S. Targeting Heat shock protein 27 in cancer: A druggable target for cancer treatment? Cancers 2019, 11, 1195. [Google Scholar] [CrossRef]
  70. Kocabiyik, S. Essential structural and functional features of small heat shock proteins in molecular chaperoning process. Protein Pept. Lett. 2009, 16, 613–622. [Google Scholar] [CrossRef]
  71. Garrido, C.; Brunet, M.; Didelot, C.; Zermati, Y.; Schmitt, E.; Kroemer, G. Heat shock proteins 27 and 70: Anti-apoptotic proteins with tumorigenic properties. Cell Cycle 2006, 5, 2592–2601. [Google Scholar] [CrossRef] [PubMed]
  72. Arrigo, A.P. Structure-functions of HspB1 (Hsp27). Methods Mol. Biol. 2011, 787, 105–119. [Google Scholar] [PubMed]
  73. Haslbeck, M.; Franzmann, T.; Weinfurtner, D.; Buchner, J. Some like it hot: The structure and function of small heat-shock proteins. Nat. Struct. Mol. Biol. 2005, 12, 842–846. [Google Scholar] [CrossRef] [PubMed]
  74. McDonald, E.T.; Bortolus, M.; Koteiche, H.A.; McHaourab, H.S. Sequence, structure, and dynamic determinants of Hsp27 (HspB1) equilibrium dissociation are encoded by the N-terminal domain. Biochemistry 2012, 51, 1257–1268. [Google Scholar] [CrossRef] [PubMed]
  75. Hayes, D.; Napoli, V.; Mazurkie, A.; Stafford, W.F.; Graceffa, P. Phosphorylation dependence of hsp27 multimeric size and molecular chaperone function. J. Biol. Chem. 2009, 284, 18801–18807. [Google Scholar] [CrossRef]
  76. Gusev, N.B.; Bogatcheva, N.V.; Marston, S.B. Structure and properties of small heat shock proteins (sHsp) and their interaction with cytoskeleton proteins. Biochemistry 2002, 67, 511–519. [Google Scholar]
  77. Mounier, N.; Arrigo, A.P. Actin cytoskeleton and small heat shock proteins: How do they interact? Cell Stress Chaperones 2002, 7, 167–176. [Google Scholar] [CrossRef]
  78. Ange, M.; Castanares-Zapatero, D.; De Poortere, J.; Dufeys, C.; Courtoy, G.E.; Bouzin, C.; Quarck, R.; Bertrand, L.; Beauloye, C.; Horman, S. Alpha1AMP-activated protein kinase protects against lipopolysaccharide-induced endothelial barrier disruption via junctional reinforcement and activation of the p38 MAPK/HSP27 pathway. Int. J. Mol. Sci. 2020, 21, 5581. [Google Scholar] [CrossRef]
  79. Wang, W.; Weng, J.; Yu, L.; Huang, Q.; Jiang, Y.; Guo, X. Role of TLR4-p38 MAPK-Hsp27 signal pathway in LPS-induced pulmonary epithelial hyperpermeability. BMC Pulm. Med. 2018, 18, 178. [Google Scholar] [CrossRef]
  80. Clements, R.T.; Feng, J.; Cordeiro, B.; Bianchi, C.; Sellke, F.W. p38 MAPK-dependent small HSP27 and alphaB-crystallin phosphorylation in regulation of myocardial function following cardioplegic arrest. Am. J. Physiol. Heart Circ. Physiol. 2011, 300, H1669–H1677. [Google Scholar] [CrossRef]
  81. Konishi, H.; Matsuzaki, H.; Tanaka, M.; Takemura, Y.; Kuroda, S.; Ono, Y.; Kikkawa, U. Activation of protein kinase B (Akt/RAC-protein kinase) by cellular stress and its association with heat shock protein Hsp27. FEBS Lett. 1997, 410, 493–498. [Google Scholar] [CrossRef] [PubMed]
