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.

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. (AU)

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. (AU)

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.

Type 1 and Type 2 Diabetes Mellitus: Commonalities, Differences and the Importance of Exercise and Nutrition.

Diabetes mellitus represents a group of physiological dysfunctions characterized by hyperglycaemia resulting directly from insulin resistance (in the case of type 2 diabetes mellitus-T2DM), inadequate insulin secretion/production, or excessive glucagon secretion (in type 1 diabetes mellitus-T1DM) [...].

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.

Efficacy of Carotenoid-Loaded Gelatin Nanoparticles in Reducing Plasma Cytokines and Adipocyte Hypertrophy in Wistar Rats.

The present study investigated the effect of gelatin-based nanoparticles (EPG) loaded with a carotenoid-rich crude extract (CE) on systemic and adipose tissue inflammatory response in a model with inflammation induced by a high glycemic index and high glycemic load diet (HGLI). Nanoparticles synthesized were characterized by different physical and chemical methods. The in vivo investigation evaluated Wistar rats (n = 20, 11 days, adult male with 21 weeks) subdivided into untreated (HGLI diet), conventional treatment (nutritionally adequate diet), treatment 1 (HGLI + crude extract (12.5 mg/kg)), and treatment 2 (HGLI + EPG (50 mg/kg)) groups. Dietary intake, caloric intake and efficiency, weight, inflammatory cytokines tissue concentration, visceral adipose tissue (VAT) weight, histopathological analysis, and antioxidant activity in plasma and VAT were investigated. EPG showed the same physical and chemical characteristics as previous batches (95.2 nm, smooth surface, and chemical interactions between materials). The EPG-treated group was the only group promoting negative ∆dietary intake, ∆caloric efficiency, and ∆weight. In addition, it presented a significant reduction (p < 0.05) in IL-6 and leptin levels and a greater presence of multilocular adipocytes. The results suggest that EPG can act as a nutraceutical in adjuvant therapy for treating inflammatory diseases associated with adipose tissue accumulation.

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).

Acute effects of a single moderate-intensity exercise bout performed in fast or fed states on cell metabolism and signaling: Comparison between lean and obese rats.

AIMS: Although the benefits of exercise can be potentiated by fasting in healthy subjects, few studies evaluated the effects of this intervention on the metabolism of obese subjects. This study investigated the immediate effects of a single moderate-intensity exercise bout performed in fast or fed states on the metabolism of gastrocnemius and soleus of lean and obese rats. MAIN METHODS: Male rats received a high-fat diet (HFD) for twelve weeks to induce obesity or were fed standard diet (SD). After this period, the animals were subdivided in groups: fed and rest (FER), fed and exercise (30 min treadmill, FEE), 8 h fasted and rest (FAR) and fasted and exercise (FAE). Muscle samples were used to investigate the oxidative capacity and gene expression of AMPK, PGC1α, SIRT1, HSF1 and HSP70. KEY FINDINGS: In relation to lean animals, obese animals' gastrocnemius glycogen decreased 60 %, triglycerides increased 31 %; glucose and alanine oxidation decreased 26 % and 38 %, respectively; in soleus, triglycerides reduced 46 % and glucose oxidation decreased 37 %. Exercise and fasting induced different effects in glycolytic and oxidative muscles of obese rats. In soleus, fasting exercise spared glycogen and increased palmitate oxidation, while in gastrocnemius, glucose oxidation increased. In obese animals' gastrocnemius, AMPK expression decreased 29 % and SIRT1 increased 28 % in relation to lean. The AMPK response was more sensitive to exercise and fasting in lean than obese rats. SIGNIFICANCE: Exercise and fasting induced different effects on the metabolism of glycolytic and oxidative muscles of obese rats that can promote health benefits in these animals.

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.

Altered muscle mitochondrial, inflammatory and trophic markers, and reduced exercise training adaptations in type 1 diabetes.

