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.

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.

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.

Ovariectomy enhances female rats' susceptibility to metabolic, oxidative, and heat shock response effects induced by a high-fat diet and fine particulate matter.

Obesity and exposure to fine particulate matter (air pollutant PM2.5) are important risk factors for metabolic and cardiovascular diseases. They are also related to early menopause. The reduction of 17ß-estradiol (E2) levels during female climacteric, marked by menopause, is of significant concern because of its imminent influence on metabolism, redox and inflammatory status. This complex homeostasis-threatening scenario may induce a heat shock response (HSR) in cells, enhancing the expression of the 70 kDa heat shock protein (HSP70). A failure in this mechanism could predispose women to cardiovascular diseases. In this study, we evaluated if the climacteric could represent an additional risk among obese rats exposed to PM2.5 by worsening lipid, oxidative, and inflammatory parameters and HSP70 in cardiac tissue. We induced obesity in female Wistar rats using a high-fat diet (HFD) (58.3% as fats) and exposed them to 50 µL of saline 0.9% (control, n = 15) or 250 µg residual oil fly ash (ROFA, the inorganic portion of PM2.5) (polluted, n = 15) by intranasal instillation, 5 days/w for 12 weeks. At the 12th week, we subdivided these animals into four groups: control (n = 6), OVX (n = 9), polluted (n = 6) and polluted + OVX (n = 9). OVX and polluted + OVX were submitted to a bilateral ovariectomy (OVX), a surgical model for menopause, while control and polluted received a false surgery (sham). ROFA exposure and HFD consumption were continued for 12 additional weeks, after which the animals were euthanized. ROFA enhanced the susceptibility to ovariectomy-induced dyslipidemia, while ovariectomy predisposed female rats to the ROFA-induced decrease of cardiac iHSP70 expression. Ovariectomy also decreased the IL-6 levels and IL-6/IL-10 in obese animals, reinforcing a metabolic impairment and a failure to respond to unfavorable conditions. Our results support the hypothesis that obese ovariectomized animals are predisposed to a metabolic worsening under polluted conditions and are at higher risk of cardiovascular diseases.

Prevalence of symptoms of COVID-19 in the state of Rio Grande do Sul: results of a population-based study with 18,000 participants / Prevalência de sintomas característicos de covid-19 no Rio Grande do Sul: resultados de um estudo de base populacional com 18 mil participantes

ABSTRACT 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.

RESUMO OBJETIVO Avaliar prevalência de relato de sintomas característicos de covid-19 entre indivíduos com e sem anticorpos e identificar aqueles com maior capacidade de predição da presença de anticorpos contra o SARS-CoV-2. MÉTODOS O presente estudo usa dados coletados nas fases de 5 a 8 do Epicovid-19-RS. A presença de anticorpos contra o SARS-CoV-2 foi avaliada por um teste rápido. Avaliou-se também a ocorrência dos sintomas tosse, febre, palpitações, dor de garganta, dificuldade para respirar, alterações no paladar e olfato, vômito, diarreia, dor no corpo, tremedeira e dor de cabeça, desde março de 2020. Então, calculou-se a capacidade de predição dos sintomas avaliados em relação a presença de anticorpos. RESULTADOS Nas fases de 5 a 8, 18 mil indivíduos foram entrevistados e 181 apresentaram anticorpos contra covid-19. A proporção de indivíduos assintomáticos foi de 19,9% entre participantes com anticorpos e 49,7% entre aqueles sem anticorpos. Todos os sintomas foram relatados com maior frequência por indivíduos com presença de anticorpos. A divisão da prevalência de sintomas entre indivíduos com anticorpos pela prevalência entre indivíduos sem anticorpos evidenciou as seguintes razões de prevalência: para alterações de olfato ou paladar (9,1), febre (4,2), tremedeira (3,9), dificuldade respiratória (3,2) e tosse (2,8 vezes). Anosmia e febre foram os sintomas com maior capacidade de predizer a presença de anticorpos. CONCLUSÃO A prevalência de sintomas foi maior entre indivíduos com anticorpos contra SARS-CoV-2. A proporção de indivíduos assintomáticos foi baixa. Alteração de olfato ou paladar e febre foram os sintomas que mais predizem a presença de anticorpos. Esses resultados podem auxiliar a identificação de casos prováveis, contribuindo para o diagnóstico clínico e triagem de pacientes para testagem e orientação de isolamento em casos positivos, especialmente em cenários de escassez de testes diagnósticos de covid-19.