  82. Santell, L.; Bartfeld, N.S.; Levin, E.G. Identification of a protein transiently phosphorylated by activators of endothelial cell function as the heat-shock protein HSP27: A possible role for protein kinase C. Biochem. J. 1992, 284 Pt 3, 705–710. [Google Scholar] [CrossRef] [PubMed]
  83. Stetler, R.A.; Gao, Y.; Zhang, L.; Weng, Z.; Zhang, F.; Hu, X.; Wang, S.; Vosler, P.; Cao, G.; Sun, D.; et al. Phosphorylation of HSP27 by protein kinase D is essential for mediating neuroprotection against ischemic neuronal injury. J. Neurosci. 2012, 32, 2667–2682. [Google Scholar] [CrossRef] [PubMed]
  84. Evans, I.M.; Britton, G.; Zachary, I.C. Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase. Cell Signal. 2008, 20, 1375–1384. [Google Scholar] [CrossRef] [PubMed]
  85. Niwa, M.; Hotta, K.; Hara, A.; Hirade, K.; Ito, H.; Kato, K.; Kozawa, O. TNF-alpha decreases hsp 27 in human blood mononuclear cells: Involvement of protein kinase c. Life Sci. 2006, 80, 181–186. [Google Scholar] [CrossRef]
  86. Hayashi, K.; Takai, S.; Matsushima-Nishiwaki, R.; Hanai, Y.; Kato, K.; Tokuda, H.; Kozawa, O. (−)-Epigallocatechin gallate reduces transforming growth factor beta-stimulated HSP27 induction through the suppression of stress-activated protein kinase/c-Jun N-terminal kinase in osteoblasts. Life Sci. 2008, 82, 1012–1017. [Google Scholar] [CrossRef]
  87. Kwon, S.M.; Kim, S.A.; Fujii, S.; Maeda, H.; Ahn, S.G.; Yoon, J.H. Transforming growth factor beta1 promotes migration of human periodontal ligament cells through heat shock protein 27 phosphorylation. Biol. Pharm. Bull. 2011, 34, 486–489. [Google Scholar] [CrossRef]
  88. Geier, A.; Hemi, R.; Haimsohn, M.; Beery, R.; Karasik, A. Phosphorylation of a 27-kDa protein correlates with survival of protein-synthesis-inhibited MCF-7 cells. In Vitro Cell Dev. Biol. Anim. 1997, 33, 129–136. [Google Scholar] [CrossRef]
  89. Vahidinia, Z.; Mahdavi, E.; Talaei, S.A.; Naderian, H.; Tamtaji, A.; Haddad Kashani, H.; Beyer, C.; Azami Tameh, A. The effect of female sex hormones on Hsp27 phosphorylation and histological changes in prefrontal cortex after tMCAO. Pathol. Res. Pract. 2021, 221, 153415. [Google Scholar] [CrossRef]
  90. Tabibzadeh, S.; Broome, J. Heat shock proteins in human endometrium throughout the menstrual cycle. Infect. Dis. Obstet. Gynecol. 1999, 7, 5–9. [Google Scholar] [CrossRef]
  91. Bi, X.; Jiang, B.; Zhou, J.; Luo, L.; Yin, Z. Phosphorylated Hsp27 prevents LPS-induced excessive inflammation in THP-1 cells via suppressing ROS-mediated upregulation of CBP. Cell Biol. Int. 2020, 44, 253–267. [Google Scholar] [CrossRef]
  92. Nahomi, R.B.; Palmer, A.; Green, K.M.; Fort, P.E.; Nagaraj, R.H. Pro-inflammatory cytokines downregulate Hsp27 and cause apoptosis of human retinal capillary endothelial cells. Biochim. Biophys. Acta 2014, 1842, 164–174. [Google Scholar] [CrossRef] [PubMed]
  93. Schmidt, A.; von Woedtke, T.; Bekeschus, S. Periodic exposure of keratinocytes to cold physical plasma: An in vitro model for redox-related diseases of the skin. Oxid. Med. Cell. Longev. 2016, 2016, 9816072. [Google Scholar] [CrossRef] [PubMed]
