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Simple Summary: The regulation of oxidative stress at rest and in response to a single session of exercise is vital for cardiovascular and metabolic health. However, the lack of regular physical activity and exercise and the presence of obesity are known to negatively impact oxidative stress under both conditions. In the present study, the oxidative stress response in circulation and within exosome-like extracellular vesicles (ELVs) released by contracting skeletal muscle during exercise was examined following maximal intensity treadmill running. As a result, we demonstrate that aerobically untrained individuals with obesity exhibit an altered oxidative stress response to maximal treadmill running compared to aerobically untrained and aerobically trained individuals without obesity. Similarly, body mass index, an index of obesity, but not cardiorespiratory fitness, was associated with an adverse oxidative response at rest and immediately following maximal treadmill running. These findings suggest that obesity, more than improved cardiorespiratory fitness, differentially regulates plasma and circulating ELV indices of oxidative stress prior to and immediately following acute maximal treadmill exercise. The impact of cardiorespiratory fitness (VO2max) and obesity on indices of oxidative stress in plasma and circulating exosome-like extracellular vesicles (ELVs) were examined following acute exercise. Indices of oxidative stress in plasma and isolated plasma ELVs were examined in aerobically trained (NW-Tr; n = 15) and untrained (NW-UTr; n = 18) normal-weight individuals and aerobically untrained individuals with obesity (Ob-Utr; n = 10) prior to and immediately following acute maximal treadmill running. Following exercise, ELV flotillin-1 expression (p = 0.008) and plasma total antioxidant capacity (TAC; p = 0.010) increased more in NW-UTr compared to NW-Tr and Ob-UTr participants, whereas plasma protein carbonyls (PC) decreased more in Ob-UTr compared to NW-Tr and NW-UTr groups. ELV glutathione (GSH) concentrations decreased more in NW-Tr compared to NW-UTr and Ob-UTr participants (p = 0.009), whereas lipid peroxidase (LPO) concentrations increased more in Ob-UTr compared to NW-Tr and NW-UTr participants (p = 0.003). Body mass index (BMI) was associated negatively with plasma TAC and PC (p < 0.05) and positively with ELV LPO concentration responses (p = 0.009). Finally, plasma-to-total (plasma + ELV) GSH ratios decreased in Ob-UTr compared to NW-Tr and NW-UTr participants (p = 0.006), PC ratios increased in NW-Tr and NW-UTr compared to Ob-UTr subjects (p = 0.008), and reactive oxygen/nitrogen species ratios increased in NW-UTr and decreased in Ob-UTr participants (p < 0.001). BMI, independently of VO2max, differentially regulates indices of oxidative stress within plasma and circulating ELVs prior to and immediately following acute maximal treadmill exercise. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to examine the hypothesis that abdominal and gluteal adipocyte turnover, lipid dynamics, and fibrogenesis are dysregulated among insulin‐resistant (IR) compared with insulin‐sensitive (IS) adolescents with obesity. Methods: Seven IS and seven IR adolescents with obesity participated in a 3‐h oral glucose tolerance test and a multi‐section magnetic resonance imaging scan of the abdominal region to examine body fat distribution patterns and liver fat content. An 8‐week 70% deuterated water (2H2O) labeling protocol examined adipocyte turnover, lipid dynamics, and fibrogenesis in vivo from biopsied abdominal and gluteal fat. Results: Abdominal and gluteal subcutaneous adipose tissue (SAT) turnover rates of lipid components were similar among IS and IR adolescents with obesity. However, the insoluble collagen (type I, subunit α2) isoform measured from abdominal, but not gluteal, SAT was elevated in IR compared with IS individuals. In addition, abdominal insoluble collagen Iα2 was associated with ratios of visceral‐to‐total (visceral adipose tissue + SAT) abdominal fat and whole‐body and adipose tissue insulin signaling, and it trended toward a positive association with liver fat content. Conclusions: Altered extracellular matrix dynamics, but not expandability, potentially decreases abdominal SAT lipid storage capacity, contributing to the pathophysiological pathways linking adipose tissue and whole‐body IR with altered ectopic storage of lipids within the liver among IR adolescents with obesity. [ABSTRACT FROM AUTHOR]

