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.

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.

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.

Air pollution combined with high-fat feeding aggravates metabolic and cardiovascular diseases: A dangerous, oxidative, and immune-inflammatory association.

Obesity and particulate air pollutant (PM2.5) are important risk factors for cardiometabolic diseases. PM2.5 exacerbates insulin resistance and lipid ectopic deposition in obese animals. The inorganic fraction of PM2.5, the Residual Oil Fly Ash (ROFA), is related to cardiovascular events, by enhancing the generation of reactive species, inflammatory cytokines, and leukocyte activation. However, the synergistic effects of ROFA and a high-fat diet (HFD) are still poorly described, and the studies were mainly conducted with males. AIMS: To investigate if ROFA could potentiate the cardiometabolic effects of diet-induced obesity in female rats. MATERIAL AND METHODS: Wistar female rats were divided into four groups: Control (n = 6), Polluted (n = 6), HFD (n = 6), and HFD + Polluted (n = 6). HFD and HFD + Polluted received a high-fat diet (HFD) (58.3 % as fats), whilst Control and Polluted groups received a standard diet (Nuvilab CR-1). In addition, Polluted and HFD + Polluted groups received intranasal instillation of ROFA (250 µg/50 µL), while Control and HFD groups received saline solution (50 µL) daily, five days per week. Both interventions occurred 24 weeks after the animals were euthanized. KEY FINDINGS: HFD combined with ROFA exposure impaired lipid profile challenged systemic and cardiac antioxidant defense, and presented a synergistic effect in inducing an immune-inflammatory condition. We found that the lipid profile disturbance is associated with HFD-induced hepatic, but not cardiac, deposition of triglycerides in female animals. SIGNIFICANCE: Our results support the hypothesis that ROFA exposure combined with bad feeding can exacerbate metabolic and cardiovascular diseases.

Disturbance of cellular calcium homeostasis plays a pivotal role in glyphosate-based herbicide-induced oxidative stress.

Glyphosate-based herbicides (GBHs) are the most worldwide used pesticides. The wide application of GBHs contaminates the soil and, consequently, water and food resources reaching human consumption. GBHs induce oxidative stress in non-target organisms, leading to a pro-inflammatory and pro-apoptotic cellular status, promoting tissue dysfunction and, thus, metabolic and neurobehavioral changes. This review presents evidence of oxidative damage induced by GBHs and the mechanism of cell damage and health consequences. To summarize, exposure to GBHs may induce disorders in calcium homeostasis related to the activation of ion channels. Also, alterations in pathways related to redox state regulation must have a primordial role in oxidative stress caused by GBHs.

Moderate aerobic training is safe and improves glucose intolerance induced by the association of high fat diet and air pollution.

Obesity and exposure to fine particulate matter (PM2.5) are risk factors for insulin resistance, to which physical exercise is the most powerful non-pharmacological strategy. However, public concern over whether exercise could be protective in a polluted environment exists. Therefore, evaluating the possible benefits of exercise in polluted conditions in different contexts (age, gender, and cardiometabolic health) is imperative. In this sense, muscle plays a major role in maintaining glucose homeostasis, and its oxidative status is closely affected during exercise. This study tested whether moderate aerobic training could alleviate the metabolic and oxidative impairment in the gastrocnemius induced by the combination of a high-fat diet (HFD) and PM2.5 exposure. Female mice (B6129SF2/J) received HFD (58.3% of fat) or standard diet, intranasal instillation of 20 µg residual oil fly ash (ROFA: inorganic portion of PM2.5), or saline seven times per week for 19 weeks. In the 13th week, animals were submitted to moderate training or remained sedentary. Trained animals followed a progressive protocol for 6 weeks, ending at swimming with 5% body weight of workload for 60 min, while sedentary animals remained in shallow water. Aerobic moderate training attenuated weight gain and glucose intolerance and prevented muscle and pancreatic mass loss induced by a HFD plus ROFA exposure. Interestingly, a HFD combined with ROFA enhanced the catalase antioxidant activity, regardless of physical exercise. Therefore, our study highlights that, even in polluted conditions, moderate training is the most powerful non-pharmacological treatment for obesity and insulin resistance.

Increased eHSP70-to-iHSP70 ratio in prediabetic and diabetic postmenopausal women: a biomarker of cardiometabolic risk.

