Resolution of inflammation in chronic disease via restoration of the heat shock response (HSR).

Effective resolution of inflammation via the heat shock response (HSR) is pivotal in averting the transition to chronic inflammatory states. This transition characterizes a spectrum of debilitating conditions, including insulin resistance, obesity, type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular ailments. This manuscript explores a range of physiological, pharmacological, and nutraceutical interventions aimed at reinstating the HSR in the context of chronic low-grade inflammation, as well as protocols to assess the HSR. Monitoring the progression or suppression of the HSR in patients and laboratory animals offers predictive insights into the organism's capacity to combat chronic inflammation, as well as the impact of exercise and hyperthermic treatments (e.g., sauna or hot tub baths) on the HSR. Interestingly, a reciprocal correlation exists between the expression of HSR components in peripheral blood leukocytes (PBL) and the extent of local tissue proinflammatory activity in individuals afflicted by chronic inflammatory disorders. Therefore, the Heck index, contrasting extracellular 70 kDa family of heat shock proteins (HSP70) (proinflammatory) and intracellular HSP70 (anti-inflammatory) in PBL, serves as a valuable metric for HSR assessment. Our laboratory has also developed straightforward protocols for evaluating HSR by subjecting whole blood samples from both rodents and human volunteers to ex vivo heat challenges. Collectively, this discussion underscores the critical role of HSR disruption in the pathogenesis of chronic inflammatory states and emphasizes the significance of simple, cost-effective tools for clinical HSR assessment. This understanding is instrumental in the development of innovative strategies for preventing and managing chronic inflammatory diseases, which continue to exert a substantial global burden on morbidity and mortality.

The dance of proteostasis and metabolism: Unveiling the caloristatic controlling switch.

The heat shock response (HSR) is an ancient and evolutionarily conserved mechanism designed to restore cellular homeostasis following proteotoxic challenges. However, it has become increasingly evident that disruptions in energy metabolism also trigger the HSR. This interplay between proteostasis and energy regulation is rooted in the fundamental need for ATP to fuel protein synthesis and repair, making the HSR an essential component of cellular energy management. Recent findings suggest that the origins of proteostasis-defending systems can be traced back over 3.6 billion years, aligning with the emergence of sugar kinases that optimized glycolysis around 3.594 billion years ago. This evolutionary connection is underscored by the spatial similarities between the nucleotide-binding domain of HSP70, the key player in protein chaperone machinery, and hexokinases. The HSR serves as a hub that integrates energy metabolism and resolution of inflammation, further highlighting its role in maintaining cellular homeostasis. Notably, 5'-adenosine monophosphate-activated protein kinase emerges as a central regulator, promoting the HSR during predominantly proteotoxic stress while suppressing it in response to predominantly metabolic stress. The complex relationship between 5'-adenosine monophosphate-activated protein kinase and the HSR is finely tuned, with paradoxical effects observed under different stress conditions. This delicate equilibrium, known as caloristasis, ensures that cellular homeostasis is maintained despite shifting environmental and intracellular conditions. Understanding the caloristatic controlling switch at the heart of this interplay is crucial. It offers insights into a wide range of conditions, including glycemic control, obesity, type 2 diabetes, cardiovascular and neurodegenerative diseases, reproductive abnormalities, and the optimization of exercise routines. These findings highlight the profound interconnectedness of proteostasis and energy metabolism in cellular function and adaptation.

Heat shock response during the resolution of inflammation and its progressive suppression in chronic-degenerative inflammatory diseases.

The heat shock response (HSR) is a crucial biochemical pathway that orchestrates the resolution of inflammation, primarily under proteotoxic stress conditions. This process hinges on the upregulation of heat shock proteins (HSPs) and other chaperones, notably the 70 kDa family of heat shock proteins, under the command of the heat shock transcription factor-1. However, in the context of chronic degenerative disorders characterized by persistent low-grade inflammation (such as insulin resistance, obesity, type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases) a gradual suppression of the HSR does occur. This work delves into the mechanisms behind this phenomenon. It explores how the Western diet and sedentary lifestyle, culminating in the endoplasmic reticulum stress within adipose tissue cells, trigger a cascade of events. This cascade includes the unfolded protein response and activation of the NOD-like receptor pyrin domain-containing protein-3 inflammasome, leading to the emergence of the senescence-associated secretory phenotype and the propagation of inflammation throughout the body. Notably, the activation of the NOD-like receptor pyrin domain-containing protein-3 inflammasome not only fuels inflammation but also sabotages the HSR by degrading human antigen R, a crucial mRNA-binding protein responsible for maintaining heat shock transcription factor-1 mRNA expression and stability on heat shock gene promoters. This paper underscores the imperative need to comprehend how chronic inflammation stifles the HSR and the clinical significance of evaluating the HSR using cost-effective and accessible tools. Such understanding is pivotal in the development of innovative strategies aimed at the prevention and treatment of these chronic inflammatory ailments, which continue to take a heavy toll on global health and well-being.