  94. Schmidt, A.; Bekeschus, S.; Jarick, K.; Hasse, S.; von Woedtke, T.; Wende, K. Cold physical plasma modulates p53 and mitogen-activated protein kinase signaling in keratinocytes. Oxid. Med. Cell Longev. 2019, 2019, 7017363. [Google Scholar] [CrossRef] [PubMed]
  95. Landry, S.J. Structure and energetics of an allele-specific genetic interaction between dnaJ and dnaK: Correlation of nuclear magnetic resonance chemical shift perturbations in the J-domain of Hsp40/DnaJ with binding affinity for the ATPase domain of Hsp70/DnaK. Biochemistry 2003, 42, 4926–4936. [Google Scholar] [CrossRef] [PubMed]
  96. Qiu, X.B.; Shao, Y.M.; Miao, S.; Wang, L. The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones. Cell Mol. Life Sci. 2006, 63, 2560–2570. [Google Scholar] [CrossRef]
  97. Kaida, A.; Yamamoto, S.; Parrales, A.; Young, E.D.; Ranjan, A.; Alalem, M.A.; Morita, K.I.; Oikawa, Y.; Harada, H.; Ikeda, T.; et al. DNAJA1 promotes cancer metastasis through interaction with mutant p53. Oncogene 2021, 40, 5013–5025. [Google Scholar] [CrossRef] [PubMed]
  98. Parrales, A.; Ranjan, A.; Iyer, S.V.; Padhye, S.; Weir, S.J.; Roy, A.; Iwakuma, T. DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway. Nat. Cell Biol. 2016, 18, 1233–1243. [Google Scholar] [CrossRef]
  99. Gotoh, T.; Terada, K.; Oyadomari, S.; Mori, M. hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria. Cell Death Differ. 2004, 11, 390–402. [Google Scholar] [CrossRef]
  100. Beere, H.M. “The stress of dying”: The role of heat shock proteins in the regulation of apoptosis. J. Cell Sci. 2004, 117, 2641–2651. [Google Scholar] [CrossRef]
  101. Kabbage, M.; Dickman, M.B. The BAG proteins: A ubiquitous family of chaperone regulators. Cell Mol. Life Sci. 2008, 65, 1390–1402. [Google Scholar] [CrossRef] [PubMed]
  102. Bross, P.; Fernandez-Guerra, P. Disease-associated mutations in the HSPD1 gene encoding the large subunit of the mitochondrial HSP60/HSP10 chaperonin complex. Front Mol. Biosci. 2016, 3, 49. [Google Scholar] [CrossRef] [PubMed]
  103. Kaufman, B.A.; Newman, S.M.; Hallberg, R.L.; Slaughter, C.A.; Perlman, P.S.; Butow, R.A. In organello formaldehyde crosslinking of proteins to mtDNA: Identification of bifunctional proteins. Proc. Natl. Acad. Sci. USA 2000, 97, 7772–7777. [Google Scholar] [CrossRef]
  104. Kaufman, B.A.; Kolesar, J.E.; Perlman, P.S.; Butow, R.A. A function for the mitochondrial chaperonin Hsp60 in the structure and transmission of mitochondrial DNA nucleoids in Saccharomyces cerevisiae. J. Cell Biol. 2003, 163, 457–461. [Google Scholar] [CrossRef] [PubMed]
  105. Bigman, L.S.; Horovitz, A. Reconciling the controversy regarding the functional importance of bullet- and football-shaped GroE complexes. J. Biol. Chem. 2019, 294, 13527–13529. [Google Scholar] [CrossRef] [PubMed]
  106. Erb, H.H.H.; Streitborger, A.; Mustea, A.; Stope, M.B. Physiological and genetically engineered expression modulation methods do not affect cellular levels of the heat shock protein HSP60 in prostate cancer cells. In Vivo 2022, 36, 596–602. [Google Scholar] [CrossRef] [PubMed]