Growing evidence of impaired skeletal muscle health in people with type 1 diabetes points toward the presence of a mild myopathy in this population. However, this myopathic condition is not yet well characterised and often overlooked, even though it might affect the whole-body glucose homeostasis and the development of comorbidities. This study aimed to compare skeletal muscle adaptations and changes in glycaemic control after 12 weeks of combined resistance and aerobic (COMB) training between people with type 1 diabetes and healthy controls, and to determine whether the impaired muscle health in type 1 diabetes can affect the exercise-induced adaptations. The COMB training intervention increased aerobic capacity and muscle strength in both healthy and type 1 diabetes sedentary participants, although these improvements were higher in the control group. Better glucose control, reduced glycaemic fluctuations and fewer hypoglycaemic events were recorded at post- compared to pre-intervention in type 1 diabetes. Analysis of muscle biopsies showed an alteration of muscle markers of mitochondrial functions, inflammation, ageing and growth/atrophy compared to the control group. These muscular molecular differences were only partially modified by the COMB training and might explain the reduced exercise adaptation observed in type 1 diabetes. In brief, type 1 diabetes impairs many aspects of skeletal muscle health and might affect the exercise-induced adaptations. Defining the magnitude of diabetic myopathy and the effect of exercise, including longer duration of the intervention, will drive the development of strategies to maximise muscle health in the type 1 diabetes population. KEY POINTS: Type 1 diabetes negatively affects skeletal muscle health; however, the effect of structured exercise training on markers of mitochondrial function, inflammation and regeneration is not known. Even though participants with type 1 diabetes and healthy control were comparable for cardiorespiratory fitness ( V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ ) and muscle strength at baseline, molecular markers related to muscle health were decreased in type 1 diabetes. After training, both groups increased V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ and muscle strength; however, a larger improvement was achieved by the control group. The training intervention decreased glucose fluctuations and occurrence of hypoglycaemic events in type 1 diabetes, while signs of mild myopathy found in the muscle of participants with type 1 diabetes only partially improved after training Improving muscle health by specific exercise protocols is of considerable clinical interest in therapeutic strategies for improving type 1 diabetes management and preventing or delaying long-term complications.

The Impact of Dehydration and Hyperthermia on Circulatory Glutathione Metabolism after Exercise in the Heat with Insights into the Role of Erythrocytes.

BACKGROUND: Reduced glutathione (GSH) is one of the main thiols involved in antioxidant defense. Changes in circulatory levels of GSH during exercise are associated with hyperthermia and dehydration. The mechanisms by which these alterations occur are not entirely known. We hypothesize that erythrocytes could be an important source of circulatory GSH during heat stress conditions. We performed two separate experiments to address this hypothesis. METHODS: In the first experiment, we sought to investigate the impact of exercise in the heat and dehydration on erythrocyte levels of GSH. A total of 10 men performed 60 min of cycling at 60% VO2peak in the heat (38.0 ± 0.9 °C) or in a control temperate environment (23.0 ± 1.0 °C), both with and without dehydration. Relative humidity ranged from 50 to 70%. Blood samples were taken before and after exercise to measure GSH and oxidized (GSSG) glutathione. In the second experiment, erythrocytes were isolated from blood samples taken at rest and heated in vitro to determine the impact of heat on erythrocyte glutathione content. Tubes with erythrocytes were exposed to water baths at different temperatures; one tube was exposed to a water bath at 35 °C and the other tube to a water bath at 41 °C for a period of 30 min. After exposure to heat, plasma and erythrocytes were extracted for GSH and GSSG analyses. RESULTS: Dehydration decreased circulatory GSH, regardless of ambient temperature (temperate and heat decreased 15.35% and 30.31%, respectively), resulting in an altered redox balance. Heat increased GSH levels in vitro. CONCLUSION: Our data suggest that dehydration decreases circulatory GSH levels regardless of environmental temperature. In addition, in vitro data suggests that erythrocytes may contribute to the release of GSH during exposure to heat stress.

Metabolic and Molecular Subacute Effects of a Single Moderate-Intensity Exercise Bout, Performed in the Fasted State, in Obese Male Rats.