Estresse oxidativo e diminuição de HSP70 tecidual envolvidos na gênese da sepse: HSP70 como alvo terapêutico / Oxidative stress and decreased tissue HSP70 are involved in the genesis of sepsis: HSP70 as a therapeutic target

RESUMO A sepse é uma infecção sistêmica que acarreta disfunção múltipla dos órgãos. A HSP70 é uma proteína responsiva ao estresse celular, assim como o estresse oxidativo. Esta revisão da literatura buscou investigar a HSP70 e o estresse oxidativo quanto à fisiopatologia da sepse e ao papel da HSP70 como possível alvo terapêutico. A HSP70 exerce efeito protetor quando localizada na célula (iHSP70), e sua diminuição, assim como seu aumento no ambiente extracelular (eHSP70) e o estresse oxidativo, é um biomarcador de gravidade na sepse. Além disso, terapias que aumentam a iHSP70 ou o próprio tratamento com HSP70 promovem a melhora na sepse.

Abstract Sepsis is a systemic infection that causes multiple organ dysfunction. HSP70 is a protein responsive to cell stress, in particular oxidative stress. Therefore, this literature review sought to investigate the roles of HSP70 and oxidative stress in the pathophysiology of sepsis and the possibility of HSP70 as a therapeutic target. HSP70 exerts a protective effect when located in cells (iHSP70), and its decrease, as well as its increase in the extracellular environment (eHSP70), under oxidative stress is a biomarker of sepsis severity. In addition, therapies that increase iHSP70 and treatment with HSP70 promote sepsis improvement.

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.

Cardiorespiratory responses to isokinetic exercise in patients with coronary artery disease / Respostas cardiorrespiratórias ao exercício isocinético em pacientes com doença arterial coronariana / Respuestas cardiorrespiratorias al ejercicio isocinético en pacientes con enfermedad arterial coronaria

ABSTRACT Introduction Exercise training using an isokinetic dynamometer is an alternative for improving muscle strength in patients with coronary artery disease (CAD). Few studies have shown metabolic and cardiorespiratory responses to submaximal isokinetic exercises in patients in cardiac rehabilitation programs. Objective To describe cardiorespiratory responses at two intensities of isokinetic exercise. Additionally, we compared the cardiorespiratory responses of isokinetic exercise with data from the incremental cardiopulmonary exercise test (CPET). Methods Eight individuals with CAD (61.7 ± 6.6 years) performed the following tests: 1) CPET on a treadmill; 2) Peak torque test (five repetitions) and fatigue resistance test (20 repetitions) of knee flexion-extension at angular speeds of 120°/s and 180°/s; 3) Two sets of 20 repetitions were performed at 30-40% (low-intensity, LI) and 50-60% (moderate-intensity, MI) of peak torque at angular speeds of 120°/s and 180°/s, using an isokinetic dynamometer. During the exercises, the individuals were connected to an expired gases analyzer with simultaneous monitoring of the electrocardiogram trace, heart rate (HR), oxygen consumption (VO2), carbon dioxide production, and minute ventilation (VE). The differences (∆) between the peak measurements during exercises and the baseline values were calculated. Results Both LI and MI produced cardiorespiratory responses below the anaerobic threshold (82.8 ± 8.1% of HRmax and 74.4 ± 9.6% of VO2peak) compared to the CPET data ( P < 0.01). MI showed higher ∆ HR (9.8 ± 5.5 vs. 6.3 ± 4.6 bpm; P = 0.01), ∆ rate pressure product (3015 ± 2286 vs. 1957 ± 1932 mmHg·bpm; P = 0.01), and ∆VE (10.2 ± 6.2 vs. 6.9 ± 7 L·min-1; P = 0.03) than LI at the angular velocity of 180°/s. Conclusion These results suggest that this isokinetic exercise protocol may be used as a strategy for cardiac rehabilitation programs in patients with CAD. Level of evidence IV; Case series.

