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In this study, we evaluated the effects of autologous serum collected after two types of exercise on the in vitro inflammatory profile and T cell phenotype of resting peripheral blood mononuclear cells (PBMCs) in obese men. Serum samples and PBMCs were obtained from eight obese men who performed two exercise bouts—high intensity interval exercise (HIIE) and exhaustive exercise session to voluntary fatigue—in a randomized cross-over trial. Pre-exercise PBMCs were incubated with 50% autologous serum (collected before and after each exercise bout) for 4 h. In vitro experiments revealed that post-HIIE serum reduced the histone H4 acetylation status and NF-κB content of PBMCs and suppressed the production of both TNF-α and IL-6 by PBMCs, while increasing IL-10 production. Post-exhaustive exercise serum induced histone H4 hyperacetylation and mitochondrial depolarization in lymphocytes and increased TNF-α production. In vitro post-HIIE serum incubation resulted in an increase in the frequencies of CD4 + CTLA-4 + and CD4 + CD25+ T cells expressing CD39 and CD73. Post-exhaustive exercise serum decreased the frequency of CD4 + CD25 + CD73+ T cells but increased CD4 + CD25-CD39 + T cell frequency. Both post-exercise serums increased the proportions of CD4 + PD-1 + and CD8 + PD-1+ T cells. Blood serum factors released during exercise altered the immune response and T cell phenotype. The type of exercise impacted the immunomodulatory activity of the post-exercise serum on PBMCs.

Lifelong exercise is associated with beneficial immune adaptations, but the extent to which these adaptations manifest during an acute inflammatory challenge remains unclear. Therefore, we aimed to compare the inflammatory responses to ex vivo whole blood and peripheral blood mononuclear cells [PBMCs] cultures from young and master athletes, before and after a single bout of moderate-intensity exercise. Young (n=7; 22 ± 4 years) and master (n=12; 52 ± 9 years) female and male athletes with similar performance levels performed a 30-minute bout of moderate-intensity exercise. Blood samples were collected before and post-exercise to assess cytokine production in whole blood and PBMCs after stimulation with lipopolysaccharide [LPS] and a cocktail with phorbol 12-myristate 13-acetate [PMA] plus ionomycin. In whole blood, LPS induced higher interleukin [IL]-6 release in both groups, with a greater increase in young athletes at post-exercise (p=0.014). Tumor necrosis factor [TNF]-α levels increased only in young athletes (p<0.0001). In PBMCs, master athletes showed lower LPS-induced TNF-α release, increasing only post-exercise (p<0.034), whereas young athletes responded at both baseline (p<0.001) and post-exercise (p=0.003). Under PMA/ionomycin stimulation, TNF-α (p<0.0001) and interferon (IFN)-γ (p=0.007) release increased only in young athletes, while IL-6 production decreased in young athletes at baseline (p=0.002) and post-exercise (p=0.003). Young athletes exhibit a stronger cytokine response to ex vivo inflammatory stimuli, while master athletes demonstrate a more controlled and regulated inflammatory profile.

The phenolic diterpene carnosic acid (CA, C 20 H 28 O 4 ) exerts antioxidant, anti-inflammatory, anti-apoptotic, and anti-cancer effects in mammalian cells. CA activates the nuclear factor erythroid 2-related factor 2 (Nrf2), among other signaling pathways, and restores cell viability in several in vitro and in vivo experimental models. We have previously reported that CA affords mitochondrial protection against various chemical challenges. However, it was not clear yet whether CA would prevent chemically induced impairment of the tricarboxylic acid cycle (TCA) function in mammalian cells. In the present work, we found that a pretreatment of human neuroblastoma SH-SY5Y cells with CA at 1 μM for 12 h prevented the hydrogen peroxide (H 2 O 2 )-induced impairment of the TCA enzymes (aconitase, α-ketoglutarate dehydrogenase (α-KGDH), succinate dehydrogenase (SDH)) and abolished the inhibition of the complexes I and V and restored the levels of ATP by a mechanism associated with Nrf2. CA also exhibited antioxidant abilities by enhancing the levels of reduced glutathione (GSH) and decreasing the content oxidative stress markers (cellular 8-oxo-2′-deoxyguanosine (8-oxo-dG), and mitochondrial malondialdehyde (MDA), protein carbonyl, and 3-nitrotyrosine). Silencing of Nrf2 by small interfering RNA (siRNA) abrogated the protective effects elicited by CA in mitochondria of SH-SY5Y cells. Therefore, CA prevented the H 2 O 2 -triggered mitochondrial impairment by an Nrf2-dependent mechanism. The specific role of Nrf2 in ameliorating the function of TCA enzymes function needs further research.

