Objective: Resistance exercise can induce muscle damage that impairs sports performance and cellular repair. Myokines, particularly mitochondrial myokines, play an important role in regulating energy metabolism and muscle recovery. The ACTN3 R577X polymorphism, which alters the expression of α-actinin-3 in muscle fibers, may influence myokine responses by modulating exercise adaptation and recovery. Methods: Seventy-five amateur runners (30–55 years) from the São Paulo International Marathon were evaluated. Plasma levels of mitochondrial myokines (BDNF, FGF-21, FSTL, IL-6, apelin, IL-15, musclin, and myostatin) were measured before and after the race and correlated with ACTN3 R577X genotypes. Results: In this study, the genotypic frequencies of the ACTN3 R577X polymorphism were 36% (RR), 39% (RX), and 14% (XX). Plasma concentrations of BDNF, FSTL, FGF-21, and IL-6 increased immediately after running across all genotypes, with no significant differences observed between genotypes. In contrast, plasma levels of myostatin, musclin, IL-15, and apelin decreased during the recovery period only among runners carrying the R allele. Conclusions: Mitochondrial myokine responses to resistance exercise were not substantially different among genotypes of the ACTN3 R577X polymorphism. However, myokines associated with protein breakdown and bioenergetic adaptation were reduced during the recovery period in runners carrying the R allele, which may impact muscle repair and bioenergetic adaptation.

BACKGROUND:In this study, Pinto et al. identified significantly higher levels of neuron-specific enolase and Tau protein in older patients with sepsis-associated delirium in the emergency department, suggesting the potential of these biomarkers as diagnostic tools in this population. OBJECTIVE:Sepsis-associated delirium is a common cerebral manifestation in patients with sepsis, potentially caused by a combination of neuroinflammation and other neurophysiological disorders. This study investigated the expression of neuron-specific enolase and Tau protein as biomarkers in patients with sepsis-associated delirium. While neuron-specific enolase and Tau protein are known to be associated with brain injury, their diagnostic potential in patients with sepsis-associated delirium is not well understood. METHODS:This cross-sectional pilot study evaluated plasma levels of neuron-specific enolase and Tau protein in patients with delirium and sepsis to explore their potential for identifying sepsis in patients admitted to the emergency department. RESULTS:A total of 25 patients with delirium were analyzed, 56% of whom had sepsis. Patients with sepsis exhibited significantly higher neuron-specific enolase levels (2.7ng/mL [95%CI= 2.2-3.2] versus 1.3 ng/mL [95%CI= 0.8-2.5], p<0.003) and Tau protein levels (96.1pg/mL [95%CI= 77.0-111.3] versus 43.0pg/mL [95%CI= 31.2-84.5], p<0.003) compared to patients without sepsis. Neuron-specific enolase and Tau protein thresholds of >2.08ng/mL and >59.27pg/mL, respectively, demonstrated 90% specificity for identifying sepsis in patients. CONCLUSION:Neuron-specific enolase and Tau protein levels were significantly higher in patients with sepsis than in those without, underscoring their potential ability to identify the infectious etiology of delirium in older patients admitted to emergency departments. Clinical Trials #RBR-233bct. BACKGROUND:■ Biomarkers of brain injury, such as neuron-specific enolase and Tau proteins, are higher in older patients with sepsis and delirium. BACKGROUND:■ Diagnosing sepsis in patients with delirium can be challenging. BACKGROUND:■ Early identification of sepsis is key to managing sepsisassociated delirium.

SARS-CoV-2 presents a hyperinflammatory scenario due to systemic inflammatory response syndrome with intense cytokine release, with consequent extrapulmonary involvement in 20 % of patients. The authors studied whether COVID-19 intestinal damage is a direct action of the virus on intestinal epithelial cells, with damage mainly at the tight junction. This is a retrospective observational study in a tertiary hospital emergency department. The authors studied 87 patients (46 patients over 61 years and 41 patients under 60 years old) with severe SARS-CoV-2 infection. The authors measured two plasma markers, LPS-Binding Protein (LBP) and ileal Fatty Acid-Binding Protein (iFABP). Furthermore, the authors evaluated the interaction between the two markers. TNF-α and IL-1 β were higher in bacterial co-infected patients and TNF-α was also higher in the older patients. Plasma iFABP levels were not statistically different in patients with bacterial co-infection; however, higher levels were found in the older population. Plasma LBP levels were higher in patients with bacterial co-infection when compared to patients without infection; however, when comparing plasma LBP levels in the older population with younger patients, no differences could be found. LBP, FABP, and cytokines can discriminate between bacterially infected patients and also discriminate elderly patients. The present study suggests that intestinal barrier dysfunction in SARS-CoV-2 infections is mainly due to damage to the intestinal tight junction complex with a disproportionately lower damage to enterocyte. In the older population, the authors also observed an increase in intestinal epithelial damage.