RESUMO Introdução O treinamento no dinamômetro isocinético é uma alternativa para aumentar a força muscular em pacientes com doença arterial coronariana (DAC). Poucos estudos têm investigado as respostas metabólicas e cardiorrespiratórias do exercício isocinético submáximo em pacientes de um programa de reabilitação cardíaca. Objetivos Descrever as respostas cardiorrespiratórias em duas intensidades de exercícios isocinéticos. Adicionalmente, comparamos as respostas cardiorrespiratórias do exercício isocinético com os dados de um teste de exercício cardiopulmonar (TECP) incremental. Métodos Oito indivíduos com DAC (61,7± 6,6 anos) realizaram os seguintes testes: 1) TECP em esteira ergométrica; 2) Teste de pico de torque (cinco repetições) e resistência à fadiga (20 repetições) de flexão-extensão de joelho nas velocidades angulares de 120º /s e 180º/s; 3) Duas séries de 20 repetições em 30% a 40% (baixa intensidade, BI) e 50% a 60% (moderada intensidade, MI) do pico de torque nas velocidades angulares de 120 o /s e 180º/s no dinamômetro isocinético. Durante os exercícios, os indivíduos foram conectados ao analisador de gases expirados com monitoração simultânea do traçado eletrocardiográfico, frequência cardíaca (FC), consumo de oxigênio (VO2), produção de dióxido de carbono e ventilação minuto (VE). Foi calculada a diferença (∆) entre a medida pico durante os exercícios e os valores basais. Resultados Tanto a BI quanto a MI produziram respostas cardiorrespiratórias abaixo do limiar anaeróbico (82,8 ± 8,1% da FCmáx e 74,4 ± 9,6% do VO2pico) comparadas com os dados do TECP (P < 0,01). A MI mostrou valores maiores de ∆ FC (9,8 ± 5,5 vs. 6,3 ± 4,6 bpm; P = 0,01), ∆ duplo produto frequência-pressão (3.015 ± 2.286 vs. 1.957 ± 1.932 mmHg.bpm; P = 0,01) e ∆VE (10,2 ± 6,2 vs. 6,9 ± 7 L.min-1; P = 0,03) quando comparado com a BI na velocidade angular de 180º/s. Conclusão Esses resultados sugerem que este protocolo de exercícios isocinéticos pode ser usado como estratégia para programas de reabilitação cardíaca em pacientes com DAC. Nível de evidência IV; Série de casos.

RESUMEN Introducción El entrenamiento en el dinamómetro isocinético es una alternativa para aumentar la fuerza muscular en pacientes con enfermedad arterial coronaria (EAC). Pocos estudios han investigado las respuestas metabólicas y cardiorrespiratorias del ejercicio isocinético submáximo en pacientes de un programa de rehabilitación cardíaca. Objetivos Describir las respuestas cardiorrespiratorias en dos intensidades de ejercicios isocinéticos. Además, comparamos las respuestas cardiorrespiratorias del ejercicio isocinético con los datos de un test de ejercicio cardiopulmonar (TECP) incremental. Métodos Ocho individuos con EAC (61,7 ± 6,6 años) realizaron los siguientes tests: 1) TECP en cinta ergométrica; 2) Test de pico de torque (cinco repeticiones) y resistencia a la fatiga (20 repeticiones) de flexión-extensión de la rodilla en las velocidades angulares de 120º/s y 180º/s; 3) Dos series de 20 repeticiones en 30% a 40% (baja intensidad, BI) y 50% a 60% (moderada intensidad, MI) del pico de torque en las velocidades angulares de 120º/s y 180º/s en el dinamómetro isocinético. Durante los ejercicios, los individuos fueron conectados al analizador de gases expirados con monitorización simultánea del trazado electrocardiográfico, frecuencia cardiaca (FC), consumo de oxígeno (VO2), producción de dióxido de carbono y ventilación minuto (VE). Fue calculada la diferencia (∆) entre la medida pico durante los ejercicios y los valores basales. Resultados Tanto BI como MI produjeron respuestas cardiorrespiratorias por debajo del umbral anaeróbico (82,8 ± 8,1% de la FCmax y 74,4 ± 9,6% del VO2pico) en comparación con los datos de la TECP (P < 0,01). La MI mostró valores mayores de ∆ FC (9,8 ± 5,5 vs 6,3 ± 4,6 lpm; P = 0,01), ∆ producto frecuencia-presión (3015±2286 vs. 1957±1932 mmHg.lpm; P = 0,01) y ∆VE (10,2±6,2 vs. 6,9±7 L.min-1; P = 0,03) en comparación con la BI en la velocidad angular de 180°/s. Conclusión Estos resultados sugieren que este protocolo de ejercicios isocinéticos puede ser utilizado como estrategia para programas de rehabilitación cardíaca en pacientes con EAC. Nivel de evidencia IV; Serie de casos.

