Renoprotective mechanisms of exercise training against acute and chronic renal diseases - A perspective based on experimental studies.

Regular exercise training can lead to several health benefits, reduce mortality risk, and increase life expectancy. On the other hand, a sedentary lifestyle is a known risk factor for chronic diseases and increased mortality. Acute kidney injury (AKI) and chronic kidney disease (CKD) represent a significant global health problem, affecting millions of people worldwide. The progression from AKI to CKD is well-recognized in the literature, and exercise training has emerged as a potential renoprotective strategy. Thus, this article aims to review the main molecular mechanisms underlying the renoprotective actions of exercise training in the context of AKI and CKD, focusing on its antioxidative, anti-inflammatory, anti-apoptotic, anti-fibrotic, and autophagy regulatory effects. For that, bibliographical research was carried out in Medline/PubMed and Scielo databases. Although the pathophysiological mechanisms involved in renal diseases are not fully understood, experimental studies demonstrate that oxidative stress, inflammation, apoptosis, and dysregulation of fibrotic and autophagic processes play central roles in the development of tissue damage. Increasing evidence has suggested that exercise can beneficially modulate these mechanisms, potentially becoming a safe and effective non-pharmacological strategy for kidney health protection and promotion. Thus, the evidence base discussed in this review suggests that an adequate training program emerges as a valuable tool for preserving renal function in experimental animals, mainly through the production of antioxidant enzymes, nitric oxide (NO), irisin, IL-10, and IL-11. Future research can continue to explore these mechanisms to develop specific guidelines for the prescription of exercise training in different populations of patients with kidney diseases.

An integrated view of cisplatin-induced nephrotoxicity, hepatotoxicity, and cardiotoxicity: characteristics, common molecular mechanisms, and current clinical management.

Cisplatin (CP) is a chemotherapy drug widely prescribed to treat various neoplasms. Although fundamental for the therapeutic action of the drug, its cytotoxic mechanisms trigger adverse effects in several tissues, such as the kidney, liver, and heart, which limit its clinical use. In this sense, studies point to an essential role of damage to nuclear and mitochondrial DNA associated with oxidative stress, inflammation, and apoptosis in the pathophysiology of tissue injuries. Due to the limitation of effective preventive and therapeutic measures against CP-induced toxicity, new strategies with potential cytoprotective effects have been studied. Therefore, this article is timely in reviewing the characteristics and main molecular mechanisms common to renal, hepatic, and cardiac toxicity previously described, in addition to addressing the main validated strategies for the current management of these adverse events in clinical practice. We also handle the main promising antioxidant substances recently presented in the literature to encourage the development of new research that consolidates their potential preventive and therapeutic effects against CP-induced cytotoxicity.

Renal functional and structural alterations induced by intramuscular injection of Bothrops leucurus venom.

Acute kidney injury (AKI) is the main cause of death from Bothrops snakebite. Although many studies have investigated the nephrotoxicity induced by other Bothrops species, no study has assessed the renal alterations induced by intramuscular (i.m.) injection of Bothrops leucurus venom. In this study, we evaluated the nephrotoxicity induced by B. leucurus venom by analyzing renal function and histology. Wistar rats were submitted to i. m. injection of B. leucurus venom or saline and divided into two groups: Control group (C), rats submitted to i. m. injections of saline, and B. leucurus group (Bl), rats submitted to i. m. injections of B. leucurus venom (1 mg/kg). After venom or saline injection, serum and urine were collected to measure creatinine, albumin, sodium, and potassium levels. The glomerular filtration rate (GFR), urinary flow urinary, creatinine/serum creatinine ratio, and albuminuria-urinary creatinine ratio were determined. All rats were euthanized 72 h following the injections, and the kidneys were removed for histology and immunohistochemical studies. B. leucurus experimental envenoming was accompanied by an increase of 236% in serum creatine kinase activity in the Bl group. The weights of the right and left kidneys were, respectively, 26 and 22% higher in rats of the Bl group than in control rats. Regarding renal function, the Bl group showed a decrease of 37% in GFR compared to control group. The rats of the Bl group also presented increased cortical (8.20 ± 1.35) and medullar (6.17 ± 2.00) tubulointerstitial lesion area when compared to control group (0.02 ± 0.00) (1.20 ± 0.73), respectively. The number of macrophages was also higher in the renal cortex (6.66 ± 0.06) and medulla (1.22 ± 0.10) of rats from the Bl group when compared to control rats (1.04 ± 0.55), (0.65 ± 0.10), respectively. Our results indicate that B. leucurus venom promoted significant histological and functional renal alterations following intramuscular inoculation, which simulates the majority of snakebites observed in the clinical practice.

