Consensus of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy (ABHH) and the Brazilian Ministry of Health - General management of blood and blood products on the tests necessary for the release of exceptional medicines for sickle cell disease.

To date, hydroxyurea is the only effective and safe drug that significantly reduces morbidity and mortality of individuals with Sickle cell disease. Twenty years of real-life experience has demonstrated that hydroxyurea reduces pain attacks, vaso-occlusive events, including acute chest syndrome, the number and duration of hospitalizations and the need for transfusion. The therapeutic success of hydroxyurea is directly linked to access to the drug, the dose used and adherence to treatment which, in part, is correlated to the availability of hydroxyurea. This consensus aims to reduce the number of mandatory exams needed to access the drug, prioritizing the requesting physician's report, without affecting patient safety.

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.

HPOSS: A hierarchical portfolio optimization stacking strategy to reduce the generalization error of ensembles of models.

Surrogate models are frequently used to replace costly engineering simulations. A single surrogate is frequently chosen based on previous experience or by fitting multiple surrogates and selecting one based on mean cross-validation errors. A novel stacking strategy will be presented in this paper. This new strategy results from reinterpreting the model selection process based on the generalization error. For the first time, this problem is proposed to be translated into a well-studied financial problem: portfolio management and optimization. In short, it is demonstrated that the individual residues calculated by leave-one-out procedures are samples from a given random variable ϵi, whose second non-central moment is the i-th model's generalization error. Thus, a stacking methodology based solely on evaluating the behavior of the linear combination of the random variables ϵi is proposed. At first, several surrogate models are calibrated. The Directed Bubble Hierarchical Tree (DBHT) clustering algorithm is then used to determine which models are worth stacking. The stacking weights can be calculated using any financial approach to the portfolio optimization problem. This alternative understanding of the problem enables practitioners to use established financial methodologies to calculate the models' weights, significantly improving the ensemble of models' out-of-sample performance. A study case is carried out to demonstrate the applicability of the new methodology. Overall, a total of 124 models were trained using a specific dataset: 40 Machine Learning models and 84 Polynomial Chaos Expansion models (which considered 3 types of base random variables, 7 least square algorithms for fitting the up to fourth order expansion's coefficients). Among those, 99 models could be fitted without convergence and other numerical issues. The DBHT algorithm with Pearson correlation distance and generalization error similarity was able to select a subgroup of 23 models from the 99 fitted ones, implying a reduction of about 77% in the total number of models, representing a good filtering scheme which still preserves diversity. Finally, it has been demonstrated that the weights obtained by building a Hierarchical Risk Parity (HPR) portfolio perform better for various input random variables, indicating better out-of-sample performance. In this way, an economic stacking strategy has demonstrated its worth in improving the out-of-sample capabilities of stacked models, which illustrates how the new understanding of model stacking methodologies may be useful.

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.

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.

Development and In Vitro Validation of Antibacterial Paints Containing Chloroxylenol and Terpineol.

The establishment of self-disinfecting surfaces is an important method to avoid surface contamination. Recently, paints with antimicrobial properties have been developed to be applied on different surfaces, avoiding contamination with pathogens. In this work, self-disinfecting paints containing Chloroxylenol (CLX), Terpineol (TRP), and a mixture of both substances were developed. The goal was to evaluate and validate these paints using international standards for eventual commercialization and application in scenarios where surface contamination represents a problem. The paints were challenged with five different bacteria, Gram-positive and Gram-negative, before and after a scrub resistance test, where the long-term efficacy of the paints was evaluated. The antibacterial activity assessment was performed following ISO 22196 and JIS Z2801. In general, the paints showed very promising results, demonstrating their antibacterial activity, before and after scrub resistance test. The paint incorporating the mixture of CLX and TRP (CLX+TRP) stood out by revealing consistent results of antibacterial activity both before and after the scrub resistance test for most of the tested bacteria. The cytotoxicity of the developed paints was assessed in vitro by performing tests by direct contact with a human skin cell line, HaCaT, and testes on extracts with HaCaT and a pulmonary cell line, A549. The methodologies for cytotoxicity assessment were developed based in ISO 10993. For genotoxicity assessment, alkaline comet assay was conducted on both cell lines. The cytotoxicity assessment revealed promising results with the paints, demonstrating values of cellular viability above 70% and values of lactate dehydrogenase (LDH) leakage below 30%. The genotoxic assessment also revealed acceptable values of primary DNA damage for the developed antibacterial paints. In general, the selected methodologies presented good potential to be applied in the validation of both efficacy and safety of the antimicrobial paints, aiming to be applied in real scenarios.