Effects of resistance training on heat shock response (HSR), HSP70 expression, oxidative stress, inflammation, and metabolism in middle-aged people.

Resistance training (RT) can increase the heat shock response (HSR) in the elderly. As middle-aged subjects already suffer physiological declines related to aging, it is hypothesized that RT may increase the HSR in these people. To assess the effects of resistance training on heat shock response, intra and extracellular HSP70, oxidative stress, inflammation, body composition, and metabolism in middle-aged subjects. Sixteen volunteers (40 - 59 years) were allocated to two groups: the trained group (n = 7), which performed 12 weeks of RT; and the physically inactive-control group (n = 9), which did not perform any type of exercise. The RT program consisted of 9 whole-body exercises (using standard gym equipment) and functional exercises, carried out 3 times/week. Before and after the intervention, body composition, muscle mass, strength, functional capacity, and blood sample measurements (lipid profile, glucose, insulin, oxidative damage, TNF-α, the HSR, HSP70 expression in leukocytes, and HSP72 in plasma) were performed. The HSR analysis demonstrated that this response is maintained at normal levels in middle-aged people and that RT did not cause any improvement. Also, RT increases muscle mass, strength, and functional capacity. Despite no additional changes of RT on the antioxidant defenses (catalase, glutathione peroxidase, and reductase) or inflammation, lipid peroxidation was diminished by RT (group x time interaction, p = 0.009), indicating that other antioxidant defenses may be improved after RT. HSR is preserved in middle-aged subjects without metabolic complications. In addition, RT reduces lipid peroxidation and can retard muscle mass and strength loss related to the aging process.

Influence of body composition and cardiorespiratory fitness on plasma HSP72, norepinephrine, insulin, and glucose responses to an acute aerobic exercise bout performed in the fed state.

Being overweight is already considered a metabolic risk factor, which can be overcome by increasing cardiorespiratory fitness (CRF). Acute exercise is known to induce changes in plasma hormones and heat shock proteins release. However, there is a lack of studies investigating the impact of body composition and CRF on these variables following acute aerobic exercise. To assess the influence of body composition and cardiorespiratory fitness on plasma heat shock protein 72 kDa (HSP72), norepinephrine (NE), insulin, and glucose responses to an acute aerobic exercise bout in the fed state. Twenty-four healthy male adults were recruited and allocated into three groups: overweight sedentary (n = 8), normal weight sedentary (n = 8), and normal weight active (n = 8). The volunteers performed an acute moderate exercise session on a treadmill at 70% of VO2 peak. Blood samples were drawn at baseline, immediately post-exercise, and at 1-h post-exercise. The exercise session did not induce changes in HSP72 nor NE but changes in glucose and insulin were affected by body mass index. Also, subjects with elevated CRF maintain reduced NE through exercise. At baseline, the overweight sedentary group showed elevated NE, insulin, and glucose; these last two impacting the HOMA-IR index. Thirty minutes of aerobic exercise at 70% VO2 peak, in the fed state, did not change the levels of plasma NE and HSP72. Elevated body composition seems to impact metabolic profile and increase sympathetic activity. Conversely, subjects with increased cardiorespiratory fitness seem to have attenuated sympathetic activity.

Extra and intra cellular HSP70 levels in adults with and without metabolic disorders: a systematic review and meta-analysis.