Ovariectomy predisposes female rats to fine particulate matter exposure's effects by altering metabolic, oxidative, pro-inflammatory, and heat-shock protein levels.

The reduction of estrogen levels, as a result of menopause, is associated with the development of metabolic diseases caused by alterations in oxidative stress (OS), inflammatory biomarkers, and 70-kDa heat-shock protein (HSP70) expression. Additionally, exposure to fine particulate matter air pollution modifies liver OS levels and predisposes organisms to metabolic diseases, such as type 2 diabetes (T2DM). We investigated whether ovariectomy affects hepatic tissue and alters glucose metabolism in female rats exposed to particulate air pollution. First, 24 female Wistar rats received an intranasal instillation of saline or particles suspended in saline 5 times per week for 12 weeks. The animals then received either bilateral ovariectomy (OVX) or false surgery (sham) and continued to receive saline or particles for 12 additional weeks, comprising four groups: CTRL, Polluted, OVX, and Polluted+OVX. Ovariectomy increased body weight and adiposity and promoted edema in hepatic tissue, hypercholesterolemia, glucose intolerance, and a pro-inflammatory profile (reduced IL-10 levels and increased IL-6/IL-10 ratio levels), independent of particle exposure. The Polluted+OVX group showed an increase in neutrophils and neutrophil/lymphocyte ratios, decreased antioxidant defense (SOD activity), and increased liver iHSP70 levels. In conclusion, alterations in the reproductive system predispose female organisms to particulate matter air pollution effects by affecting metabolic, oxidative, pro-inflammatory, and heat-shock protein expression.

Subacute exposure to residual oil fly ash (ROFA) increases eHSP70 content and extracellular-to-intracellular HSP70 ratio: a relation with oxidative stress markers.

The purpose of this study was to evaluate whether exposure to particles induces an imbalance in 70-kDa heat shock proteins (HSP70). Since intracellularly (iHSP70) it has anti-inflammatory roles whereas extracellularly (eHSP70) it has pro-inflammatory roles, we evaluate the effect of residual oil fly ash (ROFA) exposure on eHSP70-to-iHSP70 ratio (H index), a biomarker of inflammatory status that is related to oxidative stress in plasma and lymphoid tissue. Wistar rats that received ROFA suspension for three consecutive days (750 µg) showed an increase in plasma eHSP70 levels (mainly the 72-kDa inducible form). Also, ROFA promoted alterations on plasma oxidative stress (increased protein carbonyl groups and superoxide dismutase activity, and decrease sulfhydryl groups). There was an increase in H index of the plasma/thymus with no changes in circulating leukocyte level, iHSP70, or oxidative stress markers in lymphoid tissues. Our results support the hypothesis that eHSP70 content and H index represent inflammatory and oxidative biomarkers.

Biomarcadores na rinite alérgica: qual a importância e potencial diagnóstico? / Biomarkers in allergic rhinitis: its importance and diagnostic potential

O objetivo deste estudo é apontar quais os novos potenciais marcadores biológicos na rinite alérgica (RA). Buscou-se nas bases de dados Scielo e PUBMED artigos com os descritores "Rinite Alérgica" e "Biomarcadores" ou "Citocinas" ou "Interleucinas" ou "Eicosanoides", bem como na língua inglesa. A perspectiva do uso de novos biomarcadores na rinite alérgica vem sendo pesquisada, visto que marcadores sensíveis e específicos da doença poderiam permitir rápido diagnóstico, avaliação do estágio da doença e estimação da resposta ao tratamento. Vários métodos para coleta de amostras não invasivos ou semi-invasivos nas vias aéreas oferecem a possibilidade de mensuração de uma grande quantidade de novos biomarcadores na RA. Como potenciais biomarcadores, a análise do perfil de citocinas nasais apresenta uma boa caracterização diagnóstica (IL-5 e IL-13), além da relação de severidade da doença (IL-9 e IL-17B). Como avaliação isolada, a dosagem sérica de Proteína da Célula de Clara (CC16) parece ter grande potencial, pois permite o diagnóstico e seus níveis estão inversamente relacionados com a severidade da doença. Além disso, a dosagem de FeNO vem como uma arma importante para predizer asma nos pacientes com RA.