Effects of 5α-dihydrotestosterone on the modulation of monocyte/macrophage response to Staphylococcus aureus: an in vitro study.

BACKGROUND: Staphylococcus aureus (S. aureus) is a pathogen responsible for a wide range of clinical manifestations and potentially fatal conditions. There is a paucity of information on the influence of androgens in the immune response to S. aureus infection. In this study, we evaluated the influence of the hormone 5α-dihydrotestosterone (DHT) on mouse peritoneal macrophages (MPMs) and human peripheral blood monocytes (HPBMs) induced by S. aureus. METHODS: An in vitro model of MPMs from BALB/c sham males, orchiectomised (OQX) males, and females was used. Cells were inoculated with 10 µL of S. aureus, phage-type 80 or sterile saline (control) for 6 h. The MPMs of OQX males and females were pre-treated with 100 µL of 10-2 M DHT for 24 h before inoculation with S. aureus. The concentration of the cytokines TNF-α, IL-1α, IL-6, IL-8, and IL-10; total nitrites (NO-2); and hydrogen peroxide (H2O2) were measured in the supernatant of MPM cultures. In addition, the toll-like receptor 2 (TLR2) and nuclear factor kappa B (NF-kB) genes that are involved in immune responses were analysed. For the in vitro model of HPBMs, nine men and nine women of childbearing age were selected and HPBMs were isolated from samples of the volunteers' peripheral blood. In women, blood was collected during the periovulatory period. The HPBMs were inoculated with S. aureus for 6 h and the supernatant was collected for the analysis of cytokines TNF-α, IL-6, IL-12; and GM-CSF, NO-2, and H2O2. The HPBMs were then removed for the analysis of 84 genes involved in the host's response to bacterial infections by RT-PCR array. GraphPad was used for statistical analysis with a p value < 0.05. RESULTS: Our data demonstrated that MPMs from sham males inoculated with S. aureus displayed higher concentrations of inflammatory cytokines and lower concentrations of IL-10, NO-2, and H2O2 when compared with MPMs from OQX males and females. A similar result was observed in the HPBMs of men when compared with those of women. Previous treatment with DHT in women HPBMs increased the production of pro-inflammatory cytokines and decreased the levels of IL-10, NO-2, and H2O2. The analysis of gene expression showed that DHT increased the activity of the TLR2 and NF-kB pathways in both MPMs and HPBMs. CONCLUSIONS: We found that DHT acts as an inflammatory modulator in the monocyte/macrophage response induced by S. aureus and females exhibit a better immune defence response against this pathogen.

Natural Compounds: Co-Delivery Strategies with Chemotherapeutic Agents or Nucleic Acids Using Lipid-Based Nanocarriers.

Cancer is one of the leading causes of death, and latest predictions indicate that cancer- related deaths will increase over the next few decades. Despite significant advances in conventional therapies, treatments remain far from ideal due to limitations such as lack of selectivity, non-specific distribution, and multidrug resistance. Current research is focusing on the development of several strategies to improve the efficiency of chemotherapeutic agents and, as a result, overcome the challenges associated with conventional therapies. In this regard, combined therapy with natural compounds and other therapeutic agents, such as chemotherapeutics or nucleic acids, has recently emerged as a new strategy for tackling the drawbacks of conventional therapies. Taking this strategy into consideration, the co-delivery of the above-mentioned agents in lipid-based nanocarriers provides some advantages by improving the potential of the therapeutic agents carried. In this review, we present an analysis of the synergistic anticancer outcomes resulting from the combination of natural compounds and chemotherapeutics or nucleic acids. We also emphasize the importance of these co-delivery strategies when reducing multidrug resistance and adverse toxic effects. Furthermore, the review delves into the challenges and opportunities surrounding the application of these co-delivery strategies towards tangible clinical translation for cancer treatment.

