Heat shock proteins and the biogenesis of cellular membranes.

The successful function of cells is importantly contributed by lipid membranes that are more than a simple physical barrier. The major components of cellular membranes are lipids, in particular glycerophospholipids, that have the capacity to assemble spontaneously into vesicles containing a lipid bilayer after exposure to an aqueous milieu due to their amphiphilic characteristics. The lipid capacity to form vesicles and encapsulate substrates has been proposed as a fundamental event during the biogenesis of cells. However, the stability of small vesicles is compromised during their expansion into larger and more complex particles. Recent observations by (Cornell et al. Proc Natl Acad Sci U S A 116:17239-17244, 2019) have shown that the insertion of amino acids into rudimentary vesicles could play a stabilizing role that was critical to the formation of early cells. Fatty acids were likely substituted by glycerophospholipids and amino acids replaced by polypeptides during the evolution of protocells. Thus, archaic peptides displaying lipid-binding and membrane-penetrating capacities could have played a key function in the development of current cells. In this regard, heat shock proteins (HSP), particularly the Hsp70 (HSPA) and small HSP (HSPB) families, could have portrayed that role. Indeed, bacterial DnaK is closest in sequence to the earliest members of the Hsp70 family and inserts into lipid membranes spontaneously. Moreover, extensive studies by the Vigh group have shown that, certainly, Hsp70s stabilize membranes. Thus, the ability of ancestral HSP70s and small HSPs to associate with lipids and stabilize membranes could have been a fundamental event in the genesis of cells.

Coronaviruses and stress: from cellular to global.

Near the end of 2019, SARS-CoV-2, a novel highly contagious coronavirus phylogenetically related to the SARS virus, entered the human population with lethal consequences. This special issue devoted to the resulting disease COVID-19 was not planned but instead the articles accumulated organically as researchers in the cell stress response field noticed similarities among the pathophysiology of COVID-19 infections and the responses that they studied in contexts unrelated to viral infection. We preface the issue with an introductory article which begins with a brief review of the structure and biology of SARS-CoV-2. As we collected and compared the COVID-19 articles, several shared themes emerged. In the second part of the introduction, each article is summarized briefly and the common themes that link each into a spontaneously arising chain of ideas and hypotheses are emphasized. These themes include growing evidence of molecular mimicry among the viral proteins and the proteins of patients. The realization that much of the consequences of such immune mimicry may play out on the plasma membrane of vascular endothelial cells raised the specter of autoimmune-induced vascular endothelial damage in multiple organs. Proposals of new therapeutic approaches have coalesced around the theme of inducing protection of the vascular endothelium. New chemical treatments that are proposed include stannous chloride, inducers of the gasotransmitter hydrogen sulfide such as sodium thiosulfate and inducers of the cytoprotective stress protein heme oxygenase. Oxygen delivered by ventilators is already in extensive use to provide life support for patients with severe COVID-19. Two articles propose to advance the use of oxygen to the level of a therapeutic treatment early in the detection of the virus in infected patients by delivering oxygen under elevated pressure in hyperbaric chambers. At elevated blood plasma concentrations, hyperbaric oxygen is capable of achieving results far beyond the capability of ventilators as it promotes the activation of transcription factors that control the establishment of inducible cellular defense systems.

The effect of hyperbaric oxygen on mitochondrial and glycolytic energy metabolism: the caloristasis concept.

We present new data on the effects of HBOT on human kidney (HK-2) cell metabolism using a SeaHorse XF Analyzer to evaluate separately the state of mitochondrial and glycolytic energy metabolism. The data are discussed in the context of the concept of cellular caloristasis networks. The information on the changes in cellular energy metabolism stimulated by HBOT presented here provides new insights into the cellular energy state and mitochondrial environment in which sHSPs function. These data will be useful in forming testable hypotheses about the functions of translocated sHSPs in human mitochondria responding to stressors.

Small heat shock proteins: multifaceted proteins with important implications for life.

Small Heat Shock Proteins (sHSPs) evolved early in the history of life; they are present in archaea, bacteria, and eukaryota. sHSPs belong to the superfamily of molecular chaperones: they are components of the cellular protein quality control machinery and are thought to act as the first line of defense against conditions that endanger the cellular proteome. In plants, sHSPs protect cells against abiotic stresses, providing innovative targets for sustainable agricultural production. In humans, sHSPs (also known as HSPBs) are associated with the development of several neurological diseases. Thus, manipulation of sHSP expression may represent an attractive therapeutic strategy for disease treatment. Experimental evidence demonstrates that enhancing the chaperone function of sHSPs protects against age-related protein conformation diseases, which are characterized by protein aggregation. Moreover, sHSPs can promote longevity and healthy aging in vivo. In addition, sHSPs have been implicated in the prognosis of several types of cancer. Here, sHSP upregulation, by enhancing cellular health, could promote cancer development; on the other hand, their downregulation, by sensitizing cells to external stressors and chemotherapeutics, may have beneficial outcomes. The complexity and diversity of sHSP function and properties and the need to identify their specific clients, as well as their implication in human disease, have been discussed by many of the world's experts in the sHSP field during a dedicated workshop in Québec City, Canada, on 26-29 August 2018.