Decreased estrogen levels in menopause are associated with anthropometric, metabolic, and inflammatory impairments, predisposing women to cardiometabolic risk factors such as diabetes. Menopause and type two diabetes (DM2) are marked by altered heat shock response (HSR), shown by decreased expression of the 70-kDa heat shock protein in the intracellular milieu (iHSP70). While iHSP70 plays an anti-inflammatory role, extracellular HSP70 (eHSP70) may mediate pro-inflammatory pathways and has been associated with insulin resistance in DM2. Considering the roles of these proteins according to localization, the eHSP70-to-iHSP70 ratio (H-index) has been proposed as a biomarker for HSR. We, therefore, evaluated whether this biomarker is associated with glycemic and inflammatory status in postmenopausal women. In this transversal study, 36 postmenopausal women were grouped according to fasting glycemia status as either the control group (normoglycemic, ≤ 99 mg/dL) or DM2 (prediabetic and diabetic, glycemia ≥ 100 mg/dL). DM2 group showed higher triglyceride/glucose (TyG) index and plasma atherogenic index (PAI), both of which are indicators of cardiometabolic risk. In addition, we found that the eHSP70-to-iHSP70 ratio (plasma/peripheral blood mononuclear cells-PBMC ratio) was higher in the DM2 group, compared with the control group. Furthermore, blood leukocyte and glycemia levels were positively correlated with the eHSP70-to-iHSP70 ratio in women that presented H-index values above 1.0 (a.u.). Taken together, our results highlight the eHSP70-to-iHSP70 ratio as a biomarker of altered HSR in DM2 postmenopausal women.

Adapted Murine Sepsis Score: Improving the Research in Experimental Sepsis Mouse Model.

The Murine Sepsis Score (MSS) is used to assess the severity of sepsis in rats and mice based on observational characteristics. The quantitative variables of glycemia, body weight, and temperature are predictors of severity in experimental models of sepsis. Therefore, our study sought to adapt the MSS with the same variables to indicate earlier the severity of the disease in murine models of the disease. Sepsis mice presented hypoglycemia, weight loss, and hypothermia. Therefore, these variables were included in the Adapted Murine Sepsis Score (A-MSS). The A-MASS presented 100% specificity and 87.5% sensibility been able to differentiate the early sepsis symptoms and its severity. The A-MSS allows an early and more complete diagnosis of sepsis in mice and might be considered as a procedure to improve the analysis of systemic sepsis dysfunction in murine experimental models.

Inflammation, oxidative stress and altered heat shock response in type 2 diabetes: the basis for new pharmacological and non-pharmacological interventions.

Type 2 diabetes mellitus (DM2) is a chronic disease characterised by variable degrees of insulin resistance and impaired insulin secretion. Besides, several pieces of evidence have shown that chronic inflammation, oxidative stress, and 70 kDa heat shock proteins (HSP70) are strongly involved in DM2 and its complications, and various pharmacological and non-pharmacological treatment alternatives act in these processes/molecules to modulate them and ameliorate the disease. Besides, uncontrolled hyperglycaemia is related to several complications as diabetic retinopathy, neuropathy and hepatic, renal and cardiac complications. In this review, we address discuss the involvement of different inflammatory and pro-oxidant pathways related to DM2, and we described molecular targets modulated by therapeutics currently available to treat DM2.

Chaperone duality: the role of extracellular and intracellular HSP70 as a biomarker of endothelial dysfunction in the development of atherosclerosis.

The 70-kDa heat shock proteins (HSP70) may provide relevant information about the endothelial dysfunction in cardiovascular diseases. Located in the intracellular milieu (iHSP70), they are essential chaperones that inhibit nuclear factor kappa B activation, stimulate nitric oxide production and superoxide dismutase activity, and inhibit apoptosis. However, under stressful conditions, HSP70 can be released into the extracellular medium (eHSP70) and act as an inflammatory mediator. Although studies have reported the vasoprotective role of iHSP70, the evidence regarding eHSP70 is contradictory. eHSP70 can activate NFκB and activator protein-1, thus stimulating the release of inflammatory cytokines and production of reactive oxygen species. Due to the antagonistic nature of HSP70 according to its location, the eHSP70/iHSP70 ratio (Heck index) has been proposed as a better marker of inflammatory status; however, more studies are required to confirm this hypothesis. Therefore, this review summarises studies that, together, describe the role of HSP70 in endothelial dysfunction.