Therapeutic or lifelong training effects on pancreatic morphological and functional parameters in an animal model of aging and obesity.

AIMS: Obesity, aging, and physical training are factors influencing pancreatic functional and morphological parameters. Aiming to clarify the impact of the interaction of these factors, we analyzed the effect of therapeutic or lifelong physical training on body adiposity and pancreatic functional and morphological parameters of aged and obese rats. METHODS: 24 male Wistar rats were (initial age = 4 months and final age = 14 months) randomly divided into three aged and obese experimental groups (n = 8/group): untrained, therapeutic trained, and lifelong trained. Body adiposity, plasmatic concentration and pancreatic immunostaining of insulin, markers of tissue inflammation, lipid peroxidation, activity and immunostaining of antioxidant enzymes, and parameters of pancreatic morphology were evaluated. RESULTS: Lifelong physical training improved the body adiposity, plasmatic insulin concentration, and macrophage immunostaining in the pancreas. The animals submitted to therapeutic and lifelong training showed an increase in the density of the pancreatic islets; lower insulin, Nuclear Factor Kappa B (NF-κB), and Transforming Growth Factor beta (TGF-ß) immunostaining in the pancreatic parenchyma, as well as lower pancreatic tissue lipid peroxidation, lower fibrosis area, increased catalase and glutathione peroxidase (GPx) activity and increased heme oxygenase-1 (HO-1) immunostaining, with the greatest effect in the lifelong training group. CONCLUSION: Lifelong training promoted greater beneficial effects on the pancreatic functional and morphological parameters of aged and obese animals compared to therapeutic exercise.

Benefits of high-intensity interval training compared to continuous training to reduce apoptotic markers in female rats with cisplatin nephrotoxicity - possible modulatory role of IL-11.

Apoptotic signaling pathways are involved in acute kidney injury (AKI) induced by the antineoplastic drug cisplatin (Cis). Mechanical stress is known to increase interleukin (IL) -11, a pleiotropic cytokine with antiapoptotic and antinecrotic effects. We compared the impact of high-intensity interval training (HIIT) with low-intensity continuous training (LICT) and moderate-intensity continuous training (MICT) on renal levels of IL-11 and the expression of apoptotic markers in female rats with nephrotoxicity induced by Cis. For that, the animals were divided into five groups (n = 7): control and sedentary (C + S); Cis and sedentary (Cis + S); Cis and LICT (Cis + LICT); Cis and MICT (Cis + MICT) and Cis and HIIT (Cis + HIIT). At the end of 8 weeks of treadmill running, the rats received a single injection of Cis (5 mg/kg), and 7 days later they were euthanized. Serum and kidney samples were collected to assess the blood urea nitrogen (BUN), gene expression of TNF receptor 1 (TNFR1) and 2 (TNFR2), caspase-3, (p38) MAPK (MAPK14), p53, Bax, Bak, Bcl-2, and Bcl-xL, renal levels of IL-11, IL-8, and p53, and immunolocalization of cleaved caspase-3, Bax, Bcl-2, and (p38) MAPK in renal tissue. Our data indicate that all trained groups showed a significant intensity-dependent increase in renal levels of IL-11 associated with reduced local expression of proapoptotic and increased antiapoptotic markers, but these effects were more pronounced with HIIT. So, HIIT appears to provide superior renoprotection than traditional continuous training by modulating apoptotic signaling pathways, and this effect can be related to the increase in renal levels of IL-11.

Dietary Soy Isoflavones Prevent Metabolic Disturbs Associated with a Deleterious Combination of Obesity and Menopause.

