A systematic review of the effects of cold exposure on pathological cardiac remodeling in mice.

Exposure to cold promotes cardiac remodeling, characterized by deleterious effects on structure and function, contributing to increased mortality from cardiovascular diseases. The mechanisms associated with these changes are poorly understood. This review gathers the literature data on the main alterations and mechanisms associated with the adverse cardiac structural and functional remodeling induced by cold exposure in mice. Original studies were identified by searching PubMed, Scopus, and Embase databases from January 1990 to June 2022. This systematic review was conducted in accordance with the criteria established by PRISMA and registered in PROSPERO (CRD42022350637). The risk of bias was evaluated by the SYRCLE. Eligible studies included original papers published in English that evaluated cardiac outcomes in mice submitted to short- or long-time cold exposure and had a control group at room temperature. Seventeen original articles were included in this review. Cold exposure induces pathological cardiac remodeling, characterized by detrimental structural and functional parameters, changes in metabolism and autophagy process, and increases in oxidative stress, inflammation, and apoptosis. In addition, Nppa, AT1A, Fbp3, BECN, ETA, and MT, appear to play fundamental roles in regulating cardiac remodeling. We suggest that strategies that seek to minimize the CVD risk and adverse effects of cold exposure should target these agents.

Mineralocorticoid receptor antagonists lead to increased adenosine bioavailability and modulate contractile cardiac parameters.

Activation of mineralocorticoid receptor antagonists (MRAs) is cardioprotective; however, this property is lost upon blockade or inactivation of adenosine (ADO) receptor A2b. In this study, we investigated whether the effects of MRAs are mediated by an interaction between cardioprotective ADO receptors A1 and A3. Spironolactone (SPI) or eplerenone (EPL) increased ADO levels in the plasma of treated animals compared to control animals. SPI or EPL increased the protein and activity levels of ecto-5'-nucleotidase (NT5E), an enzyme that synthesizes ADO, compared to control. The levels of ADO deaminase (ADA), which degrades ADO, were not affected by SPI or EPL; however, the activity of ADA was reduced in SPI-treated rats compared to control. Using an isolated cardiomyocyte model, we found inotropic and chronotropic effects, and increased calcium transient [Ca2+]i in cells treated with ADO receptor A1 or A3 antagonists compared to control groups. Upon co-treatment with MRAs, EPL and SPI fully and partially reverted the effects of receptor A1 or A3 antagonism, respectively. Collectively, MRAs in vivo lead to increased ADO bioavailability. In vitro, the rapid effects of SPI and EPL are mediated by an interaction between ADO receptors A1 and A3.

Exposure of cultured fibroblasts to the peptide PR-11 for the identification of induced proteome alterations and discovery of novel potential ligands.

The PR-11 peptide corresponds to the N-terminal and active region of the endogenously synthesized PR-39 molecule, of porcine origin. It is known to possess various biological effects including antimicrobial properties, angiogenic and anti-inflammatory activities. Apart from its reported activity as a proteasome inhibitor, a more comprehensive understanding of its function, at the molecular level, is still lacking. In this study, we used a label-free shotgun strategy to evaluate the proteomic alterations caused by exposure of cultured fibroblasts to the peptide PR-11. This approach revealed that more than half of the identified molecules were related to signalling, transcription and translation. Proteins directly associated to regulation of angiogenesis and interaction with the hypoxia-inducible factor 1-α (HIF-1α) were significantly altered. In addition, at least three differentially expressed molecules of the NF-κB pathway were detected, suggesting an anti-inflammatory property of PR-11. At last, we demonstrated novel potential ligands of PR-11, through its immobilization for affinity chromatography. Among the eluted molecules, gC1qR, a known complement receptor, appeared markedly enriched. This provided preliminary evidence of a PR-11 ligand possibly involved in the internalization of this peptide. Altogether, our findings contributed to a better understanding of the cellular pathways affected by PR-39 derived molecules.