Part of the regulation of telomerase activity includes the alternative splicing (AS) of the catalytic subunit telomerase reverse transcriptase (TERT). Although a therapeutic window for telomerase/TERT inhibition exists between cancer cells and somatic cells, stem cells express TERT and rely on telomerase activity for physiological replacement of cells. Therefore, identifying differences in TERT regulation between stem cells and cancer cells is essential for developing telomerase inhibition-based cancer therapies that reduce damage to stem cells. In this study, we measured TERT splice variant expression and telomerase activity in induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs), and non-small cell lung cancer cells (NSCLC, Calu-6 cells). We observed that a NOVA1-PTBP1-PTBP2 axis regulates TERT alternative splicing (AS) in iPSCs and their differentiation into NPCs. We also found that splice-switching of TERT, which regulates telomerase activity, is induced by different cell densities in stem cells but not cancer cells. Lastly, we identified cell type-specific splicing factors that regulate TERT AS. Overall, our findings represent an important step forward in understanding the regulation of TERT AS in stem cells and cancer cells. [ABSTRACT FROM AUTHOR]

Pentraxin 3 (PTX3), a cardioprotective protein, has recently been shown to be associated with improved insulin resistance (IR) and glucose metabolism. Therefore, the primary purpose of this study was to examine whether or not increased plasma PTX3 following maximal aerobic exercise would differ between obese and normal-mass subjects, and its association with the homeostatic model assessment of insulin resistance (HOMA-IR) and glucose response. Twenty-five untrained obese (n = 13 [6 males and 7 females]) and normal-mass (n = 12 [5 males and 7 females]) subjects performed an acute bout of maximal aerobic exercise to assess maximal oxygen consumption ([VO.sub.2max]). At baseline, plasma PTX3 concentrations are decreased in obese compared with normal-mass subjects and are negatively associated with plasma insulin and HOMA-IR values. In response to maximal exercise, plasma PTX3 responses were similar in obese and normal-mass subjects while the intensity of plasma PTX3 response as indicated by area under the curve analysis (AUCi) was not associated with HOMA-IR or glucose AUCi. However, PTX3 AUCi was positively associated with cardiorespiratory fitness levels (relative [VO.sub.2max]). These findings suggest that PTX3 could serve as a biomarker for both metabolic health, as well as a measurement to monitor the effectiveness of exercise interventions in obesity. Key words: pentraxin 3, obesity, aerobic exercise, insulin resistance, cardiorespiratory fitness. On a montre recemment que la pentraxine 3 (PTX3), une proteine dotee de proprietes de cardioprotection, est associee a des ameliorations sur le plan de la resistance a l'insuline (IR) et du metabolisme du glucose. Par consequent, le principal objectif des presents travaux etait d'evaluer si l'augmentation des taux plasmatiques de PTX3 apres un effort physique aerobie maximal serait differente chez les sujets obeses comparativement aux sujets dont le poids est normal, et si cette observation serait associee a des modifications sur le plan de l'homeostasie de la resistance a l'insuline (ou HOMA-IR pour << homeostatic model assessment of insulin resistance >>) et de la reponse glycemique. Pour ce faire, 25 sujets non entraines obeses (n = 13 [6 hommes et 7 femmes]) et de poids normal (n = 12 [5 hommes et 7 femmes]) ont effectue un effort physique aerobie maximal intense en vue d'evaluer la consommation maximale d'oxygene ([VO.sub.2max]). Au debut de l'etude, les concentrations plasmatiques de PTX3 etaient plus basses chez les sujets obeses que chez les sujets de poids normal et inversement proportionnelles aux taux d'insuline plasmatique et aux valeurs de l'HOMA-IR. En reponse a l'effort physique maximal, les taux plasmatiques de PTX3 observes etaient semblables dans les 2 groupes, et l'aire sous la courbe << en ce qu'elle concerne l'augmentation des taux >> (ASCa) n'etait pas associee a l'ASCa des valeurs de l'HOMA-IR ni de la reponse glycemique. Cependant, l'ASCa des taux de PTX3 etait proportionnelle au degre de forme physique dont le [VO.sub.2max] temoignait. Ces observations semblent indiquer que la PTX3 pourrait etre utile comme biomarqueur de la sante metabolique ainsi que pour evaluer l'efficacite de l'entrainement physique en presence d'obesite. [Traduit par la Redaction] Mots-cles : pentraxine 3, obesite, effort physique aerobie, resistance a l'insuline, forme cardiorespiratoire., Introduction Obesity is characterized as a chronic state of low-grade proinflammation by the enlargement of adipocytes and increased infiltration of circulating monocytes differentiated into resident adipose tissue macrophages (Weisberg et [...]