Current analysis deals with the new potential biological markers in allergic rhinitis. Scielo and PUBMED databases were researched for articles through descriptors "Allergic rhinitis" and "Biomarkers" or "Cytokines" or "Interleukins" or "Eicosanoids", in English and Portuguese. The use of new biomarkers for allergic rhinitis is researched since sensitive and specific markers provide a quick diagnosis, assessment of the disease´s stage and estimates of treatment responses. Several invasive and semi-invasive methods for sample collection from the aerial pathways make possible the measurement of a great number of new biomarkers in allergic rhinitis. As potential biomarkers, the analysis of nasal cytokines offers a good diagnose (IL-5 and IL-13), coupled to the disease´s severity (IL-9 and IL-17B). As an isolated evaluation, serum dosage of Clara Cell Protein (CC16) seems to be highly promising since it favors diagnosis with inversely related levels for the disease´s severity. Further, FeNO dosage is an important tool to predict asthma in AR patients.

Modulation of rat monocyte/macrophage innate functions by increasing intensities of swimming exercise is associated with heat shock protein status.

Moderate exercise positively impacts innate immune functions, bringing about a better resistance against infections and general immunosurveillance. Exercise of high workloads (i.e., high intensity and/or duration) such as elite marathon, on the other hand, may have detrimental effects over immune function, but neither how long nor how intense should be the exercise sessions to be deleterious is known, this being a matter of intense dispute. Exercise is, at the same time, one of the most powerful inducers of the 70 kDa family of heat shock proteins (HSPAs, formerly known as HSP70s), which are protein chaperones characterized by a marked anti-inflammatory potency, when located intracellularly (iHSPA), but may act as pro-inflammatory cytokines if in the extracellular space (eHSPA). The above observations led us to suppose that short-term exercise could impose long-lasting effects on macrophage function that should be related to the eHSPA-to-iHSPA ratio, viz. H-index. Sedentary adult male Wistar rats were then submitted to 20 min swimming sessions with an overload (as a percentage of body weight attached to the tail base) of either 2, 4, 6, or 8 %. Control animals were maintained at rest in shallow water. Monocyte/macrophage functions (phagocytic capacity, nitric oxide [NO], and hydrogen peroxide [H2O2]) were assessed just after and 12 h after exercise and compared with HSPA status and oxidative stress markers. The results showed that exercise increased phagocytosis and H2O2 immediately after the bouts in a workload-dependent way. This was accompanied by increased H-index but no alteration in the redox status. Enhanced phagocytic capacity persisted for up to 12 h, when a marked rise in NO production was also observed, but H-index resumes its control values, suggesting that immune alertness returned to basal levels. Of note was the detection of the cognate form of eHSPA (encoded by hspa8 gene and formerly known as HSP73) in the rat sera. In total, acute exercise may evoke 12 h long workload-dependent effects associated with HSPA status.

Heat shock proteins and heat therapy for type 2 diabetes: pros and cons.

PURPOSE OF REVIEW: Heat therapy, such as sauna and hot tub, has become an increasingly regular therapeutical practice around the world since several studies have shown benefits of heat therapy in metabolic and cardiovascular diseases. The use of heat therapy in people with type 2 diabetes mellitus revealed a striking reduction of 1% unit in the glycated hemoglobin, suggesting this therapy for the treatment of diabetes. Herein, we shall discuss the use of heat therapy and the mechanisms involved, and suggest a provisional guide for the use of heat therapy in obesity and diabetes. RECENT FINDINGS: Human studies indicate that heat therapy reduces fasting glycemia, glycated hemoglobin, body weight, and adiposity. Animal studies have indicated that nitric oxide and the increase in heat shock protein 70 expression is involved in the improvements induced by heat therapy on insulin sensitivity, adiposity, inflammation, and vasomotricity. SUMMARY: Heat therapy is a promising and inexpensive tool for the treatment of obesity and diabetes. We proposed that transient increments in nitric oxide and heat shock protein 70 levels may explain the benefits of heat therapy. We suggest that heat therapy (sauna: 80-100°C; hot tub: at 40°C) for 15 min, three times a week, for 3 months, is a safe method to test its efficiency.

Estrogen deprivation does not affect vascular heat shock response in female rats: a comparison with oxidative stress markers.