  107. Rottach, A.M.; Ahrend, H.; Martin, B.; Walther, R.; Zimmermann, U.; Burchardt, M.; Stope, M.B. Cabazitaxel inhibits prostate cancer cell growth by inhibition of androgen receptor and heat shock protein expression. World J. Urol. 2019, 37, 2137–2145. [Google Scholar] [CrossRef] [PubMed]
  108. Cappello, F.; Conway de Macario, E.; Marasa, L.; Zummo, G.; Macario, A.J. Hsp60 expression, new locations, functions and perspectives for cancer diagnosis and therapy. Cancer Biol. Ther. 2008, 7, 801–809. [Google Scholar] [CrossRef]
  109. Itoh, H.; Komatsuda, A.; Ohtani, H.; Wakui, H.; Imai, H.; Sawada, K.; Otaka, M.; Ogura, M.; Suzuki, A.; Hamada, F. Mammalian HSP60 is quickly sorted into the mitochondria under conditions of dehydration. Eur. J. Biochem. 2002, 269, 5931–5938. [Google Scholar] [CrossRef]
  110. Bhatt, J.M.; Enriquez, A.S.; Wang, J.; Rojo, H.M.; Molugu, S.K.; Hildenbrand, Z.L.; Bernal, R.A. Single-ring intermediates are essential for some chaperonins. Front. Mol. Biosci. 2018, 5, 42. [Google Scholar] [CrossRef]
  111. Weiss, C.; Jebara, F.; Nisemblat, S.; Azem, A. Dynamic complexes in the chaperonin-mediated protein folding cycle. Front. Mol. Biosci. 2016, 3, 80. [Google Scholar] [CrossRef] [PubMed]
  112. Pellegrino, M.W.; Nargund, A.M.; Haynes, C.M. Signaling the mitochondrial unfolded protein response. Biochim. Biophys. Acta 2013, 1833, 410–416. [Google Scholar] [CrossRef] [PubMed]
  113. Katiyar, A.; Fujimoto, M.; Tan, K.; Kurashima, A.; Srivastava, P.; Okada, M.; Takii, R.; Nakai, A. HSF1 is required for induction of mitochondrial chaperones during the mitochondrial unfolded protein response. FEBS Open Bio 2020, 10, 1135–1148. [Google Scholar] [CrossRef] [PubMed]
  114. Tan, K.; Fujimoto, M.; Takii, R.; Takaki, E.; Hayashida, N.; Nakai, A. Mitochondrial SSBP1 protects cells from proteotoxic stresses by potentiating stress-induced HSF1 transcriptional activity. Nat. Commun. 2015, 6, 6580. [Google Scholar] [CrossRef] [PubMed]
  115. Chandra, D.; Choy, G.; Tang, D.G. Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: Evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3. J. Biol. Chem. 2007, 282, 31289–31301. [Google Scholar] [CrossRef] [PubMed]
  116. Samali, A.; Cai, J.; Zhivotovsky, B.; Jones, D.P.; Orrenius, S. Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells. EMBO J. 1999, 18, 2040–2048. [Google Scholar] [CrossRef]
  117. Huang, Y.H.; Yeh, C.T. Functional compartmentalization of HSP60-survivin interaction between mitochondria and cytosol in cancer cells. Cells 2019, 9, 23. [Google Scholar] [CrossRef]
  118. Shan, Y.X.; Liu, T.J.; Su, H.F.; Samsamshariat, A.; Mestril, R.; Wang, P.H. Hsp10 and Hsp60 modulate Bcl-2 family and mitochondria apoptosis signaling induced by doxorubicin in cardiac muscle cells. J. Mol. Cell Cardiol. 2003, 35, 1135–1143. [Google Scholar] [CrossRef]
  119. Song, E.; Tang, S.; Xu, J.; Yin, B.; Bao, E.; Hartung, J. Lenti-siRNA Hsp60 promote bax in mitochondria and induces apoptosis during heat stress. Biochem. Biophys. Res. Commun. 2016, 481, 125–131. [Google Scholar] [CrossRef]