Objective: Nonalcoholic fatty liver disease (NAFLD), the most common liver disease among youth with obesity, precedes more severe metabolic and liver diseases. However, the impact of the Sars‐CoV‐2 global pandemic on the prevalence and severity of NAFLD and the associated metabolic phenotype among youth with obesity is unknown. Methods: Participants were recruited from the Yale Pediatric Obesity Clinic during the Sars‐CoV‐2 global pandemic (August 2020 to May 2022) and were compared with a frequency‐matched control group of youth with obesity studied before the Sars‐CoV‐2 global pandemic (January 2017 to November 2019). Glucose metabolism differences were assessed during an extended 180‐minute oral glucose tolerance test. Magnetic resonance imaging‐derived proton density fat fraction (PDFF) was used to determine intrahepatic fat content in those with NAFLD (PDFF ≥ 5.5). Results: NAFLD prevalence increased in participants prior to (36.2%) versus during the Sars‐CoV‐2 pandemic (60.9%), with higher PDFF values observed in participants with NAFLD (PDFF ≥ 5.5%) during versus before the pandemic. An increase in visceral adipose tissue and a hyperresponsiveness in insulin secretion during the oral glucose tolerance test were also observed. Conclusions: Hepatic health differences were likely exacerbated by environmental and behavioral changes associated with the pandemic, which are critically important for clinicians to consider when engaging in patient care to help minimize the future risk for metabolic perturbations. [ABSTRACT FROM AUTHOR]

Initiating from Hans Selye's conceptualization of stress physiology, to our present understanding of allostatic load as the cumulative burden of chronic psychological stress and life events, investigators have sought to identify the physiological mechanisms that link stress to health and disease. Of particular interest has been the link between psychological stress and cardiovascular disease (CVD), the number one cause of death in the United States. In this regard, attention has been directed toward alterations in the immune system in response to stress that lead to increased levels of systemic inflammation as a potential pathway by which stress contributes to the development of CVD. More specifically, psychological stress is an independent risk factor for CVD, and as such, mechanisms that explain the connection of stress hormones to systemic inflammation have been examined to gain a greater understanding of the etiology of CVD. Research on proinflammatory cellular mechanisms that are activated in response to psychological stress demonstrates that the ensuing low-grade inflammation mediates pathways that contribute to the development of CVD. Interestingly, physical activity, along with its direct benefits to cardiovascular health, has been shown to buffer against the harmful consequences of psychological stress by "toughening" the SAM system, HPA axis, and immune system as "cross-stressor adaptations" that maintain allostasis and prevent allostatic load. Thus, physical activity training reduces psychological stress induced proinflammation and attenuates the activation of mechanisms associated with the development of cardiovascular disease. Finally, COVID-19 associated psychological stress and its associated health risks has provided another model for examining the stress-health relationship. [ABSTRACT FROM AUTHOR]