Hot flashes, which involve a tiny rise in core temperature, are the most common complaint of peri- and post-menopausal women, being tightly related to decrease in estrogen levels. On the other hand, estradiol (E2) induces the expression of HSP72, a member of the 70 kDa family of heat shock proteins (HSP70), which are cytoprotective, cardioprotective, and heat inducible. Since HSP70 expression is compromised in age-related inflammatory diseases, we argued whether the capacity of triggering a robust heat shock (HS) response would be still present after E2 withdrawal. Hence, we studied the effects of HS treatment (hot tub) in female Wistar rats subjected to bilateral ovariectomy (OVX) after a 7-day washout period. Twelve h after HS, the animals were killed and aortic arches were surgically excised for molecular analyses. The results were compared with oxidative stress markers in the plasma (superoxide dismutase, catalase, and lipoperoxidation) because HSP70 expression is also sensitive to redox regulation. Extracellular (plasma) to intracellular HSP70 ratio, an index of systemic inflammatory status, was also investigated. The results showed that HS response was preserved in OVX animals, as inferred from HSP70 expression (up to 40% rise, p < 0.01) in the aortas, which was accompanied by no further alterations in oxidative stress, hematological parameters, and glycemic control either. This suggests that the lack of estrogen per se could not be solely ascribed as the unique source of low HSP70 expression as observed in long-term post-menopausal individuals. As a consequence, periodic evaluation of HSP70 status (iHSP70 vs. eHSP70) may be of clinical relevance because decreased HS response capacity is at the center of the onset of menopause-related dysfunctions.

L-glutamine supplementations enhance liver glutamine-glutathione axis and heat shock factor-1 expression in endurance-exercise trained rats.

Liver L-glutamine is an important vehicle for the transport of ammonia and intermediary metabolism of amino acids between tissues, particularly under catabolic situations, such as high-intensity exercise. Hence, the aim of this study was to investigate the effects of oral supplementations with L-glutamine in its free or dipeptide forms (with L-alanine) on liver glutamine-glutathione (GSH) axis, and 70 kDa heat shock proteins (HSP70)/heat shock transcription factor 1 (HSF1) expressions. Adult male Wistar rats were 8-week trained (60 min/day, 5 days/week) on a treadmill. During the last 21 days, the animals were daily supplemented with 1 g of L-glutamine/kg body weight per day in either l-alanyl-L-glutamine dipeptide (DIP) form or a solution containing L-glutamine and l-alanine in their free forms (GLN+ALA) or water (controls). Exercise training increased cytosolic and nuclear HSF1 and HSP70 expression, as compared with sedentary animals. However, both DIP and GLN+ALA supplements enhanced HSF1 expression (in both cytosolic and nuclear fractions) in relation to exercised controls. Interestingly, HSF1 rises were not followed by enhanced HSP70 expression. DIP and GLN+ALA supplements increased plasma glutamine concentrations (by 62% and 59%, respectively) and glutamine to glutamate plasma ratio in relation to trained controls. This was in parallel with a decrease in plasma ammonium levels. Supplementations increased liver GSH (by 90%), attenuating the glutathione disulfide (GSSG) to GSH ratio, suggesting a redox state protection. In conclusion, oral administration with DIP and GLN+ALA supplements in endurance-trained rats improve liver glutamine-GSH axis and modulate HSF1 pathway.

Short-term but not long-term hypoglycaemia enhances plasma levels and hepatic expression of HSP72 in insulin-treated rats: an effect associated with increased IL-6 levels but not with IL-10 or TNF-α.

The inducible expression of the 70-kDa heat shock proteins (HSP70) is associated with homeostatically stressful situations. Stresses involving sympathetic nervous system (SNS) activation, including α1-adrenergic agonists and physical exercise, are capable of inducing HSP70 expression and release of the HSP70 inducible form, HSP72. However, whether hypoglycaemia is capable of influencing HSP70 status under a stressful situation such as insulin-induced hypoglycaemia (IIH), which also involves SNS activation, is unsettled. Hence, we decided to investigate whether the predominant signal for HSP70 expression and delivery into the blood comes from either low glucose, high insulin, or both during short-term IIH (STIIH) and long-term IIH (LTIIH). Our data indicated that low glucose level (up to 1.56 ± 0.14 mM), but not insulin, is the triggering factor responsible for a dramatic rise in HSP72 plasma concentrations (from 0.15 ± 0.01 in fed state to 0.77 ± 0.13 ng/mL during hypoglycaemic episodes). This was observed in parallel with up to 7-fold increases in interleukin-6 (IL-6) but not interleukin-10 (IL-10) or tumour necrosis factor-α (TNF-α) at STIIH. Together, the observations may suggest that HSP72 is released under hypoglycaemic conditions as a part of the homeostatic stress response, whereas at long-term, both hypoglycaemia and insulin may influence HSP72 expression in the liver, but not in kidneys. Secreted extracellular HSP72 (eHSP72) may be purely a danger signal to all the tissues of the body for the enhancement of immune and metabolic surveillance state or actively participates in glycaemic control under stressful situations.