This study aimed to evaluate the effects of soy isoflavone supplementation (25 mg/kg) on insulin resistance and inflammation in adipose tissue in an experimental model of menopause-obesity. Twenty-four female Wistar rats were ovariectomized (O) and distributed among the groups: OSD-ovariectomized rats submitted to normocaloric standard diet (n = 6); OHF-ovariectomized rats submitted to high-fat diet (n = 9); and OHFI-ovariectomized rats submitted to high-fat diet with isoflavones (n = 9). Weight gain, body adiposity, food and caloric intake, blood pressure, and glucose tolerance were assessed. After 24 weeks, the rats were euthanized; the thoracic blood collected for serum insulin determination and the homeostatic model assessment-insulin resistance) (HOMA-IR) and homeostatic model assessment-ß cell (HOMA-ß) indices were calculated. Abdominal adipose tissues were removed, weighed, and fixed for immunohistochemical and morphometric studies. Isoflavones decreased weight gain and blood pressure without changing the food and caloric intake (P < .05). Isoflavones did not affect the weight of the abdominal adipose tissue depots (P < .05). Although they did not alter glucose tolerance, the isoflavones reduced HOMA-IR and HOMA-ß, serum insulin levels, in addition to reducing adipocytes' size (P < .05). The number of macrophages, lymphocytes, and crown-like structures in adipose tissue was lower in the group treated with isoflavones (P < .05). In conclusion, our data show that dietary soy isoflavones' supplementation prevents many of well-known deleterious combination of obesity and menopause on metabolism, such as body overweight, adipocyte hypertrophy, and hypertension, as well as insulin resistance and adipose tissue inflammation.

COVID-19 and Acute Kidney Injury - Direct and Indirect Pathophysiological Mechanisms Underlying Lesion Development.

COVID-19 is a pandemic disease caused by the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) responsible for millions of deaths worldwide. Although the respiratory system is the main target of COVID-19, the disease can affect other organs, including the kidneys. Acute Kidney Injury (AKI), commonly seen in patients infected with COVID-19, has a multifactorial cause. Several studies associate this injury with the direct involvement of the virus in renal cells and the indirect damage stimulated by the infection. The direct cytopathic effects of SARS-CoV-2 are due to the entry and replication of the virus in renal cells, changing several regulatory pathways, especially the renin-angiotensin-aldosterone system (RAAS), with repercussions on the kallikrein-kinin system (KKS). Furthermore, the virus can deregulate the immune system, leading to an exaggerated response of inflammatory cells, characterizing the state of hypercytokinemia. The such exaggerated inflammatory response is commonly associated with hemodynamic changes, reduced renal perfusion, tissue hypoxia, generation of reactive oxygen species (ROS), endothelial damage, and coagulopathies, which can result in severe damage to the renal parenchyma. Thereby, understanding the molecular mechanisms and pathophysiology of kidney injuries induced by SARS-COV-2 is of fundamental importance to obtaining new therapeutic insights for the prevention and management of AKI.

Ovariectomy exacerbates glycerol-induced acute kidney injury in rats / A ovariectomia intensifica a lesão renal aguda induzida pelo glicerol em ratas

Objective: This study aimed to evaluate the effects of ovariectomy on glycerol-induced renal changes in rats. Methods: Twenty-four female Wistar rats were submitted to ovariectomized (OVX) or sham surgery. One week after surgery, the animals received an intramuscular injection (8ml/kg) of 50% glycerol or saline (0.15 M) solution. These animals were divided into the following groups (n=6 per group): Sham, sham-operated female rats injected with saline; OVX, ovariectomized female rats injected with saline; Sham+Gly, sham-operated female rats injected with glycerol; OVX+Gly, ovariectomized female rats injected with glycerol. All rats were euthanized 3 days after the injections and the kidneys were removed for histological and immunohistochemical studies. Blood and urine samples were also collected for renal function studies. Results: The OVX+Gly group presented higher creatinine serum levels, as well as greater fractional excretion of sodium and urinary flow than the Sham+Gly group. Histological lesions and tubulointerstitial staining for macrophages, nuclear factor-kappa B, and nitrotyrosine were more pronounced in the renal cortex of the OVX+Gly group compared to the Sham+Gly group. Conclusion: We conclude that ovariectomy aggravated changes in renal function and structure in glycerol-induced acute kidney injury by the intensification of the proinflammatory tissue response.