Genomic and rapid effects of aldosterone: what we know and do not know thus far.

Aldosterone is the most known mineralocorticoid hormone synthesized by the adrenal cortex. The genomic pathway displayed by aldosterone is attributed to the mineralocorticoid receptor (MR) signaling. Even though the rapid effects displayed by aldosterone are long known, our knowledge regarding the receptor responsible for such event is still poor. It is intense that the debate whether the MR or another receptor-the "unknown receptor"-is the receptor responsible for the rapid effects of aldosterone. Recently, G protein-coupled estrogen receptor-1 (GPER-1) was elegantly shown to mediate some aldosterone-induced rapid effects in several tissues, a fact that strongly places GPER-1 as the unknown receptor. It has also been suggested that angiotensin receptor type 1 (AT1) also participates in the aldosterone-induced rapid effects. Despite this open question, the relevance of the beneficial effects of aldosterone is clear in the kidneys, colon, and CNS as aldosterone controls the important water reabsorption process; on the other hand, detrimental effects displayed by aldosterone have been reported in the cardiovascular system and in the kidneys. In this line, the MR antagonists are well-known drugs that display beneficial effects in patients with heart failure and hypertension; it has been proposed that MR antagonists could also play an important role in vascular disease, obesity, obesity-related hypertension, and metabolic syndrome. Taken altogether, our goal here was to (1) bring a historical perspective of both genomic and rapid effects of aldosterone in several tissues, and the receptors and signaling pathways involved in such processes; and (2) critically address the controversial points within the literature as regarding which receptor participates in the rapid pathway display by aldosterone.

Rapid effects of aldosterone in primary cultures of cardiomyocytes - do they suggest the existence of a membrane-bound receptor?

Aldosterone acts on its target tissue through a classical mechanism or through the rapid pathway through a putative membrane-bound receptor. Our goal here was to better understand the molecular and biochemical rapid mechanisms responsible for aldosterone-induced cardiomyocyte hypertrophy. We have evaluated the hypertrophic process through the levels of ANP, which was confirmed by the analysis of the superficial area of cardiomyocytes. Aldosterone increased the levels of ANP and the cellular area of the cardiomyocytes; spironolactone reduced the aldosterone-increased ANP level and cellular area of cardiomyocytes. Aldosterone or spironolactone alone did not increase the level of cyclic 3',5'-adenosine monophosphate (cAMP), but aldosterone plus spironolactone led to increased cAMP level; the treatment with aldosterone + spironolactone + BAPTA-AM reduced the levels of cAMP. These data suggest that aldosterone-induced cAMP increase is independent of mineralocorticoid receptor (MR) and dependent on Ca(2+). Next, we have evaluated the role of A-kinase anchor proteins (AKAP) in the aldosterone-induced hypertrophic response. We have found that St-Ht31 (AKAP inhibitor) reduced the increased level of ANP which was induced by aldosterone; in addition, we have found an increase on protein kinase C (PKC) and extracellular signal-regulated kinase 5 (ERK5) activity when cells were treated with aldosterone alone, spironolactone alone and with a combination of both. Our data suggest that PKC could be responsible for ERK5 aldosterone-induced phosphorylation. Our study suggests that the aldosterone through its rapid effects promotes a hypertrophic response in cardiomyocytes that is controlled by an AKAP, being dependent on ERK5 and PKC, but not on cAMP/cAMP-dependent protein kinase signaling pathways. Lastly, we provide evidence that the targeting of AKAPs could be relevant in patients with aldosterone-induced cardiac hypertrophy and heart failure.

The role of key genes and pathways involved in the tumorigenesis of Malignant Mesothelioma.

Malignant Mesothelioma (MM) is a very aggressive cancer with low survival rates and often diagnosed at an advanced stage. Several players have been implicated in the development of this cancer, such as asbestos, erionite and the simian virus 40 (SV40). Here, we have reviewed the involvement of erionite, SV40, as well as, the role of several genes (p16(INK4a), p14(ARF), NF2, LATS2, SAV, CTNNB1 and among others), the pathways (RAS, PI3K, Wnt, BCL and Hippo), and their respective roles in the development of MM.