Introduction and objectives: Obesity represents a major global public health problem. Its etiology is multifactorial and includes poor dietary habits, such as hypercaloric and hyperlipidic diets (HFDs), physical inactivity, and genetic factors. Regular exercise is, per se, a tool for the treatment and prevention of obesity, and recent studies suggest that the beneficial effects of exercise can be potentiated by the fasting state, thus potentially promoting additional effects. Despite the significant number of studies showing results that corroborate such hypothesis, very few have evaluated the effects of fasted-state exercise in overweight/obese populations. Therefore, the aim of this study was to evaluate the subacute effects (12 h after conclusion) of a single moderate-intensity exercise bout, performed in either a fed or an 8 h fasted state, on serum profile, substrate-content and heat shock pathway-related muscle protein immunocontent in obese male rats. Methods: Male Wistar rats received a modified high-fat diet for 12 weeks to induce obesity and insulin resistance. The animals were allocated to four groups: fed rest (FER), fed exercise (FEE), fasted rest (FAR) and fasted exercise (FAE). The exercise protocol was a 30 min session on a treadmill, with an intensity of 60% of VO2max. The duration of the fasting period was 8 h prior to the exercise session. After a 12 h recovery, the animals were killed and metabolic parameters of blood, liver, heart, gastrocnemius and soleus muscles were evaluated, as well as SIRT1 and HSP70 immunocontent in the muscles. Results: HFD induced obesity and insulin resistance. Soleus glycogen concentration decreased in the fasted groups and hepatic glycogen decreased in the fed exercise group. The combination of exercise and fasting promoted a decreased concentration of serum total cholesterol and triglycerides. In the heart, combination fasting plus exercise was able to decrease triglycerides to control levels. In the soleus muscle, both fasting and fasting plus exercise were able to decrease triglyceride concentrations. In addition, heat shock protein 70 and sirtuin 1 immunocontent increased after exercise in the gastrocnemius and soleus muscles. Conclusions: An acute bout of moderate intensity aerobic exercise, when realized in fasting, may induce, in obese rats with metabolic dysfunctions, beneficial adaptations to their health, such as better biochemical and molecular adaptations that last for at least 12 h. Considering the fact that overweight/obese populations present an increased risk of cardiovascular events/diseases, significant reductions in such plasma markers of lipid metabolism are an important achievement for these populations.

Differential effects of whole blood heat treatment on the ex vivo inflammatory profile of untrained and trained men.

This study evaluated the effects of heat stress on the ex vivo inflammatory profile in untrained and trained men. Whole blood samples from untrained (UT) and trained (TR) individuals were incubated for 2 h at 37 °C or 40 °C. The whole blood of a subsample of the participants (n = 5 in both TR and UT groups) were stimulated with lipopolysaccharide (LPS, 10 ng/mL) concomitant to heat treatment (37 °C versus 40 °C). Flow cytometry was used to assess the intracellular NF-κB activation in CD4+ T cells and CD14+ monocytes, the expression of Toll-Like Receptor-4 (TLR-4), the frequencies of CD4+CD25-CD39+ and CD4+CD25+CD39+ T cells and monocyte subsets (CD14+CD16-; CD14+CD16+; CD14-CD16+), the mitochondrial membrane potential (MMP) and the reactive oxygen species (ROS) production by lymphocytes and monocytes. The production of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha (TNF-α) by LPS-stimulated whole blood were also evaluated. Heat treatment (40 °C) increased the proportions of CD14+CD16- and CD14+CD16+ monocytes and the lymphocyte MMP in the UT group. The frequencies of CD14-CD16+ monocytes and the activation of NF-κB in CD14+ monocytes decreased in UT and TR groups after heat treatment, while a reduction in CD4+CD25-CD39+ T-cells was observed only in the UT group. Higher TLR-4 and NF-κB activation were found in LPS-stimulated monocytes of UT men concomitant with higher TNF-α production and diminished IL-10 production after heat treatment. TR individuals presented lower NF- κB activation in LPS-stimulated monocytes after heat treatment. Our data suggest that the training status of individuals may impact on the anti-inflammatory response of heat treatment.

Comparison between two cryopreservation techniques of human ovarian cortex: morphological aspects and the heat shock response (HSR).