Introduction: Aerobic exercise maintains telomere length through increased human telomerase reverse transcriptase (hTERT) expression and telomerase enzyme activity. The impact of acute exercise on hTERT alternative splicing (AS) is unknown. Purpose: This study aimed to examine hTERT AS in response to acute treadmill running. Methods: A bacterial artificial chromosome mouse model containing the 54-kilobase hTERT gene locus inserted into its genome (hTERT -BAC) was utilized. The gastrocnemius, left ventricle, and brain were excised before (Pre), upon cessation (Post), and during recovery (1, 24, 48, and 72 h; n = 5/time point) from treadmill running (30 min at 60% maximum speed). Full-length (FL) hTERT and the "minus beta" (−β) AS variant (skips exons 7 and 8 and does not code for active telomerase) were measured by gel-based and droplet digital reverse transcription–polymerase chain reaction methods. SF3B4 and SRSF2 protein expression were measured by Western blotting. Results: Compared with Pre, FL hTERT increased at Post before decreasing during recovery in the gastrocnemius (48 and 72 h; P ≤ 0.001) and left ventricle (24 h; P = 0.004). The percentage of FL hTERT in the gastrocnemius also increased during recovery (1 and 72 h; P ≤ 0.017), whereas a decrease was observed in the left ventricle (1, 24, and 48 h; P ≤ 0.041). hTERT decreased in the brain (48 h), whereas FL hTERT percentage remained unaltered. SF3B4 protein expression decreased throughout recovery in the gastrocnemius and tended to be associated with FL hTERT (r = −0.348, P = 0.075) and –β in opposite directions (r = 0.345, P = 0.067). Conclusions: Endurance exercise increased hTERT gene expression, and altered FL hTERT splicing in contractile tissues and may maintain telomere length necessary to improve the function and health of the organism. [ABSTRACT FROM AUTHOR]

Autophagy is a critical molecular process in promoting cell survival against apoptosis. This study examined whether maximal aerobic exercise-mediated apoptosis in obesity might be underlying the involvement of autophagy in the peripheral blood mononuclear cells (PBMCs). Twelve healthy male subjects (6 obese and 6 normal-weight) were recruited to participate in a maximal graded exercise test on a treadmill. Obese subjects exhibited a significantly lower Bax, but a higher Bcl-2 protein level in conjunction with a reduced Bax/Bcl-2 AUCi compared to normal-weight subjects following exercise. Furthermore, a greater LC3-II/LC3-I ratio and LC3-II/LC3-I AUCi was observed in obese subjects compared to normal-weight subjects. LC3-II/LC3-I AUCi was also positively associated with obesity-associated parameters (BMI, waist/hip circumference, and fasting insulin level), but was negatively correlated with Bax/Bcl-2 AUCi. These findings demonstrate that maximal aerobic exercise differentially mediates the intrinsic apoptotic pathway and autophagic activity in human PBMCs isolated from obese compared to normal-weight individuals. [ABSTRACT FROM AUTHOR]

Age-related elevations in proinflammatory cytokines, known as inflamm-aging, are associated with shorter immune cell telomere lengths. Purpose. This study examined the relationship of plasma PTX3 concentrations, a biomarker of appropriate immune function, with telomere length in 15 middle-aged (40-64 years) and 15 young adults (20-31 years). In addition, PBMCs were isolated from middle-aged and young adults to examine their capacity to express a key mechanistic component of telomere length maintenance, human telomerase reverse transcriptase (hTERT), following ex vivo cellular stimulation. Methods. Plasma PTX3 and inflammatory cytokines (i.e., IL-6, IL-10, TGF-β, and TNF-α), PBMC telomere lengths, and PBMC hTERT gene expression and inflammatory protein secretion following exposure to LPS, PTX3, and PTX3+LPS were measured. Results. Aging was accompanied by the accumulation of centrally located visceral adipose tissue, without changes in body weight and BMI, and alterations in the systemic inflammatory milieu (decreased plasma PTX3 and TGF-β; increased TNF-α (p≤0.050)). In addition, shorter telomere lengths in middle-aged compared to young adults (p=0.011) were negatively associated with age, body fat percentages, and plasma TNF-α (r=−0.404, p=0.027; r=−0.427, p=0.019; and r=−0.323, p=0.041, respectively). Finally, the capacity of PBMCs to increase hTERT gene expression following ex vivo stimulation was impaired in middle-aged compared to young adults (p=0.033) and negatively associated with telomere lengths (r=0.353, p=0.028). Conclusions. Proinflammation and the impaired hTERT gene expression capacity of PBMCs may contribute to age-related telomere attrition and disease. [ABSTRACT FROM AUTHOR]