Non-genomic effects of spironolactone and eplerenone in cardiomyocytes of neonatal Wistar rats: do they evoke cardioprotective pathways?

Mineralocorticoid receptor (MR) antagonists of aldosterone (spironolactone and eplerenone) display beneficial effects in the treatment of cardiopathies; however, many of these responses are independent of this antagonism. The mechanisms of action of these drugs are not well known; few studies have comparatively evaluated whether eplerenone as well as spironolactone display cardioprotective effects independent of the blockade of aldosterone. To study these mechanisms, which lead to cardioprotective responses, and to evaluate comparatively their effects in vitro, we have evaluated the proliferative effect of spironolactone and eplerenone in primary culture of cardiomyocytes and fibroblasts of neonatal Wistar rats in the presence and absence of aldosterone. Spironolactone and eplerenone promoted proliferation of cardiomyocyte even in the absence of aldosterone, suggesting a signaling pathway independent of the antagonism over aldosterone. Spironolactone was able to reduce the proliferation of fibroblasts and to reverse the proliferation promoted by aldosterone, which was also displayed by eplerenone. To elucidate the biochemical pathways evoked by these drugs, we sought to analyze Ca(2+), cAMP, and cGMP, and the activity of PKC and ERK1/2. Spironolactone and eplerenone increased the levels of Ca(2+), cGMP and activity of ERK 1/2, and reversed the action of aldosterone on the activity of PKC and ERK1/2. Interestingly, only spironolactone increased the levels of cAMP. Our data support the fact that in addition to aldosterone, both spironolactone and eplerenone display rapid responses (non-genomic) such as an increase on cAMP, Ca(2+), and cGMP by spironolactone, and Ca(2+) and cGMP by eplerenone. We have observed a more consistent cardioprotection promoted by spironolactone; however, these effects have yet to be tested clinically. Therefore, our data show that these drugs do not only act as an antagonist of MR, but could lead to a new pharmacological classification of these drugs.

The function, mechanisms, and role of the genes PTEN and TP53 and the effects of asbestos in the development of malignant mesothelioma: a review focused on the genes' molecular mechanisms.

The malignant mesothelioma is an aggressive form of cancer with a mean survival rate of less than a year. Moreover, environmental exposure to minerals is an important factor in the development of malignant mesothelioma (MM), especially the mineral asbestos, which has a well-documented role in MM, and more recently, the mineral erionite has been proven to be a strong carcinogenic inducer of MM. In addition, the virus simian virus 40 has been implicated as a co-carcinogenic player in MM. However, the molecular mechanisms involved in the pathogenesis of this cancer are still not fully understood. Indeed, it is known that several genes are altered or mutated in MM, among those are p16(INK4A), p14(ARF), and neurofibromatosis type II. Furthermore, TP53 has been reported to be mutated in the majority of the cancers; however, in MM, it is very uncommon mutations in this gene. Also, the PTEN gene has been shown to play an important role in endometrial cancer and glioblastoma, although the role of PTEN in MM has yet to be established. Taken altogether, this review focuses on the historical aspects, molecular mechanisms, interaction with other genes and proteins, and the role of these genes in MM. Lastly, this review questions the cancer theory of the two hits because the functions of both PTEN and TP53 are not fully explained by this theory.

Resistance Exercise Training Mitigates Cardiac Remodeling Induced by a High-Fat Diet in Rodents: A Systematic Review. / O Treinamento Resistido Atenua a Remodelação Cardíaca Induzida por uma Dieta Hiperlipídica em Roedores: Uma Revisão Sistemática.