This study was tailored to compare the cryopreservation of the human ovarian cortex using closed metal container vitrification or the slow-freezing technique. Superficial ovarian cortical tissue biopsies were collected from 12 participants who underwent gynaecological videolaparoscopy. The fragmented samples were allocated to three experimental conditions: (a) fresh ovarian tissue, (b) slow-freezing, and (c) vitrification with a metal closed container. After thawing or rewarming, cellular morphological analyses were performed to determine tissue viability. The cellular response to thermal stress was measured by a putative increase in the immune quantification of the heat shock protein 70 kDa (heat shock protein 70 kDa response - HSR) after a heat challenge (2 h exposure at 42 °C). Both the total number of intact follicles and the frequency of primordial follicles were higher in fresh ovarian tissue than in the preserved samples, regardless of the technique employed. There was a trend towards an increase in the absolute number of intact follicles in the tissue preserved by vitrification. After cryopreservation, a higher HSR was obtained after slow-freezing. These results indicate that both cryopreservation techniques present advantages and may be used as alternatives to ovarian tissue cryopreservation.

Effects of acute aerobic, resistance and combined exercises on 24-h glucose variability and skeletal muscle signalling responses in type 1 diabetics.

PURPOSE: To compare the effect of high-intensity aerobic (AER), resistance (RES), and combined (COMB: RES + AER) exercise, on interstitial glucose (IG) variability and skeletal muscle signalling pathways in type 1 diabetes (T1D). METHODS: T1D participants (6 M/6F) wore a flash glucose monitoring system in four randomized sessions: one control (CONT), and one AER, RES and COMB (40 min each). Mean amplitude of glycemic excursions (MAGE), standard deviation (SD) and coefficient variation (CV) of IG were used to compare the 24 h post-exercise IG variability. Blood and muscle samples were collected to compare exercise-induced systemic and muscle signalling responses related to metabolic, growth and inflammatory adaptations. RESULTS: Both RES and COMB decreased the 24 h MAGE compared to CONT; additionally, COMB decreased the 24 h SD and CV. In the 6-12 h post-exercise, all exercise modalities reduced the IG CV while SD decreased only after COMB. Both AER and COMB stimulated the PGC-1α mRNA expression and promoted the splicing of IGF-1Ea variant, while Akt and p38MAPK phosphorylation increased only after RES and COMB. Additionally, COMB enhanced eEF2 activation and RES increased myogenin and MRF4 mRNA expression. Blood lactate and glycerol levels and muscle IL-6, TNF-α, and MCP-1 mRNAs increased after all exercise sessions, while serum CK and LDH level did not change. CONCLUSION: COMB is more effective in reducing IG fluctuations compared to single-mode AER or RES exercise. Moreover, COMB simultaneously activates muscle signalling pathways involved in substrate metabolism and anabolic adaptations, which can help to improve glycaemic control and maintain muscle health in T1D.

Coronavirus infection (SARS-CoV-2) in obesity and diabetes comorbidities: is heat shock response determinant for the disease complications?

Chronic inflammation is involved in the pathogenesis of several metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). With the recent worldwide outbreak of coronavirus disease (SARS-CoV-2), it has been observed that individuals with these metabolic diseases are more likely to develop complications, increasing the severity of the disease and a poorer outcome. Coronavirus infection leads to the activation of adaptive and innate immune responses, resulting in massive inflammation (to so called cytokine storm), which in turn can lead to damage to various tissues, septic shock and multiple organ failure. Recent evidence suggests that the common link between metabolic diseases and SARS-CoV-2 is the inflammatory response (chronic/low-grade for metabolic diseases and acute/intense in coronavirus infection). However, the ability of the infected individuals to resolve the inflammation has not yet been explored. The heat shock response (HSR), an important anti-inflammatory pathway, is reduced in patients with metabolic diseases and, consequently, may impair inflammation resolution and control in patients with SARS-CoV-2, thus enabling its amplification and propagation through all tissues. Herein, we present a new hypothesis that aims to explain the increased severity of SARS-CoV-2 infection in people with metabolic diseases, and the possible benefits of HSR-inducing therapies to improve the inflammatory profile in these patients.

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.