This study compared markers of muscle damage and myokines between adult and middle-aged runners before and after the marathon. Seventy-four male runners: 48 adults aged 30-44 years (AA group), and 26 middle-aged individuals aged 45-59 years (MA group) participated of the study. Blood samples were collected 24 hours before, immediately after, 24 hours and 72 hours after the marathon to measure skeletal and cardiac muscle damage markers (CK, LDH, troponin, and proBNP) and myokines (IL-6, IL-15, decorin, BDNF, GDF-15, FGF-21, apelin, musclin, myostatin, and follistatin). Before the marathon, it was observed that serum concentrations of BDNF were higher, and those of IL-15, GDF-15, apelin, and musclin were lower in the MA group. Immediately after the marathon, both groups showed higher activity of CK and LDH, as well as higher serum concentrations of ProBNP, troponin, IL-6, decorin, FGF-21, BDNF, and GDF-15. After the marathon and in the recovery period, GDF-15 concentrations remained lower and BDNF concentrations higher in the MA group compared to the AA group. In both groups, long-distance running induced muscle and cardiac damage and modulated myokines responsible for skeletal and cardiac muscle repair/adaptation. Middle-aged individuals show a reduction in the serum concentration of myokines that may contribute to muscle and cardiometabolic dysfunction in senescence. The role of higher levels of BDNF in middle-aged runners on cardiometabolic adaptation should be investigated to elucidate the molecular mechanisms of senescence.

Mitochondrial dysfunction is a recognized feature of sepsis, characterized by ultrastructural damage, diminished oxidative phosphorylation, and depletion of mitochondrial antioxidant capacity observed in deceased septic patients. LPS tolerance induces a controlled response to sepsis. This study aimed to evaluate the function of tolerant mitochondria after cecal ligation and puncture (CLP)-induced sepsis. Mytochondrial oxygen consumption was determined using polarography. Extraction and quantification of RNA for the expression of Tfam, Nrf-1, and Ppargc-1 alpha, and respiratory complex activity were measured. CLP-tolerant animals presented preserved respiratory rates of S3 and S4 and a ratio of respiratory control (RCR) compared to CLP-nontolerant animals with reduced oxidative phosphorylation and increased uncoupled respiration. Complex I Vmax was reduced in septic animals; however, CLP animals sustained normal Vmax. Mitochondrial biogenesis was preserved in CLP-tolerant animals compared to the CLP-nontolerant group, likely due to increased TFAM expression. LPS tolerance protected septic animals from mitochondrial dysfunction, favoring mitochondrial biogenesis and preserving mitochondrial respiration and respiratory complex I activity.

The collaboration between the microbiota, mucosa, and intestinal epithelium is crucial for defending against pathogens and external antigens. Dysbiosis disrupts this balance, allowing pathogens to thrive and potentially enter the bloodstream, triggering immune dysregulation and potentially leading to sepsis. Antimicrobial peptides like LL-37 and CRAMP are pivotal in innate immune defense. Their expression varies with infection severity, exhibiting a dual pro- and anti-inflammatory response. Understanding this dynamic is key to comprehending sepsis progression. In our study, we examined the inflammatory response in CRAMP knockout mice post-cecal ligation and puncture (CLP). We assessed its impact on brain tissue damage and the intestinal microbiota. Our findings revealed higher gene expression of S100A8 and S100A9 in the prefrontal cortex of wild-type mice versus CRAMP-knockout mice. This trend was consistent in the hippocampus and cerebellum, although protein concentrations remained constant. Notably, there was a notable increase in Escherichia coli, Lactobacillus spp., and Enterococcus faecalis populations in wild-type mice 24 h post-CLP compared to the CRAMP-deficient group. These results align with our previous data suggesting that the absence of CRAMP may confer protection in this sepsis model.