Objetivo: Avaliar os efeitos da ovariectomia nas alterações renais induzidas pelo glicerol em ratas. Métodos: Vinte e quatro ratas Wistar foram submetidas à ovariectomia (OVX) ou cirurgia sham (intervenção falsa). Uma semana após a cirurgia, os animais receberam injeção intramuscular (8ml/kg) de glicerol a 50% ou solução salina (0,15 M). As ratas foram divididas nos seguintes grupos (n=6 por grupo): Sham, fêmeas sham-operadas e injetadas com solução salina; OVX, fêmeas ovariectomizadas e injetadas com solução salina; Sham+Gly, fêmeas sham-operadas e injetados com glicerol; OVX+Gly, fêmeas ovariectomizadas e injetadas com glicerol. Todas as ratas foram eutanasiadas 3 dias após as injeções e os rins foram removidos para estudos histológicos e imuno-histoquímicos. Amostras de sangue e urina também foram coletadas para estudos de função renal. Resultados: O grupo OVX+Gly apresentou maiores níveis séricos de creatinina, assim como maiores fração de excreção de sódio e fluxo urinário do que o grupo Sham+Gly. As lesões histológicas e imunomarcação tubulointersticial para macrófagos, fator nuclear-kappa B e nitrotirosina foram mais pronunciadas no córtex renal do grupo OVX+Gly em comparação ao grupo Sham+Gly. Conclusão: Concluímos que a ovariectomia agravou as alterações na função e estrutura renal, na lesão renal aguda induzida por glicerol, pela intensificação da resposta tecidual pró-inflamatória.

Antimicrobial photodynamic therapy (aPDT) with curcumin controls intradermal infection by Staphylococcus aureus in mice with type 1 diabetes mellitus: a pilot study.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the main pathogens that cause infections in diabetic individuals. In this paper, we report the outcomes of our investigation on the intradermal application of antimicrobial photodynamic therapy (PDT) with curcumin in an infection induced by MRSA ATCC 43300 strain in the ear of mice with Type 1 Diabetes Mellitus (T1DM). A solution containing 100 µg of curcumin was photoactivated ex vivo with a LED light (450 nm) delivering a fluency of 13.5 J/cm3. This solution was administered in the ear intradermally, at the same inoculum site as the MRSA ATCC 43300 strain (PDT Group). This study also included the use of two control groups (both infected): One was treated with saline and the other was treated with non-photoactivated curcumin. The animals were euthanized 24 h after these treatments and samples of draining lymph node and treated ear were collected for examination. The PDT group showed lower bacterial load in the draining lymph node when compared to the saline and curcumin groups (p-value <0.05) 24 h after treatment. In addition to bacterial load, the PDT group presented a higher concentration of nitrates and nitrites in the draining lymph node when compared to the saline and curcumin groups (p-value <0.001). Examining the infectious site, despite apparently having similar inflammatory cell recruitment compared with the control groups, the PDT group showed a profile with less intense activity in the myeloperoxidase expression when compared to the saline group (p-value <0.001). Additionally, the detected concentration of cytokines such as IL-1ß, IL-12, and IL-10 was significantly lower in the PDT group when compared to the saline group (p-value <0.01; p-value <0.05; p-value <0.05, respectively), thus presenting a less intense inflammatory response during infection resolution. Our pilot study showed for the first time the therapeutic potential of PDT using curcumin when administered intradermally in the treatment of infections caused by S. aureus in mice with T1DM.

Effects of 17ß-Estradiol on Monocyte/Macrophage Response to Staphylococcus aureus: An In Vitro Study.