Prevalence of symptoms of COVID-19 in the state of Rio Grande do Sul: results of a population-based study with 18,000 participants.

OBJECTIVE: To evaluate the prevalence of reports of symptoms of COVID-19 among individuals with and without antibodies and identify those with greater capability to predict the presence of antibodies against SARS-CoV-2. METHODS: The study uses data collected in phases 5 to 8 of Epicovid-19-RS. The presence of antibodies against SARS-CoV-2 was evaluated by a rapid test. The occurrence of cough, fever, palpitations, sore throat, difficulty breathing, changes in taste and smell, vomiting, diarrhea, body pain, shaking, and headache since March 2020 was also evaluated. Then, the capability to predict the evaluated symptoms concerning the presence of antibodies was calculated. RESULTS: A total of 18,000 individuals were interviewed and 181 had antibodies against COVID-19 in phases 5 to 8. The proportion of asymptomatic individuals was 19.9% among participants with antibodies and 49.7% among those without antibodies. All symptoms were reported more frequently by individuals with antibodies. The division of the prevalence of symptoms among individuals with antibodies by the prevalence among individuals without antibodies showed the following prevalence ratios: for changes in smell or taste (9.1), fever (4.2), tremors (3.9), breathing difficulty (3.2) and cough (2.8 times). Anosmia and fever were the symptoms with a greater capability to predict the presence of antibodies. CONCLUSION: The prevalence of symptoms was higher among individuals with antibodies against SARS-CoV-2. The proportion of asymptomatic individuals was low. Altered smell or taste and fever were the symptoms that most predict the presence of antibodies. These results can help to identify probable cases, contributing to the clinical diagnosis and screening of patients for testing and isolation guidance in positive cases, especially in scenarios of the scarcity of diagnostic COVID-19 tests.

HSP70 as a biomarker of the thin threshold between benefit and injury due to physical exercise when exposed to air pollution.

Physical exercise has acute and chronic effects on inflammatory balance, metabolic regulation, and redox status. Exercise-induced adaptations are mediated by enhanced 70-kDa heat shock protein (HSP70) levels and an improved heat shock response (HSR). Therefore, exercise could be useful against disease conditions [obesity, diabetes mellitus (DM), and exposure to atmospheric pollutants] marked by an impaired HSR. However, exercise performed by obese or diabetic subjects under pollution conditions might also be dangerous at certain intensities. Intensity correlates with an increase in HSP70 levels during physical exercise until a critical point at which the effort becomes harmful and impairs the HSR. Establishing a unique biomarker able to indicate the exercise intensity on metabolism and cellular fatigue is essential to ensure adequate and safe exercise recommendations for individuals with obesity or DM who require exercise to improve their metabolic status and live in polluted regions. In this review, we examined the available evidence supporting our hypothesis that HSP70 could serve as a biomarker for determining the optimal exercise intensity for subjects with obesity or diabetes when exposed to air pollution and establishing the fine threshold between anti-inflammatory and pro-inflammatory exercise effects.

Oxidative and Cellular Stress Markers in Postmenopause Women with Diabetes: The Impact of Years of Menopause.

Women live approximately one-third of their lives in postmenopause. Among postmenopausal women, type 2 diabetes mellitus (DM2) is one of the most prevalent chronic diseases. These conditions promote alterations in the oxidative, metabolic, and immune-inflammatory profiles marked by higher extracellular 72 kDa-heat shock protein (eHSP72). Here, we investigated whether the time of menopause is associated with oxidative cellular stress marker levels in postmenopausal women with DM2. Sixty-four women were recruited (56.7 ± 12.6 years old) in the pre- (n = 22) and postmenopause (n = 42) period, with (n = 19) or without DM2 (n = 45), and a fasting blood collection was made for the evaluation of metabolic, oxidative, and inflammatory markers. We found that menopause and DM2 influenced metabolic and oxidative parameters and presented synergistic effects on the plasma lipoperoxidation levels. Also, postmenopausal women had the highest eHSP72 concentration levels associated with the years in postmenopause. We conclude that the time of menopause impacts the markers of cellular stress and increases the risk of oxidative stress, mainly when it is associated with DM2.

Effects of aerobic and resistance exercise training associated with carnosine precursor supplementation on maximal strength and V̇O2max in rats with heart failure.