  120. Ghosh, J.C.; Dohi, T.; Kang, B.H.; Altieri, D.C. Hsp60 regulation of tumor cell apoptosis. J. Biol. Chem. 2008, 283, 5188–5194. [Google Scholar] [CrossRef]
  121. Ghosh, J.C.; Siegelin, M.D.; Dohi, T.; Altieri, D.C. Heat shock protein 60 regulation of the mitochondrial permeability transition pore in tumor cells. Cancer Res. 2010, 70, 8988–8993. [Google Scholar] [CrossRef]
  122. Hallberg, E.M.; Shu, Y.; Hallberg, R.L. Loss of mitochondrial hsp60 function: Nonequivalent effects on matrix-targeted and intermembrane-targeted proteins. Mol. Cell Biol. 1993, 13, 3050–3057. [Google Scholar]
  123. Rosenzweig, R.; Nillegoda, N.B.; Mayer, M.P.; Bukau, B. The Hsp70 chaperone network. Nat. Rev. Mol. Cell Biol. 2019, 20, 665–680. [Google Scholar] [CrossRef] [PubMed]
  124. Faust, O.; Rosenzweig, R. Structural and biochemical properties of Hsp40/Hsp70 chaperone system. Adv. Exp. Med. Biol. 2020, 1243, 3–20. [Google Scholar] [PubMed]
  125. Faust, O.; Abayev-Avraham, M.; Wentink, A.S.; Maurer, M.; Nillegoda, N.B.; London, N.; Bukau, B.; Rosenzweig, R. HSP40 proteins use class-specific regulation to drive HSP70 functional diversity. Nature 2020, 587, 489–494. [Google Scholar] [CrossRef] [PubMed]
  126. Lee, J.S.; Lee, J.J.; Seo, J.S. HSP70 deficiency results in activation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and caspase-3 in hyperosmolarity-induced apoptosis. J. Biol. Chem. 2005, 280, 6634–6641. [Google Scholar] [CrossRef] [PubMed]
  127. Gao, T.; Newton, A.C. The turn motif is a phosphorylation switch that regulates the binding of Hsp70 to protein kinase C. J. Biol. Chem. 2002, 277, 31585–31592. [Google Scholar] [CrossRef]
  128. Stankiewicz, A.R.; Lachapelle, G.; Foo, C.P.; Radicioni, S.M.; Mosser, D.D. Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation. J. Biol. Chem. 2005, 280, 38729–38739. [Google Scholar] [CrossRef]
  129. Matsumori, Y.; Northington, F.J.; Hong, S.M.; Kayama, T.; Sheldon, R.A.; Vexler, Z.S.; Ferriero, D.M.; Weinstein, P.R.; Liu, J. Reduction of caspase-8 and -9 cleavage is associated with increased c-FLIP and increased binding of Apaf-1 and Hsp70 after neonatal hypoxic/ischemic injury in mice overexpressing Hsp70. Stroke 2006, 37, 507–512. [Google Scholar] [CrossRef]
  130. Beere, H.M.; Wolf, B.B.; Cain, K.; Mosser, D.D.; Mahboubi, A.; Kuwana, T.; Tailor, P.; Morimoto, R.I.; Cohen, G.M.; Green, D.R. Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat. Cell Biol. 2000, 2, 469–475. [Google Scholar] [CrossRef]
  131. Cyr, D.M.; Ramos, C.H. Specification of Hsp70 function by Type I and Type II Hsp40. Subcell. Biochem. 2015, 78, 91–102. [Google Scholar] [PubMed]
  132. Attri, P.; Park, J.H.; Ali, A.; Choi, E.H. How does plasma activated media treatment differ from direct cold plasma treatment? Anticancer Agents Med. Chem. 2018, 18, 805–814. [Google Scholar] [CrossRef] [PubMed]
  133. Kletschkus, K.; Haralambiev, L.; Nitsch, A.; Pfister, F.; Klinkmann, G.; Kramer, A.; Bekeschus, S.; Mustea, A.; Stope, M.B. The application of a low-temperature physical plasma device operating under atmospheric pressure leads to the production of toxic NO2. Anticancer Res. 2020, 40, 2591–2599. [Google Scholar] [CrossRef] [PubMed]