To describe how 17ß-estradiol (E2) influence in the monocyte/macrophage response induced by S. aureus in in vitro models of murine peritoneal macrophages (MPMs) and human peripheral blood monocytes (HPBM). MPMs (2 x 105/ml) were isolated from sham (n=3) and ovariectomized (OVX) females (n = 3) and males (n = 3) after induction by thioglycolate. The MPMs obtained from OVX females and males were treated for 24 hours with 17ß-estradiol (E2) (10-7 M), and after that, inoculation with S. aureus was carried out for 6 hours. The macrophages were collected and destined to evaluate the relative gene expression of TNF-α, IL-1ß, IL-6, IL-8 and TLR2. For the in vitro model of HPBMs, six men and six women of childbearing age were selected and HPBMs were isolated from samples of the volunteers' peripheral blood. In women, blood was collected both during menstruation and in the periovulatory period. HPBMs were inoculated with S. aureus for 6 hours and the supernatant was collected for analysis of cytokines by Luminex and the HPBMs were removed for analysis of 84 genes involved in the host's response to bacterial infections by RT-PCR array. Previous treatment with E2 decreased the gene expression and production of proinflammatory cytokines, such as TNF-α, IL-1ß and IL-6 and decreased the expression of TLR2 tanto em MPMs quanto em HPBMs. The analysis of gene expression shows that E2 inhibited the NFκB pathway. It is suggested that 17ß-estradiol acts as an immunoprotective in the monocyte/macrophage response induced by S. aureus.

High-intensity interval training is more effective than continuous training to reduce inflammation markers in female rats with cisplatin nephrotoxicity.

AIMS: Cisplatin (CP) is an antineoplastic widely used in the treatment of various solid tumors, however, its clinical application is limited by nephrotoxicity. Here, we compared the impact of preconditioning with high-intensity interval training (HIIT) with continuous training of low (LIT) and moderate (MIT) intensity on innate immunity markers in female rats with CP-induced acute kidney injury. MATERIALS AND METHODS: The rats were divided into five groups (n = 7): saline control and sedentary (C + S); CP and sedentary (CP + S); CP and LIT (CP + LIT); CP and MIT (CP + MIT) and CP and HIIT (CP + HIIT). The training intensity was determined by a maximum running test. At the end of training, the rats received a single dose of CP (5 mg/kg), and 7 days later they were euthanized. We evaluated renal function parameters (serum creatinine, glomerular filtration rate and proteinuria), renal structure, macrophage tissue infiltration, immunolocalization of nuclear transcription factor kappa B (NF-κB), renal levels of tumor necrosis factor-alpha (TNF-α), interleukin 1ß (IL-1ß), and interleukin 6 (IL-6), and gene expression of monocyte chemoattractant protein-1 (MCP-1), toll-like receptor 4 (TLR4), and NF-κB in renal tissue. KEY FINDINGS: Although both MIT and HIIT attenuated the degree of renal injury, only the HIIT prevented changes in renal function. The three training protocols mitigated the increase in expression of all inflammatory markers, however, this effect was more pronounced in HIIT. SIGNIFICANCE: All training protocols promoted renoprotective actions, but HIIT was more effective in mitigating CP-induced acute kidney injury, in part by modulation of important markers of the innate immune response.

Acute kidney injury induced by glycerol is worsened by orchiectomy and attenuated by testosterone replacement.

Although several studies have demonstrated that the male gender represents an independent risk factor for renal disease, evidence shows that androgens exert renal protective actions. The findings are controversial and no studies have evaluated the effects of orchiectomy and testosterone replacement on glycerol-induced renal injury. Male Wistar rats were submitted to orchiectomy or sham surgery and divided into four groups: SC, sham control rats injected with NaCl; SG, sham rats injected with glycerol; OG, orchiectomized rats injected with glycerol; OGT, orchiectomized rats injected with glycerol and testosterone. Testosterone was administered daily for 14 days in the OGT group. After 11 days of testosterone replacement in the OGT group, SC rats were submitted to a saline injection, while SG, OG and OGT rats received glycerol. All rats were euthanized three days after injections. OG rats presented higher serum creatinine and urea, and sodium excretion, compared to SC and SG, while testosterone attenuated these changes. Acute tubular necrosis was also mitigated by testosterone. Renal immunostaining for macrophages, lymphocytes and NF-κB was higher in OG compared to SC and SG. In addition, renal interleukin-1ß, Caspase 3 and AT1 gene expression was higher in OG rats compared to SG. Testosterone attenuated these alterations, except the NF-κB immunostaining. The renal NO was lower in OG rats compared to SG. Only the OG rats presented decreases in serum NO and renal HO-1, and increased TNF-α, angiotensinogen and AT1 expression compared to SC. We conclude that orchiectomy worsened glycerol-induced kidney injury, while testosterone attenuated this renal damage.