In this study we explored the previously established leishmanicidal activity of a complementary set of 24 imidazolium salts (IS), 1-hexadecylimidazole (C 16 Im) and 1-hexadecylpyridinium chloride (C 16 PyrCl) against Leishmania (Leishmania) amazonensis and Leishmania (Leishmania) infantum chagasi . Promastigotes of L. amazonensis and L. infantum chagasi were incubated with 0.1 to 100 μM of the compounds and eight of them demonstrated leishmanicidal activity after 48 h – C 10 MImMeS (IC 50 L. amazonensis = 11.6), C 16 MImPF 6 (IC 50 L. amazonensis = 6.9), C 16 MImBr (IC 50 L. amazonensis = 6), C 16 M 2 ImCl (IC 50 L. amazonensis = 4.1), C 16 M 4 ImCl (IC 50 L. amazonensis = 1.8), (C 10 ) 2 MImCl (IC 50 L. amazonensis = 1.9), C 16 Im (IC 50 L. amazonensis = 14.6), and C 16 PyrCl (IC 50 L. amazonensis = 4).The effect of IS on reactive oxygen species production, mitochondrial membrane potential, membrane integrity and morphological alterations of promastigotes was determined, as well as on L. amazonensis -infected macrophages. Their cytotoxicity against macrophages and human erythrocytes was also evaluated. The IS C 10 MImMeS, C 16 MImPF 6 , C 16 MImBr, C 16 M 2 ImCl, C 16 M 4 ImCl and (C 10 ) 2 MImCl, and the compounds C 16 Im and C 16 PyrCl killed and inhibited the growth of promastigote forms of L. amazonensis and L. infantum chagasi in a concentration-dependent manner, contributing to a better understanding of the structure-activity relationship of IS against Leishmania . These IS induced ROS production, mitochondrial dysfunction, membrane disruption and morphological alterations in infective forms of L. amazonensis and killed intracellular amastigote forms in very low concentrations (IC 50 amastigotes ≤ 0.3), being potential drug candidates against L. amazonensis .

Sepsis is characterized by the host's dysregulated immune response to an infection followed by a potentially fatal organ dysfunction. Although there have been some advances in the treatment of sepsis, mainly focused on broad-spectrum antibiotics, mortality rates remain high, urging for the search of new therapies. Oxidative stress is one of the main features of septic patients, so antioxidants can be a good alternative treatment. is a nutraceutical rich in bioactive compounds such as polyphenols and polysaccharides, exhibiting antioxidant, antitumor, and immunomodulatory activities. Here, we investigated the immunomodulatory and antioxidant effects of aqueous extract in the cecal ligation and puncture (CLP) sepsis model. Our data showed that aqueous extract of reduced systemic inflammatory response and improved bacteria clearance and mice survival. In addition, decreased the oxidative stress markers in serum, peritoneal cavity, heart and liver of septic animals, as well as ROS production ( and ) and -Butyl hydroperoxide-induced DNA damage in peripheral blood mononuclear cells from healthy donors . In conclusion, the aqueous extract of was able to increase the survival of septic animals by a mechanism involving immunomodulatory and antioxidant protective effects.

There is currently little information on the positioning of reference electrode (RE). It is generally accepted that it must be positioned on electrically neutral tissues, such as tendons or bony prominences. The objective of this study is to analyze the characteristics of the electromyographic signal (EMG) for different positions of RE as well as at different levels of muscle contraction. Signals from the brachial biceps and triceps were recorded from 18 healthy women (BMI: 21.20 kg/m2 ± 1.72; mean age: 21.94 ± 1.98 years old) during 100 and 50% maximum flexion voluntary isometric contractions, as well as at rest. For each situation, the RE was randomly positioned in 4 different locations: a) homolateral acromion; b) homolateral brachial biceps; c) styloid process of the contralateral ulna; and d) lateral malleolus of the contralateral ankle. For statistical analysis, Shapiro-Wilk and Kruskal-Wallis tests were used, followed by Dunn’s post-hoc test, at a significance level of 5% (p < 0.05). RMS, normalized RMS, PSD, median frequency and levels of energy at 60 Hz, 120 Hz and 180 Hz were assessed for the different sites of RE. The results show that the positioning of the RE on the four experimental locations did not change important features of the electromyographic signals in the time and frequency domains, for the three levels of isometric contractions studied. Such findings compel us to re-think the current trend regarding the RE position followed by the great majority of the researches in areas such as physical therapy.