Abstract Introduction/purpose MicroRNAs (miRNAs), a class of non-coding RNAs, are involved in the regulation of gene expression and numerous biological processes, including inflammation and metabolism in obese populations. Emerging research indicates that physical activity provides health-related benefits in obesity-associated inflammatory diseases. This study examined how acute aerobic exercise would mediate the changes in plasma level of inflammation-related circulating miRNA (ci-miRNA) expression (miR-21, miR-126, miR-130b, miR-221, and miR-222) in obese and normal-weight subjects. Methods Twenty-four subjects (12 obese and 12 normal-weight) were recruited to participate in a 30-min aerobic exercise (75% VO 2max). Blood samples were taken prior to exercise, immediately following exercise, 1 h, and 2 h into recovery for analysis of target ci-miRNAs in plasma. Results A higher baseline levels of ci-miRNAs (miR-126, miR-130b, miR-221, and miR-222) were found in obese subjects than normal-weight subjects. In response to acute aerobic exercise, obese subjects exhibited a higher increase in plasma level of all ci-miRNAs: miR-21, miR-126, miR-130b, miR-221 and miR-222, even after controlling for VO 2max and insulin resistance (HOMA-IR). Furthermore, all miRNA area-under-the curves "with respect to increase" (AUCi) were higher in obese subjects and also positively correlated with each other, even after controlling for VO 2max and HOMA-IR. Conclusion These findings indicate that acute aerobic exercise elicits a higher elevation in plasma level of inflammatory ci-miRNAs in obese than normal-weight individuals, irrespective of cardiorespiratory fitness and indicator of metabolic syndrome (HOMA-IR). Highlights • Acute aerobic exercise up-regulates inflammation-associated ci-miRNAs in obesity. • Up-regulation of target ci-miRNAs is positively correlated with each other. • ci-miRNAs might have the potential to predict the effectiveness of exercise treatment in obese Individuals. [ABSTRACT FROM AUTHOR]

Pentraxin 3 (PTX3) is mainly synthesized and released by neutrophils to help regulate innate immunity. While plasma PTX3 concentrations are associated with improved glucose metabolism and overall metabolic health, there is evidence that significant elevations in plasma glucose downregulate circulating levels of PTX3. To examine whether this relationship would be altered in response to exercise, this study investigated the kinetics of the plasma glucose and PTX3 responses following high-intensity interval exercise (HIIE) and continuous moderate-intensity exercise (CMIE). It was hypothesized that the increased concentrations of plasma glucose following HIIE compared with CMIE would be associated with an attenuated plasma PTX3 response. Eight healthy male subjects participated in both HIIE and CMIE protocols administered as a randomized, counterbalanced design. Linear mixed models for repeated measures revealed that the overall plasma glucose response was greater following HIIE compared with CMIE (protocol × time effect: p = 0.037). Although the plasma PTX3 response was higher only at 19 min into HIIE compared with CMIE (protocol × time effect: p = 0.013), no relationships were observed between plasma glucose and PTX3 either at baseline or in response to both exercise protocols, as indicated by the area under the curve "with respect to increase" analysis. Our results indicate that exercise-mediated plasma PTX3 concentrations are independent of the plasma glucose response. In addition, the present study suggests that the neutrophil-mediated innate immune response, as indicated by plasma PTX3 response, may be activated earlier during HIIE compared with CMIE. [ABSTRACT FROM AUTHOR]

Background Prefrontal cortex (PFC)-dependent executive function is enhanced immediately following high intensity interval exercise (HIIE). Brain-derived neurotrophic factor (BDNF) is considered a biomarker associated with enhanced execute functioning capacity at rest and in response to exercise. However, the mechanisms responsible for the acute exercise-induced BDNF response in plasma and serum differ, and it is likely that the utilization of BDNF in plasma and/or serum as a biomarker of improved executive function following HIIE may be limited. Therefore, this study examined the impact of HIIE on the plasma and serum BDNF response to understand the efficaciousness of BDNF as a peripheral biomarker associated with improvements in PFC-dependent executive function. Thirteen healthy males (age: 23.62 ± 1.06 years) participated in a randomized, counterbalanced study, performing the Wisconsin Card Sorting Task (WCST) immediately following a 5-minute seated rest (control) and participation in a HIIE protocol administered two weeks apart. HIIE consisted of ten maximal bouts of all out pedaling on a cycle ergometer for 20 s (separated by 10 s of active recovery) against 5.5% of the subject's body weight. Whole blood was collected for the assessment of BDNF in both plasma and serum. Compared to the control session, HIIE elicited significant improvements in WCST performance, yet improvements in PFC-dependent executive function were independent of BDNF concentrations in plasma and serum. Results from this investigation demonstrate that a single session of low-volume, supramaximal HIIE significantly increases PFC-dependent executive function, thereby providing additional evidence to support the powerful benefits on HIIE on cognitive functioning. [ABSTRACT FROM AUTHOR]