Metabolic disorders, such as obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MS) are related to chronic pro-inflammatory conditions. Evidence suggests that heat shock proteins are linked to metabolic disorders. Intracellular HSP70 (iHSP70) is mandatory for normal insulin signalling, and proteostasis, and exerts a powerful anti-inflammatory role. On the other hand, the extracellular (eHSP72) is linked with a pro-inflammatory state and induces insulin resistance in humans. Then, we conducted a systematic review with meta-analysis to summarize the data of HSP70 in people with and without metabolic disorders. PubMed, Embase, Scopus, and Web of Science databases were used. Eligibility criteria included observational and baseline data of experimental studies that assessed iHSP70 and/or eHSP72 in adults with metabolic disorders and healthy people. The risk of bias was assessed by the Newcastle-Ottawa scale. Meta-analysis was performed using a random-effect model and the mean difference was estimated for eHSP72 and the standardized mean difference for iHSP70. A total of 11,255 articles were retrieved, 31 articles were assessed for eligibility and 15 were included for data extraction. There was no difference in eHSP72 between metabolic disorders and healthy controls (mean difference (MD) = 0.11; 95% confidence interval (CIs) = -0.05 to 0.27; I2 = 95%). Subgroup analysis showed higher levels of eHSP72 in T2DM people than healthy ones (MD = 0.32; 95% CIs = 0.17 to 0.47; I2 = 92%). For iHSP70 no difference was found (standardized mean difference (SMD) =-0.24; 95% CIs =-1.62 to 1.15; I2 = 86%). Our results suggest that eHSP72 levels may be dependent on metabolic condition and no difference in iHSP70 levels are attributed to high heterogeneity level between studies (PROSPERO REGISTRATION: CRD42022323514).

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

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

Heat shock response to exercise in pancreatic islets of obese mice.

Chronic obesity imposes an organismal state of low-grade inflammation because the physiological resolution of inflammation is progressively repressed giving rise to cellular senescence and its accompanying Senescence-Associated Secretory Phenotype (SASP), which avoids apoptosis but perpetuates the relay of inflammatory signals from adipose tissue toward the rest of the body. Conversely, resolution of inflammation depends on the integrity of heat shock response (HSR) pathway that leads to the expression of cytoprotective and anti-inflammatory protein chaperones of the 70 kDa family (HSP70). However, chronic exposure to the aforementioned injuring factors leads to SASP, which, in turn, suppresses the HSR. A main metabolic tissue severely jeopardized by obesity-related dysfunctions is the endocrine pancreas, particularly ß-cells of the islets of Langerhans. Because exercise is a powerful inducer of HSR and predicted to alleviate negative health outcomes of obesity, we sought whether obesity influence HSP70 expression in pancreatic islets and other metabolic tissues (adipose tissue and skeletal muscle) of adult B6.129SF2/J mice fed on a high-fat diet (HFD) for 13 weeks since the weaning and whether acute exercise as well as moderate-intensity exercise training (8 weeks) could interfere with this scenario. We showed that acute exercise of moderate intensity protects pancreatic islets against cytokine-induced cell death. In addition, acute exercise challenge time-dependently increased islet HSP70 that peaked at 12 h post-exercise in both trained and untrained mice fed on a control diet, suggesting an adequate HSR to exercise training. Unexpectedly, however, neither exercise training nor acute exercise challenges were able to increase islet HSP70 contents in trained mice submitted to HFD, but only in untrained HFD animals. In parallel, HFD disrupted glycemic status which is accompanied by loss of muscular mass resembling sarcopenic obesity that could not be rescued by exercise training. These results suggest that exercise influences HSR in pancreatic islets but obesity undermines islet, muscle and adipose tissue HSR, which is associated with metabolic abnormalities observed in such tissues.

Heat-induced extracellular HSP72 release is blunted in elderly diabetic people compared with healthy middle-aged and older adults, but it is partially restored by resistance training.

Recent evidence suggests that the anti-inflammatory heat shock response (HSR) is reduced in aging and diabetes. In this study we compared HSR between healthy middle-aged adults, healthy elderly and type 2 diabetic (T2DM) elderly, and tested whether resistance training (RT) could improve the HSR in T2DM group. Thirty sedentary participants volunteered for this study. HSR (assessed as the capacity to export HSP72 during heat stress) was measured in the blood and compared between the groups. HSR was similar between healthy middle-aged and healthy elderly volunteers, but diminished in elderly T2DM (p < 0.001). Hence, T2DM subjects (n = 12) were submitted to a 12-week RT program, because exercise is a physiological HSR inducer. HSR, cytokines, metabolic parameters and visceral adipose tissue (VAT) were measured before and after the RT. Remarkably, VAT was negatively correlated with HSR (r = - 0.49, p < 0.01) while RT improved the HSR and reduced inflammation [TNF-α: from 51.5 ±â€¯9 to 40.7 ±â€¯4 pg/mL and TNF-α/IL-10 ratio: from 1.55 ±â€¯0.3 to 1.16 ±â€¯0.2 (p < 0.001)], without affecting other parameters. All together, these findings confirm the hypothesis that the anti-inflammatory HSR is depressed in elderly diabetic people, but can be partially restored by RT.