  134. Krakowiak, J.; Zheng, X.; Patel, N.; Feder, Z.A.; Anandhakumar, J.; Valerius, K.; Gross, D.S.; Khalil, A.S.; Pincus, D. Hsf1 and Hsp70 constitute a two-component feedback loop that regulates the yeast heat shock response. eLife 2018, 7, 31668. [Google Scholar] [CrossRef]
  135. Hoter, A.; El-Sabban, M.E.; Naim, H.Y. The HSP90 family: Structure, regulation, function, and implications in health and disease. Int. J. Mol. Sci. 2018, 19, 2560. [Google Scholar] [CrossRef] [PubMed]
  136. Whitesell, L.; Lindquist, S.L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 2005, 5, 761–772. [Google Scholar] [CrossRef] [PubMed]
  137. Birbo, B.; Madu, E.E.; Madu, C.O.; Jain, A.; Lu, Y. Role of HSP90 in cancer. Int. J. Mol. Sci. 2021, 22, 10317. [Google Scholar] [CrossRef]
  138. Prodromou, C. Mechanisms of Hsp90 regulation. Biochem. J. 2016, 473, 2439–2452. [Google Scholar] [CrossRef]
  139. Workman, P. Reflections and outlook on targeting HSP90, HSP70 and HSF1 in cancer: A personal perspective. Adv. Exp. Med. Biol. 2020, 1243, 163–179. [Google Scholar]
  140. Yang, S.; Zhao, T.; Ma, A.; Huang, Z.; Yang, J.; Yuan, C.; Guo, X.; Zhu, C. Heat stress-induced HSP90 expression is dependent on ERK and HSF1 activation in turbot (Scophthalmus maximus) kidney cells. Cell Stress Chaperones 2021, 26, 173–185. [Google Scholar] [CrossRef]
  141. Pincus, D. Regulation of Hsf1 and the Heat Shock Response. Adv. Exp. Med. Biol. 2020, 1243, 41–50. [Google Scholar]
  142. Zhang, H.; Shao, S.; Zeng, Y.; Wang, X.; Qin, Y.; Ren, Q.; Xiang, S.; Wang, Y.; Xiao, J.; Sun, Y. Reversible phase separation of HSF1 is required for an acute transcriptional response during heat shock. Nat. Cell Biol. 2022, 24, 340–352. [Google Scholar] [CrossRef]
  143. Ahn, S.G.; Thiele, D.J. Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress. Genes Dev. 2003, 17, 516–528. [Google Scholar] [CrossRef]
  144. Liebmann, J.; Scherer, J.; Bibinov, N.; Rajasekaran, P.; Kovacs, R.; Gesche, R.; Awakowicz, P.; Kolb-Bachofen, V. Biological effects of nitric oxide generated by an atmospheric pressure gas-plasma on human skin cells. Nitric Oxide 2011, 24, 8–16. [Google Scholar] [CrossRef]
  145. Manucha, W.; Valles, P.G. Cytoprotective role of nitric oxide associated with Hsp70 expression in neonatal obstructive nephropathy. Nitric Oxide 2008, 18, 204–215. [Google Scholar] [CrossRef]
  146. Nash, S.; Johnstone, J.; Rahman, M.S. Elevated temperature attenuates ovarian functions and induces apoptosis and oxidative stress in the American oyster, Crassostrea virginica: Potential mechanisms and signaling pathways. Cell Stress Chaperones 2019, 24, 957–967. [Google Scholar] [CrossRef]
  147. Fucarino, A.; Pitruzzella, A. Role of HSP60/HSP10 in Lung Cancer: Simple Biomarkers or Leading Actors? J. Oncol. 2020, 2020, 4701868. [Google Scholar] [CrossRef]