Obesity is defined as the excess accumulation of intra-abdominal body fat, resulting in a state of chronic, low-grade proinflammation that can directly contribute to the development of insulin resistance. Pentraxin 3 (PTX3) is an acute-phase protein that is expressed by a variety of tissue and cell sources and provides an anti-inflammatory property to downregulate the production of proinflammatory cytokines, in particular interleukin-1 beta and tumor necrosis factor alpha. Although PTX3 may therapeutically aid in altering the proinflammatory milieu in obese individuals, and despite elevated expression of PTX3 mRNA observed in adipose tissue, the circulating level of PTX3 is reduced with obesity. Interestingly, aerobic activity has been demonstrated to elevate PTX3 levels. Therefore, the purpose of this review is to discuss the therapeutic potential of PTX3 to positively regulate obesity-related inflammation and discuss the proposition for utilizing aerobic exercise as a nonpharmacological anti-inflammatory treatment strategy to enhance circulating PTX3 concentrations in obese individuals. [ABSTRACT FROM AUTHOR]

The relationship between stress and disease, in particular cardiovascular disease, has long been recognized, whereas the study of the physiological mechanisms that explain this link has only more recently received attention. The acute response to stress is generally thought to be a critically important adaptation designed to activate the system in preparation to cope with the stressor. However, prolonged stimulation of the system (acute and chronic) can lead to deleterious adaptations including the release of inflammatory cytokines (small proteins important in cell signaling) that play a critical role in the development of atherosclerosis. Scientists have therefore used a breadth of protocols and methods to identify the complexity of our fight-or-flight response and demonstrate the synergy between perception, the stress response, physical activity, and health. In addition, the critical assessment of cellular health, the gut microbiome, and genetic polymorphisms have further advanced our understanding of additional therapeutic targets against CVD. [ABSTRACT FROM AUTHOR]

Pentraxin 3 (PTX3) is an acute phase protein expressed in response to pro-inflammatory stimuli during atherosclerosis. However, recent findings suggest that PTX3 is a counter-regulatory protein which enhances the anti-inflammatory response. Objective Therefore, the capacity of PTX3 to alter the inflammatory milieu following in vitro stimulation of PBMCs with the pro-inflammatory lipid, palmitate, was examined. Methods PBMCs from 17 healthy male donors were isolated and cultured under four separate conditions; 200 μmol/L palmitate, a physiologically relevant concentration of PTX3, in combination (pal + PTX3), and an unstimulated time-course control. Results Palmitate-induced production of the counter-regulatory protein PTX3 was positively associated with the production of the anti-inflammatory cytokine interleukin 10 (IL-10) following in vitro stimulation of human PBMCs. Furthermore, stimulation of PBMCs in vitro with 500 pg/mL PTX3 elicited a significantly greater increase in IL-10 production compared to the palmitate stimulated conditions. However, PTX3 stimulation did not result in the production of the pro-inflammatory cytokines IL-1β, IL-6, and tumor necrosis factor alpha, and when combined with palmitate, did not alter the pro-inflammatory milieu from PBMCs in this study. Conclusion These findings provide evidence supporting the role of PTX3 as a mediator of the anti-inflammatory response in physiologically relevant conditions, and suggests that PTX3 counter regulates the development of atherosclerosis by enhancing the production of IL-10. [ABSTRACT FROM AUTHOR]