Acid-Catalyzed Liquefaction of Biomasses from Poplar Clones for Short Rotation Coppice Cultivations.

Liquefaction of biomass delivers a liquid bio-oil with relevant chemical and energetic applications. In this study we coupled it with short rotation coppice (SRC) intensively managed poplar cultivations aimed at biomass production while safeguarding environmental principles of soil quality and biodiversity. We carried out acid-catalyzed liquefaction, at 160 °C and atmospheric pressure, with eight poplar clones from SRC cultivations. The bio-oil yields were high, ranging between 70.7 and 81.5%. Average gains of bio-oil, by comparison of raw biomasses, in elementary carbon and hydrogen and high heating, were 25.6, 67, and 74%, respectively. Loss of oxygen and O/C ratios averaged 38 and 51%, respectively. Amounts of elementary carbon, oxygen, and hydrogen in bio-oil were 65, 26, and 8.7%, and HHV averaged 30.5 MJkg-1. Correlation analysis showed the interrelation between elementary carbon with HHV in bio-oil or with oxygen loss. Overall, from 55 correlations, 21 significant and high correlations among a set of 11 variables were found. Among the most relevant ones, the percentage of elementary carbon presented five significant correlations with the percentage of O (-0.980), percentage of C gain (0.902), percentage of O loss (0.973), HHV gain (0.917), and O/C loss (0.943). The amount of carbon is directly correlated with the amount of oxygen, conversely, the decrease in oxygen content increases the elementary carbon and hydrogen concentration, which leads to an improvement in HHV. HHV gain showed a strong positive dependence on the percentage of C (0.917) and percentage of C gain (0.943), while the elementary oxygen (-0.885) and its percentage of O loss (0.978) adversely affect the HHV gain. Consequently, the O/C loss (0.970) increases the HHV positively. van Krevelen's analysis indicated that bio-oils are chemically compatible with liquid fossil fuels. FTIR-ATR evidenced the presence of derivatives of depolymerization of lignin and cellulose in raw biomasses in bio-oil. TGA/DTG confirmed the bio-oil burning aptitude by the high average 53% mass loss of volatiles associated with lowered peaking decomposition temperatures by 100 °C than raw biomasses. Overall, this research shows the potential of bio-oil from liquefaction of SRC biomasses for the contribution of renewable energy and chemical deliverables, and thereby, to a greener global economy.

A Brief Evaluation of Antioxidants, Antistatics, and Plasticizers Additives from Natural Sources for Polymers Formulation.

The circular economy plays an important role in the preparation and recycling of polymers. Research groups in different fields, such as materials science, pharmaceutical and engineering, have focused on building sustainable polymers to minimize the release of toxic products. Recent studies focused on the circular economy have suggested developing new polymeric materials based on renewable and sustainable sources, such as using biomass waste to obtain raw materials to prepare new functional bio-additives. This review presents some of the main characteristics of common polymer additives, such as antioxidants, antistatic agents and plasticizers, and recent research in developing bio-alternatives. Examples of these alternatives include the use of polysaccharides from agro-industrial waste streams that can be used as antioxidants, and chitosan which can be used as an antistatic agent.

Self-Disinfecting Paints with the Natural Antimicrobial Substances: Colophony and Curcumin.

The risk of infection arising from indirect sources-namely, contaminated surfaces-has been proved, particularly in healthcare facilities. In the attempt to minimize this problem, innumerable research projects involving the development of surfaces with self-disinfecting properties are being conducted. In this work, wall-paints with self-disinfecting properties were developed with the scope of being applied in environments prone to contamination, such as those at healthcare settings. Our approach was to develop new paint formulations containing two natural plant-based products with known antimicrobial activity-colophony (CLF) and curcumin (CUR). The natural substances were separately incorporated on a commercial paint and their antibacterial activity was evaluated with several bacterial species following ISO 22196. To assess the paints' safety, cytotoxicity tests were performed on HaCaT and A549 cell lines, using tests on extracts and direct contact tests, as suggested by the standardized protocol ISO 10993. In general, both paints containing CLF and CUR were able to reduce the bacterial growth after 24 h, compared with the control, the commercial unmodified paint. Colophony was even able to reduce the number of culturable bacteria by over 2 log for Staphylococcus aureus, Escherichia coli, and Bacillus cereus. Regarding the cytotoxicity tests performed (WST-1, NRU, and LDH), both formulations revealed promising results regardless of the methodology used.