BACKGROUND: Obesity is associated with the development of cardiovascular diseases and is a serious public health problem. In animal models, high-fat diet (HFD) feeding impairs cardiac structure and function and promotes oxidative stress and apoptosis. Resistance exercise training (RT), however, has been recommended as coadjutant in the treatment of cardiometabolic diseases, including obesity, because it increases energy expenditure and stimulates lipolysis. OBJECTIVE: In this systematic review, we aimed to assess the benefits of RT on the heart of rats and mice fed HFD. METHODS: Original studies were identified by searching PubMed, Scopus, and Embase databases from December 2007 to December 2022. This study was conducted in accordance with the criteria established by PRISMA and registered in PROSPERO (CRD42022369217). The risk of bias and methodological quality was evaluated by SYRCLE and CAMARADES, respectively. Eligible studies included original articles published in English that evaluated cardiac outcomes in rodents submitted to over 4 weeks of RT and controlled by a sedentary, HFD-fed control group (n = 5). RESULTS: The results showed that RT mitigates cardiac oxidative stress, inflammation, and endoplasmic reticulum stress. It also modifies the activity of structural remodeling markers, although it does not alter biometric parameters, histomorphometric parameters, or the contractile function of cardiomyocytes. CONCLUSION: Our results indicate that RT partially counteracts the HFD-induced adverse cardiac remodeling by increasing the activity of structural remodeling markers; elevating mitochondrial biogenesis; reducing oxidative stress, inflammatory markers, and endoplasmic reticulum stress; and improving hemodynamic, anthropometric, and metabolic parameters.

FUNDAMENTO: A obesidade está associada ao desenvolvimento de doenças cardiovasculares e constitui um grave problema de saúde pública. Em modelos animais, a alimentação com uma dieta hiperlipídica (DH) compromete a estrutura e a função cardíaca e promove estresse oxidativo e apoptose. O treinamento resistido (TR), entretanto, tem sido recomendado como coadjuvante no tratamento de doenças cardiometabólicas, incluindo a obesidade, porque aumenta o gasto energético e estimula a lipólise. OBJETIVO: Na presente revisão sistemática, nosso objetivo foi avaliar os benefícios do TR no coração de ratos e camundongos alimentados com DH. MÉTODOS: Foram identificados estudos originais por meio de busca nas bases de dados PubMed, Scopus e Embase de dezembro de 2007 a dezembro de 2022. O presente estudo foi conduzido de acordo com os critérios estabelecidos pelo PRISMA e registrado no PROSPERO (CRD42022369217). O risco de viés e a qualidade metodológica foram avaliados pelo SYRCLE e CAMARADES, respectivamente. Os estudos elegíveis incluíram artigos originais publicados em inglês que avaliaram desfechos cardíacos em roedores submetidos a mais de 4 semanas de TR e controlados por um grupo controle sedentário alimentado com DH (n = 5). RESULTADOS: Os resultados mostraram que o TR atenua o estresse oxidativo cardíaco, a inflamação e o estresse do retículo endoplasmático. Também modifica a atividade de marcadores de remodelamento estrutural, apesar de não alterar parâmetros biométricos, parâmetros histomorfométricos ou a função contrátil dos cardiomiócitos. CONCLUSÃO: Nossos resultados indicam que o TR parcialmente neutraliza o remodelamento cardíaco adverso induzido pela DH, aumentando a atividade dos marcadores de remodelamento estrutural; elevando a biogênese mitocondrial; reduzindo o estresse oxidativo, marcadores inflamatórios e estresse do retículo endoplasmático; e melhorando os parâmetros hemodinâmicos, antropométricos e metabólicos.

Cardiac changes in spontaneously hypertensive rats: Modulation by aerobic exercise.