Background: Hypoalbuminemia may influence the clinical response and mortality induced by endotoxemia. Sepsis impairs adequate tissue perfusion, and early volume resuscitation by albumin or crystalloid administration is critical for clinical outcomes and survival. Methods: This study analyzed in hypoalbuminemic rats the effects of endotoxemia on vascular reactivity, cardiac function, oxidative and inflammatory profile, and survival. In addition, mortality was accessed after albumin replacement. Endotoxemia was induced in male Sprague Dawley (SD) or Nagase analbuminemic rats (NAR) using either lipopolysaccharide (LPS) injection or cecal ligation and puncture (CLP), with or without subsequent albumin replacement. Survival rates were assessed every 8 h for 5 days following LPS injection. Hemodynamic evaluations were conducted 4 hours post-LPS injection by measuring mean arterial pressure (MAP), left ventricular end-diastolic pressure, dP/dtmax, and dP/dtmin. Vascular reactivity of aortic rings was recorded 4 hours post-LPS. Oxidative stress, measured by thiobarbituric acid reactive substances (TBARS), and cytokine levels, determined by ELISA, were assessed at 1.5 and 4 hours post-LPS injection. Comparisons among groups were performed using ANOVA with post-hoc Tukey-Kramer analysis Results: Survival rates were lower in NAR+LPS (25%) and NAR+CLP (10%) compared to SD+LPS (80%) and SD+CLP (40%), but albumin replacement improved survival in NAR+LPS (25%) as compared to NAR+LPS+ALB (55%). Severe hemodynamic impairments, including reduced cardiac function and vascular reactivity, were observed in NAR+LPS. Baseline and post-LPS plasma levels of TBARS and nitric oxide were elevated in NAR, while TNF, IL-6, and IL-10 were higher in SD+LPS compared to NAR+LPS. Discussion: Subgroup analysis of studies with volume infusion suggests that septic patients with hypoalbuminemia may benefit from albumin infusion during shock. To further investigate the role of prior hypoalbuminemia in septic shock and the underlying pathophysiological mechanisms, we conducted a translational study bridging clinical findings with experimental research. The results demonstrate that hypoalbuminemia cause alterations in endothelial and vascular muscle function as well as cardiac dysfunction. Conclusion: Hypoalbuminemia in rats increase mortality from endotoxemia, associated with severe cardiovascular dysfunction and oxidative stress. Albumin replacement in hypoalbuminemic rats reduced mortality in endotoxemia-induced sepsis.

Abstract Antimicrobial peptides (AMPs) constitute a complex network of 10–100 amino acid sequence molecules widely distributed in nature. While over 300 AMPs have been described in mammals, cathelicidins and defensins remain the most extensively studied. Some publications have explored the role of AMPs in COVID‐19, but these findings are preliminary, and in vivo studies are still lacking. In this study, we report the plasma levels of five AMPs (LL‐37, α‐defensin 1, α‐defensin 3, β‐defensin 1, and β‐defensin 3), using the ELISA technique (MyBioSource, San Diego, CA, United States, kits MBS2601339 (beta‐defensin 1), MBS2602513 (beta‐defensin 3), MBS703879 (alpha‐defensin 1), MBS706289 (alpha‐defensin 3), MBS7234921 (LL37)), and the measurement of six cytokines (tumor necrosis factor‐α, interleukin‐1β, interleukin‐6, interleukin‐10, interferon‐γ, and monocyte chemoattractant protein‐1), through the magnetic bead immunoassay Milliplex® and the MAGPIX® System (MilliporeSigma, Darmstadt, Germany, kit HCYTOMAG‐60 K (cytokines)), in 15 healthy volunteers, 36 COVID‐19 patients without Acute Kidney Injury (AKI) and 17 COVID‐19 patients with AKI. We found increased levels of α‐defensin 1, α‐defensin 3 and β‐defensin 3, in our COVID‐19 population, when compared to healthy controls, along with higher levels of interleukin‐6, interleukin‐10, interferon‐γ, and monocyte chemoattractant protein‐1. These findings suggest that these AMPs and cytokines may play a crucial role in the systemic inflammatory response and tissue damage characterizing severe COVID‐19. The levels of α‐defensin 1 and α‐defensin 3 were significantly higher in COVID‐19 AKI group in comparison to the non‐AKI group. Furthermore, IL‐10 and the product IL‐10 × IL‐1B showed excellent performance in discriminating AKI, with AUCs of 0.86 and 0.88, respectively. Among patients with COVID‐19, AMPs may play a key role in the inflammation process and disease progression. Additionally, α‐defensin 1 and α‐defensin 3 may mediate the AKI process in these patients, representing an opportunity for further research and potential therapeutic alternatives in the future.