Auto-Disinfectant Acrylic Paints Functionalised with Triclosan and Isoborneol-Antibacterial Assessment.

Environmental surface contamination with microorganisms is a serious concern worldwide. Triclosan and isoborneol present good antimicrobial activity. Their immobilisation to paint substrates allows for development of a material that stays effective over a longer time. In this work, we disclosed the preliminary studies to evaluate the antimicrobial activity of the active molecule after being functionalised with isocyanates for further immobilisation on the paint substrate. Overall, the newly developed non-release antimicrobial coating provides an effective way of preventing the spread of diseases and has been proven to inhibit bacterial growth and with a considerable antimicrobial activity towards S. aureus, E. coli, and K. variicola at the tested concentrations.

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.

A-family anti-inflammatory cyclopentenone prostaglandins: A novel class of non-statin inhibitors of HMG-CoA reductase.

Disruption of the intracellular lipid balance leading to cholesterol accumulation is one of the features of cells that participate in the development of atherosclerotic lesions. Evidence form our laboratory indicates that anti-inflammatory cyclopentenone prostaglandins (cyPGs) of A- and J-family deviate lipid metabolism from the synthesis of cholesterol and cholesteryl esters to the synthesis of phospholipids in foam-cell macrophages. cyPGs possessing an α,ß-unsaturated cyclopentane ring are highly electrophilic substances able to promptly react with reactive cysteines of intracellular molecules through Michael addition. On the other hand, HMG-CoA reductase (HMGCR), the enzyme responsible for the rate-limiting step in cholesterol biosynthesis, presents critically reactive cysteines at the entry of catalytic domain, particularly Cys561, that could be target of cyPG inhibition. In the present study, we showed that cyPGs (but not other non-α,ß-unsaturated PGs) physically interact with HMGCR, in a dithiothreitol- and ß-mercaptoethanol-sensitive way, and block the activity of the catalytic subunit of the enzyme (IC50 for PGA2 = 0.17 µM). PGA2 inhibits HMGCR activity in cultured rat and human macrophages/macrophage-foam cells and leads to enhanced expression of HMGCR protein, as observed with statins. In cell culture models, PGA2 effectively inhibits the reductase at non-toxic doses (e.g., 1 µM) that block cell proliferation thus suggesting that part of the well-known antiproliferative effect of PGA2 may be due to its ability of blocking HMGCR activity, as cells cannot proliferate without a robust cholesterogenesis. Therefore, besides the powerfully anti-inflammatory and antiproliferative effects, the anticholesterogenic effects of PGA2 should be exploited in atherosclerosis therapeutics.

Heat shock response in noise-induced hearing loss: effects of alanyl-glutamine dipeptide supplementation on heat shock proteins status / Resposta de choque térmico em perda auditiva induzida por ruído: efeitos da suplementação com dipeptídeos de alanil-glutamina sobre o estado das proteínas de choque térmico

Abstract Introduction: The 72 kDa heat shock protein, HSP72, located intracellularly provides cochlear cytoprotective and anti-inflammatory roles in the inner ear during stressful noise challenges. The expression of intracellular HSP72 (iHSP72) can be potentiated by alanyl-glutamine dipeptide supplementation. Conversely, these proteins act as pro-inflammatory signals in the extracellular milieu (eHSP72). Objective: We explore whether noise-induced hearing loss promotes both intracellular and extracellular HSP72 heat shock response alterations, and if alanyl-glutamine dipeptide supplementation could modify heat shock response and prevent hearing loss. Methods: Female 90 day-old Wistar rats (n = 32) were randomly divided into four groups: control, noise-induced hearing loss, treated with alanyl-glutamine dipeptide and noise-induced hearing loss plus alanyl-glutamine dipeptide. Auditory brainstem responses were evaluated before noise exposure (124 dB SPL for 2 h) and 14 days after. Cochlea, nuclear cochlear complex and plasma samples were collected for the measurement of intracellular HSP72 and extracellular HSP72 by a high-sensitivity ELISA kit. Results: We found an increase in both iHSP72 and eHSP72 levels in the noise-induced hearing loss group, which was alleviated by alanyl-glutamine dipeptide treatment. Furthermore, H-index of HSP72 (plasma/cochlea eHSP72/iHSP72 ratio) was increased in the noise-induced hearing loss group, but prevented by alanyl-glutamine dipeptide treatment, although alanyl-glutamine dipeptide had no effect on auditory threshold. Conclusions: Our data indicates that cochlear damage induced by noise exposure is accompanied by local and systemic heat shock response markers. Also, alanyl-glutamine reduced stress markers even though it had no effect on noise-induced hearing loss. Finally, plasma levels of 72 kDa heat shock proteins can be used as a biomarker of auditory stress after noise exposure.