Alanyl-glutamine and glutamine plus alanine supplements improve skeletal redox status in trained rats: involvement of heat shock protein pathways.

AIMS: We hypothesized that oral l-glutamine supplementations could attenuate muscle damage and oxidative stress, mediated by glutathione (GSH) in high-intensity aerobic exercise by increasing the 70-kDa heat shock proteins (HSP70) and heat shock factor 1 (HSF1). MAIN METHODS: Adult male Wistar rats were 8-week trained (60-min/day, 5 days/week) on a treadmill. During the last 21 days, the animals were supplemented with either l-alanyl-l-glutamine dipeptide (1.5 g/kg, DIP) or a solution containing the amino acids l-glutamine (1g/kg) and l-alanine (0.67 g/kg) in their free form (GLN+ALA) or water (controls). KEY FINDINGS: Plasma from both DIP- and GLN+ALA-treated animals showed higher l-glutamine concentrations and reduced ammonium, malondialdehyde, myoglobin and creatine kinase activity. In the soleus and gastrocnemius muscle of both supplemented groups, l-glutamine and GSH contents were increased and GSH disulfide (GSSG) to GSH ratio was attenuated (p<0.001). In the soleus muscle, cytosolic and nuclear HSP70 and HSF1 were increased by DIP supplementation. GLN+ALA group exhibited higher HSP70 (only in the nucleus) and HSF1 (cytosol and nucleus). In the gastrocnemius muscle, both supplementations were able to increase cytosolic HSP70 and cytosolic and nuclear HSF1. SIGNIFICANCE: In trained rats, oral supplementation with DIP or GLN+ALA solution increased the expression of muscle HSP70, favored muscle l-glutamine/GSH status and improved redox defenses, which attenuate markers of muscle damage, thus improving the beneficial effects of high-intensity exercise training.

Low expression of MRP1/GS-X pump ATPase in lymphocytes of Walker 256 tumour-bearing rats is associated with cyclopentenone prostaglandin accumulation and cancer immunodeficiency.

Immunosuppression is a life-threatening complication of late cancer stages. In this regard, overproduction in the host plasma of the anti-inflammatory cyclopentenone prostaglandins (CP-PGs), which are strongly antiproliferative at high concentrations, may impair immune function. In fact, lymphoid tissues of tumour-bearing rats accumulated large amounts of CP-PGs while the tumour tissue itself did not. Expression of the CP-PG-induced 72-kDa heat shock protein (hsp70) was elevated in lymphocytes from tumour-bearing animals related to controls. As the capacity for CP-PG uptake by lymphocytes is the same as tumour cells, we investigated whether the latter could overexpress the multidrug resistance-associated protein (MRP1/GS-X pump) which extrudes CP-PGs towards the extracellular space as glutathione S-conjugates. Walker 256 tumour cells extruded 15-fold more S-conjugates than lymphocytes from the same rats (p < 0.001). This did not appear to be related to deficiency in lymphocyte glutathione (GSH) metabolism, since the major GSH metabolic routes are consistent with CP-PG conjugation in lymphocytes. This was not the case, however, for the MRP1/GS-X pump activity in lymphocyte membranes (in pmol/min/mg protein: 3.1 +/- 1.7 from normal rats, 0.2 +/- 0.2 from tumour-bearing animals vs 64.3 +/- 7.0 in tumour cells) which was confirmed by Western blot analysis for MRP1 protein. Transfection of lymphocytes with MRP1 gene completely abolished CP-PG (0-40 microM) toxicity. Taken together, these findings suggest that CP-PG accumulation in lymphocytes may be, at least partially, responsible for cancer immunodeficiency. Clinical approaches for overexpressing MRP1/GS-X pump in lymphocytes could then play a role as a tool for the management of cancer therapeutics.