AbstractBackground Sepsis-associated delirium is a cerebral manifestation commonly occurring in patients with sepsis and is thought to occur due to a combination of neuroinflammation and disturbances in cerebral perfusion, the blood brain barrier (BBB) and neurotransmission. This cross-sectional pilot study aims to evaluate plasma levels and possible correlation between brain cell damage biomarkers (neuron-specific enolase [NSE] and Tau proteins) in patients with delirium and sepsis, and to obtain tools that identify sepsis in patients with delirium admitted in the Emergency Department. Results We analyzed 25 patients, and 14 (56%) had sepsis. Septic patients had higher NSE (2.7ng/mL, [95% CI: 2.2–3.2] vs. 1.7ng/mL, [95% CI: 0.8–2.5], p < 0.003) and Tau (94.2pg/mL, [95% CI: 77.0-111.3] vs. 57.8pg/mL, [95% CI 31.2–84.5], p < 0.003) than non-septic patients. The best cutoffs for NSE and Tau protein were 2.08ng/mL (LR positive: 4.71, LR negative: 0.17) and 59.27pg/mL (LR positive 3.40, LR negative: 0.09) respectively. We found a 90% specificity for developing sepsis in patients with both NSE above 1.59ng/mL and Tau above 59.27pg/mL. Conclusions NSE and Tau proteins, biomarkers of brain injury, are higher in septic patients than non-septic when analyzed older patients with delirium. Therefore, we suggest that plasma levels of these proteins may be further studied as tools to identify infectious etiology of delirium in older patients in Emergency Departments.

Septic shock is a life-threatening clinical condition characterized by a robust immune inflammatory response to disseminated infection. Little is known about its impact on the transcriptome of distinct human tissues. To address this, we performed RNA sequencing of samples from the prefrontal cortex, hippocampus, heart, lung, kidney and colon of seven individuals who succumbed to sepsis and seven uninfected controls. We identified that the lungs and colon were the most affected organs. While gene activation dominated, strong inhibitory signals were also detected, particularly in the lungs. We found that septic shock is an extremely heterogeneous disease, not only when different individuals are investigated, but also when comparing different tissues of the same patient. However, several pathways, such as respiratory electron transport and other metabolic functions, revealed distinctive alterations, providing evidence that tissue specificity is a hallmark of sepsis. Strikingly, we found evident signals of accelerated ageing in our sepsis population.

Inadequate nutrient availability has been demonstrated to be one of the main factors related to endocrine and metabolic dysfunction. We investigated the role of inadequate nutrient intakes in the myokine levels of runners. Sixty-one amateur runners participated in this study. The myokine levels were determined using the Human Magnetic Bead Panel from plasma samples collected before and after the marathon. Dietary intake was determined using a prospective method of three food records. The runners with lower carbohydrate and calcium intakes had higher percentages of fat mass (p < 0.01). The runners with a sucrose intake comprising above 10% of their energy intake and an adequate sodium intake had higher levels of BDNF (p = 0.027 and p = 0.031). After the race and in the recovery period, the runners with adequate carbohydrate intakes (g/kg) (>5 g/kg/day) had higher levels of myostatin and musclin (p < 0.05). The runners with less than 45% of carbohydrate of EI had lower levels of IL-15 (p = 0.015) and BNDF (p = 0.013). The runners with higher cholesterol intakes had lower levels of irisin (p = 0.011) and apelin (p = 0.020), and those with a low fiber intake had lower levels of irisin (p = 0.005) and BDNF (p = 0.049). The inadequate intake influenced myokine levels, which promoted cardiometabolic tissue repair and adaptations to exercise.