Ovarian hormones influence immune response to Staphylococcus aureus infection

ABSTRACT Objective: Staphylococcus aureus infections remain associated with considerable morbidity and mortality in both hospitals and the community. There is little information regarding the role of ovarian hormones in infections caused by S. aureus. The aim of this study was to evaluate the effects of ovariectomy in the immune response induced by S. aureus. Methods: Female mice BALB/c were ovariectomized (OVX) to significantly reduce the level of ovarian hormones. We also used sham-operated animals. The mice were inoculated intraperitoneally with S. aureus. Blood samples were collected for leukocyte count and bacterial quantification. The uterus and spleen were removed and weighed to calculate the uterine and splenic indexes. Lungs were removed and fractionated for immunohistochemical analysis for macrophage detection (anti-CD68) and relative gene expression of IL-6, IL-1β and TNF-α by RT-PCR. Results: Ovariectomy enlarged spleen size and generally increased circulating lymphocytes. OVX females experienced a continuation of the initial reduction of lymphocytes and a monocyte and neutrophil late response compared to shams (p ≥ 0.05). Moreover, OVX females showed neutropenia after 168 h of infection (p ≥ 0.05). Macrophage response in the lungs were less pronounced in OVX females in the initial hours of infection (p ≥ 0.01). OVX females showed a higher relative gene expression of IL-1β, IL-6 and TNF-α in the lung at the beginning of the infection compared to sham females (p ≥ 0.01). Among the uninfected females, the OVX control females showed a higher expression of IL-6 in the lung compared to the sham control females (p ≥ 0.05). In this model, the lack of ovarian hormones caused a minor increase in circulating leukocytes during the initial stage of infection by S. aureus and increased pulmonary gene expression of IL-1β, IL-6, and TNF-α. Ovariectomy alone enlarged the spleen and increased circulating lymphocytes. Ovarian hormones acted as immunoprotectors against S. aureus infection.

Ovarian hormones influence immune response to Staphylococcus aureus infection.

OBJECTIVE: Staphylococcus aureus infections remain associated with considerable morbidity and mortality in both hospitals and the community. There is little information regarding the role of ovarian hormones in infections caused by S. aureus. The aim of this study was to evaluate the effects of ovariectomy in the immune response induced by S. aureus. METHODS: Female mice BALB/c were ovariectomized (OVX) to significantly reduce the level of ovarian hormones. We also used sham-operated animals. The mice were inoculated intraperitoneally with S. aureus. Blood samples were collected for leukocyte count and bacterial quantification. The uterus and spleen were removed and weighed to calculate the uterine and splenic indexes. Lungs were removed and fractionated for immunohistochemical analysis for macrophage detection (anti-CD68) and relative gene expression of IL-6, IL-1ß and TNF-α by RT-PCR. RESULTS: Ovariectomy enlarged spleen size and generally increased circulating lymphocytes. OVX females experienced a continuation of the initial reduction of lymphocytes and a monocyte and neutrophil late response compared to shams (p≥0.05). Moreover, OVX females showed neutropenia after 168h of infection (p≥0.05). Macrophage response in the lungs were less pronounced in OVX females in the initial hours of infection (p≥0.01). OVX females showed a higher relative gene expression of IL-1ß, IL-6 and TNF-α in the lung at the beginning of the infection compared to sham females (p≥0.01). Among the uninfected females, the OVX control females showed a higher expression of IL-6 in the lung compared to the sham control females (p≥0.05). In this model, the lack of ovarian hormones caused a minor increase in circulating leukocytes during the initial stage of infection by S. aureus and increased pulmonary gene expression of IL-1ß, IL-6, and TNF-α. Ovariectomy alone enlarged the spleen and increased circulating lymphocytes. Ovarian hormones acted as immunoprotectors against S. aureus infection.

Influence of exercise training on diabetic kidney disease: A brief physiological approach.