Resumo Introdução: A proteína de choque térmico de 72 kDa, HSP72 localizada intracelularmente, tem papéis citoprotetores e anti-inflamatórios cocleares na orelha interna durante situações de ruído estressantes. A expressão dessa proteína pode ser potencializada pela suplementação com dipeptídeo de alanil-glutamina. Por outro lado, essas proteínas atuam como sinais pró-inflamatórios no meio extracelular. Objetivo: Investigar se a perda auditiva induzida por ruído promove alterações tanto das proteínas HSP72 intracelulares quanto extracelulares na resposta de choque térmico e se a suplementação com alanil-glutamina pode modificar a resposta de choque térmico e evitar a perda auditiva. Método: Ratos Wistar fêmeas, com 90 dias de idade (n = 32), foram divididos aleatoriamente em quatro grupos: controle, perda auditiva induzida por ruído, tratados com alanil-glutamina e perda auditiva induzida por ruído mais alanil-glutamina. Os potenciais evocados auditivos do tronco encefálico foram avaliados antes da exposição ao ruído (124 dB NPS por 2 h) e 14 dias após. A cóclea, o complexo nuclear coclear e amostras de plasma foram coletadas para mensuração de HSP72 intra e extracelular com um kit Elisa de alta sensibilidade. Resultados: Houve um aumento nos níveis de HSP72 intra e extracelular no grupo perda auditiva induzida por ruído, que foi minimizado pelo tratamento com alanil-glutamina. Além disso, o índice H das HSP72 (razão HSP72 extracelular/HSP72intracelular plasma/cóclea) aumentou no grupo perda auditiva induzida por ruído, mas foi limitado pelo tratamento com alanil-glutamina, embora o alanil-glutamina não tenha efeito no limiar auditivo. Conclusões: Nossos dados indicam que o dano coclear induzido pela exposição ao ruído é acompanhado por marcadores da resposta de choque térmico locais e sistêmicos. Além disso, alanil-glutamina reduziu os marcadores de estresse, mesmo não tendo efeito sobre a perda auditiva induzida por ruído. Finalmente, os níveis plasmáticos de proteínas de choque térmico de 72 kDa podem ser usados como biomarcador do estresse auditivo, após a exposição ao ruído.

Numerical Analysis of Bowing Phenomenon Due to Thermal Stresses in Marble Slabs.

Bowing is a pathology known by the deformation experienced in some external covering systems in ornamental stones, especially in marble, and thermal action is one of the key factors that lead to this degradation. Previous studies presented remarkable contributions about the mechanical behavior of bowing but they were based on classical beam's theory and improper assumptions might mislead the evaluation of internal stresses. This study proposes to evaluate internal stresses in bowing due to thermal loading considering the true deformed shape in continuum media. Finite displacement concepts are proposed to calculate stress-strain relationship and comparison with linear elastic theory is also addressed. Internal stresses not predictable in the Euler-Bernoulli beam were found in parametric analyses. Moreover, the numerical analysis accomplished in this paper indicates that transient heat flux should induce higher stresses than just considering higher gradients of temperature in steady flux which could explain the larger decohesion through width in bowing tests.

Suppressed anti-inflammatory heat shock response in high-risk COVID-19 patients: lessons from basic research (inclusive bats), light on conceivable therapies.

The major risk factors to fatal outcome in COVID-19 patients, i.e., elderliness and pre-existing metabolic and cardiovascular diseases (CVD), share in common the characteristic of being chronic degenerative diseases of inflammatory nature associated with defective heat shock response (HSR). The molecular components of the HSR, the principal metabolic pathway leading to the physiological resolution of inflammation, is an anti-inflammatory biochemical pathway that involves molecular chaperones of the heat shock protein (HSP) family during homeostasis-threatening stressful situations (e.g., thermal, oxidative and metabolic stresses). The entry of SARS coronaviruses in target cells, on the other hand, aggravates the already-jeopardized HSR of this specific group of patients. In addition, cellular counterattack against virus involves interferon (IFN)-mediated inflammatory responses. Therefore, individuals with impaired HSR cannot resolve virus-induced inflammatory burst physiologically, being susceptible to exacerbated forms of inflammation, which leads to a fatal "cytokine storm". Interestingly, some species of bats that are natural reservoirs of zoonotic viruses, including SARS-CoV-2, possess an IFN-based antiviral inflammatory response perpetually activated but do not show any sign of disease or cytokine storm. This is possible because bats present a constitutive HSR that is by far (hundreds of times) more intense and rapid than that of human, being associated with a high core temperature. Similarly in humans, fever is a physiological inducer of HSR while antipyretics, which block the initial phase of inflammation, impair the resolution phase of inflammation through the HSR. These findings offer a rationale for the reevaluation of patient care and fever reduction in SARS, including COVID-19.