Background Sepsis is a life-threatening condition and septic encephalopathy is an early and frequent manifestation of this disease. Antimicrobial peptides are important components of innate immunity playing a crucial role during bacterial infections. Here, we investigate the protein levels of several neuropeptides in CRAMP-deficient and wild-type mice, in healthy conditions and following experimental sepsis. Methods Mice were submitted to cecal ligation and puncture and the protein levels of neurotensin, substance P, oxytocin and β-endorphin were evaluated in the brain. Results We found that CRAMP-deficient mice produce significantly less neurotensin and substance P than wild-type mice in the hippocampus, both before and 24 hours following experimental sepsis, but not 15 days post-septic shock. Conclusions The hippocampus is a complex structure, highly vulnerable during sepsis. The role of antimicrobial peptides and their interplay with neuropeptides should be further evaluated in this scenario.

We investigate the effect of the banana green peels extract (BPE) as a preventive treatment against NAFLD in high-fat diet fed mice. Mice received daily doses of 100 or 250 mg/kg of BPE for 12 weeks along with the high-fat diet. BPE reduced weight gain (p < .0001), adipose tissue hypertrophy (p < .0001), and improved glucose homeostasis (p < .0001). Plasma levels of glucose-dependent insulinotropic polypeptide, triglycerides, total cholesterol, LDL-cholesterol, non-esterified fatty acids, aspartate and alanine transaminase, leptin, and resistin were decreased in BPE treated mice (p < .05). BPE effects on lipid metabolism were associated with decreased gene expression of lipogenic enzymes and increased expression of enzymes related to fatty acid and cholesterol degradation (p < .05). Plasma and liver bile acid (BA) profiles were modulated by BPE, with positive correlations between specific BA and UCP-1, CPT-1 and PGC-1 beta expression in brown adipose tissue (p < .05). BPE reduced hepatic steatosis and inflammation, possibly due to reduced p65 NF-kappa B nuclear translocation (p < .05) and modulation of oxidative stress (p < .05). These data indicate that BPE is a source of phytochemical compounds with promising effects toward the prevention of metabolic disorders associated with obesity.

Systemic inflammatory response, as observed in sepsis and severe COVID-19, may lead to endothelial damage. Therefore, we aim to compare the extent of endothelial injury and its relationship to inflammation in both diseases. We included patients diagnosed with sepsis (SEPSIS group, n = 21), mild COVID-19 (MILD group, n = 31), and severe COVID-19 (SEVERE group, n = 24). Clinical and routine laboratory data were obtained, circulating cytokines (INF-gamma, TNF-alpha, and IL-10) and endothelial injury markers (E-Selectin, Tissue Factor (TF) and von Willebrand factor (vWF)) were measured. Compared to the SEPSIS group, patients with severe COVID-19 present similar clinical and laboratory data, except for lower circulating IL-10 and E-Selectin levels. Compared to the MILD group, patients in the SEVERE group showed higher levels of TNF-alpha, IL-10, and TF. There was no clear relationship between cytokines and endothelial injury markers among the three studied groups; however, in SEVERE COVID-19 patients, there is a positive relationship between INF-gamma with TF and a negative relationship between IL-10 and vWF. In conclusion, COVID-19 and septic patients have a similar pattern of cytokines and endothelial dysfunction markers. These findings highlight the importance of endothelium dysfunction in COVID-19 and suggest that endothelium should be better evaluated as a therapeutic target for the disease.

Renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) have a different site of interaction and modulate vascular tone and inflammatory response as well on exercise adaptation, which is modulated by exercise-induced cytokines. The aim of the study was to evaluate the role of ACE I/D and BDKRB2 +9/−9 polymorphism on exercise-induced cytokine response. Seventy-four male marathon finishers, aged 30 to 55 years, participated in this study. Plasma levels of exercise-induced cytokines were determined 24 h before, immediately after, and 24 h and 72 h after the São Paulo International Marathon. Plasma concentrations of MCP-1, IL-6 and FGF-21 increased after marathon in all genotypes of BDKRB2. IL-10, FSTL and BDNF increased significantly after marathon in the genotypes with the presence of the −9 allele. FSTL and BDNF concentrations were higher in the −9/−9 genotype compared to the +9/+9 genotype before (p = 0.006) and after the race (p = 0.023), respectively. Apelin, IL-15, musclin and myostatin concentrations were significantly reduced after the race only in the presence of −9 allele. Marathon increased plasma concentrations of MCP1, IL-6, BDNF and FGF-21 in all genotypes of ACE I/D polymorphism. Plasma concentrations of IL-8 and MIP-1alpha before the race (p = 0.015 and p = 0.031, respectively), of MIP-1alpha and IL-10 after the race (p = 0.033 and p = 0.047, respectively) and VEGF 72 h after the race (p = 0.018) were lower in II homozygotes compared to runners with the presence of D allele. One day after the race we also observed lower levels of MIP-1alpha in runners with II homozygotes compared to DD homozygotes (p = 0.026). Before the marathon race myostatin concentrations were higher in DD compared to II genotypes (p = 0.009). Myostatin, musclin, IL-15, IL-6 and apelin levels decreased after race in genotypes with the presence of D allele. After the race ACE activity was negatively correlated with MCP1 (r = −56, p < 0.016) and positively correlated with IL-8, IL-10 and MIP1-alpha (r = 0.72, p < 0.0007, r = 0.72, p < 0.0007, r = 0.47, p < 0.048, respectively). The runners with the −9/−9 genotype have greater response in exercise-induced cytokines related to muscle repair and cardioprotection indicating that BDKRB2 participate on exercise adaptations and runners with DD genotype have greater inflammatory response as well as ACE activity was positively correlated with inflammatory mediators. DD homozygotes also had higher myostatin levels which modulates protein homeostasis.

Cardiomyopathy is a well-known complication of sepsis that may deteriorate when accompanied by obesity. To test this hypothesis we fed C57black/6 male mice for 6 week with a high fat diet (60% energy) and submitted them to endotoxemic shock using E. coli LPS (10 mg/kg). Inflammatory markers (cytokines and adhesion molecules) were determined in plasma and heart tissue, as well as heart mitochondrial biogenesis and function. Obesity markedly shortened the survival rate of mouse after LPS injection and induced a persistent systemic inflammation since TNFα, IL-1β, IL-6 and resistin plasma levels were higher 24 h after LPS injection. Heart tissue inflammation was significantly higher in obese mice, as detected by elevated mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6 and TNFα). Obese animals presented reduced maximum respiratory rate after LPS injection, however fatty acid oxidation increased in both groups. LPS decreased mitochondrial DNA content and mitochondria biogenesis factors, such as PGC1α and PGC1β, in both groups, while NRF1 expression was significantly stimulated in obese mice hearts. Mitochondrial fusion/fission balance was only altered by obesity, with no influence of endotoxemia. Obesity accelerated endotoxemia death rate due to higher systemic inflammation and decreased heart mitochondrial respiratory capacity.

OBJECTIVE:The pulmonary vascular remodeling in systemic sclerosis (SSc) is poorly understood and animal models are lacking. Type V collagen (COLV) is elevated in SSc and is implicated in the pathogenesis, and immunization with human COLV induces SSc-like skin and lung changes in rabbits and mice. Here we tested the hypothesis that COLV immunization will induce pathological and functional changes that phenocopy SSc-associated pulmonary vascular disease.METHODS:Pulmonary vascular changes in rabbits immunized with human COLV were extensively characterized by a combination of histology, electron microscopy and immunohistochemistry. Physiologic changes induced by COLV in explanted pulmonary artery rings were evaluated. The pattern of histopathologic alterations and gene expression induced in immunized rabbits were compared to those in SSc patients.RESULTS:COLV immunization was accompanied by striking pulmonary vascular abnormalities, characterized by reduced capillary density, perivascular inflammation, endothelial cell injury and collagen accumulation, that closely phenocopy changes seen in SSc patients. Moreover, pulmonary arteries from immunized rabbits showed impaired ex vivo vascular relaxation. Expression of COL5A2 was significantly increased in the lungs from immunized rabbits (p = 0.02), as well as in patients with SSc (P = 0.02).CONCLUSION:COLV immunity in rabbits is associated with marked vascular remodeling in the lung that phenocopies early-stage human SSc-associated pulmonary vascular disease. COLV immunization therefore represents a novel approach to model SSc pulmonary vascular pathology. Moreover, our findings suggest that COLV might represent a novel pathogenic autoantigen in SSc and future studies with the present model should be developed for possible association with PAH.