BACKGROUND: Combined exercise training (CET) has been associated with positive responses in the clinical status of patients with heart failure (HF). Other nonpharmacological tools, such as amino acid supplementation, may further enhance its adaptation. The aim was to test whether CET associated with supplementing carnosine precursors could present better responses in the functional capacity and biochemical variables of rats with HF. METHODS: Twenty-one male Wistar rats were subjected to myocardial infarction and allocated to three groups: sedentary (SED, n = 7), CET supplemented with placebo (CETP, n = 7), and CET with HF supplemented with ß-alanine and L-histidine (CETS, n = 7). The trained animals were submitted to a strength protocol three times per week. Aerobic training was conducted twice per week. The supplemented group received ß-alanine and L-histidine orally (250 mg/kg per day). RESULTS: Maximum oxygen uptake, running distance, time to exhaustion and maximum strength were higher in the CET-P group than that in the SED group and even higher in the CET-S group than that in the CET-P group (P < 0.01). CET-S showed lower oxidative stress and inflammation markers and higher heat shock protein 72 kDa content and mRNA expression for calcium transporters in the skeletal muscle compared to SED. CONCLUSION: CET together with ß-alanine and L-histidine supplementation in rats with HF can elicit adaptations in both maximum oxygen uptake, running distance, time to exhaustion, maximum strength, oxidative stress, inflammation and mRNA expression. Carnosine may influence beneficial adjustments in the cell stress response in the skeletal muscle and upregulate the mRNA expression of calcium transporters.

Insufficient social distancing may contribute to COVID-19 outbreak: The case of Ijuí city in Brazil.

The coronavirus disease that emerged in 2019 (COVID-19) is highly contagious and has given way to a global pandemic. A present COVID-19 has high transmission rates worldwide, including in small Brazilian cities such as Ijuí. Located in the northwest part of the state of Rio Grande do Sul (RS) and with a population of 83,475, Ijuí was selected as the site of a population-based survey involving 2,222 subjects, from April to June 2020. Subjects were tested for the presence of antibodies against coronavirus (SARS-CoV-2) and answered questions regarding social distance adherence (SDA), daily preventive routines (DPR), comorbidities, and sociodemographic characteristics. In parallel, the local government registered the official COVID-19 cases in Ijuí, as well as the mobile social distancing index (MSDI). In this study, we demonstrate that there was a decrease in the levels of SDA, DPR and MSDI before the beginning of COVID-19 community transmission in Ijuí. Furthermore, we provide predictions for the number of COVID-19 cases, hospitalizations, and deaths in the city. We conclude that insufficient social distancing, as evidenced by different methods, may be related to the rapid increase of COVID-19 cases in Ijuí. Our study predicts an approaching outbreak of COVID-19 in Ijuí through community spread, which could be avoided or attenuated with increased levels of social distancing among the population.

Ovariectomy reduces the cardiac cytoprotection in rats exposed to particulate air pollutant.

Fine particulate matter (PM2.5) has been considered a risk factor for cardiovascular diseases by inducing an oxidative and inflammatory phenotype. Besides, the reduction of 17ß-estradiol (E2) levels during menopause is a natural risk for cardiovascular outcomes. During the E2 downfall, there is a high requirement of the 70-kDa heat shock proteins (HSP70), which present essential antioxidant, anti-inflammatory, and anti-senescence roles. We investigated if the ovariectomy, an animal model for menopause, could induce additional effects in cardiac health by impairing oxidative and heat shock response parameters of female rats chronically exposed to residual oil fly ash (ROFA; an inorganic fraction of PM2.5). Thus, ROFA was obtained from São Paulo (Brazil) and solubilized it in saline. Further, female Wistar rats were exposed to 50 µL of saline (control group) or ROFA solution (250 µg) (polluted) by intranasal instillation, 5 days/week, 12 weeks. At the 12th week, animals were subdivided into four groups (n = 6 p/group): control, OVX, polluted, and polluted + OVX. Control and polluted were submitted to false surgery, while OVX and polluted + OVX were ovariectomized. ROFA or saline exposure continued for 12 weeks. Ovariectomy reduced the cardiac catalase activity and iHSP70 expression in female rats exposed to ROFA. Neither plasma eHSP72 levels nor H-index (eHSP72 to cardiac iHSP70 ratio) was affected. In conclusion, ovariectomy reduces the cardiac cytoprotection and antioxidant defense, and enhances the susceptibility to premature cellular senescence in rats exposed to ROFA.