The objective of this study was to examine whether acute aerobic exercise-mediated calprotectin in plasma would be associated with monocyte chemotactic protein-1 (MCP-1), myeloperoxidase (MPO), and interleukin-6 (IL-6) in healthy individuals. Eleven healthy participants, aged 18 to 30 years, were recruited to perform a 30-min bout of aerobic exercise at 75% maximal oxygen uptake. Acute aerobic exercise elicited a significant elevation across time in plasma calprotectin, MCP-1, MPO, and IL-6. Body mass index (BMI) was positively correlated with calprotectin area-under-the-curve with 'respect to increase' (AUCi) and IL-6 AUCi. Furthermore, calprotectin AUCi was positively correlated with IL-6 AUCi and MPO AUCi, even after controlling for BMI. Although MPO AUCi was positively correlated with IL-6 AUCi, this relationship no longer existed after controlling for BMI. These results suggest that acute aerobic exercise could mediate innate immune response associated with calprotectin and its related leukocyte chemotactic and inflammatory mediators, especially in individuals with elevated BMI. [ABSTRACT FROM AUTHOR]

Obesity is associated with enhanced inflammation and mental stress, but limited information has addressed the potential additive effect of psychological stress on obesity-associated inflammation. This study examined whether obese subjects would elicit a greater host immune response ( IL-6 m RNA and cytokine) to lipopolysaccharide ( LPS) in response to mental stress. Blood samples for LPS-stimulated IL-6 m RNA and cytokine were collected prior to and following mental stress. Results showed that obese subjects elicited a greater LPS-induced IL-6 along with its m RNA expression following mental stress compared to normal-weight subjects. Stress-induced IL-6 cytokine response to LPS was correlated with the baseline levels of plasma LPS binding protein ( LBP) and leptin. These findings are consistent with the idea that endogenous inflammatory agents (e.g., LBP and leptin), often elevated with obesity, enhance inflammatory responses to psychological stress. [ABSTRACT FROM AUTHOR]

Full length human telomerase reverse transcriptase (FL hTERT) is the rate-limiting, catalytic component necessary for telomerase enzyme activity and telomere length maintenance. Unlike rodents, humans evolved elongated introns with cis-elements that when bound by specific RNA binding proteins (RNAbp) splice hTERT to FL transcripts or produce inactive variants through alternative splicing (AS). Our working hypothesis is that hTERT AS regulates the amount of active telomerase. Evidence from human studies have shown that aerobic exercise maintains telomere length through increased hTERT expression and telomerase enzyme activity, however the impact of acute exercise on hTERT AS is unknown. PURPOSE: To examine hTERT AS regulation in response to acute treadmill running. METHODS: A bacterial artificial chromosome mouse model containing the full hTERT gene (5' and 3' regulatory elements; 16 exons and 15 introns) inserted into its genome (hTERT-BAC) was utilized. Gastrocnemius (Gas.) and heart (Hrt.) were excised from 10-week old hTERT-BAC mice prior to (PRE), upon cessation (POST), and during recovery (1, 24, 48, and 72H; n = 5/time point) from 30 min. of treadmill running (60% max. speed). Primers specific to hTERT were utilized to measure FL and the most common AS variant minus beta (-β, which skips exons 7 and 8) by two different RT-PCR methods - gel based and droplet digital PCR. Gene expression of the RNAbp PTBP1 was also measured. RESULTS: The expected human patterns of hTERT AS was recapitulated across all tissues examined. Compared to PRE, FL hTERT gene expression increased at POST before decreasing in the Gas. (48 and 72H; p ≤ 0.001) and Hrt. (24H; p = 0.004). Acute exercise also increased the percentage of FL hTERT in the Gas. at 1 and 72H (p ≤ 0.017), whereas a decrease was observed in the Hrt. at 1, 24, and 48H (p ≤ 0.041). Finally, Ptbp1 decreased at POST (Gas.) and at 1, 24, 48, and 72H (Gas. and Hrt.; p ≤ 0.05). CONCLUSIONS: Evolutionarily conserved mouse splicing machinery (RNAbp) recognize hTERT cis-elements to recapitulate human AS patterns and highlight the importance of the intronic elements in regulating hTERT splicing choice in humans. The hTERT-BAC mouse is a valuable resource to study the exercise-induced adaptive mechanisms that maintain telomere lengths in endurance trained individuals across the lifespan. [ABSTRACT FROM AUTHOR]