The IXth CSSI international symposium on heat shock proteins in biology and medicine: stress responses in health and disease : Alexandria Old Town, Alexandria, Virginia, November 10-13, 2018.

The stress response has been studied now for over 50 years and is known to have significance in the survival of organisms in a challenging environment and in the healthy development of all known descendants of the last common universal ancestor (LUCA). This meeting was concentrated mostly on the responses of cells and organisms to environmental and cell stress including the impact of thermal stress, which was a major theme throughout this meeting. One emphasis was on the deployment of the heat shock response that permits damage to proteins to be detected and responded to by the abundant synthesis of heat shock proteins (HSPs). Speakers and presenters of posters responded to the questions of how are the HSPs rapidly induced by stressors? By which mechanisms are they are regulated in the cell by protein-protein interactions or posttranslational modification? And, what are the consequences when these abundantly expressed proteins escape the confines of the cell and influence the extracellular microenvironment? Key among the questions was how does stress influence longevity and aging and what happens in terms of disease control (malignant, neurodegenerative) when stress responses become compromised? In this context, many presenters addressed the question of pharmacologically modifying the heat shock response and HSP functions and thus improving responses to a range of disease types.

Might hyperbaric oxygen therapy (HBOT) reduce renal injury in diabetic people with diabetes mellitus? From preclinical models to human metabolomics.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure in the western world. Current treatment of diabetic kidney disease relies on nutritional management and drug therapies to achieve metabolic control. Here, we discuss the potential application of hyperbaric oxygen therapy (HBOT) for the treatment of diabetic kidney disease (DKD), a treatment which requires patients to breathe in 100% oxygen at elevated ambient pressures. HBOT has traditionally been used to diabetic foot ulcers (DFU) refractory to conventional medical treatments. Successful clinic responses seen in the DFU provide the underlying therapeutic rationale for testing HBOT in the setting of DKD. Both the DFU and DKD have microvascular endothelial disease as a common underlying pathologic feature. Supporting evidence for HBOT of DKD comes from previous animal studies and from our preliminary prospective clinical trial reported here. We report urinary metabolomic data obtained from patients undergoing HBOT for DFU, before and after exposure to 6 weeks of HBOT. The preliminary data support the concept that HBOT can reduce biomarkers of renal injury, oxidant stress, and mitochondrial dysfunction in patients receiving HBOT for DFU. Further studies are needed to confirm these initial findings and correlate them with simultaneous measures of renal function. HBOT is a safe and effective treatment for DFU and could also be for individuals with DKD.

The VIII International Congress on Stress Proteins in Biology and Medicine: täynnä henkeä.

About 150 international scientists gathered in Turku, Finland, in August of 2017 for the eighth in a series of international congresses about the roles of stress proteins in biology and medicine. The scientific theme and title of the 2017 Congress was "Stress Management Mechanisms and Pathways." The meeting covered a broad range of topics, reflecting the wide scope of the Cell Stress Society International (CSSI) and highlighting the numerous recent breakthroughs in stress response biology and medicine. The keynote lecturers included Marja Jäättelä, Richard Morimoto, Anne Bertolotti, and Peter Walter. The Executive Council of the CSSI elected new Fellows and Senior Fellows. The Spirit of Budapest Award was presented to Peter Csermely, Wolfgang Schumann, and Subhash Lakhotia in recognition of pioneering service contributions to the CSSI. The CSSI Medallion for Career Achievement was awarded to Larry Hightower and CSSI president Gabriella Santoro proclaimed Tuesday, August 15, 2017, Robert M. Tanguay Day at the congress in recognition of Robert's many years of scientific accomplishment and work on behalf of the CSSI. Additional special events were the awarding of the Ferruccio Ritossa Early Career Award to Serena Carra and the Alfred Tissières Young Investigator Award to Ayesha Murshid. As is the tradition at CSSI congresses, there were social events that included an exciting piano performance by a trio of young Finnish pianists, at the Sibelius Museum.

The growing world of small heat shock proteins: from structure to functions.