Chronic heat treatment positively impacts metabolic profile of ovariectomized rats: association with heat shock response pathways.

Low estrogen levels may predispose women to increased bodyweight and dyslipidemia. Previous studies from our laboratory suggest an involvement of depressed heat shock response (HSR) in this scenario because estrogen potently stimulates HSR. As heat treatment induces the expression of the anti-inflammatory heat shock proteins of the 70-kDa family (HSP70) and its accompanying HSR, we aimed to investigate whether chronic heat treatment promotes beneficial effects on biometric, lipid profile, oxidative stress, and HSR in ovariectomized rats. Wistar adult female rats (n = 32) were divided into four groups: control (C, n = 7), ovariectomized (OVX, n = 9), heat-treated (HT, n = 9), and heat-treated ovariectomized rats (OVX+HT, n = 7). HT and OVX+HT rats were anesthetized and submitted to heat treatment (once a week for 12 weeks) in a water bath (41 °C) to increase rats' rectal temperature up to 41 °C for 15 min, while C and OVX animals were submitted to a 36 °C water bath. HT attenuated the weight gain induced by OVX and increased HDL cholesterol and triglyceride serum levels. Also, OVX rats showed increased total cholesterol and LDL cholesterol levels that were not influenced by HT. Interestingly, it was found that an overall trend for HT to decrease tissue catalase and superoxide dismutase antioxidant activities was paralleled by a decrease in malondialdehyde levels (indicative of lower lipoperoxidation), especially in the skeletal muscle. Surprisingly, OVX was not able to depress intracellular HSP70 expression in the skeletal muscle, as expected, and this remained unchanged with HT. However, chronic HT did enhance intracellular HSP70 contents in white adipose tissue of OVX animals. As both glucose and insulin tolerance tests were not affected by OVX, which was not modified by HT, we suppose that estrogen absence alone is not sufficient to determine a state of insulin resistance associated with low intramuscular HSP70 content.

Heat shock response in noise-induced hearing loss: effects of alanyl-glutamine dipeptide supplementation on heat shock proteins status.

INTRODUCTION: The 72kDa heat shock protein, HSP72, located intracellularly provides cochlear cytoprotective and anti-inflammatory roles in the inner ear during stressful noise challenges. The expression of intracellular HSP72 (iHSP72) can be potentiated by alanyl-glutamine dipeptide supplementation. Conversely, these proteins act as pro-inflammatory signals in the extracellular milieu (eHSP72). OBJECTIVE: We explore whether noise-induced hearing loss promotes both intracellular and extracellular HSP72 heat shock response alterations, and if alanyl-glutamine dipeptide supplementation could modify heat shock response and prevent hearing loss. METHODS: Female 90 day-old Wistar rats (n=32) were randomly divided into four groups: control, noise-induced hearing loss, treated with alanyl-glutamine dipeptide and noise-induced hearing loss plus alanyl-glutamine dipeptide. Auditory brainstem responses were evaluated before noise exposure (124dB SPL for 2h) and 14days after. Cochlea, nuclear cochlear complex and plasma samples were collected for the measurement of intracellular HSP72 and extracellular HSP72 by a high-sensitivity ELISA kit. RESULTS: We found an increase in both iHSP72 and eHSP72 levels in the noise-induced hearing loss group, which was alleviated by alanyl-glutamine dipeptide treatment. Furthermore, H-index of HSP72 (plasma/cochlea eHSP72/iHSP72 ratio) was increased in the noise-induced hearing loss group, but prevented by alanyl-glutamine dipeptide treatment, although alanyl-glutamine dipeptide had no effect on auditory threshold. CONCLUSIONS: Our data indicates that cochlear damage induced by noise exposure is accompanied by local and systemic heat shock response markers. Also, alanyl-glutamine reduced stress markers even though it had no effect on noise-induced hearing loss. Finally, plasma levels of 72kDa heat shock proteins can be used as a biomarker of auditory stress after noise exposure.