Abstract Recent discoveries have demonstrated that mitochondria play a critical role in innate immune signaling. By the other hand, immune responses may lead to mitochondrial deregulation. Cathelicidins play a critical role in innate immunity, promoting poorly understood cellular responses that may enhance or inhibit several signaling pathways, depending on the health conditions and subjacent microenvironment.Here, we investigated the role of CRAMP, the murine cathelicidin, in healthy mice and following experimental sepsis. We found that sepsis induces significant mitochondrial DNA damage in the prefrontal cortex and that cathelicidin protects the brain from this kind of damage in healthy animals, but not following septic shock.

The role of innate immunity in COVID-19 is not completely understood. Therefore, this study explored the impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection on the expression of Pattern Recognition Receptors (PRRs) in peripheral blood cells and their correlated cytokines. Seventy-nine patients with severe COVID-19 on admission, according to World Health Organization (WHO) classification, were divided into two groups: patients who needed mechanical ventilation and/or deceased (SEVERE, n = 50) and patients who used supplementary oxygen but not mechanical ventilation and survived (MILD, n = 29); a control group (CONTROL, n = 17) was also enrolled. In the peripheral blood, gene expression (mRNA) of Toll-like receptors (TLRs) 3, 4, 7, 8, and 9, retinoic-acid inducible gene I (RIGI), NOD-like receptor family pyrin domain containing 3 (NLRP3), interferon alpha (IFN-α), interferon beta (IFN-β), interferon gamma (IFN-γ), interferon lambda (IFN-λ), pro-interleukin(IL)-1β (pro-IL-1β), and IL-18 was determined on admission, between 5–9 days, and between 10–15 days. Circulating cytokines in plasma were also measured. When compared to the COVID-19 MILD group, the COVID-19 SEVERE group had lower expression of TLR3 and overexpression of TLR4.

Endurance exercise induces an increase in the expression of exercise-induced peptides that participate in the repair and regeneration of skeletal muscles. The present study aimed to evaluate the time course and role of exercise-induced cytokines in muscle damage and repair after a marathon race. Fifty-seven Brazilian male amateur marathon finishers, aged 30–55 years, participated in this study. The blood samples were collected 24 h before, immediately after, and 24 and 72 h after the São Paulo International Marathon. The leukogram and muscle damage markers were analyzed using routine automated methodology in the clinical laboratory. The plasma levels of the exercise-induced cytokines were determined using the Human Magnetic Bead Panel or enzyme-linked immunosorbent assays [decorin and growth differentiation factor 15 (GDF-15)]. A muscle damage was characterized by an increase in plasma myocellular proteins and immune changes (leukocytosis and neutrophilia). Running the marathon increased interleukin (IL)-6 (4-fold), IL-8 (1.5-fold), monocyte chemoattractant protein-1 (2.4-fold), tumor necrosis factor alpha (TNF-α) (1.5-fold), IL-10 (11-fold), decorin (1.9-fold), GDF-15 (1.8-fold), brain-derived neurotrophic factor (BDNF) (2.7-fold), follistatin (2-fold), and fibroblast growth factor (FGF-21) (3.4-fold) plasma levels. We also observed a reduction in musclin, myostatin, IL-15, and apelin levels immediately after the race (by 22–36%), 24 h (by 26–52%), and 72 h after the race (by 25–53%). The changes in BDNF levels were negatively correlated with the variations in troponin levels (r = −0.36). The variations in IL-6 concentrations were correlated with the changes in follistatin (r = 0.33) and FGF-21 (r = 0.31) levels after the race and with myostatin and irisin levels 72 h after the race. The changes in IL-8 and IL-10 levels had positive correlation with variation in musclin (p < 0.05). Regeneration of exercise-induced muscle damage involves the participation of classical inflammatory mediators, as well as GDF-15, BDNF, follistatin, decorin, and FGF-21, whose functions include myogenesis, mytophagia, satellite cell activation, and downregulation of protein degradation. The skeletal muscle damage markers were not associated to myokines response. However, BDNF had a negative correlation with a myocardial damage marker. The classical anti-inflammatory mediators (IL-10, IL-8, and IL-6) induced by exercise are associated to myokines response immediately after the race and in the recovery period and may affect the dynamics of muscle tissue repair.