Systemic arterial hypertension is a multifactorial clinical condition characterized by high and sustained levels of blood pressure. For a better understanding of the pathophysiology of hypertension, studies are conducted with spontaneously hypertensive animals, which allow the investigation of physiological changes that in most cases cannot be studied in humans. In these animals, myocardial remodeling, increased pro-inflammatory markers, redox imbalance and contractile dysfunctions that lead to changes in cardiac function can be observed. However, it can be inferring that aerobic training improves cardiac function and cardiomyocyte contractility, in addition to controlling inflammation and reducing oxidative stress in cardiac muscle, despite this, the precise mechanisms by which physical exercise improves cardiovascular control are not fully understood. In this review, we provide an overview of the pathophysiological changes that affect the heart of spontaneously hypertensive animals and their modulation by aerobic exercise.

The role of environmental signals in the expression of rhythmic cardiac proteins and their influence on cardiac pathologies.

We know that numerous proteins expressed in the heart are influenced by environmental signals (such as light and diet), which cause either an increase or decrease in their expression. Cardiovascular health is sensitive to diet composition (macronutrient content), as well as the percentage of energy, frequency and regularity of meal intake during the 24-hour cycle, and the fasting period. Furthermore, light is an important synchronizer of the circadian clock and, in turn, of several physiological processes, among them cardiovascular physiology. In this chapter, we address the effects of these environmental cues and the known mechanisms that lead to this variation in protein expression in the heart, as well as cardiac function.

Nitric oxide at the CVLM is involved in the attenuation of the reflex bradycardia in renovascular hypertensive rats.

Hypertension is associated to an increase in central oxidative stress and an attenuation of the baroreflex control of arterial pressure. The present study evaluated the effect of alterations in the levels of nitric oxide (NO) and superoxide anion in the caudal ventrolateral medulla (CVLM), a key area of the brainstem for the baroreflex control of arterial pressure, in renovascular hypertensive rats (2K1C). Baseline mean arterial pressure (MAP), heart rate (HR), and reflex bradycardia were evaluated 30 days after renal artery occlusion in anesthetized (urethane, 1.2 g/kg, i.p.) 2K1C or normotensive (SHAM) rats. The MAP, HR, and baroreflex control of HR were evaluated before and after CVLM microinjections of the non-selective NOS inhibitor L-NAME (10 nmol), the NO precursor L-ARG (50 nmol), or the antioxidant ascorbic acid, Vit C (10 nmol). In both 2K1C and SHAM animals, CVLM microinjection of L-NAME produced a decrease in MAP, whereas L-ARG induced a significant increase in MAP. However, microinjection of Vit C into the CVLM produced a decrease in MAP and HR only in 2K1C and not in SHAM rats. Cardiovascular effects produced by microinjection of l-ARG into the CVLM were abolished by prior microinjection of L-NAME in the CVLM of 2K1C and SHAM rats. Microinjection of L-NAME into the CVLM increased the sensitivity of reflex bradycardia in 2K1C animals. In contrast, the CVLM microinjection of L-ARG reduced reflex bradycardia only in SHAM rats. Vit C in the CVLM did not change reflex bradycardia in either 2K1C or in SHAM rats. These results suggest that increased oxidative stress in the CVLM during hypertension contributes to the reduced baroreflex sensitivity and to maintain hypertension in the 2K1C model.

The Effect of Diet on the Cardiac Circadian Clock in Mice: A Systematic Review.

Circadian rhythms play important roles in regulating physiological and behavioral processes. These are adjusted by environmental cues, such as diet, which acts by synchronizing or attenuating the circadian rhythms of peripheral clocks, such as the liver, intestine, pancreas, white and brown adipose tissue, lungs, kidneys, as well as the heart. Some studies point to the influence of diet composition, feeding timing, and dietary restriction on metabolic homeostasis and circadian rhythms at various levels. Therefore, this systematic review aimed to discuss studies addressing the effect of diet on the heart clock in animal models and, additionally, the chronodisruption of the clock and its relation to the development of cardiovascular disorders in the last 15 years. A search was conducted in the PubMed, Scopus, and Embase databases. The PRISMA guide was used to construct the article. Nineteen studies met all inclusion and exclusion criteria. In summary, these studies have linked the circadian clock to cardiovascular health and suggested that maintaining a robust circadian system may reduce the risks of cardiometabolic and cardiovascular diseases. The effect of time-of-day-dependent eating on the modulation of circadian rhythms of the cardiac clock and energy homeostasis is notable, among its deleterious effects predominantly in the sleep (light) phase and/or at the end of the active phase.