Small heat shock proteins (sHSPs) are present in all kingdoms of life and play fundamental roles in cell biology. sHSPs are key components of the cellular protein quality control system, acting as the first line of defense against conditions that affect protein homeostasis and proteome stability, from bacteria to plants to humans. sHSPs have the ability to bind to a large subset of substrates and to maintain them in a state competent for refolding or clearance with the assistance of the HSP70 machinery. sHSPs participate in a number of biological processes, from the cell cycle, to cell differentiation, from adaptation to stressful conditions, to apoptosis, and, even, to the transformation of a cell into a malignant state. As a consequence, sHSP malfunction has been implicated in abnormal placental development and preterm deliveries, in the prognosis of several types of cancer, and in the development of neurological diseases. Moreover, mutations in the genes encoding several mammalian sHSPs result in neurological, muscular, or cardiac age-related diseases in humans. Loss of protein homeostasis due to protein aggregation is typical of many age-related neurodegenerative and neuromuscular diseases. In light of the role of sHSPs in the clearance of un/misfolded aggregation-prone substrates, pharmacological modulation of sHSP expression or function and rescue of defective sHSPs represent possible routes to alleviate or cure protein conformation diseases. Here, we report the latest news and views on sHSPs discussed by many of the world's experts in the sHSP field during a dedicated workshop organized in Italy (Bertinoro, CEUB, October 12-15, 2016).

The remarkable multivalency of the Hsp70 chaperones.

Hsp70 proteins are key to maintaining intracellular protein homeostasis. To carry out this task, they employ a large number of cochaperones and adapter proteins. Here, we review what is known about the interaction between the chaperones and partners, with a strong slant toward structural biology. Hsp70s in general, and Hsc70 (HSPA8) in particular, display an amazing array of interfaces with their protein cofactors. We also review the known interactions between Hsp70s with lipids and with active compounds that may become leads toward Hsp70 modulation for treatment of a variety of diseases.

Stress and health Huangshan-style.

The Seventh International Congress of the Cell Stress Society International (CSSI) was held as a joint meeting with the newly organized committee of Stress Physiology, the Chinese Association for Physiological Sciences (CAPS). There were over 200 colleagues and their students in attendance from 22 different countries. The topics of the congress were core scientific areas in the field of stress and health. The keynote speakers were Fu-Chu He (China), E.R. (Ron) de Kloet (The Netherlands), and Kazuhiro Nagata (Japan). The CSSI Medallion for Career Achievement in the cell stress and chaperones field was awarded to Kazutoshi Mori (Japan). Twelve student post awards were given in recognition of a very high quality poster session. In the tradition of this series of congresses, cultural events were an important part of the program. In addition, participants became better acquainted during trips to the ancient shopping street, an evening at the Chinese opera, and a lesson in Tai Chi from a master. The first groups of CSSI Fellows and Senior Fellows were presented their rosettes and certificates during the congress.

Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice.

The disease burden from diabetic kidney disease is large and growing. Effective therapies are lacking, despite an urgent need. Hyperbaric oxygen therapy (HBOT) activates Nrf2 and cellular antioxidant defenses; therefore, it may be generally useful for treating conditions that feature chronic oxidative tissue damage. Herein, we determined how periodic exposure to oxygen at elevated pressure affected type 2 diabetes mellitus-related changes in the kidneys of db/db mice. Two groups of db/db mice, designated 2.4 ATA and 1.5 ATA, were treated four times per week with 100 % oxygen at either 1.5 or 2.4 ATA (atmospheres absolute) followed by tests to assess kidney damage and function. The sham group of db/db mice and the Hets group of db/+ mice were handled but did not receive HBOT. Several markers of kidney damage were reduced significantly in the HBOT groups including urinary biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CyC) along with significantly lower levels of caspase-3 activity in kidney tissue extracts. Other stress biomarkers also showed trends to improvement in the HBOT groups, including urinary albumin levels. Expressions of the stress response genes NRF2, HMOX1, MT1, and HSPA1A were reduced in the HBOT groups at the end of the experiment, consistent with reduced kidney damage in treated mice. Urinary albumin/creatinine ratio (ACR), a measure of albuminuria, was significantly reduced in the db/db mice receiving HBOT. All of the db/db mouse groups had qualitatively similar changes in renal histopathology. Glycogenated nuclei, not previously reported in db/db mice, were observed in these three experimental groups but not in the control group of nondiabetic mice. Overall, our findings are consistent with therapeutic HBOT alleviating stress and damage in the diabetic kidney through cytoprotective responses. These findings support an emerging paradigm in which tissue oxygenation and cellular defenses effectively limit damage from chronic oxidative stress more effectively than chemical antioxidants.

Report on the VIIth International Symposium on Heat Shock Proteins in Biology & Medicine.

This seventh symposium in a series on heat shock proteins in biology and medicine was held November 1-5, 2014, at the Hilton Hotel in Old Town Alexandria, Virginia. Approximately 70 participants including principal investigators, postdoctoral fellows, and graduate students were in attendance. The major themes were: new properties of heat shock proteins (HSPs) and heat shock factor (HSF) and role in the etiology of cancer, molecular chaperones in aging, extracellular HSPs in inflammation and immunity, role of heat shock and the heat shock response in immunity and cancer, protein aggregation disorders and HSP expression, and Hsp70 in blood cell differentiation. The next meeting is planned for the fall of 2016 in the same venue.