IMPACT STATEMENT: Diabetic kidney disease (DKD) is associated with increased mortality in diabetic patients and has a negative impact on public health. The identification of potential therapies that help the management of DKD can contribute to the improvement of health and quality of life of patients. Thus, this paper is timely and relevant because, in addition to presenting a concise review of the pathogenesis and major pathophysiological mechanisms of DKD, it addresses the most recent findings on the impact of exercise training on this disease. Thus, since non-pharmacological interventions have gained increasing attention in the fight against chronic diseases, this paper appears as an important tool to increase knowledge and stimulate innovative research on the impact of exercise on kidney disease.

Preventive effect of exercise training on diabetic kidney disease in ovariectomized rats with type 1 diabetes.

IMPACT STATEMENT: To date, no studies have been found evaluating the effects of physical exercise on renal function and structure changes in ovariectomized rats with type 1 diabetes. Therefore, this work emerges with an important tool for strengthening and expanding innovative research on exercise with potential for the prevention of renal diseases in ovariectomized diabetic rats, and future development of studies that seek to increase scientific knowledge about the beneficial effects of physical exercise on renal diseases in humans.

Therapeutic and preventive effects of exercise on cardiometabolic parameters in aging and obese rats.

BACKGROUND AND AIMS: Aging, obesity and sedentarism are among the most important predictors of cardiometabolic diseases. Aiming to reduce the impact of the combination of these three factors, we tested the therapeutic and preventive effects of exercise in aging and obese rats on the following cardiometabolic disease risk parameters: body fat, blood pressure, blood lipids, and glycemic homeostasis. METHODS: Eighteen male Wistar rats (initial age = 4 months, and final age = 14 months) were randomly distributed into three aging and obese groups: sedentary, therapeutic exercise and preventive exercise. Food and caloric intake, body adiposity, muscle mass, cardiovascular parameters, biochemical markers, glycemic homeostasis, and gene expression of insulin-dependent, insulin-independent and insulin resistance pathways in skeletal muscle were evaluated. RESULTS: Therapeutic and preventive exercises were associated with higher food and caloric intake, and expression of TBC1D1 in the soleus muscle, as well as lower total cholesterol/HDL and LDL/HDL ratios, glucose levels at the end (90 min) of the glucose tolerance test and IKBKB expression in the gastrocnemius and soleus muscles. Only the preventive exercise improved the cardiovascular and body composition parameters, glucose tolerance, insulin resistance and insulin sensitivity, besides reducing total cholesterol, triglycerides, triglycerides/HDL ratio, plasmatic insulin and MAPK8 expression in soleus. The preventive exercise group also presented greater expression of INRS, IRS1, IRS2, PIK3CA, AKT1, and SLC2A4 in gastrocnemius and soleus, TBC1D1 in gastrocnemius, and AKT2 and PRKAA1 in soleus. CONCLUSIONS: Therapeutic exercise promoted some improvements on cardiometabolic parameters in aging and obese rats, however, the best benefits were achieved through the preventive exercise.

A Molecular Biophysical Approach to Diclofenac Topical Gastrointestinal Damage.

Diclofenac (DCF), the most widely consumed non-steroidal anti-inflammatory drug (NSAID) worldwide, is associated with adverse typical effects, including gastrointestinal (GI) complications. The present study aims to better understand the topical toxicity induced by DCF using membrane models that mimic the physiological, biophysical, and chemical environments of GI mucosa segments. For this purpose, phospholipidic model systems that mimic the GI protective lining and lipid models of the inner mitochondrial membrane were used together with a wide set of techniques: derivative spectrophotometry to evaluate drug distribution at the membrane; steady-state and time-resolved fluorescence to predict drug location at the membrane; fluorescence anisotropy, differential scanning calorimetry (DSC), dynamic light scattering (DLS), and calcein leakage studies to evaluate the drug-induced disturbance on membrane microviscosity and permeability; and small- and wide-angle X-ray scattering studies (SAXS and WAXS, respectively), to evaluate the effects of DCF at the membrane structure. Results demonstrated that DCF interacts chemically with the phospholipids of the GI protective barrier in a pH-dependent manner and confirmed the DCF location at the lipid headgroup region, as well as DCF's higher distribution at mitochondrial membrane contact points where the impairment of biophysical properties is consistent with the uncoupling effects reported for this drug.