Pre- and Post-Conditioning of the Heart: An Overview of Cardioprotective Signaling Pathways.

Since the discovery of ischemic pre- and post-conditioning, more than 30 years ago, the knowledge about the mechanisms and signaling pathways involved in these processes has significantly increased. In clinical practice, on the other hand, such advancement has yet to be seen. This article provides an overview of ischemic pre-, post-, remote, and pharmacological conditioning related to the heart. In addition, we reviewed the cardioprotective signaling pathways and therapeutic agents involved in the above-mentioned processes, aiming to provide a comprehensive evaluation of the advancements in the field. The advancements made over the last decades cannot be ignored and with the exponential growth in techniques and applications. The future of pre- and post-conditioning is promising.

Effects of aerobic exercise training and açai supplementation on cardiac structure and function in rats submitted to a high-fat diet.

This study evaluated the effect of aerobic exercise training (AET) and supplementation with açai on cardiac structure and function in rats submitted to a high-fat diet. Two-month old Fischer male rats were divided into 5 groups: Control (C), High-fat Diet (H), High-fat Diet + Açai (HA), High-fat Diet + AET (HT), High-fat Diet + Açai + AET (HAT). The high-fat diet had 21.8% lard and 1% cholesterol (H and HT), or supplemented with 1% lyophilized açai pulp (HA and HAT). The HT and HAT groups performed AET on a treadmill (5 days/week, 1 h/day, 60% of the maximum running speed) for 8 weeks. Exercise tolerance test were performed, and adiposity index calculated. After euthanasia, the left ventricle (LV) was dissected and processed for histological, single myocyte intracellular calcium ([Ca2+]i) transient and contractility, oxidative stress and gene expression analysis. AET improved running capacity and reduced the adiposity index. Both AET and açai supplementation inhibited the increase in the LV collagen content, the deleterious effects on the [Ca2+]i transient and contractility in cardiomyocytes and the increment in oxidative stress, caused by the consumption of a high-fat diet. Aerobic exercise training and açai supplementation can mitigate damage caused by high-fat diet in cardiac structure and function, though the combination of treatments had no additional effects.

Light modulates the melanophore response to alpha-MSH in Xenopus laevis: an analysis of the signal transduction crosstalk mechanisms involved.

Melanin granule (melanosome) dispersion within Xenopus laevis melanophores is evoked either by light or alpha-MSH. We have previously demonstrated that the initial biochemical steps of light and alpha-MSH signaling are distinct, since the increase in cAMP observed in response to alpha-MSH was not seen after light exposure. cAMP concentrations in response to alpha-MSH were significantly lower in cells pre-exposed to light as compared to the levels in dark-adapted melanophores. Here we demonstrate the presence of an adenylyl cyclase (AC) in the Xenopus melanophore, similar to the mammalian type IX which is inhibited by Ca(2+)-calmodulin-activated phosphatase. This finding supports the hypothesis that the cyclase could be negatively modulated by a light-promoted Ca(2+) increase. In fact, the activity of calcineurin PP2B phosphatase was increased by light, which could result in AC IX inhibition, thus decreasing the response to alpha-MSH. St-Ht31, a disrupting agent of protein kinase A (PKA)-anchoring kinase A protein (AKAP) complex totally blocked the melanosome dispersing response to alpha-MSH, but did not impair the photo-response in Xenopus melanophores. Sequence comparison of a melanophore AKAP partial clone with GenBank sequences showed that the anchoring protein was a gravin-like adaptor previously sequenced from Xenopus non-pigmentary tissues. Co-immunoprecipitation of Xenopus AKAP and the catalytic subunit of PKA demonstrated that PKA is associated with AKAP and it is released in the presence of alpha-MSH. We conclude that in X. laevis melanophores, AKAP12 (gravin-like) contains a site for binding the inactive PKA thus compartmentalizing PKA signaling and also possesses binding sites for PKC. Light diminishes alpha-MSH-induced increase of cAMP by increasing calcineurin (PP2B) activity, which in turn inhibits adenylyl cyclase type IX, and/or by activating PKC, which phosphorylates the gravin-like molecule, thus destabilizing its binding to the cell membrane.