Pinocembrin (PB; 5,7-dihydroxyflavanone) is found in propolis and exhibits antioxidant activity in several experimental models. The antioxidant capacity of PB is associated with the activation of the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. The Nrf2/ARE axis mediates the expression of antioxidant and detoxifying enzymes, such as glutathione peroxidase (GPx), glutathione reductase (GR), heme oxygenase-1 (HO-1), and the catalytic (GCLC) and regulatory (GCLM) subunits of the rate-limiting enzyme in the synthesis of glutathione (GSH), γ-glutamate-cysteine ligase (γ-GCL). Nonetheless, it is not clear how PB exerts mitochondrial protection in mammalian cells. Human neuroblastoma SH-SY5Y cells were pretreated (4 h) with PB (0–25 µM) and then exposed to methylglyoxal (MG; 500 µM) for further 24 h. Mitochondria were isolated by differential centrifugation. PB (25 µM) provided mitochondrial protection (decreased lipid peroxidation, protein carbonylation, and protein nitration in mitochondrial membranes; decreased mitochondrial free radical production; enhanced the content of GSH in mitochondria; rescued mitochondrial membrane potential—MMP) and blocked MG-triggered cell death by a mechanism dependent on the activation of the extracellular-related kinase (Erk1/2) and consequent upregulation of Nrf2. PB increased the levels of GPx, GR, HO-1, and mitochondrial GSH. The PB-induced effects were suppressed by silencing of Nrf2 with siRNA. Therefore, PB activated the Erk1/2–Nrf2 signaling pathway resulting in mitochondrial protection in SH-SY5Y cells exposed to MG. Our work shows that PB is a strong candidate to figure among mitochondria-focusing agents with pharmacological potential.

Higher endotoxin in the circulation may indicate a compromised state of host immune response against coinfections in severe COVID-19 patients. We evaluated the inflammatory response of monocytes from COVID-19 patients after lipopolysaccharide (LPS) challenge. Whole blood samples of healthy controls, patients with mild COVID-19, and patients with severe COVID-19 were incubated with LPS for 2 h. Severe COVID-19 patients presented higher LPS and sCD14 levels in the plasma than healthy controls and mild COVID-19 patients. In non-stimulated in vitro condition, severe COVID-19 patients presented higher inflammatory cytokines and PGE-2 levels and CD14 + HLA-DRlow monocytes frequency than controls. Moreover, severe COVID-19 patients presented higher NF-κB p65 phosphorylation in CD14 + HLA-DRlow, as well as higher expression of TLR-4 and NF-κB p65 phosphorylation in CD14 + HLA-DRhigh compared to controls. The stimulation of LPS in whole blood of severe COVID-19 patients leads to lower cytokine production but higher PGE-2 levels compared to controls. Endotoxin challenge with both concentrations reduced the frequency of CD14 + HLA-DRlow in severe COVID-19 patients, but the increases in TLR-4 expression and NF-κB p65 phosphorylation were more pronounced in both CD14 + monocytes of healthy controls and mild COVID-19 patients compared to severe COVID-19 group. We conclude that acute SARS-CoV-2 infection is associated with diminished endotoxin response in monocytes. Key messagesSevere COVID-19 patients had higher levels of LPS and systemic IL-6 and TNF-α.Severe COVID-19 patients presented higher CD14+HLA-DRlow monocytes.Increased TLR-4/NF-κB axis was identified in monocytes of severe COVID-19.Blunted production of cytokines after whole blood LPS stimulation in severe COVID-19.Lower TLR-4/NF-κB activation in monocytes after LPS stimulation in severe COVID-19.

Mitochondria are susceptible to redox impairment, which has been associated with neurodegeneration. These organelles are both a source and target of reactive species. In that context, there is increasing interest in finding natural compounds that modulate mitochondrial function and mitochondria-related signaling in order to prevent or to treat diseases involving mitochondrial impairment. Herein, we investigated whether and how pinocembrin (PB) would prevent mitochondrial dysfunction elicited by the exposure of human neuroblastoma SH-SY5Y cells to hydrogen peroxide (H 2 O 2 ). PB (25 μM) was administrated for 4 h before H 2 O 2 treatment (300 μM for 24 h). PB prevented H 2 O 2 -induced loss of cell viability mitochondrial depolarization in SH-SY5Y cells. PB also attenuated redox impairment in mitochondrial membranes. The production of superoxide anion radical (O 2 −• ) and nitric oxide (NO • ) was alleviated by PB in cells exposed to H 2 O 2 . PB suppressed the H 2 O 2 -induced inhibition of the tricarboxylic acid (TCA) cycle enzymes aconitase, α-ketoglutarate dehydrogenase, and succinate dehydrogenase. Furthermore, PB induced anti-inflammatory effects by abolishing the H 2 O 2 -dependent activation of the nuclear factor-κB (NF-κB) and upregulation of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). The PB-induced antioxidant and anti-inflammatory effects are dependent on the heme oxygenate-1 (HO-1) enzyme and on the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), since HO-1 inhibition (with 0.5 μM ZnPP IX) or Nrf2 silencing (with small interfering RNA (siRNA)) abolished the effects of PB. Overall, PB afforded cytoprotection by the Nrf2/HO-1 axis in H 2 O 2 -treated SH-SY5Y cells.