  148. Yadav, K.; Yadav, A.; Vashistha, P.; Pandey, V.P.; Dwivedi, U.N. Protein Misfolding Diseases and Therapeutic Approaches. Curr. Protein Pept. Sci. 2019, 20, 1226–1245. [Google Scholar] [CrossRef]
  149. David, S.; Bucchieri, F.; Corrao, S.; Czarnecka, A.M.; Campanella, C.; Farina, F.; Peri, G.; Tomasello, G.; Sciume, C.; Modica, G.; et al. Hsp10: Anatomic distribution, functions, and involvement in human disease. Front. Biosci. 2013, 5, 768–778. [Google Scholar] [CrossRef]
Biomedicines 11 01471 g001 550
Figure 1. Heat shock proteins (HSP) are substantial cellular regulators of the eukaryotic stress response. HSP are named according to their molecular weights. The major members of the HSP superfamily are classified as HSP27, HSP40, HSP60, HSP70 and HSP90. Heat shock transcription factor 1 (HSF1) is considered the central factor of HSP expression. HSP mediate inducible protective mechanisms against chemical and physical noxae, including chemical and physical therapy approaches. HSP also exhibit cytoprotective and thus prooncogenic effects in tumor diseases and the interaction of cancer cells with the microenvironment and tumor-associated components of the immune system. At the molecular level, HSP control the correct folding of proteins, but also determine their stability and turnover, and thus the functionality of protein factors in cell physiology. For details, please refer to the text.
Figure 1. Heat shock proteins (HSP) are substantial cellular regulators of the eukaryotic stress response. HSP are named according to their molecular weights. The major members of the HSP superfamily are classified as HSP27, HSP40, HSP60, HSP70 and HSP90. Heat shock transcription factor 1 (HSF1) is considered the central factor of HSP expression. HSP mediate inducible protective mechanisms against chemical and physical noxae, including chemical and physical therapy approaches. HSP also exhibit cytoprotective and thus prooncogenic effects in tumor diseases and the interaction of cancer cells with the microenvironment and tumor-associated components of the immune system. At the molecular level, HSP control the correct folding of proteins, but also determine their stability and turnover, and thus the functionality of protein factors in cell physiology. For details, please refer to the text.
Biomedicines 11 01471 g001
Biomedicines 11 01471 g002 550
Figure 2. Non-invasive physical plasma (NIPP) treatment introduces reactive oxygen species (ROS) such as ozone (O3), superoxide anion (O2−•), and hydroxyl radical (OH−•) into the tissue. Within the cells, a stress-induced response of the heat shock protein (HSP) system occurs. Mediated by transcriptionally active heat shock factor-1 (HSF-1), HSP27 and HSP60 are induced, partially phosphorylated (pHSP27), and secreted (sHPS27), controlling cytoskeletal and mitochondrial functionality. Furthermore, large HSP70 and HSP90 and the co-chaperone HSP40 are activated. As part of the NIPP effect, HSP90 can also be cleaved and thus inactivated. Cell responses controlled by HSP include morphology, motility, cytoprotection and, depending on the redox state, apoptosis and cell death.