Alternative RNA splicing impacts the majority (>90%) of eukaryotic multi-exon genes, expanding the coding capacity and regulating the abundance of gene isoforms. Telomerase (hTERT) is a key example of a gene that is alternatively spliced during human fetal development and becomes dysregulated in nearly all cancers. Approximately 90% of human tumors use telomerase to synthesize de novo telomere repeats and obtain telomere-dependent cellular immortality. Paradigm shifting data indicates that hTERT alternative splicing, in addition to transcription, plays an important role in the regulation of active telomerase in cells. Our group and others are pursuing the basic science studies to progress this emerging area of telomerase biology. Recent evidence demonstrates that switching splicing of hTERT from the telomerase activity producing full-length hTERT isoform to alternatively spliced, non-coding isoforms may be a novel telomerase inhibition strategy to prevent cancer growth and survival. Thus, the goals of this review are to detail the general roles of telomerase in cancer development, explore the emerging regulatory mechanisms of alternative RNA splicing of the hTERT gene in various somatic and cancer cell types, define the known and potential roles of hTERT splice isoforms in cancer cell biology, and provide insight into new treatment strategies targeting hTERT in telomerase-positive cancers. [ABSTRACT FROM AUTHOR]

The reactivation of telomerase in cancer cells remains incompletely understood. The catalytic component of telomerase, hTERT, is thought to be the limiting component in cancer cells for the formation of active enzymes. hTERT gene expression is regulated at several levels including chromatin, DNA methylation, transcription factors, and RNA processing events. Of these regulatory events, RNA processing has received little attention until recently. RNA processing and alternative splicing regulation have been explored to understand how hTERT is regulated in cancer cells. The cis- and trans-acting factors that regulate the alternative splicing choice of hTERT in the reverse transcriptase domain have been investigated. Further, it was discovered that the splicing factors that promote the production of full-length hTERT were also involved in cancer cell growth and survival. The goals are to review telomerase regulation via alternative splicing and the function of hTERT splicing variants and to point out how bioinformatics approaches are leading the way in elucidating the networks that regulate hTERT splicing choice and ultimately cancer growth. [ABSTRACT FROM AUTHOR]

Purpose Calprotectin promotes the release of inflammatory mediators (e.g., monocyte chemoattractant protein-1 [MCP-1] and myeloperoxidase [MPO]) during the innate immune response as a mechanism to augment leukocyte chemotaxis and phagocytosis. Although plasma calprotectin is elevated with traditional continuous moderate-intensity exercise (CME) as an indicator of the inflammatory response, high-intensity interval exercise (HIIE) has been shown to attenuate systemic inflammation while providing similar improvements in cardiovascular health. Therefore, the purpose of this study was to compare plasma levels of calprotectin, MCP-1, and MPO between acute HIIE vs. CME. Methods Nine healthy males (24.67 ± 3.27 yrs) were recruited to participate in HIIE and CME on a cycle ergometer. HIIE consisted of 10 repeated 60 s of cycling at 90% max watts (W max ) separated by 2 min of active recovery intensity of interval exercise, whereas CME consisted of 28 min of cycling at 60% W max . Blood samples were collected prior to, immediately post, and 30 and 60 min into recovery following exercise. Results Acute HIIE elicited a lower elevation in calprotectin and MPO compared to CME. An increase in MCP-1 was observed across time in both exercise protocols. Furthermore, our analyses did not reveal any significant correlation in percent change (baseline to immediately following exercise) among calprotectin, MCP1, and MPO in neither HIIE nor CME. However, a significant positive correlation was observed in the overall release of calprotectin and MPO across all four time points in both HIIE and CME. Conclusions Our findings indicate that acute HIIE may potentially diminish the systemic release of inflammatory mediators (calprotectin and MPO) compared to CME. [ABSTRACT FROM AUTHOR]