Does a high-fat diet affect the circadian clock, or is it the other way around? A systematic review.

This paper reviews studies that addressed the influence of diet on circadian rhythmicity in mice and, in turn, circadian clock chronodisruption and its role in the development of metabolic disorders. Studies from the past 14 years were selected via a systematic search conducted using the PubMed electronic database. After applying the inclusion and exclusion criteria, 291 studies were selected, of which 13 were chosen using the following inclusion criteria: use of a high-fat diet for mice, evaluation of clock gene expression, and the association between chronodisruption and lipid metabolism disorders. These studies reported changes in animals' biological clock when they developed metabolic disorders by consuming a high-fat diet. It was also evident that some clock gene mutations or deletions triggered metabolic changes. Disturbances of clock gene machinery may play important roles in lipid metabolism and the development of atherosclerotic processes. However, many metabolic processes also affect the function of clock genes and circadian systems. In summary, this review's results may provide new insights into the reciprocal regulation of energy homeostasis and the biological clock.

O Treinamento Resistido Atenua a Remodelação Cardíaca Induzida por uma Dieta Hiperlipídica em Roedores: Uma Revisão Sistemática / Resistance Exercise Training Mitigates Cardiac Remodeling Induced by a High-Fat Diet in Rodents: A Systematic Review

Resumo Fundamento A obesidade está associada ao desenvolvimento de doenças cardiovasculares e constitui um grave problema de saúde pública. Em modelos animais, a alimentação com uma dieta hiperlipídica (DH) compromete a estrutura e a função cardíaca e promove estresse oxidativo e apoptose. O treinamento resistido (TR), entretanto, tem sido recomendado como coadjuvante no tratamento de doenças cardiometabólicas, incluindo a obesidade, porque aumenta o gasto energético e estimula a lipólise. Objetivo Na presente revisão sistemática, nosso objetivo foi avaliar os benefícios do TR no coração de ratos e camundongos alimentados com DH. Métodos Foram identificados estudos originais por meio de busca nas bases de dados PubMed, Scopus e Embase de dezembro de 2007 a dezembro de 2022. O presente estudo foi conduzido de acordo com os critérios estabelecidos pelo PRISMA e registrado no PROSPERO (CRD42022369217). O risco de viés e a qualidade metodológica foram avaliados pelo SYRCLE e CAMARADES, respectivamente. Os estudos elegíveis incluíram artigos originais publicados em inglês que avaliaram desfechos cardíacos em roedores submetidos a mais de 4 semanas de TR e controlados por um grupo controle sedentário alimentado com DH (n = 5). Resultados Os resultados mostraram que o TR atenua o estresse oxidativo cardíaco, a inflamação e o estresse do retículo endoplasmático. Também modifica a atividade de marcadores de remodelamento estrutural, apesar de não alterar parâmetros biométricos, parâmetros histomorfométricos ou a função contrátil dos cardiomiócitos. Conclusão Nossos resultados indicam que o TR parcialmente neutraliza o remodelamento cardíaco adverso induzido pela DH, aumentando a atividade dos marcadores de remodelamento estrutural; elevando a biogênese mitocondrial; reduzindo o estresse oxidativo, marcadores inflamatórios e estresse do retículo endoplasmático; e melhorando os parâmetros hemodinâmicos, antropométricos e metabólicos.

Abstract Background Obesity is associated with the development of cardiovascular diseases and is a serious public health problem. In animal models, high-fat diet (HFD) feeding impairs cardiac structure and function and promotes oxidative stress and apoptosis. Resistance exercise training (RT), however, has been recommended as coadjutant in the treatment of cardiometabolic diseases, including obesity, because it increases energy expenditure and stimulates lipolysis. Objective In this systematic review, we aimed to assess the benefits of RT on the heart of rats and mice fed HFD. Methods Original studies were identified by searching PubMed, Scopus, and Embase databases from December 2007 to December 2022. This study was conducted in accordance with the criteria established by PRISMA and registered in PROSPERO (CRD42022369217). The risk of bias and methodological quality was evaluated by SYRCLE and CAMARADES, respectively. Eligible studies included original articles published in English that evaluated cardiac outcomes in rodents submitted to over 4 weeks of RT and controlled by a sedentary, HFD-fed control group (n = 5). Results The results showed that RT mitigates cardiac oxidative stress, inflammation, and endoplasmic reticulum stress. It also modifies the activity of structural remodeling markers, although it does not alter biometric parameters, histomorphometric parameters, or the contractile function of cardiomyocytes. Conclusion Our results indicate that RT partially counteracts the HFD-induced adverse cardiac remodeling by increasing the activity of structural remodeling markers; elevating mitochondrial biogenesis; reducing oxidative stress, inflammatory markers, and endoplasmic reticulum stress; and improving hemodynamic, anthropometric, and metabolic parameters.

Aerobic Exercise Increases the Damage to the Femoral Properties of Growing Rats with Protein-Based Malnutrition

Abstract The present study investigated the effects of aerobic physical training on the femoral morphological, densitometric and biomechanical properties in growing male rats subjected to protein-based malnutrition. Four-week-old male Wistar rats were randomized into groups of 10 animals: Control Sedentary (CS), Control Trained (CT), Malnourished Sedentary (MS) and Malnourished Trained (MT). Control and malnourished animals received diets with 12% protein and 6% protein, respectively. The trained groups were submitted to a treadmill running program for 8 weeks. Total proteins and albumin were analyzed in the animals' blood plasma. Histological, densitometric and biomechanical analyzes were performed on the animals' femur. Body mass gain, physical performance, biochemical markers and the femoral morphological, densitometric and biomechanical properties were determined. Exercise tolerance increased in trained groups. Malnourished animals exhibited lower serum protein and albumin levels than controls. Porosity and trabecular bone density were not different between groups. The femoral maximum load, maximum load until fracture, resilience, stiffness, tenacity and densitometric properties were reduced by malnutrition. Physical training associated with malnutrition exacerbated the impairment in the femoral maximum load, maximum load until fracture, bone mineral content and density. Aerobic physical training worsens the damages induced by protein-based malnutrition in the femoral biomechanical and densitometric properties of growing male rats.

Anti-cancer drugs: molecular mechanisms of action.

Genetic alterations are responsible for all cancers. These mutations produce, in turn, alterations in key proteins of certain signaling pathways. Amongst the best known and studied alterations related to malignant transformations are those which occur in Ras protein and p53. In most cases mutations in Ras and p53 lead to the appearance of practically most malignant transformations. Mutated Ras genes exist in approximately 20 to 30% of all human cancers. Ras proteins are switches that regulate diverse functions such as cell proliferation, differentiation and apoptosis. Normal p53 expression, also known as the "genome guardian", is a key molecule for suppressing cell proliferation. The great importance of these proteins rests on their intimacy with the events leading to cell proliferation or death. The comprehension of the extent of transformation on Ras and p53, and of the diverse biochemical pathways of intracellular signaling, activated by them, is of extreme importance for the understanding of malignant transformation, as well as its control, through the creation, for example, of new drugs which contribute to the elimination of these cells. To clarify the consequences originated by transformed Ras, p53 and their biochemical interlinks in the different intracellular pathways, besides the possible intervening points and pharmacological controls presently used in combating cancer, are the aims of this review.