Figure 2. Non-invasive physical plasma (NIPP) treatment introduces reactive oxygen species (ROS) such as ozone (O3), superoxide anion (O2−•), and hydroxyl radical (OH−•) into the tissue. Within the cells, a stress-induced response of the heat shock protein (HSP) system occurs. Mediated by transcriptionally active heat shock factor-1 (HSF-1), HSP27 and HSP60 are induced, partially phosphorylated (pHSP27), and secreted (sHPS27), controlling cytoskeletal and mitochondrial functionality. Furthermore, large HSP70 and HSP90 and the co-chaperone HSP40 are activated. As part of the NIPP effect, HSP90 can also be cleaved and thus inactivated. Cell responses controlled by HSP include morphology, motility, cytoprotection and, depending on the redox state, apoptosis and cell death.
Biomedicines 11 01471 g002
Table
Table 1. Technical parameters, where published, of NIPP devices used in the studies to modulate HSP functionality after NIPP exposure.
Table 1. Technical parameters, where published, of NIPP devices used in the studies to modulate HSP functionality after NIPP exposure.
TechnologyPlasma SourceVoltageFrequencyAirflowReference
JetArgon2–6 kVN/A5 L/min[59]
JetHeliumN/AN/A1/3/5 L/min[60]
JetArgon + N218 kV20 kHz2 L/min[61]
JetArgon5 kV10 kHz3 L/min[62]
JetArgonN/AN/AN/A[63]
DBD-based volume NIPPArgon7 kV10 kHz3 L/min[64]
Jet Argon2–6 kV1.1 MHz3 L/min[65]
JetN/AN/AN/AN/A[66]
Jet ArgonN/A1 MHz4 L/min[67]
Table
Table 2. Overview of the non-invasive plasma physical (NIPP) devices used in research, the biological models used and which heat shock proteins (HSP) were characterized. Western blot (WB); polymerase chain reaction (PCR); immunofluorescence (IF); enzyme-linked immunosorbent assay (ELISA).
Table 2. Overview of the non-invasive plasma physical (NIPP) devices used in research, the biological models used and which heat shock proteins (HSP) were characterized. Western blot (WB); polymerase chain reaction (PCR); immunofluorescence (IF); enzyme-linked immunosorbent assay (ELISA).
TechnologyModelHSPMethodologyReference
JetHaCat CellsHSP27WB[59]
JetSaOS-2 CellsHSP60WB[60]
JetU937 CellsHSP40/70PCR[61]
JetWistar Rat IF[62]
JetMDA-MB-s31HSP90WB[63]
DBD-based volume CAPHuman Wound Skin IF[64]
JetTHP-1 CellsHSP27WB[65]
JetLNCaP/PC-3 CellsHSP27ELISA[66]
JetOVCAR3 CellsHSP27ELISA[67]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Wang, Y.; Abazid, A.; Badendieck, S.; Mustea, A.; Stope, M.B. Impact of Non-Invasive Physical Plasma on Heat Shock Protein Functionality in Eukaryotic Cells. Biomedicines 2023, 11, 1471. https://doi.org/10.3390/biomedicines11051471

AMA Style

Wang Y, Abazid A, Badendieck S, Mustea A, Stope MB. Impact of Non-Invasive Physical Plasma on Heat Shock Protein Functionality in Eukaryotic Cells. Biomedicines. 2023; 11(5):1471. https://doi.org/10.3390/biomedicines11051471

Chicago/Turabian Style

Wang, Yanqing, Alexander Abazid, Steffen Badendieck, Alexander Mustea, and Matthias B. Stope. 2023. "Impact of Non-Invasive Physical Plasma on Heat Shock Protein Functionality in Eukaryotic Cells" Biomedicines 11, no. 5: 1471. https://doi.org/10.3390/biomedicines11051471

APA Style

Wang, Y., Abazid, A., Badendieck, S., Mustea, A., & Stope, M. B. (2023). Impact of Non-Invasive Physical Plasma on Heat Shock Protein Functionality in Eukaryotic Cells. Biomedicines, 11(5), 1471. https://doi.org/10.3390/biomedicines11051471

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop